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BackgroundInnovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.ObjectiveTo present the results from the APCCC 2019.Design, setting, and participantsSimilar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.Outcome measurements and statistical analysisThe panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.Results and limitationsPanellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.ConclusionsThese voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.Patient summaryThe Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.

At the Advanced Prostate Cancer Consensus Conference 2021, three important areas of controversy in management of advanced prostate cancer were identified and discussed, and experts voted on 107 predefined consensus questions. The full report of the results is summarised here. Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence. To present the voting results from APCCC 2021. The experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions. The panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process. The voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material. These voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical evidence and logistic and economic constraints. Enrolment in clinical trials should be strongly encouraged. Importantly, APCCC 2021 once again identified salient questions that merit evaluation in specifically designed trials. The Advanced Prostate Cancer Consensus Conference is a forum for discussing current diagnosis and treatment options for patients with advanced prostate cancer. An expert panel votes on predefined questions focused on the most clinically relevant areas for treatment of advanced prostate cancer for which there are gaps in knowledge. The voting results provide a practical guide to help clinicians in discussing treatment options with patients as part of shared decision-making. [ABSTRACT FROM AUTHOR]

BackgroundData describing urinary health in elderly, community-dwelling prostate cancer (PCa) survivors are limited.ObjectiveTo elucidate the prevalence of lower urinary tract symptoms, urinary bother, and incontinence in elderly PCa survivors compared with peers without PCa.Design, setting, and participantsA cross-sectional analysis of 5990 participants in the Osteoporotic Fractures in Men Research Group, a cohort study of community-dwelling men ≥ 65 yr.Outcome measurements and statistical analysisWe characterized urinary health using self-reported urinary incontinence and the American Urological Association Symptom Index (AUA-SI). We compared urinary health measures according to type of PCa treatment in men with PCa and men without PCa using multivariate log-binomial regression to generate prevalence ratios (PRs).Results and limitationsAt baseline, 706 men (12%) reported a history of PCa, with a mean time since diagnosis of 6.3 yr. Of these men, 426 (60%) reported urinary incontinence. In adjusted analyses, observation (PR: 2.11; 95% confidence interval [CI], 1.22-3.65; p=0.007), surgery (PR: 4.41; 95% CI, 3.79-5.13; p

The impact of biochemical recurrence (BCR) after radical treatment of prostate cancer on oncological outcomes remains unclear. A new European Association of Urology BCR risk stratification (low and high risk) has been proposed. To validate these risk groups, we retrospectively analyzed data for 1125 post-radical prostatectomy (RP) BCR patients (surgery between 1992 and 2006). Univariable Kaplan-Meier plots and multivariable Cox regression models with time-dependent covariates were used to test the independent predictor status of the risk grouping on metastatic progression (MP) and prostate cancer-specific mortality (PCSM). The 5-yr MP-free and PCSM-free survival rates were significantly higher among patients with low BCR risk compared to their high-risk counterparts. In multivariable analyses, the BCR risk grouping reached independent predictor status for MP (hazard ratio [HR] 3.46; p < 0.001) and PCSM (HR 5.12; p < 0.001). Salvage radiation therapy, especially when delivered at prostate-specific antigen <0.5 ng/ml, was highly protective. Our findings corroborate the validity of this novel BCR risk grouping, which is easily applicable in daily practice and could be valuable in decision-making for salvage therapy and clinical trials. The European Association of Urology grouping for the risk of biochemical recurrence of prostate cancer after radical prostatectomy was valid when applied in a European study cohort. Our findings corroborate the validity of the novel European Association of Urology biochemical recurrence risk grouping, which is easily applicable in daily practice and could be valuable in decision-making for salvage therapy and clinical trials. [ABSTRACT FROM AUTHOR]

Clinical registries provide physicians with a means for making data-driven decisions but few opportunities exist for patients to interact with registry data to help make decisions. We sought to develop a web-based system that uses a prostate cancer (CaP) registry to provide newly diagnosed men with a platform to view predicted treatment decisions based on patients with similar characteristics. The Michigan Urological Surgery Improvement Collaborative (MUSIC) is a quality improvement consortium of urology practices that maintains a prospective registry of men with CaP. We used registry data from 45 MUSIC urology practices from 2015 to 2017 to develop and validate a random forest machine learning model. After fitting the random forest model to a derivation cohort consisting of a random two-thirds sample of patients after stratifying by practice location, we evaluated the model performance in a validation cohort consisting of the remaining one-third of patients using a multiclass area under the curve (AUC) measure and calibration plots. We identified 7543 men diagnosed with CaP, of whom 45% underwent radical prostatectomy, 30% surveillance, 17% radiation therapy, 5.6% androgen deprivation, and 1.8% watchful waiting. The personalized prediction for patients in the validation cohort was highly accurate (AUC 0.81). Using clinical registry data and machine learning methods, we created a web-based platform for patients that generates accurate predictions for most CaP treatments. We have developed and tested a tool to help men newly diagnosed with prostate cancer to view predicted treatment decisions based on similar patients from our registry. We have made this tool available online for patients to use. We have developed and tested a tool to help men newly diagnosed with prostate cancer to view predicted treatment decisions based on similar patients from our registry. We have made this tool available online for patient use. [ABSTRACT FROM AUTHOR]

Abstract Platinum-based regimens have not been proved to increase survival from advanced prostate cancer (PCa). Incontrovertible evidence that a proportion of prostate cancers have homologous recombination DNA (HRD) repair defects, and that such genomic aberrations are synthetically lethal with both poly(ADP)-ribose polymerase inhibition and platinum, has increased interest in the utilisation of these drugs against a subset of these diseases. Here in we report three patients with advanced castration-resistant PCa with HRD defects having exceptional responses to carboplatin. [ABSTRACT FROM AUTHOR]

Abstract Psychological distress is prevalent among men with prostate cancer (PCa). However, the variation in antidepressant use among individuals throughout the survivorship period is unknown. We sought to examine the variation and trends in receipt of antidepressants after PCa treatment, among patients with nonmetastatic PCa. Using population-based linked administrative data, we identified men ≥66 yr old who underwent surgery (n = 4952), radiotherapy (n = 4994), or surveillance (n = 2136), and these men were matched to general population controls (n = 57 127). One year prior to PCa treatment, 7.7% of men received an antidepressant prescription, which increased to 10.5% in the year after treatment. In difference-in-differences analysis, adjusted for demographic and health characteristics, men had increased odds of antidepressant receipt up to 5 yr after surgery (odds ratio [OR] 1.49; 95% confidence interval [CI] 1.35–1.64; p ≤ 0.0001) or radiotherapy (OR 1.33; 95% CI 1.21–1.47; p ≤ 0.0001). Men did not have an increased risk of antidepressant receipt up to 5 yr after surveillance (OR 1.15; 95% CI 0.94–1.41; p = 0.16). Limitations include the potential for selection bias and misclassification due to the retrospective design of the study and the use of administrative databases. Thus, men with nonmetastatic PCa who initially receive surgery or radiotherapy, but not those who initially undergo surveillance, have an increased risk of antidepressant receipt after treatment. Patient summary In this report, we examined antidepressant prescription for men after treatment of nonmetastatic prostate cancer across the entire population of men ≥66 yr in Ontario, Canada, from 2002 to 2009. For men diagnosed with nonmetastatic prostate cancer, the risk of antidepressant receipt at 5 yr after treatment was significantly increased after surgery or radiotherapy, but not after surveillance. Providers and patients should consider the psychological effects of prostate cancer treatment during the survivorship period. Take Home Message Patients treated for nonmetastatic prostate cancer with surgery or radiation have an increased risk of receiving antidepressant prescriptions for at least 5 yr, whereas patients undergoing surveillance do not. Thus, psychological support after treatment is an important part of prostate cancer care. [ABSTRACT FROM AUTHOR]

Abstract Context Introduction of novel agents for the management of advanced prostate cancer provides a range of treatment options with notable benefits for men with metastatic castration-resistant prostate cancer (mCRPC). At the same time, understanding of optimal patient selection, effective sequential use, and development of resistance patterns remains incomplete. Objective To review current systemic therapies and recent advances in drug development for mCRPC and strategies to aid in patient selection and optimal sequencing. Evidence acquisition A literature review of PubMed/Medline, Cochrane Library, Current Contents Medicine, Web of Science, Clinical Trial.Gov, WHO-ICTRP (January 2004–November 2017), and the proceedings of major international meetings (2015/2016/2017) was performed in November 2017. Evidence synthesis In the last few years, several new options for treatment of mCRPC have shown a survival benefit in phase III trials besides docetaxel:abiraterone, enzalutamide, cabazitaxel, radium-223, and sipuleucel-T. Radium-223 and denosumab have increased options in management of bone metastases. Currently, novel agents such as next-generation androgen receptor (AR) axis-targeting treatments, immunotherapeutics, or therapies targeting other oncogenic and genomic pathways, particularly poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors and PD-1 inhibitors, are under clinical investigation. With increasing treatment options for mCRPC, information on how to personalize management and how to select and sequence existing therapies is beginning to emerge, as are predictive biomarkers (homologous repair mutations, mismatch repair mutations, AR splice variant 7). Finally, early use of active agents in the castration-sensitive state will likely also change the clinical management of the disease when it becomes castrate resistant. Conclusions The emergence of new drugs for mCRPC has improved treatment options dramatically. Currently, systemic treatment options for mCRPC include hormonal therapy, chemotherapy, immunotherapy, and radionuclide therapy as well as bone-modifying agents and palliative or supportive measures. Further, new genetically targeted agents (PARP inhibitors and PD-1 inhibitors) are on the horizon for certain subsets of biomarker-selected patients. The best strategies for patient selection and optimal sequential use to achieve the longest cumulative survival improvement and to prevent early resistance remain unclear. Patient summary The current literature and proceedings from relevant congresses related to available systemic agents for the treatment of metastatic castration-resistant prostate cancer, including novel genetically targeted therapies, including poly(adenosine diphosphate–ribose) polymerase inhibitors and PD-1 inhibitors, were reviewed. Current therapies and ongoing developments are discussed. Take Home Message In the last few years, new therapeutics for the treatment of metastatic castration-resistant prostate cancer have increased survival substantially. While promising novel agents are currently under trial, including genetically targeted therapies (poly(adenosine diphosphate–ribose) polymerase inhibitors and PD-1 inhibitors), further clinical and translational research in predictive biomarkers is needed to optimize treatment selection and sequencing strategies for existing drugs. [ABSTRACT FROM AUTHOR]

Abstract Context Systemic therapies, combined with local treatment for high-risk prostate cancer, are recommended by the international guidelines for specific subgroups of patients; however, for many of the clinical scenarios, it remains a research field. Objective To perform a systematic review, and describe current evidence and perspectives about the multimodal treatment of high-risk prostate cancer. Evidence acquisition We performed a systematic review of PubMED, Embase, Cochrane Library, European Society of Medical Oncology/American Society of Clinical Oncology Annual proceedings, and clinicalTrial.gov between January 2010 and February 2018 following the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Evidence synthesis Seventy-seven prospective trials were identified. According to multiple randomized trials, combining androgen deprivation therapy (ADT) with external-beam radiotherapy (EBRT) outperforms EBRT alone for both relapse-free and overall survival. Neoadjuvant ADT did not show significant improvement compared with prostatectomy alone. The role of adjuvant ADT after prostatectomy in patients with high-risk disease is still debated, with lack of data from phase 3 trials in pN0 patients. Novel androgen pathway inhibitors have been tested only in early-phase trials in addition to primary treatment. GETUG 12, RTOG 0521, and nonmetastatic subgroup of the STAMPEDE trial showed improved relapse-free survival for docetaxel in patients treated with EBRT plus ADT, although mature metastasis-free survival data are still pending. Both the SPCG-12 and the VACSP#553 trial showed no improvement in relapse-free survival for adjuvant docetaxel after prostatectomy. Conclusions In contrast to the clearly demonstrated survival benefits of long-term adjuvant ADT when used with EBRT, its role after prostatectomy remains unclear especially in pN0 patients. Adding docetaxel to EBRT-ADT improves relapse-free survival, with immature results on overall survival. Novel androgen receptor pathway inhibitors are currently being tested in the neoadjuvant and adjuvant setting. Patient summary Treatment of high-risk prostate cancer is based on a multimodality approach that includes systemic treatments. The best treatment or therapy combination remains to be defined. Take Home Message Androgen deprivation therapy improves overall survival when combined with radiotherapy, and such evidence is missing when the primary local treatment is radical prostatectomy. Docetaxel is associated with improved relapse-free survival in high-risk prostate cancer, but long-term follow-up is needed to assess its impact on survival. Bisphosphonates do not postpone the onset of bone metastases. [ABSTRACT FROM AUTHOR]

Abstract Background Clinically significant nonmetastatic prostate cancer (PCa) is currently treated using whole-gland therapy. This approach is effective but can have urinary, sexual, and rectal side effects. Objective To report on 5-yr PCa control following focal high-intensity focused ultrasound (HIFU) therapy to treat individual areas of cancer within the prostate. Design, setting, and participants This was a prospective study of 625 consecutive patients with nonmetastatic clinically significant PCa undergoing focal HIFU therapy (Sonablate) in secondary care centres between January 1, 2006 and December 31, 2015. A minimum of 6-mo follow-up was available for599 patients. Intermediate- or high-risk PCa was found in 505 patients (84%). Intervention Disease was localised using multiparametric magnetic resonance imaging (mpMRI) combined with targeted and systematic biopsies, or transperineal mapping biopsies. Areas of significant disease were treated. Follow-up included prostate-specific antigen (PSA) measurement, mpMRI, and biopsies. Outcome measurements and statistical analysis The primary endpoint, failure-free survival (FFS), was defined as freedom from radical or systemic therapy, metastases, and cancer-specific mortality. Results and limitations The median follow-up was 56 mo (interquartile range [IQR] 35–70). The median age was 65 yr (IQR 61–71) and median preoperative PSA was 7.2 ng/ml (IQR 5.2–10.0). FFS was 99% (95% confidence interval [CI] 98–100%) at 1 yr, 92% (95% CI 90–95%) at 3 yr, and 88% (95% 85–91%) at 5 yr. For the whole patient cohort, metastasis-free, cancer-specific, and overall survival at 5 yr was 98% (95% CI 97–99%), 100%, and 99% (95% CI 97–100%), respectively. Among patients who returned validated questionnaires, 241/247 (98%) achieved complete pad-free urinary continence and none required more than 1 pad/d. Limitations include the lack of long-term follow-up. Conclusions Focal therapy for select patients with clinically significant nonmetastatic prostate cancer is effective in the medium term and has a low probability of side effects. Patient summary In this multicentre study of 625 patients undergoing focal therapy using high-intensity focused ultrasound (HIFU), failure-free survival, metastasis-free survival, cancer-specific survival, and overall survival were 88%, 98%, 100%, and 99%, respectively. Urinary incontinence (any pad use) was 2%. Focal HIFU therapy for patients with clinically significant prostate cancer that has not spread has a low probability of side effects and is effective at 5 yr. Take Home Message Our study shows that at median follow-up of approximately 5 yr after focal high-intensity focused ultrasound, nine out of ten patients with predominantly intermediate- or high-risk prostate cancer are able to avoid surgery, radiotherapy, and systemic therapy. Prostate cancer–specific survival was 100%. There was a low probability of urinary incontinence (2%), erectile dysfunction (15%), and rectal side effects (rare). [ABSTRACT FROM AUTHOR]

Abstract Background Stereotactic ablative body radiotherapy (SABR) is an emerging treatment option for oligometastatic prostate cancer. However, limited prospective evidence is available. Objective To determine the safety and feasibility of single fraction SABR for patients with oligometastatic prostate cancer. Secondary endpoints were local and distant progression-free survival (LPFS and DPFS), toxicity, quality of life (QoL), and prostate-specific antigen response. Design, setting, and participants In a prospective clinical trial, patients were screened with computed tomography, bone scan, and sodium fluoride positron emission tomography scan and had one to three oligometastases. Kaplan-Meier methods were used to determine LPFS and DPFS. Toxicity was graded using Common Terminology Criteria for Adverse Event version 4.0. QoL was assessed using European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-BM22 at 1, 3,12, and 24 mo. Intervention A single fraction of 20-Gy SABR to each lesion. Results and limitations Between 2013 and 2014, 33 consecutive patients received SABR to a total of 50 oligometastases and were followed for 2 yr. The median age was 70 yr. The Gleason score was ≥8 in 15 patients (45%). Twenty patients had bone only, 12 had node only, and one had mixed disease. SABR was feasible and delivered as planned in 97% of cases. There was one grade 3 adverse event (3.0%, vertebral fracture). No patient died. The 1 and 2-yr LPFS was 97% (95% confidence interval [CI]: 91–100) and 93% (95% CI: 84–100), and DPFS was 58% (95% CI: 43–77) and 39% (95% CI: 25–60), respectively. In those not on androgen deprivation therapy (ADT; n = 22), the 2-yr freedom from ADT was 48%. There was no significant difference from baseline QoL observed. Limitations include small sample size, limited duration of follow-up, and lack of a control arm. Conclusions A single SABR session was feasible and associated with low morbidity in this cohort. Over one-third of patients did not progress and were free from ADT at 2-yr. QoL measures were maintained with this treatment strategy. Patient summary This clinical trial investigated single treatment stereotactic radiotherapy for low volume advanced prostate cancer. The approach was found to be safe with avoidance of hormone therapy in almost half of the participants at 2 yr. Take Home Message For patients with one to three oligometastases from prostate cancer, single fraction 20-Gy stereotactic ablative body radiotherapy was both safe and feasible. Local and distant progression-free survival at 2 yr were 93% and 39%, respectively. Quality of life was maintained at baseline levels using this treatment strategy. [ABSTRACT FROM AUTHOR]

Abstract Background Long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for patients with localized high-risk prostate cancer (HRPC). However, the optimal duration of ADT is not yet defined. Objective The aim of this superiority randomized trial was to compare outcomes of RT combined with either 36 or 18 mo of ADT. Design, setting and participants From October 2000 to January 2008, 630 patients with HRPC were randomized, 310 to pelvic and prostate RT combined with 36 mo (long arm) and 320 to the same RT with 18 mo (short arm) of ADT. Outcome measurements and statistical analysis Overall survival (OS) and quality of life (QoL) were primary end points. OS rates were compared with Cox Regression model and QoL data were analyzed through mixed linear model. Results and limitations With a median follow-up of 9.4 yr, 290 patients had died (147 long arm vs 143 short arm). The 5-yr OS rates (95% confidence interval) were 91% for long arm (88–95%) and 86% for short arm (83–90%), p = 0.07. QoL analysis showed a significant difference (p < 0.001) in six scales and 13 items favoring 18 mo ADT with two of them presenting a clinically relevant difference in mean scores of ≥10 points. Conclusions In localized HRPC, our results support that 36 mo is not superior to 18 mo of ADT. ADT combined with RT can potentially be reduced to 18 mo in selected men without compromising survival or QoL. Thus, 18 mo of ADT appears to represent a valid option in HRPC. Patient summary In this study, we report outcomes from high-risk prostate cancer patients treated with radiotherapy and either 36 or 18 mo of androgen deprivation therapy. There was no difference in survival between the two groups, with the 18-mo group experiencing a better quality of life. Take Home Message In localized high-risk prostate cancer, the use of 18 mo of androgen deprivation therapy in combination with radiotherapy represents a valid therapeutic option. Moreover, the shorter hormonal duration improves quality of life and decreases health costs. [ABSTRACT FROM AUTHOR]

Abstract Background Intermediate clinical endpoints (ICEs) prognostic for overall survival (OS) are needed for men receiving postprostatectomy radiation therapy (PORT) to improve clinical trial design. Objective To identify a potential ICE for men receiving PORT. Design, setting, and participants We performed an institutional review board–approved multi-institutional retrospective study of 566 men consecutively treated with PORT at tertiary care centers from 1986 to 2013. The median follow-up was 8.2 yr. Outcome measurements and statistical analysis Biochemical failure (BF), distant metastases (DM), and castrate-resistant prostate cancer (CRPC) were evaluated for correlation with OS and assessed as time-dependent variables in a multivariable Cox proportional hazards model and in landmark analyses at 1, 3, 5, and 7 yr after PORT. Cross-validated concordance (c) indices were used to assess model discrimination. Results and limitations OS at 1, 3, 5, and 7 yr after PORT was 98%, 95%, 90%, and 82%, respectively. In a time-varying model controlling for clinical and pathologic variables, BF (hazard ratio [HR] 2.32, 95% confidence interval [CI] 1.45–3.71; p < 0.001), DM (HR 6.52, 95% CI 4.20–10.1; p < 0.001), and CRPC (HR 2.47, 95% CI 1.56–3.92; p < 0.001) were associated with OS. In landmark analyses, 5-yr DM had the highest c index when adjusting for baseline covariates (0.78), with 5-yr DM also providing the greatest increase in discriminatory power over a model only including baseline covariates. These findings require validation in prospective randomized data. Conclusions While limited by the retrospective nature of the data, 5-yr DM is associated with lower OS following PORT, outperforming the prognostic capability of BF and CRPC at 1, 3, 5, or 7 yr after treatment. Confirmation of this ICE as a surrogate for OS is needed from randomized trial data so that it can be incorporated into future clinical trial design. Patient summary We assessed potential intermediate clinical endpoints prognostic for overall survival in a cohort of men receiving radiotherapy after prostatectomy. We identified the development of metastatic disease within 5 yr after treatment as the strongest predictor of overall survival. Take Home Message We assessed potential intermediate clinical endpoints prognostic for overall survival in a cohort of men receiving radiotherapy after prostatectomy. We identified the development of metastatic disease within 5 yr after treatment as the strongest predictor of overall survival. [ABSTRACT FROM AUTHOR]

Abstract Background Among men with clinically low-risk prostate cancer, we have previously documented heterogeneity in terms of clinical characteristics and genomic risk scores. Objective To further study the underlying tumor biology of this patient population, by interrogating broader patterns of gene expression among men with clinically low-risk tumors. Design, setting, and participants Prostate biopsies from 427 patients considered potentially suitable for active surveillance underwent central pathology review and genome-wide expression profiling. These cases were compared with 1290 higher-risk biopsy cases with diverse clinical features from a prospective genomic registry. Outcome measurements and statistical analysis Average genomic risk (AGR) was determined from 18 published prognostic signatures, and MSigDB hallmark gene sets were analyzed using bootstrapped clustering methods. These sets were examined in relation to clinical variables and pathological and biochemical outcomes using multivariable regression analysis. Results and limitations A total of 408 (96%) biopsies passed RNA quality control. Based on AGR quartiles defined by the high-risk multicenter cases, the University of California, San Francisco (UCSF) low-risk patients were distributed across the quartiles as 219 (54%), 107 (26%), 61 (15%), and 21 (5%). Unsupervised clustering analysis of the hallmark gene set scores revealed three clusters, which were enriched for the previously described PAM50 luminal A, luminal B, and basal subtypes. AGR, but not the clusters, was associated with both pathological (odds ratio 1.34, 95% confidence interval [CI] 1.14–1.58) and biochemical outcomes (hazard ratio 1.53, 95% CI 1.19–1.93). These results may underestimate within-prostate genomic heterogeneity. Conclusions Prostate cancers that are homogeneously low risk by traditional characteristics demonstrate substantial diversity at the level of genomic expression. Molecular substratification of low-risk prostate cancer will yield a better understanding of its divergent biology and, in the future may help personalize treatment recommendations. Patient summary We studied the genomic characteristics of tumors from men diagnosed with low-risk prostate cancer. We found three main subtypes of prostate cancer with divergent tumor biology, similar to what has previously been found in women with breast cancer. In addition, we found that genomic risk scores were associated with worse pathology findings and prostate-specific antigen recurrence after surgery. These results suggest even greater genomic diversity among low-risk patients than has previously been documented with more limited signatures. Take Home Message In a large cohort of men who were candidates for active surveillance, genomic profiling finds a high degree of heterogeneity in biological pathway activation and genomic risk scores that predict adverse outcomes after radical prostatectomy. [ABSTRACT FROM AUTHOR]

Context 68 Gallium prostate-specific membrane antigen positron emission tomography ( 68 Ga-PSMA PET) is an emerging imaging modality for assessment of prostate cancer. Recent studies show promising results regarding its ability to detect recurrent or metastatic prostate cancer superior to that of conventional imaging modalities. However, the impact of 68 Ga-PSMA PET on management of patients with prostate cancer has not been well established. Objective To perform a systematic review and meta-analysis to evaluate the impact of 68 Ga-PSMA PET on management of patients with prostate cancer. Evidence acquisition Pubmed and EMBASE databases were searched up to January 20, 2018. We included studies that reported proportion of management change after 68 Ga-PSMA PET in patients with prostate cancer. The quality of the studies was evaluated using the GRADE system. The proportion of management changes were pooled using random-effects model. Subgroup analyses and meta-regression analyses were performed to explore heterogeneity. Evidence synthesis Fifteen studies (1163 patients) were included. The pooled proportion of management changes was 54% (95% confidence interval 47–60%). At meta-regression analyses, PET positivity (%) was a significant factor of heterogeneity ( p = 0.0486). For patients with biochemical failure, the proportion of radiotherapy (from 56% to 61%), surgery (from 1% to 7%), focal therapy (from 1% to 2%), and multimodal treatment (from 2% to 6%) increased, whereas that of systemic treatment (from 26% to 12%) and no treatment (from 14% to 11%) decreased with 68 Ga-PSMA PET. Conclusions 68 Ga-PSMA PET had a large impact on the management of patients with prostate cancer. Greater PET positivity was associated with higher proportion of management changes. Patient summary We reviewed all previous studies assessing the impact of 68 Gallium prostate-specific membrane antigen positron emission tomography ( 68 Ga-PSMA PET) in patients with prostate cancer. We found that 68 Ga-PSMA PET altered the management in approximately half of the patients. [ABSTRACT FROM AUTHOR]

Background The consequences of low prostate-specific antigen (PSA) in high-grade (Gleason 8–10) prostate cancer are unknown. Objective To evaluate the clinical implications and genomic features of low-PSA, high-grade disease. Design, setting, and participants This was a retrospective study of clinical data for 494 793 patients from the National Cancer Data Base and 136 113 patients from the Surveillance, Epidemiology, and End Results program with cT1–4N0M0 prostate cancer (median follow-up 48.9 and 25.0 mo, respectively), and genomic data for 4960 patients from the Decipher Genomic Resource Information Database. Data were collected for 2004–2017. Outcome measurements and statistical analysis Multivariable Fine-Gray and Cox regressions were used to analyze prostate cancer–specific mortality (PCSM) and all-cause mortality, respectively. Results and limitations For Gleason 8–10 disease, using PSA 4.1–10.0 ng/ml ( n = 38 719) as referent, the distribution of PCSM by PSA was U-shaped, with an adjusted hazard ratio (AHR) of 2.70 for PSA ≤2.5 ng/ml ( n = 3862, p < 0.001) versus 1.97, 1.36, and 2.56 for PSA of 2.6–4.0 ( n = 4199), 10.1–20.0 ( n = 17 372), and >20.0 ng/ml ( n = 16 114), respectively. By contrast, the distribution of PCSM by PSA was linear for Gleason ≤7 (using PSA 4.1–10.0 ng/ml as the referent, n = 359 898), with an AHR of 0.41 ( p = 0.13) for PSA ≤2.5 ng/ml ( n = 37 812) versus 1.38, 2.28, and 4.61 for PSA of 2.6–4.0 ( n = 54 152), 10.1–20.0 ( n = 63 319), and >20.0 ng/ml ( n = 35 459), respectively ( p interaction < 0.001). Gleason 8–10, PSA ≤2.5 ng/ml disease had a significantly higher PCSM than standard high-risk/very high-risk disease with PSA >2.5 ng/ml (AHR 2.15, p = 0.002; 47-mo PCSM 14% vs 4.9%). Among Gleason 8–10 patients treated with radiotherapy, androgen deprivation therapy was associated with a survival benefit for PSA >2.5 ng/ml (AHR 0.87; p < 0.001) but not ≤2.5 ng/ml (AHR 1.36; p = 0.084; p interaction = 0.021). For Gleason 8–10 tumors, PSA ≤2.5 ng/ml was associated with higher expression of neuroendocrine/small-cell markers compared to >2.5 ng/ml ( p = 0.046), with no such relationship for Gleason ≤7 disease. Conclusions Low-PSA, high-grade prostate cancer has very high risk for PCSM, potentially responds poorly to androgen deprivation therapy, and is associated with neuroendocrine genomic features. Patient summary In this study, we found that low–prostate-specific antigen, high-grade prostate cancer has a very high risk for prostate cancer death, may not respond well to androgen deprivation therapy, and is associated with neuroendocrine genomic features. These findings suggest that current nomograms and treatment paradigms may need modification. [ABSTRACT FROM AUTHOR]

Up to 50% of patients recur after salvage radiation therapy (sRT) for prostate-specific antigen (PSA) rise following radical prostatectomy (RP). Notably, the importance of lymph node dissection (LND) at the time of RP with regard to recurrence risk following sRT has not been previously determined. Therefore, we evaluated the association between nodal yield at RP and recurrence after sRT. We performed a multi-institutional review of men with a rising PSA after RP treated with sRT. Clinicopathologic variables were abstracted, and the associations between lymph node yield and biochemical (BCR) as well as clinical recurrence (CR) after sRT were assessed using multivariable Cox proportional hazards regression models. In total, 728 patients were identified; of these, 221 and 116 were diagnosed with BCR and CR, respectively, during a median follow-up of 8.4 (interquartile range: 4.2–11.2) yr. On multivariable analysis, the risk of BCR after sRT was inversely associated with the number of nodes resected at RP (hazards ratio [HR]: 0.98; 95% confidence interval [CI]: 0.96–0.99; p = 0.049). Increased extent of dissection was also independently associated with a decreased risk of CR after sRT (HR: 0.97; 95%CI: 0.94–0.99; p = 0.042). These data support the importance of an extensive LND at surgery and may be used in prognosis assessment when sRT is being considered. Patient summary We found that patients who had increased number of lymph nodes resected at surgery had improved outcomes after the receipt of salvage radiation therapy. These findings support the use of the extended lymph node dissection at initial surgery and should serve to improve counseling among patients who require salvage radiation therapy. [ABSTRACT FROM AUTHOR]

Background Whether prostate cancer severity modifies patient-reported functional outcomes after radical prostatectomy (RP) or external beam radiotherapy (EBRT) for localized cancer is unknown. Objective The purpose of this study was to determine whether differences in predicted function over time between RP and EBRT varied by risk group. Design, setting, and participants The Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) study is a prospective, population-based, observational study that enrolled men with localized prostate cancer in 2011–2012. Among 2117 CEASAR participants who underwent RP or EBRT, 817 had low-risk, 902 intermediate-risk, and 398 high-risk disease. Outcome measurements and statistical analysis Patient-reported, disease-specific function was measured using the 26-item Expanded Prostate Index Composite (at baseline and 6, 12, and 36 mo). Predicted function was estimated using regression models and compared by disease risk. Results and limitations Low-risk EBRT patients reported 3-yr sexual function scores 12 points higher than those of low-risk RP patients (RP, 39 points [95% confidence interval {CI}, 37–42] vs EBRT, 52 points [95% CI, 47–56]; p < 0.001). The difference in 3-yr scores for high-risk patients was not clinically significant (RP, 32 points [95% CI, 28–35] vs EBRT, 38 points [95% CI, 33–42]; p = 0.03). However, when using a commonly used binary definition of sexual function (erections firm enough for intercourse), no major differences were noted between RP and EBRT at 3 yr across low-, intermediate-, and high-risk disease strata. No clinically significant interactive effects between treatment and cancer severity were observed for incontinence, bowel, irritative voiding, and hormone domains. The primary limitation is the lack of firmly established thresholds for clinically significant differences in Expanded Prostate Index Composite domain scores. Conclusions For men with low-risk prostate cancer, EBRT was associated with higher sexual function scores at 3 yr than RP; however, for men with high-risk prostate cancer, no clinically significant difference was noted. Men with high-risk prostate cancer should be counseled that EBRT and RP carry similar sexual function outcomes at 3 yr. Patient summary In this report, we studied the urinary, sexual, bowel, and hormonal functions of patients 3 yr after undergoing prostate cancer surgery or radiation. We found that for patients with high-risk disease, sexual function was similar between surgery and radiation. We conclude that high-risk patients undergoing radiation therapy should be counseled that sexual function may not be as good as low-risk patients undergoing radiation. [ABSTRACT FROM AUTHOR]

Radical treatment of localised prostate cancer is recognised to be an unnecessary intervention or overtreatment in many men. Consequently, there has been a rapid uptake in the use of focal ablative therapies. However, there are several biological and practical concerns about such approaches as they have yet to be proved as robust treatment options. In particular, the multifocal nature of prostate cancer argues against unifocal treatment, while limitations in imaging can preclude the accurate identification of the number, location, and extent of prostate cancer foci. To date, a number of ablative options have reported results on mainly low-risk disease. Most series are relatively immature, with a lack of consistent follow-up, and the morbidity of retreatment is often not considered. The authors consider focal therapy to be an investigational modality, and encourage prospective recording of outcomes and recruitment of suitable patients. Patient summary Focal therapy of prostate cancer is the targeted destruction of cancer within a specific part of the prostate gland, sparing the rest of the prostate and nearby tissue. This procedure could potentially reduce side effects when compared with established standard treatments, such as surgery or radiotherapy, which treat the entire prostate. Studies show that for most men with low-risk cancer, active surveillance is the preferred treatment option. However, the available data regarding all forms of focal therapy are still poor and inconclusive. Consequently, due to both the lack of clear results associated with focal therapy and the difficulties in detecting all cancerous areas of the prostate, focal therapy should be considered an investigational modality only. [ABSTRACT FROM AUTHOR]

Current immunotherapy has limited efficacy on metastatic castrate-resistant prostate cancer (mCRPC). We therefore sought to improve the antitumor ability of mCRPC patient-derived CD8 + T-cells by the endowment of specificity to prostate-specific membrane antigen (PSMA) and insensitivity to immunosuppressant molecule transforming growth factor-β (TGF-ß) under the control of herpes simplex virus-1 thymidine kinase. CD8 + T-cells were collected by leukapheresis and cultured in a Food and Drug Administration-approved Cell Processing Work Station. We developed a chimeric antigen receptor retroviral construct using an anti-PSMA chimeric immunoglobulin-T-cell receptor(ζ) gene ( PZ1 ) and dominant negative TGF-ß type II receptor (TßRIIDN), that could induce CD8 + T-cells to be PSMA reactive and insensitive to TGF-ß. Cr 51 release assay was performed on PC-3 and PC-3-PSMA. The further antitumor functions of PSMA-specific, TGF-ß insensitive CD8 + T-cells was evaluated using an immunodeficient RAG-1 –/– mouse model. We found PSMA-specific, TGF-ß insensitive CD8 + T-cells from mCRPC were expanded with strong expression of PZ1 and thymidine kinase genes, and their growth was not suppressed by TGF-ß. The survival of these cells decreased sharply after treatment with ganciclovir. Treatment of PSMA-specific TGF-ß, insensitive CD8 + T-cells was associated with 61.58% specific lysis on PC-3-PSMA, and significantly suppressed PC3-PSMA tumor compared with the PC3 tumor. A large amount of tumor apoptosis and CD8 + T-cell infiltration were found only in the PC3-PSMA tumor. This study verified that PSMA-specific, TGF-ß insensitive CD8 + T-cells derived from mCRPC patients could be successfully expanded and used to overcome the immunosuppressive effects of the tumor microenvironment to control PSMA-expressing PC in vitro and in vivo. This may provide a promising approach for men with mCRPC who fail androgen deprivation therapy. Patient summary We investigated the role of a novel chimeric antigen receptor T-immunotherapy based on autologous metastatic castrate-resistant prostate cancer patient-derived prostate-specific membrane antigen (PSMA)-specific, transforming growth factor-ß insensitive CD8 + T-cells on PSMA-positive prostate cancer. We found that this chimeric antigen receptor T-cells could kill PSMA-positive prostate cancer specifically. The results suggest that this novel immunotherapy treatment is a potential new approach for men with metastatic castrate-resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Background Androgen receptor splice variant 7 (AR-V7) has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity. Objective To address current limitations in precision measurement of AR-V7 by developing a novel junction-specific AR-V7 RNA in situ hybridization (RISH) assay compatible with automated quantification. Design, setting, and participants We designed a RISH method to visualize single splice junctions in cells and tissue. Using the validated assay for junction-specific detection of the full-length AR (AR-FL) and AR-V7, we generated quantitative data, blinded to clinical data, for 63 prostate tumor biopsies. Outcome measurements and statistical analysis We evaluated clinical correlates of AR-FL/AR-V7 measurements, including association with prostate-specific antigen progression-free survival (PSA-PFS) and clinical and radiographic progression-free survival (PFS), in a subset of patients starting treatment with abiraterone or enzalutamide following biopsy. Results and limitations Quantitative AR-FL/AR-V7 data were generated from 56 of the 63 (88.9%) biopsy specimens examined, of which 44 were mCRPC biopsies. Positive AR-V7 signals were detected in 34.1% (15/44) mCRPC specimens, all of which also co-expressed AR-FL. The median AR-V7/AR-FL ratio was 11.9% (range 2.7–30.3%). Positive detection of AR-V7 was correlated with indicators of high disease burden at baseline. Among the 25 CRPC biopsies collected before treatment with abiraterone or enzalutamide, positive AR-V7 detection, but not higher AR-FL, was significantly associated with shorter PSA-PFS (hazard ratio 2.789, 95% confidence interval 1.12–6.95; p = 0.0081). Conclusions We report for the first time a RISH method for highly specific and quantifiable detection of splice junctions, allowing further characterization of AR-V7 and its clinical significance. Patient summary Higher AR-V7 levels detected and quantified using a novel method were associated with poorer response to abiraterone or enzalutamide in prostate cancer. [ABSTRACT FROM AUTHOR]

Background Hormonal manipulation concomitant to salvage radiotherapy (SRT) given for biochemical recurrence (BCR) after radical prostatectomy (RP) improved outcomes in two randomized trials. However, neither of these studies focused on men treated at low prostate-specific antigen (PSA) levels. Objective To test if the impact of androgen deprivation therapy (ADT) on metastasis in patients undergoing early SRT varies according to prostate cancer (PCa) features. Design, setting, and participants A total of 525 patients received SRT at PSA levels ≤2 ng/ml. Outcome measurements and statistical analyses Multivariable Cox regression analyses assessed factors associated with metastasis. We tested the hypothesis that the impact of ADT varied according to the risk of metastasis. An interaction with groups (concomitant ADT vs no ADT) and the probability of distant metastasis according to a newly developed model was tested. A nonparametric curve explored the relationship between the risk of metastasis and 10-yr metastasis rates according to ADT. Results and limitations Median PSA and radiotherapy dose were 0.42 ng/ml and 66 Gy, respectively. Overall, 178 (34%) patients received ADT. At a median follow-up of 104 mo, 71 patients experienced metastasis. Grade group ≥4 (hazard ratio [HR]: 1.66; 95% confidence interval [CI]: 1.01–3.30), pT3b/4 (HR: 2.61; 95% CI: 1.51–4.52), and dose (HR: 0.82; 95% CI: 0.76–0.89) were associated with metastasis. The impact of ADT differed according to the risk of metastasis calculated using a multivariable model ( p = 0.01). This was confirmed when considering patients treated with early SRT ( p = 0.046), where ADT was associated with a reduction in the rate of metastasis only in eSRT; patients with more aggressive characteristics (ie, pT3b/4 and grade group ≥4, or pT3b/4 and PSA at eSRT ≥0.4 ng/ml). Conclusions The beneficial effect of ADT concomitant to eSRT varied significantly according to disease characteristics, such that only men with more aggressive PCa features benefit from ADT in the eSRT setting for BCR after RP. Patient summary The oncological benefits of concomitant androgen deprivation therapy (ADT) in patients undergoing salvage radiotherapy (SRT) vary according to pathological characteristics. Only patients with more aggressive disease characteristics seemed to benefit from the use of hormonal manipulation at the time of early SRT. Conversely, the potential side effects of ADT could be spared in patients with low prostate-specific antigen levels and favorable pathological features. [ABSTRACT FROM AUTHOR]

Background Prostate cancer treatment is a significant source of morbidity and spending. Some men with prostate cancer, particularly those with significant health problems, are unlikely to benefit from treatment. Objective To assess relationships between financial incentives associated with urologist ownership of radiation facilities and treatment for prostate cancer. Design, setting, and participants A retrospective cohort of Medicare beneficiaries with prostate cancer diagnosed between 2010 and 2012. Patients were further classified by their risk of dying from noncancer causes in the 10 yr following their cancer diagnosis by using a mortality model derived from comparable patients known to be cancer-free. Intervention Urologists were categorized by their practice affiliation (single-specialty groups by size, multispecialty group) and ownership of a radiation facility. Outcome measurements and analysis Use of intensity-modulated radiation therapy (IMRT) and use of any treatment within 1 yr of diagnosis. Generalized estimating equations were used to adjust for patient differences. Results Among men with newly diagnosed prostate cancer, use of IMRT ranged from 24% in multispecialty groups to 37% in large urology groups ( p < 0.001). Patients managed in groups with IMRT ownership ( n = 5133) were more likely to receive IMRT than those managed by single-specialty groups without ownership (43% vs 30%, p < 0.001), regardless of group size. Among patients with a very high risk (> 75%) of noncancer mortality within 10 yr of diagnosis, both IMRT use (42% vs 26%, p < 0.001) and overall treatment (53% vs 44%, p < 0.001) were more likely in groups with ownership than in those without, respectively. Conclusions Urologists practicing in single-specialty groups with an ownership interest in radiation therapy are more likely to treat men with prostate cancer, including those with a high risk of noncancer mortality. Patient summary We assessed treatment for prostate cancer among urologists with varying levels of financial incentives favoring intervention. Those with stronger incentives, as determined by ownership interest in a radiation facility, were more likely to treat prostate cancer, even when treatment was unlikely to provide a survival benefit to the patient. [ABSTRACT FROM AUTHOR]

Background Salvage radiation therapy (SRT) is a recommended treatment option for biochemical recurrence after radical prostatectomy (RP). However, its effectiveness may be limited to specific categories of patients. Objective We aimed to identify the optimal candidates for early SRT after RP. Design, setting, and participants The study included 925 node-negative patients treated with SRT after RP at seven institutions. Patients received SRT for either prostate-specific antigen (PSA) rising, or PSA persistence after RP that was defined as PSA level ≥0.1 ng/ml at 1 mo after surgery. All patients received local radiation to the prostate and seminal vesicle bed. Outcome measurements and statistical analysis The primary outcome measured was distant metastasis after SRT. Regression tree analysis was used to develop a risk-stratification tool. Multivariable Cox regression analysis and nonparametric curve fitting methods were used to explore the relationship between PSA level at SRT and the probability of metastasis-free survival at 8 yr. Results and limitations At a median follow-up of 8.0 yr, 130 patients developed distant metastasis. At multivariable analysis, pre-SRT PSA level was significantly associated with distant metastasis (hazard ratio: 1.06, p < 0.0001). However, when patients were stratified into five risk groups using regression tree analysis (area under the curve: 85%), early SRT administration provided better metastasis-free survival in three groups only: (1) low risk: undetectable PSA after RP, Gleason score ≤7, and tumour stage ≥pT3b, (2) intermediate risk: undetectable PSA after RP with Gleason score ≥8, (3) high risk: PSA persistence after RP with Gleason score ≤7. Conclusions We developed an accurate risk stratification tool to facilitate the individualised recommendation for early SRT based on prostate cancer characteristics. Early SRT proved to be beneficial only in selected groups of patients who are more likely to be affected by clinically significant but not yet systemic recurrence at the time of salvage treatment administration. Patient summary In patients affected by prostate cancer recurrence after radical prostatectomy, the early administration of salvage radiation therapy is beneficial only for selected subgroups of patients. In this study, these groups of patients were identified. [ABSTRACT FROM AUTHOR]

Background There is limited evidence supporting the use of local treatment (LT) for prostate cancer (PCa) patients with clinically pelvic lymph node-positive (cN1) disease. Objective To examine the efficacy of any form of LT ± androgen deprivation therapy (ADT) in treating these individuals. Design, setting, and participants Using the National Cancer Database (2003–2011), we retrospectively identified 2967 individuals who received LT ± ADT versus ADT alone for cN1 PCa. Only radical prostatectomy (RP) and radiation therapy (RT) were considered as definitive LT. Intervention LT ± ADT versus ADT alone. Outcome measurements and statistical analysis Instrumental variable analyses (IVA) were performed using a two-stage residual inclusion approach to compare overall mortality (OM)-free survival between patients who received LT ± ADT versus ADT alone. The same methodology was used to further compare OM-free survival between patients who received RP ± ADT versus RT ± ADT. Results and limitations Overall, 1987 (67%) and 980 (33%) patients received LT ± ADT and ADT alone, respectively. In the LT ± ADT group, 751 (37.8%) and 1236 (62.2%) patients received RP ± ADT and RT ± ADT, respectively. In IVA, LT ± ADT was associated with a significant OM-free survival benefit (hazard ratio = 0.31, 95% confidence interval [CI] = 0.13–0.74, p = 0.007), when compared with ADT alone. At 5 yr, OM-free survival was 78.8% (95% CI: 74.1–83.9%) versus 49.2% (95% CI: 33.9–71.4%) in the LT ± ADT versus ADT alone groups. When comparing RP ± ADT versus RT ± ADT, IVA showed no significant difference in OM-free survival between the two treatment modalities (hazard ratio = 0.54, 95% CI = 0.19–1.52, p = 0.2). Despite the use of an IVA, our study may be limited by residual unmeasured confounding. Conclusions Our findings show that PCa patients with clinically pelvic lymph node-positive disease may benefit from any form of LT ± ADT over ADT alone. While not necessarily curative by itself, the use of RP or RT could be the first step in a multi-modality approach aiming at providing the best cancer control outcomes for these individuals. Patients summary We examined the role of local treatment for clinically pelvic lymph node-positive prostate cancer. We found that the delivery of radical prostatectomy or radiation therapy may be associated with an overall mortality-free survival benefit compared with androgen deprivation therapy alone. [ABSTRACT FROM AUTHOR]

Background Global disparities in prostate cancer (PCa) incidence highlight the urgent need to identify genomic abnormalities in prostate tumors in different ethnic populations including Asian men. Objective To systematically explore the genomic complexity and define disease-driven genetic alterations in PCa. Design, setting, and participants The study sequenced whole-genome and transcriptome of tumor-benign paired tissues from 65 treatment-naive Chinese PCa patients. Subsequent targeted deep sequencing of 293 PCa-relevant genes was performed in another cohort of 145 prostate tumors. Outcome measurements and statistical analysis The genomic alteration landscape in PCa was analyzed using an integrated computational pipeline. Relationships with PCa progression and survival were analyzed using nonparametric test, log-rank, and multivariable Cox regression analyses. Results and limitations We demonstrated an association of high frequency of CHD1 deletion with a low rate of TMPRSS2-ERG fusion and relatively high percentage of mutations in androgen receptor upstream activator genes in Chinese patients. We identified five putative clustered deleted tumor suppressor genes and provided experimental and clinical evidence that PCDH9 , deleted/loss in approximately 23% of tumors, functions as a novel tumor suppressor gene with prognostic potential in PCa. Furthermore, axon guidance pathway genes were frequently deregulated, including gain/amplification of PLXNA1 gene in approximately 17% of tumors. Functional and clinical data analyses showed that increased expression of PLXNA1 promoted prostate tumor growth and independently predicted prostate tumor biochemical recurrence, metastasis, and poor survival in multi-institutional cohorts of patients with PCa. A limitation of this study is that other genetic alterations were not experimentally investigated. Conclusions There are shared and salient genetic characteristics of PCa in Chinese and Caucasian men. Novel genetic alterations in PCDH9 and PLXNA1 were associated with disease progression. Patient summary We reported the first large-scale and comprehensive genomic data of prostate cancer from Asian population. Identification of these genetic alterations may help advance prostate cancer diagnosis, prognosis, and treatment. [ABSTRACT FROM AUTHOR]

Background The gap in prostate cancer (PCa) survival between Blacks and Whites has widened over the past decade. Investigators hypothesize that this disparity may be partially attributable to differences in rates of definitive therapy between races. Objective To examine facility level variation in the use of definitive therapy among Black and White men for localized PCa. Design, setting, and participants Using data from the National Cancer Data Base, we identified 223 873 White and 59 262 Black men ≥40 yr of age receiving care within the USA with biopsy confirmed localized intermediate/high-risk PCa diagnosed between January 2004 and December 2013. Outcome measurements and statistical analysis Multilevel logistic regression was fitted to predict the odds of receiving definitive therapy for PCa. Sensitivity and subgroup analyses were performed to adjust for inherent patient and facility-level differences when appropriate. Results and limitations Eighty-three percent ( n = 185 647) of White men received definitive therapy compared with 74% ( n = 43 662) of Black men between 2004 and 2013. Overall rates of definitive therapy during that time increased for both White (81% vs 83%, p < 0.001) and Black (73% vs 75%, p = 0.001) men. However, 39% of treating facilities demonstrated significantly higher rates of definitive therapy in White men, compared with just 1% favoring Black men. Our study is limited by potential selection bias and effect modification. Conclusions After adjusting for sociodemographic and clinical factors, we found that most facilities favored definitive therapy in Whites. Health care providers should be aware of these inherit biases when counseling patients on treatment options for localized PCa. Our study is limited by the retrospective nature of the cohort. Patient summary We found significant differences in rates of radiation and surgical treatment for prostate cancer among White and Black men, with most facilities favoring Whites. Nonclinical factors such as treatment facility type and location influenced rates of therapy. [ABSTRACT FROM AUTHOR]

Background Although active surveillance is increasingly used for the management of low-risk prostate cancer, many eligible patients are still nonetheless subject to curative treatment. One argument for considering surgery rather than active surveillance is that the probability of postoperative recovery of erectile function is age dependent, that is, patients who delay surgery may lose the window of opportunity to recover erectile function after surgery. Objective To model erectile function over a 10-yr period for immediate surgery versus active surveillance. Design, setting, and participants Data from 1103 men who underwent radical prostatectomy at a tertiary referral center were used. Outcome measurements and statistical analysis Patients completed the International Index of Erectile Function (IIEF-6) pre- and postoperatively as a routine part of clinical care. Preoperative IIEF-6 scores were plotted against age to assess the natural rate of functional decline due to aging. Reported erectile scores in the 2-yr period following surgery were used to assess post-surgical recovery. Results and limitations Each year increase in patient age resulted in a 0.27 reduction in IIEF scores. In addition to IIEF reducing with increased age, the amount of erectile function that is recovered from presurgery to 12-mo postsurgery also decreases (−0.16 IIF points/yr, 95% confidence interval −0.27, −0.05, p = 0.006). However, delayed radical prostatectomy increased the mean IIEF-6 score over a 10-yr period compared with immediate surgery ( p = 0.001), even under the assumption that all men placed on active surveillance are treated within 5 yr. Conclusions Small differences in erectile function recovery in younger men are offset by a longer period of time living with decreased postoperative function. Better erectile recovery in younger men should not be a factor used to recommend immediate surgery in patients suitable for active surveillance, even if crossover to surgery is predicted within a short period of time. Patient summary Younger men have better recovery of erectile function after surgery for prostate cancer. This has led to the suggestion that delaying surgery for low-risk disease may lead patients to miss a window of opportunity to recover erectile function postoperatively. We conducted a modeling study and found that predicted erectile recovery was far superior on delayed treatment because slightly better recovery in younger men is offset by a longer period of time living with poorer postoperative function in those choosing immediate surgery. [ABSTRACT FROM AUTHOR]

Background Prostate cancer (PCa) patients with prostate-specific antigen (PSA) persistence after radical prostatectomy (RP) are at increased risk of mortality, although the natural history of these men is heterogeneous and the optimal management has not been established. Objective To develop a model to predict cancer-specific mortality (CSM) and to test the impact of radiotherapy (RT) on survival in this setting. Design, setting, and participants We identified 496 patients treated with RP and lymph node dissection at two referral centers between 1994 and 2014 who had PSA persistence, defined as a PSA level between 0.1 and 2 ng/ml at 6–8 wk after RP. Outcome measurements and statistical analyses A multivariable model predicting CSM was developed. We assessed whether the impact of postoperative PSA levels on survival differed according to baseline CSM risk. The nonparametric curve fitting method was then used to explore the relationship between baseline CSM risk and 10-yr CSM rates according to postoperative RT. Results and limitations Median follow-up for survivors was 110 mo. Overall, 49 patients experienced CSM. The 10-yr CSM-free survival was 88%. Pathologic grade group and pathologic stage were independent predictors of CSM (all p = 0.01). The association between CSM-free survival and PSA at 6–8 wk differed by the baseline CSM risk, whereby the effect of increasing PSA was evident only in patients with a CSM risk of ≥10%. Postoperative RT was beneficial when the predicted risk of CSM was ≥30% ( p = 0.001 by an interaction test). Our study is limited by its retrospective design. Conclusions Increasing PSA levels should be considered as predictors of mortality exclusively in men with worse pathologic characteristics. Postoperative RT in this setting was associated with a survival benefit in patients with a CSM risk of ≥30%. Conversely, individuals with a CSM risk of <30% should be initially managed expectantly. Patient summary Not all patients with prostate-specific antigen persistence have a poor prognosis. Pathologic characteristics should be used to estimate the risk of cancer-specific mortality in these individuals and to identify patients who could benefit from postoperative radiotherapy. [ABSTRACT FROM AUTHOR]

Background In observational studies, men with prostate cancer treated with gonadotropin-releasing hormone (GnRH) agonists had a higher risk of cardiovascular disease (CVD) compared to men who had undergone orchiectomy. However, selection bias may have influenced the difference in risk. Objective To investigate the association of type of androgen deprivation therapy (ADT) with risk of CVD while minimising selection bias. Design, setting, and participants Semi-ecologic study of 6556 men who received GnRH agonists and 3330 men who underwent orchiectomy as primary treatment during 1992–1999 in the Prostate Cancer Database Sweden 3.0. Outcome measurements and statistical analysis We measured the proportion of men who received GnRH agonists as primary treatment in 580 experimental units defined by healthcare provider, diagnostic time period, and age at diagnosis. Incident or fatal CVD events in units with high and units with low use of GnRH agonists were compared. Net and crude probabilities were also analysed. Results and limitations The risk of CVD was similar between units with the highest and units with the lowest proportion of GnRH agonist use (relative risk 1.01, 95% confidence interval [CI] 0.93–1.11). Accordingly, there was no difference in the net probability of CVD after GnRH agonist compared to orchiectomy (hazard ratio 1.02, 95% CI 0.96–1.09). The 10-yr crude probability of CVD was 0.56 (95% CI 0.55–0.57) for men on GnRH agonists and 0.52 (95% CI 0.50–0.54) for men treated with orchiectomy. The main limitation was the nonrandom allocation to treatment, with younger men with lower comorbidity and less advanced cancer more likely to receive GnRH agonists. Conclusion Our data do not support previous observations that GnRH agonists increase the risk of CVD in comparison to orchiectomy. Patient summary We found a similar risk of cardiovascular disease between medical and surgical treatment as androgen deprivation therapy for prostate cancer. [ABSTRACT FROM AUTHOR]

Background Large prospective cohort studies need to confirm the associations between recreational physical activity (PA), including the most common type—walking, and prostate cancer–specific mortality (PCSM) among prostate cancer patients. Objective To investigate the associations of recreational PA, reported before and after diagnosis, with PCSM, overall and by tumor risk category. Design, setting, and participants In a prospective cohort study conducted in the USA, men diagnosed with nonmetastatic prostate cancer between 1992/1993 and June 2011 were followed for mortality until 2012. Patients were included in pre- ( n = 7328) and/or postdiagnosis ( n = 5319) analyses. Outcome measurements and statistical analysis Cox proportional hazards models were used to assess PCSM with recreational PA. Results and limitations A total of 454 and 261 prostate cancer deaths occurred during pre- and postdiagnosis follow-up, respectively. Prior to diagnosis, engaging in ≥17.5 metabolic equivalent hours per week (MET-h/wk) of recreational PA, compared with 3.5–<8.75 MET-h/wk, was associated with a significant 37% lower risk of PCSM (hazard ratio: 0.63, 95% confidence interval: 0.43–0.91, p trend = 0.03) only among men with lower-risk tumors (Gleason score 2–7 and T1–T2; p interaction = 0.02). A similar result was seen for walking but not for other recreational PA. After diagnosis, the same comparison (≥17.5 vs 3.5–<8.75 MET-h/wk) was associated with a significant 31% lower risk of overall PCSM (hazard ratio: 0.69, 95% confidence interval: 0.49–0.95, p trend = 0.006), which did not differ by tumor risk category. Postdiagnosis walking had a suggestive inverse association with PCSM ( p trend = 0.07). These results were observational and may not be generalized to patients with metastatic prostate cancer. Residual confounding due to a higher screening rate among men with lower-risk tumors cannot be ruled out. Conclusions The findings provide additional evidence for prostate cancer survivors to adhere to PA recommendations, and support clinical trials of exercise among prostate cancer survivors with progression or mortality as outcomes. Patient summary In a large follow-up study of men diagnosed with nonmetastatic prostate cancer, those who exercise more after diagnosis had a lower risk of dying from prostate cancer. [ABSTRACT FROM AUTHOR]

Context Current evidence-based management for clinically localised prostate cancer includes active surveillance, surgery, external beam radiotherapy (EBRT) and brachytherapy. The impact of these treatment modalities on quality of life (QoL) is uncertain. Objective To systematically review comparative studies investigating disease-specific QoL outcomes as assessed by validated cancer-specific patient-reported outcome measures with at least 1 yr of follow-up after primary treatment for clinically localised prostate cancer. Evidence acquisition MEDLINE, EMBASE, AMED, PsycINFO, and Cochrane Library were searched to identify relevant studies. Studies were critically appraised for the risk of bias. A narrative synthesis was undertaken. Evidence synthesis Of 11 486 articles identified, 18 studies were eligible for inclusion, including three randomised controlled trials (RCTs; follow-up range: 60–72 mo) and 15 nonrandomised comparative studies (follow-up range: 12–180 mo) recruiting a total of 13 604 patients. Two RCTs recruited small cohorts and only one was judged to have a low risk of bias. The quality of evidence from observational studies was low to moderate. For a follow-up of up to 6 yr, active surveillance was found to have the lowest impact on cancer-specific QoL, surgery had a negative impact on urinary and sexual function when compared with active surveillance and EBRT, and EBRT had a negative impact on bowel function when compared with active surveillance and surgery. Data from one small RCT reported that brachytherapy has a negative impact on urinary function 1 yr post-treatment, but no significant urinary toxicity was reported at 5 yr. Conclusions This is the first systematic review comparing the impact of different primary treatments on cancer-specific QoL for men with clinically localised prostate cancer, using validated cancer-specific patient-reported outcome measures only. There is robust evidence that choice of primary treatment for localised prostate cancer has distinct impacts on patients’ QoL. This should be discussed in detail with patients during pretreatment counselling. Patient summary Our review of the current evidence suggests that for a period of up to 6 yr after treatment, men with localised prostate cancer who were managed with active surveillance reported high levels of quality of life (QoL). Men treated with surgery reported mainly urinary and sexual problems, while those treated with external beam radiotherapy reported mainly bowel problems. Men eligible for brachytherapy reported urinary problems up to a year after therapy, but then their QoL returned gradually to as it was before treatment. [ABSTRACT FROM AUTHOR]

Background An increasing proportion of prostate cancer is being managed conservatively. However, there are no randomized trials or consensus regarding the optimal follow-up strategy. Objective To compare life expectancy and quality of life between watchful waiting (WW) versus different strategies of active surveillance (AS). Design, setting, and participants A Markov model was created for US men starting at age 50, diagnosed with localized prostate cancer who chose conservative management by WW or AS using different testing protocols (prostate-specific antigen every 3–6 mo, biopsy every 1–5 yr, or magnetic resonance imaging based). Transition probabilities and utilities were obtained from the literature. Outcome measurements and statistical analysis Primary outcomes were life years and quality-adjusted life years (QALYs). Secondary outcomes include radical treatment, metastasis, and prostate cancer death. Results and limitations All AS strategies yielded more life years compared with WW. Lifetime risks of prostate cancer death and metastasis were, respectively, 5.42% and 6.40% with AS versus 8.72% and 10.30% with WW. AS yielded more QALYs than WW except in cohorts age >65 yr at diagnosis, or when treatment-related complications were long term. The preferred follow-up strategy was also sensitive to whether people value short-term over long-term benefits (time preference). Depending on the AS protocol, 30–41% underwent radical treatment within 10 yr. Extending the surveillance biopsy interval from 1 to 5 yr reduced life years slightly, with a 0.26 difference in QALYs. Conclusions AS extends life more than WW, particularly for men with higher-risk features, but this is partly offset by the decrement in quality of life since many men eventually receive treatment. Patient summary More intensive active surveillance protocols extend life more than watchful waiting, but this is partly offset by decrements in quality of life from subsequent treatment. [ABSTRACT FROM AUTHOR]

Background Decipher is a validated genomic classifier developed to determine the biological potential for metastasis after radical prostatectomy (RP). Objective To evaluate the ability of biopsy Decipher to predict metastasis and Prostate cancer-specific mortality (PCSM) in primarily intermediate- to high-risk patients treated with RP or radiation therapy (RT). Design, setting, and participants Two hundred and thirty-five patients treated with either RP ( n = 105) or RT ± androgen deprivation therapy ( n = 130) with available genomic expression profiles generated from diagnostic biopsy specimens from seven tertiary referral centers. The highest-grade core was sampled and Decipher was calculated based on a locked random forest model. Outcome measurements and statistical analysis Metastasis and PCSM were the primary and secondary outcomes of the study, respectively. Cox analysis and c-index were used to evaluate the performance of Decipher. Results and limitations With a median follow-up of 6 yr among censored patients, 34 patients developed metastases and 11 died of prostate cancer. On multivariable analysis, biopsy Decipher remained a significant predictor of metastasis (hazard ratio: 1.37 per 10% increase in score, 95% confidence interval [CI]: 1.06–1.78, p = 0.018) after adjusting for clinical variables. For predicting metastasis 5-yr post-biopsy, Cancer of the Prostate Risk Assessment score had a c-index of 0.60 (95% CI: 0.50–0.69), while Cancer of the Prostate Risk Assessment plus biopsy Decipher had a c-index of 0.71 (95% CI: 0.60–0.82). National Comprehensive Cancer Network risk group had a c-index of 0.66 (95% CI: 0.53–0.77), while National Comprehensive Cancer Network plus biopsy Decipher had a c-index of 0.74 (95% CI: 0.66–0.82). Biopsy Decipher was a significant predictor of PCSM (hazard ratio: 1.57 per 10% increase in score, 95% CI: 1.03–2.48, p = 0.037), with a 5-yr PCSM rate of 0%, 0%, and 9.4% for Decipher low, intermediate, and high, respectively. Conclusions Biopsy Decipher predicted metastasis and PCSM from diagnostic biopsy specimens of primarily intermediate- and high-risk men treated with first-line RT or RP. Patient summary Biopsy Decipher predicted metastasis and prostate cancer-specific mortality risk from diagnostic biopsy specimens. [ABSTRACT FROM AUTHOR]

Context Prostate cancer (PCa) patients found to have adverse pathologic features following radical prostatectomy (RP) are less likely to be cured with surgery alone. Objective To analyze the role of postoperative radiotherapy (RT) in patients with aggressive PCa. Evidence acquisition We performed a systematic literature review of the Medline and EMBASE databases. The search strategy included the terms radical prostatectomy, adjuvant radiotherapy, and salvage radiotherapy, alone or in combination. We limited our search to studies published between January 2009 and August 2016. Evidence synthesis Three randomized trials demonstrated that immediate RT after RP reduces the risk of recurrence in patients with aggressive PCa. However, immediate postoperative RT is associated with an increased risk of acute and late side effects ranging from 15% to 35% and 2% to 8%, respectively. Retrospective studies support the oncologic efficacy of initial observation followed by salvage RT administered at the first sign of recurrence; however, the impact of this delay on long-term control remains uncertain. Hopefully, ongoing randomized trials will shed light on the role of adjuvant RT versus observation ± salvage RT in individuals with adverse features at RP. Accurate patient selection based on clinical characteristics and molecular profile is crucial. Dose escalation, whole-pelvis RT, novel techniques, and the use of hormonal therapy might improve the outcomes of postoperative RT. Conclusions Immediate RT reduces the risk of recurrence after RP in patients with aggressive disease. However, this approach is associated with an increase in the incidence of short- and long-term side effects. Observation followed by salvage RT administered at the first sign of recurrence might be associated with durable cancer control, but prospective randomized comparison with adjuvant RT is still awaited. Dose escalation, refinements in the technique, and the concomitant use of hormonal therapies might improve outcomes of patients undergoing postoperative RT. Patient summary Postoperative radiotherapy has an impact on oncologic outcomes in patients with aggressive disease characteristics. Salvage radiotherapy administered at the first sign of recurrence might be associated with durable cancer control in selected patients but might compromise cure in others. [ABSTRACT FROM AUTHOR]

Background There are limited comparative survival data for prostate cancer (PCa) patients managed with a low-dose rate brachytherapy (LDR-B) boost and dose-escalated external-beam radiotherapy (DE-EBRT) alone. Objective To compare overall survival (OS) for men with unfavorable PCa between LDR-B and DE-EBRT groups. Design, setting, and participants Using the National Cancer Data Base, we identified men with unfavorable PCa treated between 2004 and 2012 with androgen suppression (AS) and either EBRT followed by LDR-B or DE-EBRT (75.6–86.4 Gy). Outcome measurements and statistical analysis Treatment selection was evaluated using logistic regression and annual percentage proportions. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards, and propensity score matching. Results and limitation We identified 25 038 men between 2004 and 2012, during which LDR-B boost utilization decreased from 29% to 14%. LDR-B was associated with better OS on univariate (7-yr OS: 82% vs 73%; p < 0.001) and multivariate analyses (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.64–0.77). Propensity score matching verified an OS benefit associated with LDR-B boost (HR 0.74, 95% CI 0.66–0.89). The OS benefit of LDR-B boost persisted when limited to men aged <60 yr with no comorbidities. On subset analysis, there was no interaction between treatment and age, risk group, or radiation dose. Limitations include the retrospective design, nonrandomized selection bias, and the absence of treatment toxicity, hormone duration, and cancer-specific outcomes. Conclusions Between 2004 and 2012, LDR-B boost utilization declined and was associated with better OS compared to DE-EBRT alone. LDR-B boost is probably the ideal treatment option for men with unfavorable PCa, pending long-term results of randomized trials. Patient summary We compared radiotherapy utilization and survival for prostate cancer (PCa) patients using a national database. We found that low-dose rate brachytherapy (LDR-B) boost, a method being used less frequently, was associated with better overall survival when compared to dose-escalated external-beam radiotherapy alone for men with unfavorable PCa. Randomized trials are needed to confirm that LDR-B boost is the ideal treatment. [ABSTRACT FROM AUTHOR]

Context Some of the high costs of robot-assisted radical prostatectomy (RARP), intensity-modulated radiotherapy (IMRT), and proton beam therapy may be offset by better outcomes or less resource use during the treatment episode. Objective To systematically review the literature to identify the key economic trade-offs implicit in a particular treatment choice for prostate cancer. Evidence acquisition We systematically reviewed the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement and protocol. We searched Medline, Embase, and Web of Science for articles published between January 2001 and July 2016, which compared the treatment costs of RARP, IMRT, or proton beam therapy to the standard treatment. We identified 37, nine, and three studies, respectively. Evidence synthesis RARP is costlier than radical retropubic prostatectomy for hospitals and payers. However, RARP has the potential for a moderate cost advantage for payers and society over a longer time horizon when optimal cancer and quality-of-life outcomes are achieved. IMRT is more expensive from a payer's perspective compared with three-dimensional conformal radiotherapy, but also more cost effective when defined by an incremental cost effectiveness ratio <$50 000 per quality-adjusted life year. Proton beam therapy is costlier than IMRT and its cost effectiveness remains unclear given the limited comparative data on outcomes. Using the Grades of Recommendation, Assessment, Development and Evaluation approach, the quality of evidence was low for RARP and IMRT, and very low for proton beam therapy. Conclusions Treatment with new versus traditional technologies is costlier. However, given the low quality of evidence and the inconsistencies across studies, the precise difference in costs remains unclear. Attempts to estimate whether this increased cost is worth the expense are hampered by the uncertainty surrounding improvements in outcomes, such as cancer control and side effects of treatment. If the new technologies can consistently achieve better outcomes, then they may be cost effective. Patient summary We review the cost and cost effectiveness of robot-assisted radical prostatectomy, intensity-modulated radiotherapy, and proton beam therapy in prostate cancer treatment. These technologies are costlier than their traditional counterparts. It remains unclear whether their use is associated with improved cure and reduced morbidity, and whether the increased cost is worth the expense. [ABSTRACT FROM AUTHOR]

Background Regular aspirin use probably protects against some malignancies including prostate cancer (PC), but its impact on lethal PC is particularly unclear. Objective To investigate the association between regular aspirin and (1) the risk of lethal PC in a large prospective cohort and (2) survival after PC diagnosis. Design, setting, and participants In 1981/82, the Physicians’ Health Study randomized 22 071 healthy male physicians to aspirin, β-carotene, both, or placebo. After the trial ended in 1988, annual questionnaires have obtained data on aspirin use, cancer diagnoses, and outcomes up to 2009 for the whole cohort, and to 2015 for PC patients. Outcome measurements and statistical analysis We evaluated the relationship between regular aspirin (>3 tablets/week) and lethal PC (metastases or PC death). Cox proportional-hazards models estimated hazard ratios (HRs) for the risk of lethal PC in the whole cohort and postdiagnosis survival among men initially diagnosed with nonlethal PC. Results and limitations Risk analysis revealed that 502 men developed lethal PC by 2009. Current and past regular aspirin was associated with a lower risk of lethal PC (current: HR 0.68, 95% confidence interval [CI] 0.52–0.89; past: HR 0.54, 95% CI 0.40–0.74) compared to never users. In the survival analysis, 407/3277 men diagnosed with nonlethal PC developed lethal disease by 2015. Current postdiagnostic aspirin was associated with lower risks of lethal PC (HR 0.68, 95% CI 0.52–0.90) and overall mortality (HR 0.72, 95% CI 0.61–0.9). We could not assess aspirin dose, and inconsistencies were observed in some sensitivity analyses. Conclusions Current regular aspirin use was associated with a lower risk of lethal PC among all participants. Current postdiagnostic use was associated with improved survival after diagnosis, consistent with a potential inhibitory effect of aspirin on PC progression. A randomized trial is warranted to confirm or refute these findings. Patient summary We examined the potential effect of regular aspirin use on lethal prostate cancer. We found that taking aspirin was associated with a lower risk of lethal prostate cancer, and taking it after diagnosis may help to prevent prostate cancer from becoming fatal. [ABSTRACT FROM AUTHOR]

Context Prostate cancer is the most frequent male cancer. Since the median age of diagnosis is 66 yr, many patients require both geriatric and urologic evaluation if treatment is to be tailored to individual circumstances including comorbidities and frailty. Objective To update the 2014 International Society of Geriatric Oncology (SIOG) guidelines on prostate cancer in men aged >70 yr. The update includes new material on health status evaluation and the treatment of localised, advanced, and castrate-resistant disease. Data acquisition A multidisciplinary SIOG task force reviewed pertinent articles published during 2013–2016 using search terms relevant to prostate cancer, the elderly, geriatric evaluation, local treatments, and castration-refractory/resistant disease. Each member of the group proposed modifications to the previous guidelines. These were collated and circulated. The final manuscript reflects the expert consensus. Data synthesis Elderly patients should be managed according to their individual health status and not according to age. Fit elderly patients should receive the same treatment as younger patients on the basis of international recommendations. At the initial evaluation, screening for cognitive impairment is mandatory to establish patient competence in making decisions. Initial evaluation of health status should use the validated G8 screening tool. Abnormal scores on the G8 should lead to a simplified geriatric assessment that evaluates comorbid conditions (using the Cumulative Illness Score Rating-Geriatrics scale), dependence (Activities of Daily Living) and nutritional status (via estimation of weight loss). When patients are frail or disabled or have severe comorbidities, a comprehensive geriatric assessment is needed. This may suggest additional geriatric interventions. Conclusions Advances in geriatric evaluation and treatments for localised and advanced disease are contributing to more appropriate management of elderly patients with prostate cancer. A better understanding of the role of active surveillance for less aggressive disease is also contributing to the individualisation of care. Patient summary Many men with prostate cancer are elderly. In the physically fit, treatment should be the same as in younger patients. However, some elderly prostate cancer patients are frail and have other medical problems. Treatment in the individual patient should be based on health status and patient preference. [ABSTRACT FROM AUTHOR]

Background Active surveillance (AS) is commonly used for men with low-risk prostate cancer (PCa). When life expectancy becomes too short for curative treatment to be beneficial, a change from AS to watchful waiting (WW) follows. Little is known about this change since it is rarely documented in medical records. Objective To model transition from AS to WW and how this is affected by age and comorbidity among men with very low-risk PCa. Design, setting, and participants National population-based healthcare registers were used for analysis. Outcome measurements and statistical analysis Using data on PCa characteristics, age, and comorbidity, a state transition model was created to estimate the probability of changes between predefined treatments to estimate transition from AS to WW. Results and limitations Our estimates indicate that 48% of men with very low-risk PCa starting AS eventually changed to WW over a life course. This proportion increased with age at time of AS initiation. Within 10 yr from start of AS, 10% of men aged 55 yr and 50% of men aged 70 yr with no comorbidity at initiation changed to WW. Our prevalence simulation suggests that the number of men on WW who were previously on AS will eventually stabilise after 30 yr. A limitation is the limited information from clinical follow-up visits (eg, repeat biopsies). Conclusions We estimated that changes from AS to WW become common among men with very low-risk PCa who are elderly. This potential change to WW should be discussed with men starting on AS. Moreover, our estimates may help in planning health care resources allocated to men on AS, as the transition to WW is associated with lower demands on outpatient resources. Patient summary Changes from active surveillance to watchful waiting will become more common among men with very low-risk prostate cancer. These observations suggest that patients need to be informed about this potential change before they start on active surveillance. [ABSTRACT FROM AUTHOR]

Background Erectile dysfunction remains the most common side effect from radical treatment of localized prostate cancer. We hypothesized that the use of vessel-sparing radiotherapy, analogous to the functional anatomy approach of nerve-sparing radical prostatectomy (RP), would improve erectile function preservation while maintaining tumor control for men with localized prostate cancer. Objective To determine erectile function rates after vessel-sparing radiotherapy. Design, setting, and participants Men with localized prostate cancer were enrolled in a phase 2 single-arm trial (NCT02958787) at a single academic center. Intervention Patients received vessel-sparing radiotherapy utilizing a planning MRI and MRI-angiogram to delineate and avoid the erectile vasculature. Outcome measurements and statistical analysis Both physician- and patient-reported inventories were used to capture erectile function at baseline and at 2 and 5 yr after treatment. Validated model-based comparisons were performed to compare vessel-sparing results to nerve-sparing RP and conventional radiotherapy. Results and limitations From 2001 to 2009, 135 men underwent vessel-sparing radiotherapy. After a planned interim analysis, the trial was stopped after meeting the primary endpoint. The median follow-up was 8.7 yr, with a ≥94% response rate to all inventories at each time point. At 5 yr, 88% of patients were sexually active with or without the use of sexual aids. The 2-yr erectile function rates were significantly improved with vessel-sparing radiotherapy (78%, 95% confidence interval [CI] 71–85%) compared to modeled rates for convention radiotherapy (42%, 95% CI 38-45%; p < 0.001) or nerve-sparing prostatectomy (24%, 95% CI 22–27%; p < 0.001). At 2 yr after treatment, 87% of baseline-potent men retained erections suitable for intercourse. The 5- and 10-yr rates of biochemical relapse–free survival were 99.3% and 89.9%, and at 5 yr the biochemical failures were limited to the National Comprehensive Cancer Network high-risk group. The single-arm design is a limitation. Conclusions Vessel-sparing radiotherapy appears to more effectively preserve erectile function when compared to historical series and model-predicted outcomes following nerve-sparing RP or conventional radiotherapy, with maintenance of tumor control. This approach warrants independent validation. Patient summary In this interim analysis we looked at using a novel approach to spare critical erectile structures to preserve erectile function after prostate cancer radiotherapy. We found that almost 90% of patients at 5 yr after treatment remained sexually active, significantly higher than previous studies with surgery or radiotherapy. [ABSTRACT FROM AUTHOR]

Background Preoperative assessment of the risk of lymph node invasion (LNI) is mandatory to identify prostate cancer (PCa) patients who should receive an extended pelvic lymph node dissection (ePLND). Objective To update a nomogram predicting LNI in contemporary PCa patients with detailed biopsy reports. Design, setting, and participants Overall, 681 patients with detailed biopsy information, evaluated by a high-volume uropathologist, treated with radical prostatectomy and ePLND between 2011 and 2016 were identified. Outcome measurements and statistical analysis A multivariable logistic regression model predicting LNI was fitted and represented the basis for a coefficient-based nomogram. The model was evaluated using the receiver operating characteristic-derived area under the curve (AUC), calibration plot, and decision-curve analyses (DCAs). Results and limitations The median number of nodes removed was 16. Overall, 79 (12%) patients had LNI. A multivariable model that included prostate-specific antigen, clinical stage, biopsy Gleason grade group, percentage of cores with highest-grade PCa, and percentage of cores with lower-grade disease represented the basis for the nomogram. After cross validation, the predictive accuracy of these predictors in our cohort was 90.8% and the DCA demonstrated improved risk prediction against threshold probabilities of LNI ≤20%. Using a cutoff of 7%, 471 (69%) ePLNDs would be spared and LNI would be missed in seven (1.5%) patients. As compared with the Briganti and Memorial Sloan Kettering Cancer Center nomograms, the novel model showed higher AUC (90.8% vs 89.5% vs 89.5%), better calibration characteristics, and a higher net benefit at DCA. Conclusions An ePLND should be avoided in patients with detailed biopsy information and a risk of nodal involvement below 7%, in order to spare approximately 70% ePLNDs at the cost of missing only 1.5% LNIs. Patient summary We developed a novel nomogram to predict lymph node invasion (LNI) in patients with clinically localized prostate cancer based on detailed biopsy reports. A lymph node dissection exclusively in men with a risk of LNI > 7% according to this model would significantly reduce the number of unnecessary pelvic nodal dissections with a risk of missing only 1.5% of patients with LNI. [ABSTRACT FROM AUTHOR]

Background Approximately 4–25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy. Objective To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy. Design, setting, and participants Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months. Outcome measurements and statistical analysis Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis. Results and limitations A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13–2.33]; p = 0.0092) and metastatic recurrence (multivariable HR = 3.20 [1.76–5.80]; p = 0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR = 2.67 [1.90–3.75]; p < 0.0001 and HR = 7.53 [4.13–13.73]; p < 0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation. Conclusions The metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential. Patient summary The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population. [ABSTRACT FROM AUTHOR]

Background: Salvage lymph node dissection has been described as a feasible treatment for the management of prostate cancer patients with nodal recurrence after primary treatment. Objective: To report perioperative, pathologic, and oncologic outcomes of robot-assisted salvage nodal dissection (RASND) in patients with nodal recurrence after radical prostatectomy (RP). Design, setting, and participants: We retrospectively evaluated 16 patients affected by nodal recurrence following RP documented by positive positron emission tomography/computed tomography scan. Surgical procedure: Surgery was performed using DaVinci Si and Xi systems. A pelvic nodal dissection that included lymphatic stations overlying the external, internal, and common iliac vessels, the obturator fossa, and the presacral nodes was performed. In 13 (81.3%) patients a retroperitoneal lymph node dissection that included all nodal tissue located between the aortic bifurcation and the renal vessels was performed. Measurements: Perioperative outcomes consisted of operative time, blood loss, length of hospital stay, and complications occurred within 30 d after surgery. Biochemical response (BR) was defined as a prostate-specific antigen level <0.2 ng/ml at 40 d after RASND. Results and limitations: Median operative time, blood loss, and length of hospital stay were 210 min, 250 ml, and 3.5 d. The median number of nodes removed was 16.5. Positive lymph nodes were detected in 11 (68.8%) patients. Overall, four (25.0%) and five (31.2%) patients experienced intraoperative and postoperative complications, respectively. Overall, one (6.3%) and four (25.0%) patients had Clavien I and II complications within 30 d after RASND, respectively. Overall, five (33.3%) patients experienced BR after surgery. Our study is limited by the small cohort of patients evaluated and by the follow-up duration. Conclusions: RASND represents a feasible procedure in patients with nodal recurrence after RP and provides acceptable short-term oncologic outcomes, where one out of three patients experience BR immediately after surgery. Long-term data are needed to confirm the effectiveness of this approach. Patient summary: We report our initial experience with robot-assisted salvage nodal dissection for the management of patients with lymph node recurrence after radical prostatectomy. This technique represents a feasible and effective approach, where no high-grade complications were recorded and one out of three patients experienced biochemical response at 40 d after surgery. [ABSTRACT FROM AUTHOR]

Background: Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed. Objective: To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study. Design, setting, and participants: We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values. Outcome measurements and statistical analysis: We measured progression to MIBC using Cox regression analysis and log-rank tests for comparing survival distributions. Results and limitations: The progression score was significantly (p < 0.001) associated with age, stage, grade, carcinoma in situ, bacillus Calmette-Guérin treatment, European Organisation for Research and Treatment of Cancer risk score, and disease progression. Univariate Cox regression analysis showed that patients molecularly classified as high risk experienced more frequent disease progression (hazard ratio 5.08, 95% confidence interval 2.2-11.6; p < 0.001). Multivariable Cox regression models showed that the progression score added independent prognostic information beyond clinical and histopathological risk factors (p < 0.001), with an increase in concordance statistic from 0.82 to 0.86. The progression score showed high correlation (R² = 0.85) between paired fresh-frozen and formalin-fixed paraffin-embedded tumour specimens, supporting translation potential in the standard clinical setting. A limitation was the relatively low progression rate (5%, 37/750 patients). Conclusions: The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens. Patient summary: Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens. [ABSTRACT FROM AUTHOR]

Background: A significant proportion of men with Gleason score 6 (GS6) prostate cancer undergo treatment with radiation or surgery. Objective: To assess pathologic stage of pure GS6 at radical prostatectomy (RP). Design, setting, and participants In the period 2003-2014, 7817 patients underwent RP at two institutions. Of 2502 patients with GS6 at surgery, 60 were identified as stage pT3a-b on initial pathologic review, 55 with pT3a (extraprostatic extension, EPE), and five with pT3b (seminal vesicle invasion; SVI). All cases of GS6 with pT3 disease underwent contemporary pathologic evaluation for Gleason grade, stage, and extent of EPE. At one institution, all GS≥7 pT3b cases were re-reviewed for downgrading. The 2014 International Society of Urological Pathology (ISUP) Gleason grading criteria and 2009 ISUP recommendations on pT3 staging were applied. Outcome measurements and statistical analysis: Calculated incidence (%) of pT3a, pT3b, pT4, and lymph node-positive disease. Results and limitations Of the 60 GS6 pT3a-b cases identified in the period 2003-2014, seven (0.28% of entire GS6 cohort) with GS6 and pT3a were identified after re-review, all focal EPE. Among the re-examined cohort, no cases of GS6 with pT3b were observed. None of the 132 GS≥7 pT3b cases were downgraded to GS6. Limitations include partial embedding of specimens and separate pathologic review at each institution. Conclusions: In a large prostatectomy cohort, GS6 never had seminal vesicle invasion (0%) and was very rarely (0.28%) associated with extraprostatic extension. Patient summary: GS6 prostate cancer rarely spreads outside the prostate. A new finding in this study was that GS6 prostate cancer never spread to the seminal vesicles. [ABSTRACT FROM AUTHOR]

Background: There is increasing low-quality evidence rationalizing the use of radical therapy for men at high risk of disseminated prostate cancer. Objective: To investigate, using high-quality epidemiologic data, whether initial radical therapy in men at high risk of disseminated prostate cancer improves survival. Design, setting, and participants: An observational population-based Swedish study from 1996 to 2010 of men at high risk of disseminated prostate cancer (prostate-specific antigen [PSA] > 50) initially treated by radical therapy (radiation therapy [n = 630] or radical prostatectomy [n = 120]) or androgen deprivation therapy (n = 17 602), and followed for up to 15 yr. Outcome measurements and statistical analysis: Prostate-cancer and other-cause mortality was estimated for the treatment groups. We also matched the two cohorts for grade, T stage, M stage, Charlson score, year of diagnosis, age, and PSA, and found androgen deprivation therapy patient matches for 575 of the radical therapy patients, and then repeated comparative effectiveness analyses. Results and limitation: Prostate-cancer mortality was substantially greater in the androgen deprivation therapy group compared with the radically treated one, in unmatched (9062/17 602 vs 86/750) and matched (177/575 vs 71/575) cohorts. Among matched cohorts, initial androgen deprivation therapy was associated with nearly three-fold higher hazard of prostate-cancer death compared with initial radical therapy (2.87; 95% confidence interval 2.16-3.82). Multiple sensitivity analyses suggested that the findings were robust, although the general limitations of nonrandomized studies remain. Further, the study cohort may have included men with both systemic and nonsystemic disease, as a sole eligibility criterion of PSA > 50 was used. Conclusions: This large and comprehensive population-based study suggests that initial radical therapy in men at high risk of disseminated prostate cancer improves survival. Patient summary: This large Swedish study suggests that men with prostate cancer that has spread beyond the prostate benefit from treating the prostate itself with radiation therapy or surgery rather than treating the disease with hormones alone. [ABSTRACT FROM AUTHOR]