Prostate Cancer Early Detection in the European Union and UK.

BACKGROUND AND OBJECTIVE: While prostate cancer (PCa) incidence and mortality rates continue to rise, early detection of PCa remains highly controversial, and the research landscape is rapidly evolving. Existing systematic reviews (SRs) and meta-analyses (MAs) provide valuable insights, but often focus on single aspects of early detection, hindering a comprehensive understanding of the topic. We aim to fill this gap by providing a comprehensive SR of contemporary SRs covering different aspects of early detection of PCa in the European Union (EU) and the UK. METHODS: On June 1, 2023, we searched four databases (Medline ALL via Ovid, Embase, Web of Science, and Cochrane Central Register of Controlled Trials) and Google Scholar. To avoid repetition of previous studies, only SRs (qualitative, quantitative, and/or MAs) were considered eligible. In the data, common themes were identified to present the evidence systematically. KEY FINDINGS AND LIMITATIONS: We identified 1358 citations, resulting in 26 SRs eligible for inclusion. Six themes were identified: (1) invitation: men at general risk should be invited at >50 yr of age, and testing should be discontinued at >70 yr or with <10 yr of life expectancy; (2) decision-making: most health authorities discourage population-based screening and instead recommend a shared decision-making (SDM) approach, but implementation of SDM in clinical practice varies widely; decision aids help men make more informed and value-consistent screening decisions and decrease men's intention to attempt screening, but these do not affect screening uptake; (3) acceptance: facilitators for men considering screening include social prompting by partners and clinician recommendations, while barriers include a lack of knowledge, low-risk perception, and masculinity attributes; (4) screening test and algorithm: prostate-specific antigen-based screening reduces PCa-specific mortality and metastatic disease in men aged 55-69 yr at randomisation if screened at least twice; (5) harms and benefits: these benefits come at the cost of unnecessary biopsies, overdiagnosis, and subsequent overtreatment; and (6) future of screening: risk-adapted screening including (prebiopsy) risk calculators, magnetic resonance imaging, and blood- and urine-based biomarkers could reduce these harms. To enable a comprehensive overview, we focused on SRs. These do not include the most recent prospective studies, which were therefore incorporated in the discussion. CONCLUSIONS AND CLINICAL IMPLICATIONS: By identifying consistent and conflicting evidence, this review highlights the evidence-based foundations that can be built upon, as well as areas requiring further research and improvement to reduce the burden of PCa in the EU and UK. PATIENT SUMMARY: This review of 26 reviews covers various aspects of prostate cancer screening such as invitation, decision-making, screening tests, harms, and benefits. This review provides insights into existing evidence, highlighting the areas of consensus and discrepancies, to guide future research and improve prostate cancer screening strategies in Europe.

Systematic Review on the Cost Effectiveness of Prostate Cancer Screening in Europe.

BACKGROUND AND OBJECTIVE: In Europe, prostate cancer (PCa) is the most common cancer in men. Screening may therefore be crucial to lower health care costs, morbidity, and mortality. This systematic review aimed to provide a contemporary overview of the costs and benefits of PCa screening programmes. METHODS: A peer-reviewed literature search was conducted, using the PICO method. A detailed search strategy was developed in four databases based on the following key search terms: "PCa", "screening", and "cost effectiveness". Any type of economic evaluation was included. The search strategy was restricted to European countries, but no restrictions were set on the year of publication. KEY FINDINGS AND LIMITATIONS: A total of 7484 studies were identified initially. Of these, 19 studies described the cost effectiveness of PCa screening in Europe. Among the studies using an initially healthy study population, most focussed on risk- and/or age- and/or magnetic resonance imaging (MRI)-based screening in addition to prostate-specific antigen (PSA) testing and compared this with no screening. Incremental cost ratios (ICERs) varied from €5872 per quality-adjusted life year (QALY) to €372 948/QALY, with a median of €56 487/QALY. Risk-based screening followed by MRI testing seemed to be a more cost-effective strategy than no screening. CONCLUSIONS AND CLINICAL IMPLICATIONS: This systematic review indicates that screening programmes incorporating a risk-based approach and MRI have the potential to be cost effective. PATIENT SUMMARY: In this review, we looked at the cost effectiveness of prostate cancer screening in Europe. We found that a risk-based approach and incorporation of magnetic resonance imaging has the potential to be cost effective. However, there remains a knowledge gap regarding cost effectiveness of prostate cancer screening. Therefore, determinants of cost effectiveness require further investigation.

Improving Patient Information and Enhanced Consent in Urology: The Impact of Simulation and Multimedia Tools. A Systematic Literature Review from the European Association of Urology Patient Office.

BACKGROUND AND OBJECTIVE: Discussions surrounding urological diagnoses and planned procedures can be challenging, and patients might experience difficulty in understanding the medical language, even when shown radiological imaging or drawings. With the introduction of virtual reality and simulation, informed consent could be enhanced by audiovisual content and interactive platforms. Our aim was to assess the role of enhanced consent in the field of urology. METHODS: A systematic review of the literature was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, using informed consent, simulation, and virtual reality in urology as the search terms. All original articles were screened. KEY FINDINGS AND LIMITATIONS: Thirteen original studies were included in the review. The overall quality of these studies was deemed good according to the Newcastle-Ottawa Scale. The studies analysed the application of different modalities for enhanced consent: 3D printed or digital models, audio visual multimedia contents, virtual simulation of procedures and interactive navigable apps. Published studies agreed upon a significantly improved effect on patient understanding of the diagnosis, including basic anatomical details, and surgery-related issues such as the aim, steps and the risks connected to the planned intervention. Patient satisfaction was unanimously reported as improved as a result of enhanced consent. CONCLUSIONS AND CLINICAL IMPLICATIONS: Simulation and multimedia tools are extremely valuable for improving patients' understanding of and satisfaction with urological procedures. Widespread application of enhanced consent would represent a milestone for patient-urologist communication. PATIENT SUMMARY: Several multimedia tools can be used to improve patients' understanding of urological conditions and procedures, such as simulation and models. Use of these tools for preoperative discussion enhances knowledge and patient satisfaction, resulting in more realistic patient expectations and better informed consent.

Navigating through the Controversies and Emerging Paradigms in Early Detection of Prostate Cancer: Bridging the Gap from Classic RCTs to Modern Population-Based Pilot Programs.

Over the last three decades, the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US-based Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening have steered the conversation around the early detection of prostate cancer. These two randomized trials assessed the effect of screening on prostate cancer disease-specific mortality. Elevated PSA levels were followed by a systematic sextant prostate biopsy. Standard repeat testing intervals were applied. After controversies from 2009 to 2016 due to contradicting results of the two trials, the results aligned in 2016 and showed that early PSA detection reduces prostate cancer-specific mortality. However, overdiagnosis rates of up to 50% were reported, and this sparked an intense debate on harms and benefits for almost 20 years. The balance between harms and benefits is highly debated and has initiated further research to investigate new ways of early detection. In the meantime, the knowledge and tools for the diagnostic algorithm improved. This is a continuously ongoing effort which focuses on individual risk-based screening algorithms that preserve the benefits of the purely PSA-based screening algorithms, while reducing the side effects. An important push towards investigating new techniques for early detection came from the European Commission on the 20th of September 2022. The European Commission published its updated recommendation to investigate prostate, lung, and gastric cancer early detection programs. This opened a new window of opportunity to move away from the trial setting to population-based early detection settings. With this review, we aim to review 30 years of historical evidence of prostate cancer screening, which led to the initiation of the 'The Prostate Cancer Awareness and Initiative for Screening in the European Union' (PRAISE-U) project, which aims to encourage the early detection and diagnosis of PCa through customized and risk-based screening programs.

Epidemiology of Renal Cell Carcinoma: 2022 Update.

CONTEXT: International variations in the rates of kidney cancer (KC) are considerable. An understanding of the risk factors for KC development is necessary to generate opportunities to reduce its incidence through prevention and surveillance. OBJECTIVE: To retrieve and summarize global incidence and mortality rates of KC and risk factors associated with its development, and to describe known familial syndromes and genetic alterations that represent biologic risk factors. EVIDENCE ACQUISITION: A systematic review was conducted via Medline (PubMed) and Scopus to include meta-analyses, reviews, and original studies regarding renal cell carcinoma, epidemiology, and risk factors. EVIDENCE SYNTHESIS: Our narrative review provides a detailed analysis of KC incidence and mortality, with significant variations across time, geography, and sex. In particular, while KC incidence has continued to increase, mortality models have leveled off. Among the many risk factors, hypertension, obesity, and smoking are the most well established. The emergence of new genetic data coupled with observational data allows for integrated management and surveillance strategies for KC care. CONCLUSIONS: KC incidence and mortality rates vary significantly by geography, sex, and age. Associations of the development of KC with modifiable and fixed risk factors such as obesity, hypertension, smoking, and chronic kidney disease (CKD)/end-stage kidney disease (ESKD) are well described. Recent advances in the genetic characterization of these cancers have led to a better understanding of the germline and somatic mutations that predispose patients to KC development, with potential for identification of therapeutic targets that may improve outcomes for these at-risk patients. PATIENT SUMMARY: We reviewed evidence on the occurrence of kidney cancer (KC) around the world. Currently, the main avoidable causes are smoking, obesity, and high blood pressure. Although other risk factors also contribute, prevention and treatment of these three factors provide the best opportunities to reduce the risk of developing KC at present.

Bringing Onco-Innovation to Europe's Healthcare Systems: The Potential of Biomarker Testing, Real World Evidence, Tumour Agnostic Therapies to Empower Personalised Medicine.

Rapid and continuing advances in biomarker testing are not being matched by uptake in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. The potential that genomics has brought to biomarker testing in diagnosis, prediction and research is being realised, pre-eminently in many cancers, but also in an ever-wider range of conditions-notably BRCA1/2 testing in ovarian, breast, pancreatic and prostate cancers. Nevertheless, the implementation of genetic testing in clinical routine setting is still challenging. Development is impeded by country-related heterogeneity, data deficiencies, and lack of policy alignment on standards, approval-and the role of real-world evidence in the process-and reimbursement. The acute nature of the problem is compellingly illustrated by the particular challenges facing the development and use of tumour agnostic therapies, where the gaps in preparedness for taking advantage of this innovative approach to cancer therapy are sharply exposed. Europe should already have in place a guarantee of universal access to a minimum suite of biomarker tests and should be planning for an optimum testing scenario with a wider range of biomarker tests integrated into a more sophisticated health system articulated around personalised medicine. Improving healthcare and winning advantages for Europe's industrial competitiveness and innovation require an appropriate policy framework-starting with an update to outdated recommendations. We show herein the main issues and proposals that emerged during the previous advisory boards organised by the European Alliance for Personalized Medicine which mainly focus on possible scenarios of harmonisation of both oncogenetic testing and management of cancer patients.

Defining the Most Informative Intermediate Clinical Endpoints for Patients Treated with Salvage Radiotherapy for Prostate-specific Antigen Rise After Radical Prostatectomy.

Intermediate clinical endpoints (ICEs) might aid in trial design and potentially expedite study results. However, little is known about the most informative ICE for patients receiving salvage radiation therapy (sRT) after radical prostatectomy. To investigate the most informative ICE for patients receiving sRT, we used a multi-institutional database encompassing patients treated at eight tertiary centers. Overall, 1301 men with node-negative disease who had not received any form of androgen deprivation therapy were identified. Associations of biochemical (BCR) and clinical recurrence (CR) within 1, 3, 5, and 7yr after surgery with the risk of overall mortality were evaluated using multivariable Cox regression analyses fitted at the landmark points of 1, 3, 5, and 7yr after sRT. The discriminative ability of each model for predicting overall survival (OS) was assessed using Harrell's c index. Median follow-up for survivors was 5.6yr (interquartile range 2.0-8.8). On multivariable analysis, progression to CR within 3yr from sRT (hazard ratio 4.19, 95% confidence interval 1.44-11.2; p= 0.008) was the most informative ICE for predicting OS (c index 0.78) compared to CR within 1, 5, and 7yr (c index 0.72, 0.75, and 0.71). In conclusion, progression to CR within 3yr after sRT, irrespective of the time of surgery, was the most informative ICE for prediction of OS. Our study is hypothesis-generating. If these results are confirmed in future prospective studies and surrogacy is met, this information could be applied for study design and could potentially expedite earlier release of results from ongoing randomized controlled trials. PATIENT SUMMARY: Clinical recurrence of prostate cancer within 3yr after salvage radiation therapy, irrespective of the time of radical prostatectomy, represents the most informative intermediate clinical endpoint for the prediction of overall survival. This information could be applied in the design of future studies and could potentially expedite earlier release of results from ongoing randomized controlled trials.

Europa Uomo Patient Reported Outcome Study (EUPROMS): Descriptive Statistics of a Prostate Cancer Survey from Patients for Patients.

BACKGROUND: Europa Uomo initiated the Europa Uomo Patient Reported Outcome Study (EUPROMS) to collect prostate cancer (PCa) patient-reported outcome (PRO) data as a primary endpoint. OBJECTIVE: To inform future PCa patients about the impact of PCa treatment through self-reported PRO data of fellow patients collected outside a clinical trial setting. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional survey was conducted among PCa patients currently receiving or having received treatment. The EUPROMS survey contained the EQ-5D-5 L (generic health), the EORTC-QLQ-C30 (cancer-specific quality of life (QoL), and the Expanded Prostate cancer Index Composite short form 26 (EPIC-26; prostate-specific health) questionnaires. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive statistics were used to assess the demographic and clinical characteristics, and to analyze the PROs of EQ-5D-5L, EORTC-QLQ-C30, and EPIC-26. RESULTS AND LIMITATIONS: Between August 21 and November 19, 2019, 2943 men from 24 European countries completed the EUPROMS survey. The median age of the respondents was 71 yr (interquartile range 65-75 yr); 81.9% was living with a spouse. In total, 1937 (65.8%) men underwent a single treatment, and 636 (21.6%), 300 (10.2%), and 70 (2.4%) underwent two, three, and four treatments, respectively. Fatigue scores are highest for men who underwent radiotherapy or chemotherapy. Progression of disease leads to more insomnia. Surgery affects urinary incontinence the most. Self-reported sexual function amounts to 27/100, with the lowest scores being reported for men who underwent surgery and radiotherapy (15/100). Overall, patients who received two or more treatments reported lower scores for all indices. CONCLUSIONS: The EUPROMS survey provided a cross-sectional picture of the current PCa patient population and their reported QoL. Initial treatment is often followed by subsequent treatments, affecting mainly sexual function, as well as fatigue and insomnia. QoL of men undergoing chemotherapy is worse for almost all domains. These data can inform physicians and patients on the true impact of PCa treatment. PATIENT SUMMARY: Patient-reported quality of life in the Europa Uomo Patient Reported Outcome Study (EUPROMS) survey-a more informal setting as compared with clinical trials-reveals that prostate cancer treatment affects mainly sexual function, fatigue, and insomnia.

The potential of tumour microenvironment markers to stratify the risk of recurrence in prostate cancer patients.

The tumour micro-environment (TME) plays a crucial role in the onset and progression of prostate cancer (PCa). Here we studied the potential of a selected panel of TME-markers to predict clinical recurrence (CLR) in PCa. Patient cohorts were matched for the presence or absence of CLR 5 years post-prostatectomy. Tissue micro-arrays (TMA) were composed with both prostate non-tumour (PNT) and PCa tissue and subsequently processed for immunohistochemistry (IHC). The IHC panel included markers for cancer activated fibroblasts (CAFs), blood vessels and steroid hormone receptors ((SHR): androgen receptor (AR), progesterone receptor (PR) and estrogen receptor (ER)). Stained slides were digitalised, selectively annotated and analysed for percentage of marker expression with standardized and validated image analysis algorithms. A univariable analysis identified several TME markers with significant impact on CR: expression of CD31 (vascular marker) in PNT stroma, expression of alpha smooth muscle actin (αSMA) in PCa stroma, and PR expression ratio between PCa stroma and PNT stroma. A multivariable model, which included CD31 expression (vascular marker) in PNT stroma and PR expression ratio between PCa stroma and PNT stroma, could significantly stratify patients for CLR, with the identification of a low risk and high-risk subgroup. If validated and confirmed in an independent prospective series, this subgroup might have clinical potential for PCa patient stratification.

Pushing the limits of metastasis-directed treatment in metastatic renal cell carcinoma in the era of targeted therapy.

OBJECTIVE: To assess the role of metastasis directed therapy and in particular surgical metastasectomy (MxT) in metastatic renal cell carcinoma (mRCC) in the era of targeted therapy. METHOD: The files of all patients who underwent MxT for treatment of mRCC in University Hospitals Leuven between 1989 and 2015 were reviewed. RESULTS: One hundred and thirty eight patients met the inclusion criteria. Mean age at MxT was 59.3 (IQR: 57.5-61.0) years. Median follow-up was 50.1 (42.3-63.8) months. Due to adequate patient selection, 91.9% of MxT achieved no evidence of disease status, which resulted in long median overall survival of 87.8 (63.8-113.4) months and median cancer specific survival of 92.8 (69.5-123.4) months. On multivariate analysis, primary tumor stage >pT2 (hazard ratio [HR] 2.79 [1.47-5.28] P= 0.002), unreached no evidence of disease status (HR 8.62 [3.19-23.32] P< 0.001), presence of nonpulmonary metastasis (HR 2.29 [1.02-5.10] P= 0.0449) and sarcomatoid dedifferentiation in the primary tumor (HR 4.52 [1.15-17.69] P= 0.03) significantly impacted overall survival. Survival did not differ for MxT performed before and after the advent of vascular endothelial growth factor receptor-tyrosine kinase inhibitors. DISCUSSION: Our study confirms the validity of MxT in mRCC in the tyrosine kinase inhibitors era. MxT should be considered in mRCC whenever the patient is fit enough to undergo surgery and complete removal of metastasis is considered possible, independent of number, location, and chronology of appearance of metastasis. Patients with pulmonary metastasis only, seem to be the best candidates for surgical MxT.

Author Correction: Introducing PIONEER: a project to harness big data in prostate cancer research.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Introducing PIONEER: a project to harness big data in prostate cancer research.

Prostate Cancer Diagnosis and Treatment Enhancement Through the Power of Big Data in Europe (PIONEER) is a European network of excellence for big data in prostate cancer, consisting of 32 private and public stakeholders from 9 countries across Europe. Launched by the Innovative Medicines Initiative 2 and part of the Big Data for Better Outcomes Programme (BD4BO), the overarching goal of PIONEER is to provide high-quality evidence on prostate cancer management by unlocking the potential of big data. The project has identified critical evidence gaps in prostate cancer care, via a detailed prioritization exercise including all key stakeholders. By standardizing and integrating existing high-quality and multidisciplinary data sources from patients with prostate cancer across different stages of the disease, the resulting big data will be assembled into a single innovative data platform for research. Based on a unique set of methodologies, PIONEER aims to advance the field of prostate cancer care with a particular focus on improving prostate-cancer-related outcomes, health system efficiency by streamlining patient management, and the quality of health and social care delivered to all men with prostate cancer and their families worldwide.

Correction to: Metastasectomy for visceral and skeletal oligorecurrent prostate cancer.

The authors have requested the removal of the Excel file in Electronic Supplementary Material to protect patient's privacy.

Bringing Greater Accuracy to Europe's Healthcare Systems: The Unexploited Potential of Biomarker Testing in Oncology.

Rapid and continuing advances in biomarker testing are not being matched by take-up in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. This paper sets out the potential of biomarker testing, the unfolding precision and range of possible diagnosis and prediction, and the many obstacles to adoption. It offers case studies of biomarker testing in breast, ovarian, prostate, lung, thyroid and colon cancers, and derives specific lessons as to the potential and actual use of each of them. It also draws lessons about how to improve access and alignment, and to remedy the data deficiencies that impede development. And it suggests solutions to outstanding issues - notably including funding and the tangled web of obtaining reimbursement or equivalent coverage that Europe's fragmented health system implies. It urges a European evolution towards an initial minimum testing scenario, which would guarantee universal access to a suite of biomarker tests for the currently most common conditions, and, further into the future, to an optimum testing scenario in which a much wider range of biomarker tests would be introduced and become part of a more sophisticated health system articulated around personalised medicine. For exploiting genomics to the full, it argues the need for a new policy framework for Europe. Biomarker testing is not an issue that can be treated in isolation, since the purpose of testing is to improve health. Its use is therefore always closely linked to specific health challenges and needs to be viewed in the broader policy context in the EU and more widely. The paper is the result of extensive engagement with experts and decision makers to develop the framework, and consequently represents a wide consensus of views on how healthcare systems should respond from push and pull factors at local, national and cross-border and EU level. It contains strong views and clear recommendations springing from the convictions of patients, clinicians, academics, medicines authorities, HTA bodies, payers, the diagnostic, pharmaceutical and ICT industries, and national policy makers.

Metastasectomy for visceral and skeletal oligorecurrent prostate cancer.

OBJECTIVES: Metastasis direct therapy (MDT) is a common practice in different fields of oncology. However, there is a lack of data on surgical MDT in visceral/skeletal oligometastatic prostate cancer (PCa). We aimed to assess the role of surgical excision of visceral and skeletal PCa recurrence. METHODS: Seventeen PCa patients experienced metachronous visceral or skeletal oligometastatic recurrence following maximal local treatment. Oligometastatic recurrence was defined as 1-3 lesions, detected with the best imaging technique available at the time of diagnosis. All patients underwent metastasectomy and were followed for a median of 43 months. Postoperative complications were graded using the Clavien-Dindo classification of surgical complications. Kaplan-Meier plots were used to assess overall survival. RESULTS: Fourteen patients (82%) had visceral lesions, two had bone lesions (12%), and one had an abdominal wall metastasis (6%). Four patients (24%) were under active ADT at the time of metastasectomy. PSA decreased after metastasectomy in 16 (94%) patients. Ten (77%) of the 13 ADT-naïve patients had a PSA decrease of ≥ 50%. Following metastasectomy, 16 (94.1%) patients developed metastatic recurrence of which 11 (64.7%) were again oligometastatic, amenable for repeated MDT. The median time to metastatic recurrence was 14 months (range 6.4-40). We observed 8% Clavien-Dindo grade 3-4 complications in 21 procedures. CONCLUSIONS: In this report, we analyzed the outcomes of surgical excision of visceral and skeletal PCa recurrence following primary treatment. We found that removing metastasis to the bone and viscera can be associated with long-term disease-free periods at a low rate of serious complications. These exploratory results should be confirmed in prospective studies.

Assessing the Role and Optimal Duration of Hormonal Treatment in Association with Salvage Radiation Therapy After Radical Prostatectomy: Results from a Multi-Institutional Study.

BACKGROUND: The optimal duration of hormonal therapy (HT) when associated with postprostatectomy radiation therapy (RT) remains controversial. OBJECTIVE: To test the impact of HT duration among patients treated with postprostatectomy RT, stratified by clinical and pathologic characteristics. DESIGN, SETTING, AND PARTICIPANTS: The study included 1264 patients who received salvage RT (SRT) to the prostatic and seminal vesicle bed at eight referral centers after radical prostatectomy (RP). Patients received SRT for either rising prostate-specific antigen (PSA) or PSA persistence after RP, defined as PSA ≥0.1ng/ml at 1mo after surgery. Administration of concomitant HT was at the discretion of the treating physician. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome of interest was clinical recurrence (CR) after SRT, as identified by imaging. Multivariable Cox regression analysis was used to test the association between CR and HT duration. We applied an interaction test between HT duration and baseline risk factors to assess the hypothesis that CR-free survival differed by HT duration according to patient profile. Three risk factors were prespecified for evaluation: pT stage ≥pT3b, pathologic Gleason ≥8, and PSA level at SRT >0.5 ng/ml. The relationship between HT duration and CR-free survival rate at 8yr was graphically explored according to the number of risk factors (0 vs 1 vs ≥2). RESULTS AND LIMITATIONS: Overall, 1125 men (89%) received SRT for rising PSA and 139 (11%) were treated for PSA persistence. Concomitant HT was administered to 363 patients (29%), with a median HT duration of 9mo. At median follow-up of 93mo after surgery, 182 patients developed CR. The 8-yr CR-free survival was 92%. On multivariable analysis, HT duration was inversely associated with the risk of CR (hazard ratio 0.95; p=0.022). A total of 531 (42%) patients had none of the prespecified risk factors, while 507 (40%) had one and 226 (18%) had two or more risk factors. The association between HT duration and CR was significantly different by risk factors (0 vs 1, p=0.001; 0 vs ≥2, p<0.0001). We observed a significant effect of HT duration for patients with two or more risk factors, for whom HT administration was beneficial when given for up to 36mo. This effect was attenuated among patients with one risk factor, with concomitant HT slightly beneficial when administered for a shorter time (<12mo). Conversely, for patients with no risk factors, the risk of CR remained low and constant regardless of HT duration. CONCLUSIONS: The oncologic benefit of HT duration among men receiving SRT for increasing PSA after RP depends on their clinical and pathologic characteristics. Our data suggested a significant effect of long-term HT for patients with two or more adverse features. Conversely, short-term HT was sufficient for patients with a single risk factor, whereas patients without any risk factors did not show a significant benefit from concomitant HT. PATIENT SUMMARY: We tested the impact of hormonal therapy (HT) duration during radiation therapy after radical prostatectomy. We identified three risk factors and observed a different impact of HT duration by clinical and pathologic characteristics. Patients with more adverse features benefit from long-term concomitant HT. On the contrary, for patients with a single risk factor, short-term HT may be reasonable. Patients without any risk factors did not show a significant benefit from concomitant HT.

Salvage high-intensity focused ultrasound versus salvage radical prostatectomy for radiation-recurrent prostate cancer: a comparative study of oncological, functional, and toxicity outcomes.

PURPOSE: To compare oncological, functional, and toxicity outcomes of patients with radiation-recurrent prostate cancer (PCa) after external beam radiation therapy (EBRT) or brachytherapy (BT) treated with salvage high-intensity focused ultrasound (S-HIFU) or salvage radical prostatectomy (S-RP). METHODS: This retrospective study compared 52 patients with radiation-recurrent PCa after EBRT or BT treated with S-HIFU (n = 27) or S-RP (n = 25) between 1998 and 2016. We estimated overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS) at 5 years. Incontinence after local salvage therapy (LST) was scored according to the number of pads used per day. Complications were graded according to the Clavien-Dindo classification. RESULTS: Both groups were similar for pre-LST tumor features, however, no S-HIFU patients received BT and S-RP patients were younger and healthier. Median follow-up was 45 months for S-HIFU and 43 months for S-RP. No significant differences were found in estimated 5-year OS (80.9% vs. 61.9%, p = 0.24), 5-year CSS (84.0% vs. 74.0%, p = 0.36), and 5-year MFS (60.3% vs. 55.2%, p = 0.55) for S-HIFU vs. S-RP, respectively. We observed a significant difference in pad-dependent status at 12 months (22.2% vs. 56.0%, p = 0.01) and in the number of Clavien ≥ III complications [9 (7/27 patients) vs. 16 (12/25 patients), p = 0.027] in favor of S-HIFU vs. S-RP, respectively. CONCLUSION: S-HIFU and S-RP could both be considered valuable LST options for patients with radiation-recurrent nonmetastatic PCa with sufficient life expectancy. S-RP is associated with more pad-dependent patients at 12 months.

Impact of neoadjuvant chemotherapy on short-term complications and survival following radical cystectomy.

OBJECTIVES: To compare perioperative and short-term postoperative complication rates between patients receiving radical cystectomy (RC) after neoadjuvant chemotherapy (NAC) and patients undergoing RC alone. Secondary objectives were to compare overall survival (OS) and cancer-specific survival (CSS). MATERIALS AND METHODS: Clinico-pathological data of all patients who received RC between 1996 and 2015 were retrospectively collected. Only patients with RC for muscle-invasive bladder cancer were included in the final analysis. Short-term (30-day) postoperative complications were assessed by registering the Clavien-Dindo classification (CDC) and dividing into sub-groups: low-grade (LGC) CDC 1-2 and high-grade (HGC) CDC 3-5. To compare populations with similar age, comorbidities and preoperative creatinine, we used a propensity score-adjusted statistical model. Pre- and perioperative predictors of short-term complications were identified using uni- and multivariable models. Survival was assessed using Kaplan-Meier analysis. RESULTS: A total of 491 patients undergoing RC were included, of whom 102 (20.8%) received NAC. After propensity score covariate adjustment, there was no significant difference in postoperative complications between patients undergoing NAC plus RC and RC alone with an overall complication rate of 69% and 66%, respectively. No significant differences in the 30-day HGC rates (11.76% and 11.83%, respectively) were observed. NAC plus RC patients had worse prognostic factors at baseline; nevertheless, after correction for group differences OS and CSS did not differ from RC only group (5-year OS 61.3% vs. 50.2%, and 5-year CSS 61.8% vs. 57.9% respectively, p > 0.05 for all). CONCLUSION: In appropriately selected patients, exposure to NAC is not associated with increased short-term complications.

Comparing the expression profiles of steroid hormone receptors and stromal cell markers in prostate cancer at different Gleason scores.

The recent developments in anti-angiogenic and immunomodulatory drugs show that the tumour micro-environment (TME) becomes increasingly important in cancer research. Here we investigated the correlation between the Gleason score (GS) and the TME by comparing tissue expression profiles of steroid hormone receptors, cancer activated fibroblast (CAF) markers and vessel densities between different GS groups. Therefore, matched patient cohorts were composed for different GS (6-7-8). Tissue micro-arrays with 6 samples/patient were processed for immunohistochemistry. Stained slides were digitised, stroma and epithelium were selectively annotated, and all selected areas were quantitatively analysed for marker expression. The most striking findings were decreased stromal expression levels of several steroid hormone receptors, increased CAF-phenotypes and increased vessel densities in high GS prostate cancer compared to low GS prostate cancer and paired prostate non-tumour tissue. The present data reveal a complex correlation between prostate cancer differentiation and TME components and suggest that different GS can be associated with different possible actionable targets in the TME. The use of standardised digital image analysis tools generated robust and reproducible quantitative data, which is novel and more informative compared to the classic semi-quantitative and observer-dependent visual scoring of immunohistochemistry.

More Extensive Lymph Node Dissection at Radical Prostatectomy is Associated with Improved Outcomes with Salvage Radiotherapy for Rising Prostate-specific Antigen After Surgery: A Long-term, Multi-institutional Analysis.

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.