Search

Background: Decipher is a genomic classifier designed to predict the development of distant metastases after surgical treatment of prostate cancer (PC). Its long-term prognostic role in a high-risk PC population has not been investigated previously., Objective: To determine the prognostic role of the Decipher genomic classifier in two high-risk PC case-control studies., Design, Setting, and Participants: Patients who developed distant metastases after surgery for high-risk, nonmetastatic PC in a European tertiary referral center from 1991 to 2011 were matched to patients not developing distant metastases (n=54). A validation study (n=298) was performed using a similar US case-control cohort. Formalin-fixed, paraffin-embedded tissue blocks from the index PC lesion were used for RNA extraction and gene expression analysis., Outcome Measurements and Statistical Analysis: The outcome investigated was the development of distant metastasis within 10-yr follow-up. Multivariable logistic regression analysis was performed, with statistical significance considered at p<0.05., Results and Limitations: In both the European and US case-control studies, the median Decipher scores were higher in the population that developed metastases. In the multivariable analysis, each 10% increase in Decipher score translated to an increase in the risk of distant metastases within 10-yr follow-up, with an odds ratio of 1.53 (95% confidence interval [CI] 1.06-2.22; p=0.025) and 1.58 (95% CI 1.31-1.92; p<0.001) for the European and US cohorts, respectively. Median follow-up for the European cohort was 12yr (interquartile range 8-12). The study limitation is the small size of the European cohort., Conclusions: Our study validates Decipher as a predictor for metastatic recurrence even in patients with high-risk, nonmetastatic PC within 10-yr follow-up., Patient Summary: Decipher is a test based on gene expression profiles in primary tumors in prostate cancer. It has already been proven to predict cancer recurrence after surgery, but this has not yet been shown for patients with high-risk prostate cancer. This is the first study confirming that Decipher predicts a patient's risk of developing cancer recurrence after surgery for high-risk prostate cancer., (Copyright © 2018. Published by Elsevier B.V.)

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.

Open retropubic radical prostatectomy has been the "gold standard" treatment for locally confined prostate cancer (PCa) but in recent years minimal invasive techniques as laparoscopy and robot-assisted prostatectomy have become widely available. The trifecta of the surgical treatment of PCa is cancer control, the preservation of continence, and erectile potency. Over the years the complication rates of radical prostatectomy have become very limited with improved cancer control and better functional results. We review the indications and the surgical technique of radical prostatectomy, be it open or laparoscopic, eventually robot-assisted as well as the pre- and postoperative measures and the surgery-related consequences.

Context: The current standard of care for metastatic prostate cancer (PCa) is androgen deprivation therapy (ADT) plus either docetaxel or abiraterone. Growing evidence suggests that metastasis-directed therapy (MDT) and/or local therapy targeted to the primary tumour (ie, prostate) may be of benefit in the setting of oligometastatic disease. Several prospective studies are underway; however, until robust evidence is available to guide treatment decisions, physicians are challenged with how best to manage patients with oligometastases., Objective: This comprehensive review aims to collate the available evidence to date for a role of MDT and/or prostate-targeted therapy in the setting of oligometastatic PCa, as well as discuss ongoing trials in this setting., Evidence Acquisition: We searched PubMed for the combination of "prostate cancer" and "oligometastatic", "oligometastases", "oligometastasis", "solitary metastases", "stereotactic body radiotherapy", "SBRT", "stereotactic ablative radiotherapy", "SABR", "salvage lymphadenectomy", or "metastasectomy" in publications over the last 20yr. We also searched ClinicalTrials.gov to identify relevant ongoing trials., Evidence Synthesis: The studies were divided according to the timing of metastasis into synchronous (ie, detected at the time of primary PCa diagnosis) and metachronous (ie, detected after treatment of the primary tumour), and according to treatment modality into MDT (including salvage lymph node dissection [sLND]) and prostate-targeted treatment. For MDT of synchronous/metachronous metastases, we included 16 completed studies and 11 ongoing prospective studies. In the case of sLND for nodal-only recurrence after primary treatment with curative intent, we included 11 completed studies. Finally, for prostate-targeted treatment of synchronous metastatic PCa, we included 25 completed studies and 11 ongoing prospective studies. In selected patients with oligorecurrent disease, early detection and aggressive treatment of metastatic lesions (surgery or radiotherapy) appears to be a feasible strategy and may delay the use of systemic therapies. MDT is a promising option in oligometastatic PCa patients, but more robust data are needed. In the setting of synchronous oligometastatic disease, aggressive cytoreductive treatment needs further data to confirm the benefits., Conclusions: In this review, we provide a comprehensive overview of the current literature on the treatment of patients with oligometastatic PCa. The data suggest that although ADT plus either docetaxel or abiraterone remains the mainstay of treatment for mPCa, in oligometastatic PCa, improved outcomes may be achieved with metastasis- and prostate-targeted therapies. The studies included in this review are mainly retrospective in nature, limiting the strength of the evidence they provide. Prospective studies are ongoing, and their results are eagerly awaited., Patient Summary: We reviewed the treatment of patients with prostate cancer that has spread to five sites or fewer. We conclude that while androgen deprivation plus either docetaxel or abiraterone should remain the standard of care, there is evidence that treatment targeted at the metastases and the primary tumour may improve the outcome for the patient and potentially delay the use of systemic treatment., (Copyright © 2018. Published by Elsevier B.V.)

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., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: This paper aims to assess the diagnostic accuracy of an 11C-choline positron emission tomography/computed tomography (PET/CT) scan in the detection of lymph node (LN) metastases in patients with biochemical recurrence after radically treated prostate cancer (PCa), as compared to histology. The secondary goal is to depict spreading patterns of metastatic LNs in recurrent PCa., Material and Methods: A single center retrospective study comprising of 30 patients who underwent retroperitoneal and/or pelvic salvage lymph node dissection (LND) due to 11C-choline PET/CT-positive nodal recurrences after radical treatment (median Prostate Specific Antigen (PSA) 1.5 ng/ml, range 0.2-11.4). Positive nodes on the preoperative PET/CT scans were mapped and compared to post-operative pathology results.LNs were marked as true positive, false positive, true negative and false negative and a patient- and a region-based analysis was performed. Sensitivity, specificity and positive/negative predictive value (PPV/NPV) were calculated., Results: Sixty positive LNs were detected on PET/CT with a median number of two positive nodes per patient (range 1-6). In 29 patients, a super-extended pelvic LND (PLND) was performed combined with a retroperitoneal LND (RPLND) in 13 of those cases. One patient underwent an inguinal LND. One hundred thirty-seven of 644 resected LNs contained metastases. The 11C-choline PET/CT scan correctly predicted 31 positive nodes (55%) while 25 nodes were falsely positive (45%). One hundred and six histologically proven metastatic nodes were not detected on the 11C-choline PET/CT scan (77%). Sensitivity, specificity, PPV and NPV of the 11C-choline PET/CT were 23%, 95%, 55% and 82%, respectively., Conclusions: 11C-choline PET/CT has a relatively low detection rate and a moderate PPV for metastatic LNs in patients with biochemical recurrence after radically treated PCa., Competing Interests: The authors declare no conflicts of interest., (Copyright by Polish Urological Association.)

Background: Metastasectomy is routinely performed in selected patients with metastatic clear-cell renal cell carcinoma (ccRCC) as an alternative to systemic therapy. In the absence of randomized trials, the benefit and best way of patient selection remain unclear. Earlier, we described four molecular ccRCC-subtypes (ccrcc1-4) that have a prognostic and predictive value upon first-line sunitinib or pazopanib., Objective: Assess the prognostic value of ccrcc1-4 subtypes after complete metastasectomy. (1) Compare outcomes of good-prognosis ccrccc2&3-tumors with intermediate/poor-prognosis ccrcc1&4-tumors. (2) Compare outcomes of the four subtypes separately., Design, Setting, and Participants: Single-center retrospective study (1995-2017), assessing 43 ccRCC patients undergoing complete metastasectomy without systemic treatment., Intervention: Molecular subtype determined with established 35-gene expression classifier., Outcome Measurements and Statistical Analysis: Median disease-free survival (DFS), time to systemic therapy, cancer-specific (CSS) and overall survival (OS) from metastasectomy, estimated with Kaplan-Meier method and tested against other predictors with multivariable Cox regression., Results and Limitations: Median DFS was 23 mo for ccrcc2&3-tumors versus 9 mo for ccrcc1&4-tumors (p=0.011, hazard ratio [HR]=2.6). Median time to systemic therapy was 92 mo versus 28 mo (p=0.003, HR=3.3). Median CSS was 133 mo versus 50 mo (p<0.001, HR=2.7). Median OS was 127 mo versus 50 mo (p=0.011, HR=2.5). The classification remained independent upon multivariable analysis. Outcomes remained significantly different when comparing four subtypes separately. The intrinsic heterogeneity of expression profiles is a limitation of this approach., Conclusion: Even after clinical patient selection, patients with a ccrcc1- or ccrcc4-tumor are at a higher risk of relapse after complete metastasectomy. Patients with a ccrcc2- or ccrcc3-tumor usually experience a long DFS. These results need validation in a larger cohort to establish the subtypes as prognostic marker., Patient Summary: Metastasectomy is recommended for some patients with metastatic clear-cell kidney cancer; however, we do not know who will benefit the most. We show that molecular subtypes increase the possibility to predict which patients are at risk for early relapse after metastasectomy and who may benefit more from other treatment options., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The possibility of predicting pathologic features before surgery can support clinicians in selecting the best treatment strategy for their patients. We sought to develop and externally validate pretreatment nomograms for the prediction of pathological features from a prospective multicentre series of robotic-assisted laparoscopic prostatectomy (RALP) procedures., Design, Setting, and Participants: Between 2009 and 2016, data from 6823 patients undergoing RALP in 25 academic and community hospitals were prospectively collected by the Belgian Cancer Registry. Logistic regression models were applied to predict extraprostatic extension (EPE; pT3a,b-4), seminal vesicle invasion (SVI; pT3b), and high-grade locally advanced disease (HGLA; pT3b-4 and Gleason score [GS] 8-10) using the following preoperative covariates: prostate-specific antigen, clinical T stage, biopsy GS, and percentage of positive biopsy cores. Internal and external validation was performed., Outcome Measurements and Statistical Analysis: The stability of the model was assessed via tenfold cross-validation using 80% of the cohort. The nomograms were independently externally validated using the test cohort. The discriminative accuracy of the nomograms was quantified as the area under the receiver operating characteristic curve and graphically represented using calibration plots., Results and Limitation: The nomograms predicting EPE, SVI, HGLA showed discriminative accuracy of 77%, 82%, and 88%, respectively. Following external validation, the accuracy remained stable. The prediction models showed excellent calibration properties., Conclusions: We developed and externally validated multi-institutional nomograms to predict pathologic features after RALP. These nomograms can be implemented in the clinical setting or patient selection in clinical trials., Patient Summary: We developed novel nomograms using nationwide data to predict postoperative pathologic features and lethal prostate cancer., (Copyright © 2018. Published by Elsevier B.V.)

Background: Recent retrospective data suggest that neoadjuvant androgen deprivation therapy can improve the prognosis of high-risk prostate cancer (PCa) patients. Novel androgen receptor pathway inhibitors are nowadays available for treatment of metastatic PCa and these compounds are promising for early stage disease. Apalutamide is a pure androgen antagonist with a very high affinity with the androgen receptor. The combination of apalutamide with degarelix, an LHRH antagonist, could increase the efficacy compared to degarelix alone., Objective: The primary objective is to assess the difference in proportions of minimal residual disease at prostatectomy specimen between apalutamide + degarelix vs placebo + degarelix. Various secondary endpoints are assessed: variations of different biomarkers at the tumour level (tissue microarrays to evaluate DNA-PKs, PARP, AR and splice variants, PSMA, etc.), whole transcriptome sequencing, exome sequencing and clinical (PSA and testosterone kinetics, early biochemical recurrence free survival, quality of life, safety, etc.) and radiological endpoints., Methods: ARNEO is a single centre, phase II, randomized, double blind, placebo-controlled trial. The plan is to include at least 42 patients per each of the two study arms. Patients with intermediate/high-risk PCa and who are amenable for radical prostatectomy with pelvic lymph node dissection can be included. After signing an informed consent, every patient will undergo a pelvic 68 Ga -PSMA-11 PSMA PET/MR and receive degarelix at standard dosage and start assuming apalutamide/placebo (60 mg 4 tablets/day) for 12 weeks. Within thirty days from the last study medication intake the same imaging will be repeated. Every patient will undergo PSA and testosterone testing the day of randomization, before the first drug intake, and after the last dose. Formalin fixed paraffin embedded tumour samples will be collected and used for transcriptome analysis, exome sequencing and immunohistochemistry., Discussion: ARNEO will allow us to answer, first, whether the combined treatment can result in an increased proportion of patients with minimal residual disease. Secondly, It will enable the study of the molecular consequences at the level of the tumour. Thirdly, what the consequences are of new generation androgen receptor pathway inhibitors on 68 Ga -PSMA-11 PET/MR. Finally, various clinical, safety and quality of life data will be collected., Trial Registration: EUDRaCT number: 2016-002854-19 (authorization date 3rd August 2017). clinicalTrial.gov: NCT03080116 .

Background: Accurate prediction of survival after radical prostatectomy (RP) is important for making decisions regarding multimodal therapies. There is a lack of tools to predict prostate cancer-related death (PCRD) in patients with high-risk features., Objective: To develop and validate a prognostic model that predicts PCRD combining pathologic features and using competing-risks analysis., Design, Setting, and Participants: This was a retrospective multi-institutional observational cohort study of 5876 patients affected by high-risk prostate cancer. Patients were treated using RP and pelvic lymph node dissection (PLND) in a multimodal setting, with median follow-up of 49 mo., Outcome Measurements and Statistical Analysis: For PCRD prediction, a multivariate model with correction for competing risks was constructed to evaluate pathologic high-risk features (pT3b-4, Gleason score ≥8, and pN1) as predictors of mortality. All possible associations of the predictors were combined, and then subgroups with similar risk of PCRD were collapsed to obtain a simplified model encoding subgroups with significantly differing risk. Eightfold cross-validation of the model was performed., Results and Limitations: After applying exclusion criteria, 2823 subjects were identified. pT3b-4, Gleason score ≥8, and pN1 were all independent predictors of PCRD. The simplified model included the following prognostic groups: good prognosis, pN0 with 0-1 additional predictors; intermediate prognosis, pN1 with 0-1 additional predictors; poor prognosis, any pN with two additional predictors. The cross-validation yielded excellent median model accuracy of 88%. The retrospective design and the short follow-up could limit our findings., Conclusions: We developed and validated a novel and easy-to-use prognostic instrument to predict PCRD after RP+PLND. This model may allow clinicians to correctly counsel patients regarding the intensity of follow-up and to tailor adjuvant treatments., Patient Summary: Prediction of mortality after primary surgery for prostate cancer is important for subsequent treatment plans. We present an accurate postoperative model to predict cancer mortality after radical prostatectomy for high-risk prostate cancer., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Urinary continence and erectile function (EF) are best preserved when meticulous dissection of prostate and nerve sparing technique are used during radical prostatectomy (RP). However, extent of lymph node dissection (LND) may also adversely affect functional results., Objective: To determine whether performing a super-extended LND (seLND) has a significant effect on recovery of urinary continence and EF after RP., Design Setting and Participants: All patients who underwent RP from January 2007 until December 2013 were handed questionnaires assessing continence and EF. All patients in whom at least an extended LND (eLND) was performed were selected. This search yielded 526 patients. 172 of these patients had filed out 2 or more questionnaires and were included in our analysis., Outcome Measurements and Statistical Analysis: All questionnaires were reviewed. We used Kaplan-Meier analyses and multivariate Cox analysis to assess the difference in recovery of continence and EF over time for eLND/seLND. Primary endpoints were full recovery of continence (no loss of urine) and full recovery of EF (successful intercourse possible). Patients who did not reach the endpoint when the last questionnaire was filled out were censored at that time. Median follow-up was 12.43 months for continence, and 18.97 months for EF., Results and Limitations: Patients undergoing seLND have a lower chance of regaining both urinary continence [hazard ratio (HR) 0.59, 95% CI 0.39-0.90, p  = 0.026] and EF (HR 0.28, 95% CI 0.13-0.57, p  = 0.009). Age at surgery had a significant influence on both continence and EF in multivariate analysis. Major limitation of the study was that no formal preoperative assessment of continence and potency was done., Conclusion: Extending the LND template beyond the eLND template may cause at least a significant delay in recovery of urinary continence and leads to less recovery of EF.

Background: Three prospective randomised trials reported discordant findings regarding the impact of adjuvant radiation therapy (aRT) versus observation for metastasis-free survival (MFS) and overall survival (OS) among patients with pT3N0 prostate cancer treated with radical prostatectomy (RP). None of these trials systematically included patients who underwent early salvage radiation therapy (esRT)., Objective: To test the hypothesis that aRT was associated with better cancer control and survival compared with observation followed by esRT., Design, Setting, and Participants: Using a multi-institutional cohort from seven tertiary referral centres, we retrospectively identified 510 pT3pN0 patients with undetectable prostate-specific antigen (PSA) after RP between 1996 and 2009. Patients were stratified into two groups: aRT (group 1) versus observation followed by esRT in case of PSA relapse (group 2). Specifically, esRT was administered at a PSA level ≤0.5ng/ml., Intervention: We compared aRT versus observation followed by esRT., Outcome Measurements and Statistical Analysis: The evaluated outcomes were MFS and OS. Multivariable Cox regression analyses tested the association between groups (aRT vs observation followed by esRT) and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), surgical margin status (negative vs positive), and year of surgery. An interaction with groups and baseline patient risk was tested for the hypothesis that the impact of aRT versus observation followed by esRT was different by pathologic characteristics. The nonparametric curve fitting method was used to explore graphically the relationship between MFS and OS at 8 yr and baseline patient risk (derived from the multivariable analysis)., Results and Limitations: Overall, 243 patients (48%) underwent aRT, and 267 (52%) underwent initial observation. Within the latter group, 141 patients experienced PSA relapse and received esRT. Median follow-up after RP was 94 mo (interquartile range [IQR]: 53-126) and 92 mo (IQR: 70-136), respectively (p=0.2). MFS (92% vs 91%; p=0.9) and OS (89% vs 92%; p=0.9) at 8 yr after surgery were not significantly different between the two groups. These results were confirmed in multivariable analysis, in which observation followed by esRT was not associated with a significantly higher risk of distant metastasis (hazard ratio [HR]: 1.35; p=0.4) and overall mortality (HR: 1.39; p=0.4) compared with aRT. Using the nonparametric curve fitting method, a comparable proportion of MFS and OS at 8 yr among groups was observed regardless of pathologic cancer features (p=0.9 and p=0.7, respectively). Limitations consisted of the retrospective nature of the study and the relatively small size of the patient population., Conclusions: At long-term follow-up, no significant differences between aRT and esRT were observed for MFS and OS. Our study, although based on retrospective data, suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT., Patient Summary: At long-term follow-up, no significant differences in terms of distant metastasis and mortality were observed between immediate postoperative adjuvant radiation therapy (aRT) and initial observation followed by early salvage radiation therapy (esRT) in case of prostate-specific antigen relapse. Our study suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: To identify the most significant cut-off of tumor volume (TV) for prediction of clinical failure (CF) among high-risk prostate cancer (hPCa) patients., Methods: Within a multi-institutional cohort, 262 patients treated with radical prostatectomy (RP) for hPCa were identified. CF was defined as local recurrence or distant metastases. A time dependent ROC curve was used to evaluate the area under the curve (AUC) using TV as single marker to predict clinical failure at 10 years. We searched for the TV cut off value with the highest combined sensitivity and specificity predicting CF. Three multivariable Cox regression analyses (MVA) tested the predictors of CF after RP. Predictors of the model 1 were pre-operative PSA, pathologic stage (PT), pathologic Gleason sum (GS), surgical margin status, and lymph node invasion. Predictors of the models 2 and 3 were the same of model 1 plus TV as a continuous or dichotomous variable using the defined cutoff, respectively. Validation (leave-one-out-cross-validation-LOOCV) of each model was performed., Results: Overall, 46 (17.6%) patients experienced CF. The TV value was 6.29 ml. In MVA of models 2 and 3, PT and GS remained independent predictors of CF. Moreover, in model 2 TV (HR:1.07,) and in model 3 TV >6.29 ml (HR:2.99,) were independently associated with CF. In LOOCV, the C-index of models 1-3 were 65.53%, 71.75%, and 70.26%, respectively., Conclusions: TV is an independent predictor of CF in hPCa patients. Patients with a TV exceeding the cut-off of 6.29 ml are more likely to develop CF. Prostate 77:3-9, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Aim: To determine the impact of the extent of lymph node invasion (LNI) on long-term oncological outcomes after radical prostatectomy (RP)., Material and Methods: In this retrospective study, we examined the data of 1,249 high-risk, non-metastatic PCa patients treated with RP and pelvic lymph node dissection (PLND) between 1989 and 2011 at eight different tertiary institutions. We fitted univariate and multivariate Cox models to assess independent predictors of cancer-specific survival (CSS) and overall survival (OS). The number of positive lymph node (LN) was dichotomized according to the most informative cutoff predicting CSS. Kaplan-Meier curves assessed CSS and OS rates. Only patients with at least 10 LNs removed at PLND were included. This cutoff was chosen as a surrogate for a well performed PNLD., Results: Mean age was 65 years (median: 66, IQR 60-70). Positive surgical margins were present in 53.7% ( n  = 671). Final Gleason score (GS) was 2-6 in 12.7% ( n  = 158), 7 in 52% ( n  = 649), and 8-10 in 35.4% ( n  = 442). The median number of LNs removed during PLND was 15 (IQR 12-17). Of all patients, 1,128 (90.3%) had 0-3 positive LNs, while 126 (9.7%) had ≥4 positive LNs. Patients with 0-3 positive LNs had significantly better CSS outcome at 10-year follow-up compared to patients with ≥4 positive LNs (87 vs. 50%; p  < 0.0001). Similar results were obtained for OS, with a 72 vs. 37% ( p  < 0.0001) survival at 10 years for patients with 0-3 vs. ≥4 positive LNs, respectively. At multivariate analysis, final GS of 8-10, salvage ADT therapy, and ≥4 (vs. <4) positive LNs were predictors of worse CSS and OS. Pathological stage pT4 was an additional predictor of worse CSS., Conclusion: Four or more positive LNs, pathological stage pT4, and final GS of 8-10 represent independent predictors for worse CSS in patients with high-risk PCa. Primary tumor biology remains a strong driver of tumor progression and patients having ≥4 positive LNs could be considered an enriched patient group in which novel treatment strategies should be studied.

Objective: In patients with a long life expectancy with high-risk (HR) prostate cancer (PCa), the chance to die from PCa is not negligible and may change significantly according to the time elapsed from surgery. The aim of this study was to evaluate long-term survival patterns in young patients treated with radical prostatectomy (RP) for HRPCa., Materials and Methods: Within a multiinstitutional cohort, 600 young patients (≤59 years) treated with RP between 1987 and 2012 for HRPCa (defined as at least one of the following adverse characteristics: prostate specific antigen>20, cT3 or higher, biopsy Gleason sum 8-10) were identified. Smoothed cumulative incidence plot was performed to assess cancer-specific mortality (CSM) and other cause mortality (OCM) rates at 10, 15, and 20 years after RP. The same analyses were performed to assess the 5-year probability of CSM and OCM in patients who survived 5, 10, and 15 years after RP. A multivariable competing risk regression model was fitted to identify predictors of CSM and OCM., Results: The 10-, 15- and 20-year CSM and OCM rates were 11.6% and 5.5% vs. 15.5% and 13.5% vs. 18.4% and 19.3%, respectively. The 5-year probability of CSM and OCM rates among patients who survived at 5, 10, and 15 years after RP, were 6.4% and 2.7% vs. 4.6% and 9.6% vs. 4.2% and 8.2%, respectively. Year of surgery, pathological stage and Gleason score, surgical margin status and lymph node invasion were the major determinants of CSM (all P≤0.03). Conversely, none of the covariates was significantly associated with OCM (all P≥ 0.09)., Conclusions: Very long-term cancer control in young high-risk patients after RP is highly satisfactory. The probability of dying from PCa in young patients is the leading cause of death during the first 10 years of survivorship after RP. Thereafter, mortality not related to PCa became the main cause of death. Consequently, surgery should be consider among young patients with high-risk disease and strict PCa follow-up should enforce during the first 10 years of survivorship after RP., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The clinical heterogeneity of prostate cancer (PCa) makes it difficult to identify those patients that could benefit from more aggressive treatments. As a contribution to a better understanding of the genomic changes in the primary tumor that are associated with the development of high-risk disease, we performed exome sequencing and copy number determination of a clinically homogeneous cohort of 47 high-risk PCas. We confirmed recurrent mutations in SPOP, PTEN and TP53 among the 850 point mutations we detected. In seven cases, we discovered genomic aberrations in the TET1 (Ten-Eleven Translocation 1) gene which encodes a DNA hydroxymethylase than can modify methylated cytosines in genomic DNA and thus is linked with gene expression changes. TET1 protein levels were reduced in tumor versus non-tumor prostate tissue in 39 of 40 cases. The clinical relevance of changes in TET1 levels was demonstrated in an independent PCa cohort, in which low TET1 mRNA levels were significantly associated with worse metastases-free survival. We also demonstrate a strong reduction in hydroxymethylated DNA in tumor tissue in 27 of 41 cases. Furthermore, we report the first exploratory (h)MeDIP-Seq analyses of eight high-risk PCa samples. This reveals a large heterogeneity in hydroxymethylation changes in tumor versus non-tumor genomes which can be linked with cell polarity., Competing Interests: No potential conflicts of interest were disclosed.

Background: No data exist on the patterns of biochemical recurrence (BCR) and their effect on survival in patients with high-risk prostate cancer (PCa) treated with surgery. The aim of our investigation was to evaluate the natural history of PCa in patients treated with radical prostatectomy (RP) alone., Materials and Methods: Overall, 2,065 patients with high-risk PCa treated with RP at 7 tertiary referral centers between 1991 and 2011 were identified. First, we calculated the probability of experiencing BCR after surgery. Particularly, we relied on conditional survival estimates for BCR after RP. Competing-risks regression analyses were then used to evaluate the effect of time to BCR on the risk of cancer-specific mortality (CSM)., Results: Median follow-up was 70 months. Overall, the 5-year BCR-free survival rate was 55.2%. Given the BCR-free survivorship at 1, 2, 3, 4, and 5 years, the BCR-free survival rates improved by+7.6%,+4.1%,+4.8%,+3.2%, and+3.7%, respectively. Overall, the 10-year CSM rate was 14.8%. When patients were stratified according to time to BCR, patients experiencing BCR within 36 months from surgery had higher 10-year CSM rates compared with those experiencing late BCR (19.1% vs. 4.4%; P<0.001). At multivariate analyses, time to BCR represented an independent predictor of CSM (P<0.001)., Conclusions: Increasing time from surgery is associated with a reduction of the risk of subsequent BCR. Additionally, time to BCR represents a predictor of CSM in these patients. These results might help provide clinicians with better follow-up strategies and more aggressive treatments for early BCR., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Pretreatment tables for the prediction of pathologic stage have been published and validated for localized prostate cancer (PCa). No such tables are available for locally advanced (cT3a) PCa., Objective: To construct tables predicting pathologic outcome after radical prostatectomy (RP) for patients with cT3a PCa with the aim to help guide treatment decisions in clinical practice., Design, Setting, and Participants: This was a multicenter retrospective cohort study including 759 consecutive patients with cT3a PCa treated with RP between 1987 and 2010., Intervention: Retropubic RP and pelvic lymphadenectomy., Outcome Measurements and Statistical Analysis: Patients were divided into pretreatment prostate-specific antigen (PSA) and biopsy Gleason score (GS) subgroups. These parameters were used to construct tables predicting pathologic outcome and the presence of positive lymph nodes (LNs) after RP for cT3a PCa using ordinal logistic regression., Results and Limitations: In the model predicting pathologic outcome, the main effects of biopsy GS and pretreatment PSA were significant. A higher GS and/or higher PSA level was associated with a more unfavorable pathologic outcome. The validation procedure, using a repeated split-sample method, showed good predictive ability. Regression analysis also showed an increasing probability of positive LNs with increasing PSA levels and/or higher GS. Limitations of the study are the retrospective design and the long study period., Conclusions: These novel tables predict pathologic stage after RP for patients with cT3a PCa based on pretreatment PSA level and biopsy GS. They can be used to guide decision making in men with locally advanced PCa., Patient Summary: Our study might provide physicians with a useful tool to predict pathologic stage in locally advanced prostate cancer that might help select patients who may need multimodal treatment., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: High-risk prostate cancer (PCa) is an extremely heterogeneous disease. A clear definition of prognostic subgroups is mandatory., Objective: To develop a pretreatment prognostic model for PCa-specific survival (PCSS) in high-risk PCa based on combinations of unfavorable risk factors., Design, Setting, and Participants: We conducted a retrospective multicenter cohort study including 1360 consecutive patients with high-risk PCa treated at eight European high-volume centers., Intervention: Retropubic radical prostatectomy with pelvic lymphadenectomy., Outcome Measurements and Statistical Analysis: Two Cox multivariable regression models were constructed to predict PCSS as a function of dichotomization of clinical stage (< cT3 vs cT3-4), Gleason score (GS) (2-7 vs 8-10), and prostate-specific antigen (PSA; ≤ 20 ng/ml vs > 20 ng/ml). The first "extended" model includes all seven possible combinations; the second "simplified" model includes three subgroups: a good prognosis subgroup (one single high-risk factor); an intermediate prognosis subgroup (PSA >20 ng/ml and stage cT3-4); and a poor prognosis subgroup (GS 8-10 in combination with at least one other high-risk factor). The predictive accuracy of the models was summarized and compared. Survival estimates and clinical and pathologic outcomes were compared between the three subgroups., Results and Limitations: The simplified model yielded an R(2) of 33% with a 5-yr area under the curve (AUC) of 0.70 with no significant loss of predictive accuracy compared with the extended model (R(2): 34%; AUC: 0.71). The 5- and 10-yr PCSS rates were 98.7% and 95.4%, 96.5% and 88.3%, 88.8% and 79.7%, for the good, intermediate, and poor prognosis subgroups, respectively (p = 0.0003). Overall survival, clinical progression-free survival, and histopathologic outcomes significantly worsened in a stepwise fashion from the good to the poor prognosis subgroups. Limitations of the study are the retrospective design and the long study period., Conclusions: This study presents an intuitive and easy-to-use stratification of high-risk PCa into three prognostic subgroups. The model is useful for counseling and decision making in the pretreatment setting., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Prostate cancer (PCa) is a major health care problem because of its high prevalence, health-related costs, and mortality. Epidemiological studies have suggested an important role of genetics in PCa development. Because of this, an increasing number of single nucleotide polymorphisms (SNPs) had been suggested to be implicated in the development and progression of PCa. While individual SNPs are only moderately associated with PCa risk, in combination, they have a stronger, dose-dependent association, currently explaining 30% of PCa familial risk. This review aims to give a brief overview of studies in which the possible role of genetic variants was investigated in clinical settings. We will highlight the major research questions in the translation of SNP identification into clinical practice.

Purpose of Review: Surgery for high-risk prostate cancer (PCa) is applied frequently nowadays. Nevertheless, this approach is still surrounded by many controversies. The present review discusses the most recent literature regarding surgery for high-risk PCa., Recent Findings: As there is no standard definition of high-risk PCa, outcome comparison between series and treatment approaches is hampered. Nevertheless, recent radical prostatectomy series have shown excellent cancer-specific survival in patients with high-risk PCa. Even for very-high-risk PCa (cT3b-T4 or any cT, N1), surgery may be applied to highly selected patients as a first step of a multimodality approach. Recent experience with robot-assisted surgery opens new possibilities for a minimally invasive approach in this field.Patient selection for surgery was also addressed in recent studies. Excellent cancer-specific survival is seen when specimen-confined PCa is found at final histopathology; a recently published nomogram enables the prediction of specimen-confined disease. Another issue in high-risk PCa is the impact of age and comorbidities on cancer-specific and overall mortality. In a recent study, it was shown that patients with low comorbidity scores, even when at least 70 years old, had a significant risk of dying from their cancer and may benefit most from a surgical approach. A modified extended pelvic lymphadenectomy template was presented, providing optimal removal of positive lymph nodes., Summary: Radical prostatectomy with extended pelvic lymphadenectomy delivers very good cancer-related outcomes in high-risk and very-high-risk PCa, often within a multimodal approach. Minimally invasive surgery and improved patient selection will be key to further improve oncological and functional outcomes.

Background: The survival impact of metastasectomy for metastatic renal cell carcinoma (mRCC) is still an active research field, particularly in the multimodal/targeted therapy era., Objective: To determine the survival impact of clinical prognostic factors and their application to stratification of patients according to their prognosis so clinicians may be aided in their management of mRCC., Design, Setting, and Participants: Retrospective, bi-institutional cohort study of 109 consecutive patients (71 male and 38 female; median age: 62 yr (range: 25-82 yr) with renal cell carcinoma (RCC) who underwent partial or radical nephrectomy and at least one metastasectomy for mRCC., Intervention: Metastasis resection from various anatomic sites with the aim of completely removing detected lesions., Outcome Measurements and Statistical Analysis: Univariable and multivariable Cox regression models were used to analyse the impact of clinical prognostic factors on cancer-specific survival (CSS). Kaplan-Meier analysis with the log-rank test was used to compare CSS. Receiver operating characteristic (ROC) analysis was performed to test accuracy of prognostic groups. The α error for statistical significance was set at 0.05., Results and Limitations: Multivariable analysis revealed that primary tumour T stage ≥ 3 (hazard ratio [HR]: 2.8; p<0.01), primary tumour Fuhrman grade ≥ 3 (HR: 2.3; p<0.03), nonpulmonary metastases (HR: 3.1; p<0.03), disease-free interval ≤ 12 mo (HR: 2.3; p<0.058), and multiorgan metastases (HR: 2.5; p<0.04) were independent pretreatment prognostic factors. Leuven-Udine (LU) prognostic groups based on these covariates were created and analysed with Kaplan-Meier and log-rank tests. The 2- and 5-yr CSS were significantly different; the respective group A CSS rates were 95.8% and 83.1%; group B, 89.9% and 56.4%; group C, 65.6% and 32.6%; and group D, 24.7% and 0% (p<0.0001). ROC analysis on the accuracy of prognostic grouping revealed respective areas under the curve of 0.87 and 0.88 at 2 and 5 yr. Main limitations to present study are the retrospective design and the presence of different metastasis sites., Conclusions: LU prognostic groups could be considered an accurate clinical tool to stratify patients according to prognosis and aid clinicians in the management of mRCC., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To describe a new geometrical stepper-guided navigation system for positioning ProACT®., Methods: The sizing of the stepper-guided navigation system was calculated using the distance from the ideal position of the device to anatomic referral points previously measured by ultrasound. The trocar and subsequently the device were maneuvered to the ideal position in accordance with the navigation system., Measurements: Treatment efficacy was evaluated with daily pad count, 1-hour pad test, Incontinence Quality of Life questionnaire (IQoL), visual analog scale and overall impression. Complications, balloon volume and number of adjustments were reported at 1, 3, 6 and 12 months follow-up visits., Results: Mean follow-up was 12 (range 3-19) months. Daily pad count showed 30 patients (71%) dry and 9 patients (21%) improved. 1 hour pad test showed 28 patients were dry (66%) and 11 patients improved (26%). IQoL increased from an average of 35.3 to 80. Average visual analog scale score was 8. Complications requiring device removal occurred in 3 patients (7%). Mean balloon volume was 3.1 ml., Conclusions: The stepper-guided navigation system to implant ProACT is feasible and extremely reproducible making this procedure more standardized., (Copyright © 2012 S. Karger AG, Basel.)