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  • Negative Multiparametric Magnetic Resonance Imaging for Prostate Cancer: What's Next?
    Eur. Urol. (IF 16.265) Pub Date : 2018-03-19
    Valeria Panebianco, Giovanni Barchetti, Giuseppe Simone, Maurizio Del Monte, Antonio Ciardi, Marcello Domenico Grompone, Riccardo Campa, Elena Lucia Indino, Flavio Barchetti, Alessandro Sciarra, Costantino Leonardo, Michele Gallucci, Carlo Catalano

    Background Multiparametric magnetic resonance imaging (mpMRI) of the prostate has excellent sensitivity in detecting clinically significant prostate cancer (csPCa). Nevertheless, the clinical utility of negative mpMRI (nMRI) is less clear. Objective To assess outcomes of men with nMRI and clinical follow-up after 7 yr of activity at a reference center. Design, setting, and participants All mpMRI performed from January 2010 to May 2015 were reviewed. We selected all patients with nMRI and divided them in group A (naïve patients) and group B (previous negative biopsy). All patients without a diagnosis of PCa had a minimum follow-up of 2 yr and at least two consecutive nMRI. Patients with positive mpMRI were also identified to assess their biopsy outcomes. Outcome measurements and statistical analysis A Kaplan-Meier analysis was performed to assess both any-grade PCa and csPCa diagnosis-free survival probabilities. Univariable and multivariable Cox regression models were fitted to identify predictors of csPCa diagnosis. Results and limitations We identified 1545 men with nMRI, and 1255 of them satisfied the inclusion criteria; 659 belonged to group A and 596 to group B. Any-grade PCa and csPCa diagnosis-free survival probabilities after 2 yr of follow-up were 94% and 95%, respectively, in group A; in group B, they were 96%. After 48 mo of follow-up, any-grade PCa diagnosis-free survival probability was 84% in group A and 96% in group B (log rank p < 0.001). Diagnosis-free survival probability for csPCa was unchanged after 48 mo of follow-up. On multivariable Cox regression analysis, increasing age (p = 0.005) was an independent predictor of lower csPCa diagnosis probability, while increasing prostate-specific antigen (PSA) and PSA density (<0.001) independently predicted higher csPCa diagnosis probability. The prevalence of and positive predictive value for csPCa were 31.6% and 45.5%, respectively. Limitations include limited follow-up and the inability to calculate true csPCa prevalence in the study population. Conclusions mpMRI is highly reliable to exclude csPCa. Nevertheless, systematic biopsy should be recommended even after nMRI, especially in younger patients with high or raising PSA levels. Patient summary It is a matter of debate whether patients with negative multiparametric magnetic resonance imaging (mpMRI) of the prostate could obviate the need to perform a systematic biopsy. In this report, we looked at the outcomes of patients with negative mpMRI and midterm clinical follow-up at a reference center. We found mpMRI to be highly reliable to exclude significant prostate cancer; nonetheless, systematic biopsy must still be recommended after negative mpMRI in patients with high clinical suspicion of prostate cancer.

  • Patient-derived Hormone-naive Prostate Cancer Xenograft Models Reveal Growth Factor Receptor Bound Protein 10 as an Androgen Receptor-repressed Gene Driving the Development of Castration-resistant Prostate Cancer
    Eur. Urol. (IF 16.265) Pub Date : 2018-03-12
    Jun Hao, Xinpei Ci, Hui Xue, Rebecca Wu, Xin Dong, Stephen Yiu Chuen Choi, Haiqing He, Yu Wang, Fang Zhang, Sifeng Qu, Fan Zhang, Anne M. Haegert, Peter W. Gout, Amina Zoubeidi, Colin Collins, Martin E. Gleave, Dong Lin, Yuzhuo Wang

    BackgroundAlthough androgen deprivation therapy is initially effective in controlling growth of hormone-naive prostate cancers (HNPCs) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops.ObjectiveTo identify CRPC driver genes that may provide new targets to enhance CRPC therapy.Design, setting, and participantsPatient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers.Outcome measurements and statistical analysisThe functionality of a potential CRPC driver was validated via its knockdown in cultured prostate cancer cells; its clinical relevance was established using data from prostate cancer patient databases.Results and limitationsEighty genes were found to be significantly upregulated at the CRPC stage, while seven of them also showed elevated expression prior to CRPC development. Among the latter, growth factor receptor bound protein 10 (GRB10) was the most significantly and consistently upregulated gene. Moreover, elevated GRB10 expression in clinical prostate cancer samples correlated with more aggressive tumor types and poorer patient treatment outcome. GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. A positive correlation between AKT activity and GRB10 expression was also found in clinical cohorts.ConclusionsGRB10 acts as a driver of CRPC and sensitizes androgen receptor pathway inhibitors, and hence GRB10 targeting provides a novel therapeutic strategy for the disease.Patient summaryDevelopment of castration-resistant prostate cancer (CRPC) is a major problem in the management of the disease. Using state-of-the-art patient-derived hormone-naive prostate cancer xenograft models, we found and validated the growth factor receptor bound protein 10 gene as a driver of CRPC, indicating that it may be used as a new molecular target to enhance current CRPC therapy.

  • 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
    Eur. Urol. (IF 16.265) Pub Date : 2018-03-12
    Nicola Fossati, William P. Parker, R. Jeffrey Karnes, Michele Colicchia, Alberto Bossi, Thomas Seisen, Nadia Di Muzio, Cesare Cozzarini, Barbara Noris Chiorda, Claudio Fiorino, Giorgio Gandaglia, Detlef Bartkowiak, Thomas Wiegel, Shahrokh Shariat, Gregor Goldner, Antonino Battaglia, Steven Joniau, Karin Haustermans, Gert De Meerleer, Valérie Fonteyne, Piet Ost, Hein Van Poppel, Francesco Montorsi, Alberto Briganti, Stephen A. Boorjian

    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 summaryWe 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.

  • The Impact of Implementation of the European Association of Urology Guidelines Panel Recommendations on Reporting and Grading Complications on Perioperative Outcomes after Robot-assisted Radical Prostatectomy
    Eur. Urol. (IF 16.265) Pub Date : 2018-03-12
    Giorgio Gandaglia, Carlo Andrea Bravi, Paolo Dell’Oglio, Elio Mazzone, Nicola Fossati, Simone Scuderi, Daniele Robesti, Francesco Barletta, Luca Grillo, Steven Maclennan, James N’Dow, Francesco Montorsi, Alberto Briganti

    The rate of postoperative complications might vary according to the method used to collect perioperative data. We aimed at assessing the impact of the prospective implementation of the European Association of Urology (EAU) guidelines on reporting and grading of complications in prostate cancer patients undergoing robot-assisted radical prostatectomy (RARP). From September 2016, an integrated method for reporting surgical morbidity based on the EAU guidelines was implemented at a single, tertiary center. Perioperative data were prospectively and systematically collected during a patient interview at 30 d after surgery as recommended by the EAU Guidelines Panel Recommendations on Reporting and Grading Complications. The rate and grading of complications of 167 patients who underwent RARP ± pelvic lymph node dissection (PLND) after the implementation of the prospective collection system (Group 1) were compared with 316 patients treated between January 2015 and August 2016 (Group 2) when a system based on patient chart review was used. No differences were observed in disease characteristics and PLND between the two groups (all p ≥ 0.1). Postoperative complications were graded according to the Clavien-Dindo classification system. Overall, the complication rate was higher when the prospective collection system based on the EAU guidelines was used (29%) than when retrospective chart review (10%; p < 0.001) was used. In particular, a substantially higher rate of grade 1 (8.4% vs 4.7%) and 2 (14% vs 2.8%) complications was detected in Group 1 versus Group 2 (p < 0.001). Although the rate of complications occurred during hospitalization did not differ (13% vs 10%; p = 0.3), 31 (19%) complications after discharge were detected in Group 1. This resulted into a readmission rate of 16%. Conversely, no complications after discharge and readmissions were recorded for Group 2. The implementation of the EAU guidelines on reporting perioperative outcomes roughly doubled the complication rate after RARP and allowed for the detection of complications after discharge in more than 15% of patients that would have been otherwise missed, where patients assessed with the EAU implemented protocol had a threefold higher likelihood of reporting complications.Patient summaryThe implementation of the European Association of Urology guidelines on reporting and grading of complications after urologic procedures in prostate cancer patients roughly doubled the complication rate after robot-assisted radical prostatectomy compared to retrospective patient chart review. Moreover, it allowed for the detection of complications after discharge in more than 15% of patients that would have been otherwise missed.

  • Repeat Transurethral Resection in Non–muscle-invasive Bladder Cancer: A Systematic Review
    Eur. Urol. (IF 16.265) Pub Date : 2018-03-06
    Marcus George Kwesi Cumberbatch, Beat Foerster, James W.F. Catto, Ashish M. Kamat, Wassim Kassouf, Ibrahim Jubber, Shahrokh F. Shariat, Richard J. Sylvester, Paolo Gontero

    ContextInitial treatment for most bladder cancers (BCs) involves transurethral resection (TUR) or tumours. Often more cancer is found after the initial treatment in around half of patients, requiring a second resection. Repeat transurethral resection (reTUR) is recommended for high-risk, non–muscle-invasive bladder cancer (NMIBC) to remove any residual disease and improve cancer outcomes.ObjectiveTo systematically review the practice and therapeutic benefit of an early reTUR for high-risk NMIBC.Evidence acquisitionA systematic review of original articles was performed using PubMed/Medline and Web of Science databases in December 2016 (initial) and October 2017 (final). We searched the references of included papers.Evidence synthesisWe screened 15 209 manuscripts and selected 31 detailing 8409 persons with high-grade Ta and T1BC for inclusion. Detrusor muscle was found at initial TUR histology in 30–100% of cases. Residual tumour at reTUR was found in 17–67% of patients following Ta and in 20–71% following T1 cancer. Most residual tumours (36–86%) were found at the original resection site. Upstaging occurred in 0–8% (Ta to ≥T1) and 0–32% (T1 to ≥T2) of cases. Conflicting data report the impact of reTUR on subsequent recurrence and cancer-specific mortality. Recurrence for Ta was 16% in the reTUR group versus 58% in the non-reTUR group. For T1, recurrence ranged from 18% to 56%, but no clear trend was identified between reTUR and control. No clear relationship between reTUR and progression was found for Ta, although for T1 rates were higher in the non-reTUR group in series with control populations (5/6 studies). Overall mortality was slightly reduced in the reTUR group in two studies with controls (22–30% vs 26–36% [no reTUR]).ConclusionsResidual tumour is common after TUR for high-risk NMIBC. The reTUR helps in the diagnosis of this residual cancer and may improve outcomes for cancers initially staged as T1.Patient summarySome bladder cancers (BCs) are aggressive but confined to the bladder surface. Initial treatment includes endoscopic resection. More cancer is found after the initial treatment in approximately half of patients. In the aggressive but confined group of BC, a second resection, a few weeks after the first, may help find this residual cancer and improve outcomes, although the evidence quality for this is weak.

  • Twenty-year Risk of Prostate Cancer Death by Midlife Prostate-specific Antigen and a Panel of Four Kallikrein Markers in a Large Population-based Cohort of Healthy Men
    Eur. Urol. (IF 16.265) Pub Date : 2018-03-05
    Daniel D. Sjoberg, Andrew J. Vickers, Melissa Assel, Anders Dahlin, Bing Ying Poon, David Ulmert, Hans Lilja

    Background Prostate-specific antigen (PSA) screening reduces prostate cancer deaths but leads to harm from overdiagnosis and overtreatment. Objective To determine the long-term risk of prostate cancer mortality using kallikrein blood markers measured at baseline in a large population of healthy men to identify men with low risk for prostate cancer death. Design, setting, participants Study based on the Malmö Diet and Cancer cohort enrolling 11 506 unscreened men aged 45–73 yr during 1991–1996, providing cryopreserved blood at enrollment and followed without PSA screening to December 31, 2014. We measured four kallikrein markers in the blood of 1223 prostate cancer cases and 3028 controls. Outcome measurements and statistical analysis Prostate cancer death (n = 317) by PSA and a prespecified statistical model based on the levels of four kallikrein markers. Results and limitations Baseline PSA predicted prostate cancer death with a concordance index of 0.86. In men with elevated PSA (≥2.0 ng/ml), predictive accuracy was enhanced by the four-kallikrein panel compared with PSA (0.80 vs 0.73; improvement 0.07; 95% confidence interval 0.04, 0.10). Nearly half of men aged 60+ yr with elevated PSA had a four-kallikrein panel score of <7.5%, translating into 1.7% risk of prostate cancer death at 15 yr—a similar estimate to that of a man with a PSA of 1.6 ng/ml. Men with a four-kallikrein panel score of ≥7.5% had a 13% risk of prostate cancer death at 15 yr. Conclusions A prespecified statistical model based on four kallikrein markers (commercially available as the 4Kscore) reclassified many men with modestly elevated PSA, to have a low long-term risk of prostate cancer death. Men with elevated PSA but low scores from the four-kallikrein panel can be monitored rather than being subject to biopsy. Patient summary Men with elevated prostate-specific antigen (PSA) are often referred for prostate biopsy. However, men with elevated PSA but low scores from the four-kallikrein panel can be monitored rather than being subject to biopsy.

  • Effect of Prostate Cancer Severity on Functional Outcomes After Localized Treatment: Comparative Effectiveness Analysis of Surgery and Radiation Study Results
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-28
    Mark Douglas Tyson II, Tatsuki Koyama, Dan Lee, Karen E. Hoffman, Matthew J. Resnick, Xiao-Cheng Wu, Matthew R. Cooperberg, Michael Goodman, Sheldon Greenfield, Ann S. Hamilton, Mia Hashibe, Lisa E. Paddock, Antoinette Stroup, Vivien Chen, Ralph Conwill, Dan McCollum, David F. Penson, Daniel A. Barocas

    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.

  • Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA)
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-28
    Niven Mehra, David Dolling, Semini Sumanasuriya, Rossitza Christova, Lorna Pope, Suzanne Carreira, George Seed, Wei Yuan, Jane Goodall, Emma Hall, Penny Flohr, Gunther Boysen, Diletta Bianchini, Oliver Sartor, Mario A. Eisenberger, Karim Fizazi, Stephane Oudard, Mustapha Chadjaa, Sandrine Macé, Johann S. de Bono

    Background Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment. Objective To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy. Design, setting, and participants Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75 mg/m2) or cabazitaxel (20 or 25 mg/m2) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25 mg/m2) as second-line chemotherapy (PROSELICA). Outcome measurements and statistical analysis Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies. Results and limitations In 2502 samples, baseline log10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR] = 1.54; 95% confidence interval [CI]: 1.15–2.08; p = 0.004), and shorter OS on taxane therapy (HR = 1.53; 95% CI: 1.18–1.97; p = 0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log10 cfDNA concentrations during the first four cycles of treatment (per cycle −0.03; 95% CI: −0.044 to −0.009; p = 0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA. Conclusions We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes. Patient summary In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cell-free DNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cell-free DNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cell-free DNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cell-free DNA concentration during the first 3–9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cell-free DNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cell-free DNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA.

  • Two-Year Outcomes of Sacral Neuromodulation Versus OnabotulinumtoxinA for Refractory Urgency Urinary Incontinence: A Randomized Trial
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-24
    Cindy L. Amundsen, Yuko M. Komesu, Christopher Chermansky, W. Thomas Gregory, Deborah L. Myers, Emily F. Honeycutt, Sandip P. Vasavada, John N. Nguyen, Tracey S. Wilson, Heidi S. Harvie, Dennis Wallace

    Background Urgency urinary incontinence (UUI) is a chronic condition for which sacral neuromodulation (SNM) (InterStim/Medtronic) and onabotulinumtoxinA (BTX) (BotoxA/Allergan) are utilized. These therapies have not been compared over extended time. Objective To compare UUI episodes (UUIE) over 24 mo following SNM or BTX. Design, setting, and participants Multicenter, open-label, randomized, extension trial (February 2012–July 2016) at nine US medical centers involving 386 women with ≥6 UUIE over 3 d inadequately managed by medications. Participants were clinical responders to treatment: ≥50% reduction in UUIEs after SNM placement or 1 mo post BTX. Intervention SNM (n = 194) versus 200 U BTX (n = 192). SNM reprogrammings occurred throughout the 24 mo. After 6 mo, two additional BTX injections were allowed. Outcome measurements and statistical analysis Primary outcome: change in mean daily UUIE over 24 mo. Secondary outcomes: no UUIE, ≥75% and ≥50% UUIE reduction; Overactive Bladder Questionnaire Short Form; Urinary Distress Inventory short form; Incontinence Impact Questionnaire; Patient Global Impression of Improvement; Overactive Bladder Satisfaction of Treatment Questionnaire; and adverse events (AEs). Primary analysis used a linear mixed model. Results and limitations Outcome data were available for 260/298 (87%) clinical responders. No difference in decreased mean UUIE was found over 24 mo (−3.88 vs −3.50 episodes/d,95% confidence interval [CI] = −0.14–0.89; p = 0.15), with no differences in UUI resolution, ≥75% or ≥50% UUIE reduction. BTX group maintained higher satisfaction (mean difference = −9.14, 95% CI = −14.38–−3.90; p < 0.001), treatment endorsement (mean difference = −12.16, 95% CI = −17.7–−6.63; p < 0.001) through 24 mo. Other secondary measures did not differ. Recurrent urinary tract infections (UTIs) were higher after BTX (24% vs 10%; p < 0.01), 6% required intermittent catheterization post second injection. SNM revision and removals occurred in 3% and 9% patients, respectively. Conclusions Both treatments offered sustainable UUI improvement, and higher BTX dosing had low clean intermittent catheterization rates, but with UTI risk. SNM revision/removal rates were low due to standardized lead placement with strict treatment response definitions. Patient summary We compared a large group of US women with severe urgency urinary incontinence (UUI) who received sacral neuromodulation (InterStim) or onabotulinumtoxinA (Botox A) therapy during a 2-yr period. We found that both therapies had similar success in reducing UUI symptoms, and adverse events were low. However, women in the BotoxA group had higher satisfaction and endorsement with their treatment, but with a higher chance of a urinary tract infection. We conclude that both therapies offer sustained reduction in daily incontinence over 2 yr.

  • Clinical and Genomic Characterization of Low–Prostate-specific Antigen, High-grade Prostate Cancer
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-22
    Brandon A. Mahal, David D. Yang, Natalie Q. Wang, Mohammed Alshalalfa, Elai Davicioni, Voleak Choeurng, Edward M. Schaeffer, Ashley E. Ross, Daniel E. Spratt, Robert B. Den, Neil E. Martin, Kent W. Mouw, Peter F. Orio 3rd, Toni K. Choueiri, Mary-Ellen Taplin, Quoc-Dien Trinh, Felix Y. Feng, Paul L. Nguyen

    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 (pinteraction < 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; pinteraction = 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.

  • Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: Clinical Experience from an Expanded Access Study in the United States
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-22
    Sumanta Kumar Pal, Jean Hoffman-Censits, Hanzhe Zheng, Constanze Kaiser, Darren Tayama, Joaquim Bellmunt

    Background Atezolizumab (anti–programmed death-ligand 1) was approved in the USA, Europe, and elsewhere for treatment-naive and platinum-treated locally advanced/metastatic urothelial carcinoma (mUC). Objective To report efficacy and safety from an atezolizumab expanded access study. Design, setting, and participants This single-arm, open-label study enrolled 218 patients at 36 US sites. Key eligibility criteria included progression during/following ≥1 platinum-based chemotherapy for mUC or in perioperative setting (progression within 12 mo) and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2. Intervention Patients received atezolizumab1200 mg intravenously every 3 wk until loss of clinical benefit, unacceptable toxicity, consent withdrawal, decision to discontinue, death, atezolizumab commercial availability, or study closure. Outcome measurements and statistical analysis Key end points reported herein included Response Evaluation Criteria in Solid Tumors v1.1 objective response rate and duration, disease control rate (DCR; response or stable disease), and safety. Results and limitations All patients received prior systemic therapy (68% mUC; 27% adjuvant; and 26% neoadjuvant). At baseline, 57% of 214 treated patients had ECOG PS ≥1, 19% had hemoglobin <10 g/dl, and 25% had liver metastases. Median treatment duration was 9 wk (interquartile range [IQR], 6–12 wk). Median follow-up duration was 2.3 mo (IQR, 1.6–3.4 mo) overall and 2.7 mo (IQR, 2.0–3.5 mo) in patients not known to have died. Seventeen of 114 evaluable patients (15%) had objective responses (16 ongoing at study termination). DCR was 49%. Treatment-related adverse events (mostly fatigue) occurred in 98 of 214 treated patients. Conclusions The benefit/risk profile of atezolizumab was consistent with that observed in previous studies, despite pretreatment and poor prognostic factors. These results suggest a potential role for atezolizumab in a broader patient range than typically eligible for phase 1–3 studies. Patient summary In this expanded access study, atezolizumab was active and tolerable in a range of patients with platinum-treated metastatic urothelial carcinoma.

  • Burden of Metastatic Castrate Naive Prostate Cancer Patients, to Identify Men More Likely to Benefit from Early Docetaxel: Further Analyses of CHAARTED and GETUG-AFU15 Studies
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-21
    Gwenaelle Gravis, Jean-Marie Boher, Yu-Hui Chen, Glenn Liu, Karim Fizazi, Michael A. Carducci, Stephane Oudard, Florence Joly, David M. Jarrard, Michel Soulie, Mario J. Eisenberger, Muriel Habibian, Robert Dreicer, Jorge A. Garcia, Maha H.M. Hussain, Manish Kohli, Nicholas J. Vogelzang, Joel Picus, Robert DiPaola, Christopher Sweeney

    Background Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is unclear whether patients with low-volume (LV) disease benefit from early D. Objective To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment [PRLT]). Design, setting, and participants Data were accessed from two independent phase III trials of ADT alone or ADT + D—GETUG-AFU15 (N = 385) and CHAARTED (N = 790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized. Outcome measurements and statistical analysis The primary end point was OS. Results and limitations Meta-analysis results of the aggregate data showed significant heterogeneity in ADT + D versus ADT effect sizes between HV and LV subgroups (p = 0.017), and failed to detect heterogeneity in ADT + D versus ADT effect sizes between upfront and PRLT subgroups (p = 0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT + D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval [CI]) 0.68 ([95% CI 0.56; 0.82], p < 0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached [NR] and 83.4; LV-ADT + D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials. Conclusions There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients. Patient summary Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits.

  • Safety of Vaginal Mesh Surgery Versus Laparoscopic Mesh Sacropexy for Cystocele Repair: Results of the Prosthetic Pelvic Floor Repair Randomized Controlled Trial
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-19
    Jean-Philippe Lucot, Michel Cosson, Georges Bader, Philippe Debodinance, Cherif Akladios, Delphine Salet-Lizée, Patrick Delporte, Denis Savary, Philippe Ferry, Xavier Deffieux, Sandrine Campagne-Loiseau, Renaud de Tayrac, Sébastien Blanc, Sandrine Fournet, Arnaud Wattiez, Richard Villet, Marion Ravit, Bernard Jacquetin, Xavier Fritel, Arnaud Fauconnier

    Background Laparoscopic mesh sacropexy (LS) or transvaginal mesh repair (TVM) are surgical techniques used to treat cystoceles. Health authorities have highlighted the need for comparative studies to evaluate the safety of surgeries with meshes. Objective To compare the rate of complications, and functional and anatomical outcomes between LS and TVM. Design, setting, and participants Multicenter randomized controlled trial from October 2012 to April 2014 in 11 French public hospitals. Women with cystocele stage ≥2 (pelvic organ prolapse quantification), aged 45–75 yr, without previous prolapse surgery. Intervention Synthetic nonabsorbable mesh placed in the vesicovaginal space, sutured to the promontory (LS) or maintained by arms through pelvic ligaments (TVM). Outcome measurements and statistical analysis Rate of surgical complications ≥grade II according to the modified Clavien–Dindo classification at 1 yr. Secondary outcomes were reintervention rate, and functional and anatomical results. Results and limitations A total of 130 women were randomized in LS and 132 in TVM; five women withdrew before intervention, leaving 129 in LS and 128 in TVM. The rate of complications ≥grade II was lower after LS than after TVM, but did not meet statistical significance (17% vs 26%, treatment difference 8.6% [95% confidence interval, CI −1.5 to 18]; p = 0.088). The rate of complications of grade III or higher was nonetheless significantly lower after LS (LS = 0.8%, TVM = 9.4%, treatment difference 8.6% [95% CI 3.4%; 15%]; p = 0.001). LS was converted to TVM in 6.3%. The total reoperation rate was lower after LS but did not meet statistical significance (LS = 4.7%, TVM = 10.9%, treatment difference 6.3% [95% CI −0.4 to 13.3]; p = 0.060). There was no difference in symptoms, quality of life, improvement, composite definition of success, anatomical results rates between groups except for the vaginal apex and length, and dyspareunia (in favor of LS). Conclusions LS is a valuable option for primary repair of cystocele in sexually active patients. LS is safer than TVM, but may not be feasible in all cases. Both techniques offer same functional outcomes, success rates, and anatomical outcomes, but sexual function is better preserved by LS. Patient summary Our study demonstrates that laparoscopic sacropexy (LS) is a valuable option for primary repair of cystocele. LS offers equivalent success rates to vaginal mesh procedures, but is safer with a lower rate of complications and reoperations, and sexual function is better preserved.

  • Molecular Subtypes of Clear-cell Renal Cell Carcinoma are Prognostic for Outcome After Complete Metastasectomy
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-17
    Annelies Verbiest, Gabrielle Couchy, Sylvie Job, Laure Caruana, Evelyne Lerut, Raymond Oyen, Aurélien de Reyniès, Lorenzo Tosco, Steven Joniau, Hendrik Van Poppel, Dirk Van Raemdonck, Kathleen Van Den Eynde, Agnieszka Wozniak, Jessica Zucman-Rossi, Benoit Beuselinck

    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.

  • Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-10
    Emmanuel S. Antonarakis, Changxue Lu, Brandon Luber, Chao Liang, Hao Wang, Yan Chen, John L. Silberstein, Danilo Piana, Zhao Lai, Yidong Chen, William B. Isaacs, Jun Luo

    Background Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. Objective To investigate the clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations. Design, setting, and participants We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide. Outcome measurements and statistical analysis We assessed the impact of germline DNA-repair gene mutation status on ≥50% and ≥90% PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. Results and limitations Among 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12% (22/172) of men, and germline BRCA/ATM mutations specifically in 5% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio [HR] 0.47; p = 0.061), PFS (HR 0.50; p = 0.090), and OS (HR 0.28; p = 0.059). In propensity score-weighted multivariable analyses, outcomes were superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95% confidence interval [CI] 0.25–0.92; p = 0.027), PFS (HR 0.52, 95% CI 0.28–0.98; p = 0.044), and OS (HR 0.34, 95% CI 0.12–0.99; p = 0.048), but not in men with non-BRCA/ATM germline mutations (all p > 0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n = 9) with BRCA/ATM mutations. Conclusions Outcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations. Patient summary Patients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide.

  • Role of Surveillance Biopsy with No Cancer as a Prognostic Marker for Reclassification: Results from the Canary Prostate Active Surveillance Study
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-09
    James T. Kearns, Anna V. Faino, Lisa F. Newcomb, James D. Brooks, Peter R. Carroll, Atreya Dash, William J. Ellis, Michael Fabrizio, Martin E. Gleave, Todd M. Morgan, Peter S. Nelson, Ian M. Thompson, Andrew A. Wagner, Yingye Zheng, Daniel W. Lin

    Background Many patients who are on active surveillance (AS) for prostate cancer will have surveillance prostate needle biopsies (PNBs) without any cancer evident. Objective To define the association between negative surveillance PNBs and risk of reclassification on AS. Design, setting, and participants All men were enrolled in the Canary Prostate Active Surveillance Study (PASS) between 2008 and 2016. Men were included if they had Gleason ≤3 + 4 prostate cancer and <34% core involvement ratio at diagnosis. Men were prescribed surveillance PNBs at 12 and 24 mo after diagnosis and then every 24 mo. Outcome measurements and statistical analysis Reclassification was defined as an increase in Gleason grade and/or an increase in the ratio of biopsy cores to cancer to ≥34%. PNB outcomes were defined as follows: (1) no cancer on biopsy, (2) cancer without reclassification, or (3) reclassification. Kaplan–Meier and Cox proportional hazard models were performed to assess the risk of reclassification. Results and limitations A total of 657 men met inclusion criteria. On first surveillance PNB, 214 (32%) had no cancer, 282 (43%) had cancer but no reclassification, and 161 (25%) reclassified. Among those who did not reclassify, 313 had a second PNB. On second PNB, 120 (38%) had no cancer, 139 (44%) had cancer but no reclassification, and 54 (17%) reclassified. In a multivariable analysis, significant predictors of decreased future reclassification after the first PNB were no cancer on PNB (hazard ratio [HR] = 0.50, p = 0.008), lower serum prostate-specific antigen, larger prostate size, and lower body mass index. A finding of no cancer on the second PNB was also associated with significantly decreased future reclassification in a multivariable analysis (HR = 0.15, p = 0.003), regardless of the first PNB result. The major limitation of this study is a relatively small number of patients with long-term follow-up. Conclusions Men who have a surveillance PNB with no evidence of cancer are significantly less likely to reclassify on AS in the PASS cohort. These findings have implications for tailoring AS protocols. Patient summary Men on active surveillance for prostate cancer who have a biopsy showing no cancer are at a decreased risk of having worse disease in the future. This may have an impact on how frequently biopsies are required to be performed in the future.

  • Refined Analysis of Prostate-specific Antigen Kinetics to Predict Prostate Cancer Active Surveillance Outcomes
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-09
    Matthew R. Cooperberg, James D. Brooks, Anna V. Faino, Lisa F. Newcomb, James T. Kearns, Peter R. Carroll, Atreya Dash, Ruth Etzioni, Michael D. Fabrizio, Martin E. Gleave, Todd M. Morgan, Peter S. Nelson, Ian M. Thompson, Andrew A. Wagner, Daniel W. Lin, Yingye Zheng

    Background For men on active surveillance for prostate cancer, utility of prostate-specific antigen (PSA) kinetics (PSAk) in predicting pathologic reclassification remains controversial. Objective To develop prediction methods for utilizing serial PSA and evaluate frequency of collection. Design, setting, and participants Data were collected from men enrolled in the multicenter Canary Prostate Active Surveillance Study, for whom PSA data were measured and biopsies performed on prespecified schedules. We developed a PSAk parameter based on a linear mixed-effect model (LMEM) that accounted for serial PSA levels. Outcome measurements and statistical analysis The association of diagnostic PSA and/or PSAk with time to reclassification (increase in cancer grade and/or volume) was evaluated using multivariable Cox proportional hazards models. Results and limitations A total of 851 men met the study criteria; 255 (30%) had a reclassification event within 5 yr. Median follow-up was 3.7 yr. After adjusting for prostate size, time since diagnosis, biopsy parameters, and diagnostic PSA, PSAk was a significant predictor of reclassification (hazard ratio for each 0.10 increase in PSAk = 1.6 [95% confidence interval 1.2–2.1, p < 0.001]). The PSAk model improved stratification of risk prediction for the top and bottom deciles of risk over a model without PSAk. Model performance was essentially identical using PSA data measured every 6 mo to those measured every 3 mo. The major limitation is the reliability of reclassification as an end point, although it drives most treatment decisions. Conclusions PSAk calculated using an LMEM statistically significantly predicts biopsy reclassification. Models that use repeat PSA measurements outperform a model incorporating only diagnostic PSA. Model performance is similar using PSA assessed every 3 or 6 mo. If validated, these results should inform optimal incorporation of PSA trends into active surveillance protocols and risk calculators. Patient summary In this report, we looked at whether repeat prostate-specific antigen (PSA) measurements, or PSA kinetics, improve prediction of biopsy outcomes in men using active surveillance to manage localized prostate cancer. We found that in a large multicenter active surveillance cohort, PSA kinetics improves the prediction of surveillance biopsy outcome.

  • Large-scale Sequencing of Testicular Germ Cell Tumour (TGCT) Cases Excludes Major TGCT Predisposition Gene
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-09
    Kevin Litchfield, Chey Loveday, Max Levy, Darshna Dudakia, Elizabeth Rapley, Jeremie Nsengimana, D. Tim Bishop, Alison Reid, Robert Huddart, Peter Broderick, Richard S. Houlston, Clare Turnbull

    Testicular germ cell tumour (TGCT), the most common cancer in young men, has a significant heritable basis that has long raised questions as to the existence of underlying major high-penetrance susceptibility gene(s). To determine the contribution of rare gene mutations to the inherited risk of TGCT, we analysed germline whole-exome data for 919 TGCT cases and 1609 cancer-free controls. We compared frequencies between TGCT cases and controls of rare (<1%) and low-frequency (1-5%) coding variants (1) individually and (2) collapsed at the gene level via burden testing (T1, disruptive; T2, all deleterious; and T3, all nonsynonymous) using Fisher's exact test with Bonferroni correction of significance thresholds. No individual variant or individual gene showed a significant association with TGCT after correction for multiple testing. In the largest whole-exome sequencing study of testicular cancer reported to date, our findings do not support the existence of a major high-penetrance TGCT susceptibility gene (of odds ratio >10 and allele frequency [combined] > 0.01%). Owing to its power, this study cannot exclude the existence of susceptibility genes responsible for occasional TGCT families or of rare mutations that confer very modest relative risks. In concert with findings from genome-wide association studies, our data support the notion that inherited susceptibility is largely polygenic with substantial contribution from common variation. Patient summary In the largest study of its kind, we sequenced ∼20 000 genes in 919 men with testicular germ cell tumour (TGCT) and 1609 TGCT-free individuals and found no evidence of a single major gene underlying predisposition to TGCT (in the manner of BRCA1 for breast cancer). Instead, familial risk of TGCT is likely to be due to varying dosages of hundreds of minor genetic factors.

  • Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-08
    Joaquin Mateo, Heather H. Cheng, Himisha Beltran, David Dolling, Wen Xu, Colin C. Pritchard, Helen Mossop, Pasquale Rescigno, Raquel Perez-Lopez, Verena Sailer, Michael Kolinsky, Ada Balasopoulou, Claudia Bertan, David M. Nanus, Scott T. Tagawa, Heather Thorne, Bruce Montgomery, Suzanne Carreira, Shahneen Sandhu, Mark A. Rubin, Peter S. Nelson, Johann S. de Bono

    Background Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear. Objective To determine whether gDDRm status impacts benefit from established therapies in mPC. Design, setting, and participants This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status. All 372 patients from Royal Marsden (UK), Weill-Cornell (NY), and University of Washington (WA) were previously included in a prevalence study (Pritchard, NEJM 2016); the remaining 18 were gBRCA1/2m carriers, from the kConFab consortium, Australia. Outcome measurements and statistical analysis Response rate (RR), progression-free survival (PFS), and overall survival (OS) data were collected. To account for potential differences between cohorts, a mixed-effect model (Weibull distribution) with random intercept per cohort was used. Results and limitations The gDDRm status was known for all 390 patients (60 carriers of gDDRm [gDDRm+], including 37 gBRCA2m, and 330 cases not found to carry gDDRm [gDDRm–]); 74% and 69% were treated with docetaxel and abiraterone/enzalutamide, respectively, and 36% received PARP inhibitors (PARPi) and/or platinum. Median OS from castration resistance was similar among groups (3.2 vs 3.0 yr, p = 0.73). Median docetaxel PFS for gDDRm+ (6.8 mo) was not significantly different from that for gDDRm– (5.1 mo), and RRs were similar (gDDRm+ = 61%; gDDRm– = 54%). There were no significant differences in median PFS and RR on first-line abiraterone/enzalutamide (gDDRm+ = 8.3 mo, gDDRm– = 8.3 mo; gDDRm+ = 46%, gDDRm– = 56%). Interaction test for PARPi/platinum and gDDRm+ resulted in an OS adjusted hazard ratio of 0.59 (95% confidence interval 0.28–1.25; p = 0.17). Results are limited by the retrospective nature of the analysis. Conclusions mPC patients with gDDRm appeared to benefit from standard therapies similarly to the overall population; prospective studies are ongoing to investigate the impact of PARPi/platinum. Patient summary Patients with inherited DNA repair mutations benefit from standard therapies similarly to other metastatic prostate cancer patients.

  • Predicting Oncologic Outcomes in Renal Cell Carcinoma After Surgery
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-03
    Bradley C. Leibovich, Christine M. Lohse, John C. Cheville, Harras B. Zaid, Stephen A. Boorjian, Igor Frank, R. Houston Thompson, William P. Parker

    Background Predicting oncologic outcomes is important for patient counseling, clinical trial design, and biomarker study testing. Objective To develop prognostic models for progression-free (PFS) and cancer-specific survival (CSS) in patients with clear cell renal cell carcinoma (ccRCC), papillary RCC (papRCC), and chromophobe RCC (chrRCC). Design, setting, and participants Retrospective cohort review of the Mayo Clinic Nephrectomy registry from 1980 to 2010, for patients with nonmetastatic ccRCC, papRCC, and chrRCC. Intervention Partial or radical nephrectomy. Outcome measurements and statistical analysis PFS and CSS from date of surgery. Multivariable Cox proportional hazards regression was used to develop parsimonious models based on clinicopathologic features to predict oncologic outcomes and were evaluated with c-indexes. Models were converted into risk scores/groupings and used to predict PFS and CSS rates after accounting for competing risks. Results and limitations A total of 3633 patients were identified, of whom 2726 (75%) had ccRCC, 607 (17%) had papRCC, and 222 (6%) had chrRCC. Models were generated for each histologic subtype and a risk score/grouping was developed for each subtype and outcome (PFS/CSS). For PFS, the c-indexes were 0.83, 0.77, and 0.78 for ccRCC, papRCC, and chrRCC, respectively. For CSS, c-indexes were 0.86 and 0.83 for ccRCC and papRCC. Due to only 22 deaths from RCC, we did not assess a multivariable model for chrRCC. Limitations include the single institution study, lack of external validation, and its retrospective nature. Conclusions Using a large institutional experience, we generated specific prognostic models for oncologic outcomes in ccRCC, papRCC, and chrRCC that rely on features previously shown—and validated—to be associated with survival. These updated models should inform patient prognosis, biomarker design, and clinical trial enrollment. Patient summary We identified routinely available clinical and pathologic features that can accurately predict progression and death from renal cell carcinoma following surgery. These updated models should inform patient prognosis, biomarker design, and clinical trial enrollment.

  • EAU Guidelines on Assessment and Nonsurgical Management of Urinary Incontinence
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-03
    Arjun K. Nambiar, Ruud Bosch, Francisco Cruz, Gary E. Lemack, Nikesh Thiruchelvam, Andrea Tubaro, Dina A. Bedretdinova, David Ambühl, Fawzy Farag, Riccardo Lombardo, Marc P. Schneider, Fiona C. Burkhard

    Context The European Association of Urology guidelines on urinary incontinence (UI) have been updated in cyclical fashion with successive major chapters being revised each year. The sections on assessment, diagnosis, and nonsurgical treatment have been updated as of mid-2016. Objective We present a condensed version of the full guideline on assessment and nonsurgical management of UI, with the aim of improving accessibility and increasing their dissemination. Evidence acquisition Our literature search was updated from the previous cut-off of July 2010 up to April 2016. Evidence synthesis was carried out by a pragmatic review of current systematic reviews and any newer subsequent high-quality studies, based on Population, Interevention, Comparator, and Outcome questions. Appraisal was conducted by an international panel of experts, working on a strictly nonprofit and voluntary basis, to develop concise evidence statements and action-based recommendations using modified Oxford and GRADE criteria. Evidence synthesis The guidelines include algorithms that summarise the suggested pathway for standard, uncomplicated patients with UI and are more useable in daily practice. The full version of the guideline is available at http://uroweb.org/guideline/urinary-incontinence/. Conclusions These updated guidelines provide an evidence-based summary of the assessment and nonsurgical management of UI, together with a clear clinical algorithm and action-based recommendations. Although these guidelines are applicable to a standard patient, it must be remembered that therapy should always be tailored to individual patients’ needs and circumstances. Patient summary Urinary incontinence is a very common condition which negatively impacts patient's quality of life. Several types of incontinence exist and since the treatments will vary, it is important that the diagnostic evaluation establishes which type is present. The diagnosis should also identify patients who need rapid referral to an appropriate specialist. These guidelines aim to provide sensible and practical evidence-based guidance on the clinical problem of urinary incontinence.

  • Docetaxel Versus Surveillance After Radical Prostatectomy for High-risk Prostate Cancer: Results from the Prospective Randomised, Open-label Phase 3 Scandinavian Prostate Cancer Group 12 Trial
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-01
    Göran M. Ahlgren, Per Flodgren, Teuvo L.J. Tammela, Pirkko Kellokumpu-Lehtinen, Michael Borre, Anders Angelsen, Jon Reidar Iversen, Asgerdur Sverrisdottir, Eirikur Jonsson, Lisa Sengelov

    Background Adjuvant chemotherapy is standard treatment for other solid tumours, but to date has not proven effective in prostate cancer. Objective o evaluate whether six cycles of docetaxel alone improve biochemical disease-free survival after radical prostatectomy for high-risk prostate cancer. Design, setting, and participants Open-label, randomised multinational phase 3 trial. Enrolment of 459 patients after prostatectomy. Inclusion criteria: high-risk pT2 margin positive or pT3a Gleason score ≥4+3, pT3b, or lymph node positive disease Gleason score ≥3 + 4. Patients assigned (1:1) to either six cycles of adjuvant docetaxel 75 mg/m2 every 3 wk without daily prednisone (Arm A) or surveillance (Arm B) until endpoint was reached. Primary endpoint was prostate-specific antigen progression ≥0.5 ng/ml. Intervention Docetaxel treatment after prostatectomy. Results and limitations Median time to progression, death, or last follow-up was 56.8 mo. Primary endpoint was reached in 190/459 patients—the risk of progression at 5 yr being 41% (45% in Arm A and 38% in Arm B). There was evidence of nonproportional hazards in Kaplan-Meier analysis, so we used the difference in restricted mean survival time as the primary estimate of effect. Restricted mean survival time to endpoint was 43 mo in Arm A versus 46 mo in Arm B (p = 0.06), a nonsignificant difference of 3.2 mo (95% confidence interval: 6.7 to –1.5 mo). A total of 116 serious adverse events were recorded in Arm A and 41 in Arm B with no treatment-related deaths. Not all patients received docetaxel by protocol. The endpoint is biochemical progression and some patients received radiation treatment before the endpoint. Conclusions Docetaxel without hormonal therapy did not significantly improve biochemical disease-free survival after radical prostatectomy. Patient summary In this randomised trial, we tested whether chemotherapy after surgery for high-risk prostate cancer decreases the risk of a rising prostate-specific antigen. We found no benefit from docetaxel given after radical prostatectomy.

  • Vibegron, a Novel Potent and Selective β3-Adrenoreceptor Agonist, for the Treatment of Patients with Overactive Bladder: A Randomized, Double-blind, Placebo-controlled Phase 3 Study
    Eur. Urol. (IF 16.265) Pub Date : 2018-02-01
    Masaki Yoshida, Masayuki Takeda, Momokazu Gotoh, Shinji Nagai, Takafumi Kurose

    Background Vibegron is a novel, potent, and selective β3-adrenoreceptor agonist for the treatment of patients with overactive bladder (OAB). Objective To evaluate the efficacy and safety of vibegron versus placebo in Japanese OAB patients. Design, setting, and participants Patients with OAB entered a 2-wk placebo run-in phase. Once eligibility (≥8 micturition/d and either ≥1 urgency episodes/d or ≥1 urgency incontinence episodes/d) was confirmed, patients entered a 12-wk double-blind treatment phase. The anticholinergic imidafenacin was used as an active reference. Intervention A total of 1232 patients were randomly assigned to one of the four 12-wk treatment groups: vibegron (50 mg or 100 mg once daily), placebo, or imidafenacin (0.1 mg twice daily). Outcome measurements and statistical analysis The primary endpoint was change in the mean number of micturitions/d at wk 12 from baseline. The secondary endpoints were changes from baselines in OAB symptom variables (daily episodes of urgency, urgency incontinence, incontinence, and nocturia, and voided volume/micturition). Quality of life (QoL) and safety were assessed. A constrained longitudinal data analysis model was used for analysis of efficacy. Results and limitations Patients taking vibegron 50 mg and 100 mg orally for 12 wk had significant improvements over the placebo in the primary and secondary endpoints. The proportions of patients with normalization of micturition, resolution of urgency, urgency incontinence, and incontinence were significantly greater than placebo. Vibegron significantly improved QoL, with high patient satisfaction. Incidences of drug-related adverse events with vibegron 50 mg and 100 mg were 7.6%, 5.4%, similar to placebo (5.1%), and less than imidafenacin (10.3%). Treatment was for just 12 wk and a long-term study is needed. Conclusions The 12-wk treatment with vibegron is effective and well tolerated in patients with OAB. Patient summary This randomized study demonstrated that vibegron is clinically useful for treatment of patients with OAB. Trial registration ​JapicCTI-152936. http://www.clinicaltrials.jp/user/cteDetail.jsp.

  • Efficacy, Predictive Factors, and Prediction Nomograms for 68Ga-labeled Prostate-specific Membrane Antigen–ligand Positron-emission Tomography/Computed Tomography in Early Biochemical Recurrent Prostate Cancer After Radical Prostatectomy
    Eur. Urol. (IF 16.265) Pub Date : 2018-01-19
    Isabel Rauscher, Charlotte Düwel, Bernhard Haller, Christoph Rischpler, Matthias M. Heck, Jürgen E. Gschwend, Markus Schwaiger, Tobias Maurer, Matthias Eiber

    Recently, 68Ga-labeled prostate-specific membrane antigen (PSMA)–ligand positron-emission tomography (PET) imaging has been shown to improve detection rates in recurrent prostate cancer (PC). However, published studies include only small patient numbers at low prostate-specific antigen (PSA) values. For this study, 272 consecutive patients with biochemical recurrence after radical prostatectomy and PSA value between 0.2 and 1 ng/ml were included. The 68Ga-PSMA-ligand PET/computed tomography (CT) was evaluated, and detection rates were determined and correlated to various clinical variables using univariate and multivariable analyses. Subgroups of patients with very low (0.2–0.5 ng/ml) and low (>0.5–1.0 ng/ml) PSA values were analyzed. In total, lesions indicative of PC recurrence were detected in 55% (74/134) and 74% (102/138) with very low and low PSA values, respectively. Main sites of recurrence were pelvic or retroperitoneal lymph nodes metastases, followed by local recurrence and bone metastases with higher probability in the low versus very low PSA subgroup. Detection rates significantly increased with higher PSA values, primary pT ≥ 3a, primary pN+ disease, grade group ≥4, previous radiation therapy, and concurrent androgen deprivation therapy (ADT) in univariate analysis. In a multivariable logistic regression model, concurrent ADT and PSA values were identified as most relevant predictors of positive 68Ga-PSMA-ligand PET/CT. Further, prediction nomograms were established, which may help in estimating pretest PSMA-ligand PET positivity in clinical practice. Patient summary In our study, 68Ga-labeled prostate-specific membrane antigen (PSMA)–ligand positron-emission tomography (PET)/computed tomography (CT) detected recurrent disease after radical prostatectomy in 55% (74/134) and 74% (102/138) of patients with very low (0.2–0.5 ng/ml) and low (>0.5–1.0 ng/ml) prostate-specific antigen values, respectively. On the basis of these data, it seems reasonable to perform 68Ga-PSMA-ligand PET/CT also in patients with early biochemical recurrence, as it can tailor further therapy decisions (eg, local vs systemic treatment). The established prediction nomograms can further assist urologists in discussions on the use of 68Ga-PSMA-ligand PET/CT with their patients in specific clinical settings.

  • Non–risk-adapted Surveillance for Stage I Testicular Cancer: Critical Review and Summary
    Eur. Urol. (IF 16.265) Pub Date : 2018-01-12
    Phillip Martin Pierorazio, Peter Albers, Peter C. Black, Torgrim Tandstad, Axel Heidenreich, Nicola Nicolai, Craig Nichols

    Context Cancer-specific survival for men with clinical stage I testicular cancer (CSITC) is uniformly excellent. Non–risk-adapted active surveillance (NRAS) is a management strategy for CSITC to minimize overtreatment and avoid possible long-term side effects of adjuvant therapy. Objective To review the evidence regarding oncologic outcomes for men with CSITC undergoing NRAS and discuss ongoing controversies in the management of CSITC. Evidence acquisition MEDLINE/PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from January 1, 1987 through January 1, 2017. Evidence synthesis A total of 68 studies were included in the critical review. The rationale for NRAS, oncologic outcomes, surveillance protocols, and comparative efficacy of risk-adjusted active surveillance (AS) were reported with strength of evidence and risk of bias evaluated. Cancer-specific survival approaches 100% for men with CSITC undergoing NRAS. Active treatment is limited to 20–30% of patients who will recur; these patients will require salvage chemotherapy and possible retroperitoneal lymph node dissection. Existing AS protocols include imaging and laboratory evaluations that are initially intensive but less frequent with increasing follow-up. Conclusions NRAS is an attractive management option for men with CSITC, which maintains outstanding long-term cancer cure while sparing most patients treatment by avoiding prophylactic chemotherapy, radiation, or surgery. Patient summary Men with clinically localized (stage I) testicular cancer have an excellent prognosis, regardless of management. Non–risk-adapted active surveillance is an attractive management option where only patients destined to relapse will receive any treatment following orchiectomy. However, individual patient preferences should be discussed in selecting a management strategy.

  • Efficacy and Safety of Sacral and Percutaneous Tibial Neuromodulation in Non-neurogenic Lower Urinary Tract Dysfunction and Chronic Pelvic Pain: A Systematic Review of the Literature
    Eur. Urol. (IF 16.265) Pub Date : 2018-01-12
    Manuela Tutolo, Enrico Ammirati, John Heesakkers, Thomas M. Kessler, Kenneth M. Peters, Tina Rashid, Karl-Dietrich Sievert, Michele Spinelli, Giacomo Novara, Frank Van der Aa, Dirk De Ridder

    Context Neuromodulation is considered in patients with non-neurogenic lower urinary tract dysfunction (LUTD) not responsive to conservative treatment. Objective To systematically review the available studies on efficacy and safety of sacral neuromodulation (SNM) and percutaneous tibial nerve stimulation (PTNS) in non-neurogenic LUTDs not responsive to conservative treatments. Evidence acquisition A literature research was conducted in PubMed/Medline and Scopus, restricted to articles in English, published between January 1998 and June 2017, with at least 20 patients and 6 mo of follow-up. Evidence synthesis Twenty-one reports were identified. Concerning SNM, the improvement of ≥50% in leakage episodes ranged widely between 29% and 76%. Overall dry rate ranged between 43% and 56%. Overall success/improvement rate in PTNS varied between 54% and 59%. Symptom improvement or efficacy in interstitial cystitis/bladder pain syndrome patients appeared to be lower compared with other indications in both techniques. Safety data showed fewer side effects in patients submitted to PTNS. Conclusions Neuromodulation gives good results and is a safe therapy for patients with overactive bladder or chronic nonobstructive urinary retention with long-lasting efficacy. Moreover, PTNS has been shown to have good success rates and fewer side effects compared with SNM. These data have to be confirmed with long-term follow-up. Patient summary Sacral neuromodulation can improve low urinary tract symptoms in selected patients; it appears to be a safe therapy for nonresponders to standard medical therapies. Percutaneous tibial nerve stimulation (PTNS) is a less invasive technique that gives good results in short time with fewer side effects. However, we must consider that PTNS has not been tested in the long term and results are lower if compared with SNM.

  • The Stockholm-3 Model for Prostate Cancer Detection: Algorithm Update, Biomarker Contribution, and Reflex Test Potential
    Eur. Urol. (IF 16.265) Pub Date : 2018-01-10
    Peter Ström, Tobias Nordström, Henrik Grönberg, Martin Eklund

    Background It has been shown that the Stockholm-3 model (S3M) outperforms prostate-specific antigen (PSA) as a screening tool for prostate cancer. Objective To update the S3M, to give a detailed account of the value of each predictor in the S3M, and to evaluate the S3M as a reflex test for men with PSA ≥3 ng/ml. Design, setting, and participants During 2012–2015, the Stockholm-3 study evaluated the S3M relative to PSA as tests for Gleason score ≥7 prostate cancers among men aged 50–69 yr. The participants (n = 59 159) underwent both tests, and biopsy was recommended if at least one was positive. A total of 5073 men had a biopsy because of elevated PSA (≥3 ng/ml). Outcome measurements and statistical analysis Logistic regression was used to update the S3M: intact PSA was removed, HOXB13 was included, and the model was fitted to data from the Stockholm-3 training and validation cohorts. To compare S3M with PSA, we fixed the sensitivity for detection of high-grade cancer and evaluated the performance as the number of biopsies needed to achieve that sensitivity for each test. Results and limitations The updated S3M slightly improved the area under the receiver operating characteristic curve compared to previously published results (0.75 vs 0.74). When used as a reflex test for men with PSA ≥3 ng/ml, S3M reduced the number of biopsies needed by 34% compared to the use of PSA alone, with equal sensitivity. A limitation is the ethnically homogeneous population. Conclusions A major problem with PSA screening—too many unnecessary biopsies—can be mitigated if S3M is used as a reflex test. Patient summary To find aggressive prostate cancer with the minimum number of negative biopsies and detection of clinically insignificant cancers, we evaluated the use of a personalized diagnostic prediction model as a second test for men with a positive prostate-specific antigen (PSA) test. We found that this two-step approach could reduce prostate biopsies by a third compared to using PSA alone.

  • Updates in the Eighth Edition of the Tumor-Node-Metastasis Staging Classification for Urologic Cancers
    Eur. Urol. (IF 16.265) Pub Date : 2018-01-09
    Gladell P. Paner, Walter M. Stadler, Donna E. Hansel, Rodolfo Montironi, Daniel W. Lin, Mahul B. Amin

    The Tumor-Node-Metastasis (TNM) classification on cancer staging, jointly developed by the American Joint Commission on Cancer (AJCC) and the Union for International Cancer Control (UICC), has been updated to its 8th edition with two contemporaneous versions published by the AJCC and UICC. While the goal of the AJCC and UICC is to have identical TNM staging systems, differences exist between these two publications including in the staging of urologic cancers. Among several new facets in the AJCC staging manual, a select few of greater import include an expanded section on imaging, presentation of levels of evidence for significant changes, and endorsement of risk assessment models that pass the AJCC quality criteria such as in prostate cancer. The updates for urologic cancers in the AJCC stage categories can be grouped into: (1) newly defined TNM categories and prognostic stage groupings, (2) clarifications and refinements of previously defined categories, and (3) more systematic and expanded presentation of prognostic factors. Changes are harmonized with the current reporting and treatment guidelines. Contributions from genitourinary pathology are evident in the AJCC classification from many of the International Society of Urological Pathology (ISUP) consensus conferences on prostate, kidney, testicular, and penile neoplasms that addressed staging issues and the timely publication of the 4th edition of the World Health Organization (WHO) classification of urinary and male genital organ tumors. New grading approaches for penile (WHO/ISUP grade), prostate (Grade group), and kidney (WHO/ISUP nucleolar grade) cancers were adopted in the AJCC system. Many of these updates in the AJCC staging manual are also included in the 8th UICC TNM edition. In an effort to achieve the optimal staging recommendations for urologic cancers, updates in the 8th TNM edition were generated through the acquisition of best evidences, tapping interdisciplinary resources including consensus recommendations, and enhanced data analysis. Patient summary In this report, we explain the seminal changes in the 8th edition of the Tumor-Node-Metastasis staging system for urologic cancers. Major stage category definitional changes are in Tumor-Node-Metastasis classifications of testicular, penile, and prostate cancer which improve patient stratification for prognosis and management.

  • Hyperaccuracy Three-dimensional Reconstruction Is Able to Maximize the Efficacy of Selective Clamping During Robot-assisted Partial Nephrectomy for Complex Renal Masses
    Eur. Urol. (IF 16.265) Pub Date : 2018-01-06
    Francesco Porpiglia, Cristian Fiori, Enrico Checcucci, Daniele Amparore, Riccardo Bertolo

    Background Available technologies could avoid global ischemia for the removal of a renal tumor. Objective To present hyperaccuracy three-dimensional (HA3D) reconstruction during robot-assisted partial nephrectomy (RAPN) and compare its efficacy in sponsoring successful selective clamping of renal arterial branches during RAPN. Design, setting, and participants Patients undergoing RAPN (January 2016–July 2017) for renal mass PADUA score ≥10 who underwent abdominal computed tomography scan with angiography. Since February 2017 HA3D reconstruction was performed. Surgical procedure HA3D reconstruction-aided RAPN and standard RAPN with selective clamping. Measurements Intraoperative variables focusing on the renal arterial pedicle management and success rate of its planned management. Results and limitations Thirty-one patients in group no HA3D and 21 in group HA3D. The median (standard deviation) tumor size was 50.9 and 50.8 mm (p = 0.97), and median PADUA scores 10.5 and 11 (p = 0.85) for groups no HA3D and HA3D, respectively. In group no HA3D, a significantly higher number of patients underwent global ischemia (80% vs 24%, p < 0.01). Of note, in 90% of the group HA3D cases, intraoperative management of the renal pedicle was performed as preoperatively planned; in 39% of the group no HA3D cases, management of the renal arterial pedicle was varied intraoperatively (p = 0.04). We disclose the limited sample size and the experimental technique. Conclusions Preoperative simulation of selective ischemia was feasible and effective with HA3D reconstruction. In all the RAPN cases performed, selective clamping was successful, avoiding ischemia of the healthy renal remnant. A strict collaboration between urologists and bioengineers is mandatory to improve the technology. Patient summary In this report, we found that an accurate three-dimensional reconstruction of the kidney before conservative surgery for renal cancer seems to help in avoiding the global ischemia of the kidney. Further studies are needed to conclude if avoiding a percentage of ischemia to the kidney is clinically relevant.

  • Two-years Postradiotherapy Biopsies: Lessons from MRC RT01 Trial
    Eur. Urol. (IF 16.265) Pub Date : 2018-01-04
    Antoine Kass-Iliyya, Gordana Jovic, Claire Murphy, Cyril Fisher, Isabel Syndikus, Chakiath Jose, Christopher D. Scrase, John D. Graham, David Nicol, Matthew R. Sydes, David Dearnaley

    Background The importance of 2-yr postradiotherapy prostate biopsy status remains uncertain. Objective To assess the value of 2 year post treatment biopsies in a randomised trial of radiotherapy dose escalation. Design, setting, and participants Between 1998 and 2001, 843 men with localised prostate cancer were randomised to receive either control-64 Gy or escalated-74 Gy conformal radiotherapy (CFRT) in the MRC RT01 trial in combination with 3–6-mo neoadjuvant androgen deprivation therapy. Prostate biopsies were planned at 2 yr from start of CFRT in suitable men. Outcome measurements and statistical analysis Prostate biopsy results and prostate-specific antigen (PSA) levels performed at 2 yr post-CFRT were evaluated with long-term biochemical progression free survival (bPFS) and overall survival. Outcome measures were timed from the 2-yr biopsy using a landmark approach. Results and limitations A 2-yr biopsy was performed in 312/843 patients. One hundred and seventy-seven patients were included in the per-protocol group with median follow-up of 7.8 yr from biopsy. Median PSA at biopsy was 0.5 ng/ml. Sixty-four bPFS events were reported: 46/145 (32%) in patients with negative, 6/18 (33%) suspicious, and 12/14 (86%) positive biopsies. A positive biopsy was prognostic of worse bPFS, going forward, compared with negative and suspicious biopsies, hazard ratio (HR) = 4.81 (95% confidence interval [CI]: 2.50–9.26, p < 0.001). The estimate for survival was HR = 1.58 (95% CI: 0.52–4.78, p = 0.42). PSA values at 2 yr between 1.01 ng/ml and 2.09 ng/ml were also associated with subsequent PSA failures (HR = 2.71, 95% CI: 1.98–3.71), bPFS events (HR = 2.45, 95% CI: 1.81–3.32), and prostate cancer-specific survival (HR = 2.87, 95% CI: 1.08–7.64) compared with PSA ≤1.0 ng/ml. Conclusions Two-year postradiotherapy prostate biopsies have limited value in patients with PSA control but both positive biopsy and higher PSA status are strongly associated with future bPFS events. A policy of selected biopsy may provide an opportunity for early salvage interventions. Patient summary Routine 2-yr postradiotherapy biopsy is not recommended but can be considered in selected patients with unfavourable post-treatment prostate-specific antigen levels who are suitable for early salvage treatments.

  • Erratum to “CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma” [Eur Urol 2017;72:962–71]
    Eur. Urol. (IF 16.265) Pub Date : 2018-01-03
    Bernard Escudier, Padmanee Sharma, David F. McDermott, Saby George, Hans J. Hammers, Sandhya Srinivas, Scott S. Tykodi, Jeffrey A. Sosman, Giuseppe Procopio, Elizabeth R. Plimack, Daniel Castellano, Howard Gurney, Frede Donskov, Katriina Peltola, John Wagstaff, Thomas C. Gauler, Takeshi Ueda, Huanyu Zhao, Ian M. Waxman, Robert J. Motzer
  • Intermediate Endpoints After Postprostatectomy Radiotherapy: 5-Year Distant Metastasis to Predict Overall Survival
    Eur. Urol. (IF 16.265) Pub Date : 2018-01-03
    William C. Jackson, Krithika Suresh, Vasu Tumati, Steven G. Allen, Robert T. Dess, Simpa S. Salami, Arvin George, Samuel D. Kaffenberger, David C. Miller, Jason W.D. Hearn, Shruti Jolly, Rohit Mehra, Brent K. Hollenbeck, Ganesh S. Palapattu, Matthew Schipper, Felix Y. Feng, Todd M. Morgan, Neil B. Desai, Daniel E. Spratt

    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.

  • Oncologic Outcomes for Patients with Residual Cancer at Cystectomy Following Neoadjuvant Chemotherapy: A Pathologic Stage-matched Analysis
    Eur. Urol. (IF 16.265) Pub Date : 2017-05-22
    Bimal Bhindi, Igor Frank, Ross J. Mason, Robert F. Tarrell, Prabin Thapa, John C. Cheville, Brian A. Costello, Lance C. Pagliaro, R. Jeffrey Karnes, R. Houston Thompson, Matthew K. Tollefson, Stephen A. Boorjian

    While it has been demonstrated that receipt of neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) improves survival compared to RC alone, the driving factor for this benefit may be from patients with ypT0 status at surgery. Meanwhile, the implications of having residual urothelial carcinoma of the bladder (rUCB) at RC after NAC are less clear. We therefore evaluated whether survival differed between patients with rUCB at RC after NAC and stage-matched controls who underwent RC alone. Patients who underwent NAC + RC (n = 180) were matched to controls who underwent RC alone (n = 324) on the basis of pT and pN stage, margin status, and year of RC. The 5-yr recurrence-free survival (RFS; 90% vs 94%; p = 1), cancer-specific survival (CSS; 82% vs 93%; p = 0.4), and overall survival (OS; 82% vs 82%; p = 0.5) were not significantly different between the NAC and control groups for patients with ypT0N0/pT0N0 disease (n = 103). Conversely, among patients with rUCB at RC (n = 401), patients who received NAC had significantly worse 5-yr RFS (50% vs 63%; p = 0.01), CSS (40% vs 59%; p = 0.003), and OS (33% vs 48%; p = 0.02). On multivariable analysis for patients with rUCB, NAC receipt remained independently associated with worse RFS (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.28–2.66; p = 0.001), CSS (HR 1.81, 95% CI 1.30–2.52; p < 0.001), and OS (HR 1.57, 95% CI 1.18–2.08; p = 0.002). Limitations include potential for selection bias owing to the retrospective observational design. Thus, while patients who achieve a complete response to NAC have excellent survival outcomes, those with rUCB after NAC have a worse prognosis compared to stage-matched controls undergoing RC alone. It may be worthwhile considering these patients for clinical trials evaluating the role of additional treatments after RC using newer agents while we await further research on predicting which patients achieve ypT0 status from NAC before RC. Patient summary On surgical removal of the bladder, patients without residual bladder cancer after neoadjuvant chemotherapy have excellent survival outcomes. However, patients with residual cancer after neoadjuvant chemotherapy and surgery have worse outcomes compared to patients undergoing surgery alone. These patients should therefore be considered for additional treatments after surgery using newer agents while we await further research on predicting which patients will benefit from neoadjuvant chemotherapy before bladder removal for cancer.

  • Efficacy Against Human Prostate Cancer by Prostate-specific Membrane Antigen-specific, Transforming Growth Factor-β Insensitive Genetically Targeted CD8+ T-cells Derived from Patients with Metastatic Castrate-resistant Disease
    Eur. Urol. (IF 16.265) Pub Date : 2017-12-21
    Qiang Zhang, Brian T. Helfand, Benedito A. Carneiro, Weijun Qin, Ximing J. Yang, Chung Lee, Weipeng Zhang, Francis J. Giles, Massimo Cristofanilli, Timothy M. Kuzel

    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. Cr51 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.

  • Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: Outcomes by Prior Number of Regimens
    Eur. Urol. (IF 16.265) Pub Date : 2017-12-20
    Jose Luis Perez-Gracia, Yohann Loriot, Jonathan E. Rosenberg, Thomas Powles, Andrea Necchi, Syed A. Hussain, Rafael Morales-Barrera, Margitta M. Retz, Günter Niegisch, Ignacio Durán, Christine Théodore, Enrique Grande, Xiaodong Shen, Jingjing Wang, Betty Nelson, Christina L. Derleth, Michiel S. van der Heijden

    Background Patients with metastatic urothelial carcinoma (mUC) who progress after platinum-based chemotherapy have had few treatment options and uniformly poor outcomes. Atezolizumab (anti-programmed death-ligand 1) was approved in the USA for cisplatin-ineligible and platinum-treated mUC based on IMvigor210, a phase 2, single-arm, two-cohort study. Objective To evaluate the efficacy and safety of atezolizumab by the number of prior lines of systemic therapy in patients with pretreated mUC. Design, setting, and participants IMvigor210 enrolled 315 patients with mUC with progression during or following platinum-based therapy at 70 international sites between May 2014 and November 2014. Key inclusion criteria included age ≥18 yr, creatinine clearance ≥30 ml/min, and Eastern Cooperative Oncology Group performance status 0–1, with no limit on prior lines of treatment. Intervention Patients in this cohort received atezolizumab 1200 mg intravenously every 3 wk until loss of clinical benefit. Outcome measurements and statistical analysis Centrally assessed Response Evaluation Criteria In Solid Tumors v1.1 objective response rate (ORR), median duration of response, overall survival (OS), and adverse events were evaluated by prior treatment. Potential differences between subgroups were evaluated using log-rank (for OS) and chi-square (for ORR and adverse events frequencies) testing. Results and limitations Three hundred and ten patients were efficacy and safety evaluable (median follow-up, 21 mo). Objective responses and prolonged OS occurred across all prespecified subgroups; median duration of response was not reached in most subgroups. In patients without prior systemic mUC therapy (first-line subgroup), ORR was 25% (95% confidence interval: 14–38), and median OS was 9.6 mo (95% confidence interval: 5.9–15.8). No significant differences in efficacy or toxicity by therapy line were observed. Conclusions Atezolizumab demonstrated comparable efficacy and safety in previously treated patients with mUC across all lines of therapy evaluated. Patient summary We investigated effects of previous treatment in patients with metastatic urothelial carcinoma that progressed after platinum-based therapy. Atezolizumab was active and tolerable no matter how many treatment regimens patients had received. ClinicalTrials.gov, NCT02108652.

  • Superior Biochemical Recurrence and Long-term Quality-of-life Outcomes Are Achievable with Robotic Radical Prostatectomy After a Long Learning Curve—Updated Analysis of a Prospective Single-surgeon Cohort of 2206 Consecutive Cases
    Eur. Urol. (IF 16.265) Pub Date : 2017-12-19
    James E. Thompson, Sam Egger, Maret Böhm, Amila R. Siriwardana, Anne-Maree Haynes, Jayne Matthews, Matthijs J. Scheltema, Phillip D. Stricker

    Background Our earlier analysis suggested that robot-assisted radical prostatectomy (RARP) achieved superiority over open radical prostatectomy (ORP) in terms of positive surgical margin (PSM) rates and functional outcomes. Objective With larger sample size and longer follow-up, the objective of this study update is to assess whether our previous findings are upheld and whether the improved PSM rates for RARP after an initial learning curve compared with ORP—as observed in our earlier analysis—ultimately resulted in improved biochemical control. Design, setting, and participants Prospective observational study comparing two surgical techniques; 2271 consecutive men underwent RARP (1520) or ORP (751) at a single centre from 2006 to 2016. Outcome measurements and statistical analysis Demographic and clinicopathological data were prospectively collected. The EPIC-QOL questionnaire was administered at baseline and 1.5, 3, 6, 12, and 24 mo. Multivariate linear regression modelled the difference in quality of life (QOL) domains against case number; logistic and Cox regression modelled the differences in PSM and biochemical recurrence (BCR) hazard ratios (HR), respectively. Results and limitations A total of 2206 men were included in BCR/PSM analysis and 1045 consented for QOL analysis. Superior pT2 surgical margins, early and late sexual outcomes, and early urinary outcomes were upheld and became more robust (narrowing of 95% confidence intervals [CIs]). The risk of BCR was initially higher for RARP, improved after 191 RARPs, and was 35% lower (hazard ratio [HR] 0.65, 95% CI 0.47–0.90) at final RARP, plateauing after 226 RARPs. Improved late (12–24 mo) urinary bother scores (adjusted mean difference [AMD] = 4.7, 95% CI 1.3–8.0) and irritative–obstructive scores (AMD = 3.8, 95% CI 0.9–5.6) at final RARP were demonstrated. Limitations include observational single surgeon data, possible residual confounding, and short follow-up. Conclusions The results from this updated analysis demonstrate that RARP can be beneficial for patients of high-volume surgeons, although more randomised studies and studies with survival outcomes are needed. Patient summary Robot-assisted radical prostatectomy was able to improve functional and oncological outcomes in this single surgeon's learning curve.

  • Role of Androgen Receptor Variants in Prostate Cancer: Report from the 2017 Mission Androgen Receptor Variants Meeting
    Eur. Urol. (IF 16.265) Pub Date : 2017-12-16
    Jun Luo, Gerhardt Attard, Steven P. Balk, Charlotte Bevan, Kerry Burnstein, Laura Cato, Artem Cherkasov, Johann S. De Bono, Yan Dong, Allen C. Gao, Martin Gleave, Hannelore Heemers, Mayuko Kanayama, Ralf Kittler, Joshua M. Lang, Richard J. Lee, Christopher J. Logothetis, Robert Matusik, Stephen Plymate, Charles L. Sawyers, Luke A. Selth, Howard Soule, Wayne Tilley, Nancy L. Weigel, Amina Zoubeidi, Scott M. Dehm, Ganesh V. Raj

    Context Although a number of studies have demonstrated the importance of constitutively active androgen receptor variants (AR-Vs) in prostate cancer, questions still remain about the precise role of AR-Vs in the progression of castration-resistant prostate cancer (CRPC). Objective Key stakeholders and opinion leaders in prostate cancer convened on May 11, 2017 in Boston to establish the current state of the field of AR-Vs. Evidence acquisition The meeting “Mission Androgen Receptor Variants” was the second of its kind sponsored by the Prostate Cancer Foundation (PCF). This invitation-only event was attended by international leaders in the field and representatives from sponsoring organizations (PCF and industry sponsors). Eighteen faculty members gave short presentations, which were followed by in-depth discussions. Discussions focused on three thematic topics: (1) potential of AR-Vs as biomarkers of therapeutic resistance; (2) role of AR-Vs as functionally active CRPC progression drivers; and (3) utility of AR-Vs as therapeutic targets in CRPC. Evidence synthesis The three meeting organizers synthesized this meeting report, which is intended to summarize major data discussed at the meeting and identify key questions as well as strategies for addressing these questions. There was a critical consensus that further study of the AR-Vs is an important research focus in CRPC. Contrasting views and emphasis, each supported by data, were presented at the meeting, discussed among the participants, and synthesized in this report. Conclusions This article highlights the state of knowledge and outlines the most pressing questions that need to be addressed to advance the AR-V field. Patient summary Although further investigation is needed to delineate the role of androgen receptor (AR) variants in metastatic castration-resistant prostate cancer, advances in measurement science have enabled development of blood-based tests for treatment selection. Detection of AR variants (eg, AR-V7) identified a patient population with poor outcomes to existing AR-targeting therapies, highlighting the need for novel therapeutic agents currently under development.

  • Prostate Cancer Death After Radiotherapy or Radical Prostatectomy: A Nationwide Population-based Observational Study
    Eur. Urol. (IF 16.265) Pub Date : 2017-12-15
    David Robinson, Hans Garmo, Ingela Franck Lissbrant, Anders Widmark, Andreas Pettersson, Adalsteinn Gunnlaugsson, Jan Adolfsson, Ola Bratt, Per Nilsson, Pär Stattin

    Background There are no conclusive results from randomized trials on radiotherapy (RT) versus radical prostatectomy (RP) for prostate cancer. Numerous observational studies have suggested that RP is associated with a lower risk of prostate cancer death, but whether results have been biased due to limited adjustments for confounding factors is unknown. Objective To compare the risk of prostate cancer death after RT versus RP. Design, setting, and participants Nationwide population-based observational study of men in the Prostate Cancer data Base Sweden 3.0 who had undergone RT or RP between 1998 and 2012. Outcome measurements and statistical analysis Prostate cancer deaths were compared. Hazard ratios (HRs) were calculated in Cox regression models, including clinical T stage, M stage, Gleason grade group, serum levels of prostate-specific antigen, proportion of biopsy cores with cancer, mode of detection, comorbidity, age, educational level, and civil status. Period analysis with left truncation was performed. Results and limitations Primary treatment was RT or RP for 41 503 men. Treatment effect was associated with disease severity. In univariate analysis of RT versus RP, risk of prostate cancer death was higher after RT—low- and intermediate-risk cancer, HR 1.82 (95% confidence interval [CI]: 1.53–2.16), and high-risk cancer, HR 1.57 (95% CI: 1.33–1.85). After full adjustment in period analysis, this difference between the treatments was attenuated—low- and intermediate-risk cancer, HR 1.24 (95% CI: 0.97–1.58), and high-risk cancer, HR 1.03 (95% CI: 0.81–1.31). Confounding remained due to nonrandom allocation to treatment. Conclusions In comparison with previous studies, the difference in prostate cancer mortality after RT and RP was much smaller. Patient summary The difference in prostate cancer mortality after contemporary radiotherapy and radical prostatectomy was small in contrast to previous studies, indicating that potential side effects should be more emphasized when selecting treatment.

  • A Multigene Signature Based on Cell Cycle Proliferation Improves Prediction of Mortality Within 5 Yr of Radical Nephrectomy for Renal Cell Carcinoma
    Eur. Urol. (IF 16.265) Pub Date : 2017-12-14
    Todd M. Morgan, Rohit Mehra, Placede Tiemeny, J. Stuart Wolf, Shulin Wu, Zaina Sangale, Michael Brawer, Steven Stone, Chin-Lee Wu, Adam S. Feldman

    Background There is a critical need for improved prognostic discrimination in patients with renal cell carcinoma (RCC) given the increasing awareness that some patients may be managed with active surveillance, while others with higher-risk disease might benefit from adjuvant therapy following surgery. Objective To determine whether a multigene proliferation signature predicts long-term oncologic outcomes in surgically resected RCC. Design, setting, and participants The cell cycle proliferation (CCP) score was determined after radical nephrectomy for localized clear cell, papillary, or chromophobe RCC in 565 patients. Outcome measurements and statistical analysis The primary end point was disease-specific mortality (DSM), and disease recurrence was a secondary end point. Association with outcomes was evaluated by Cox proportional hazards survival analysis. The CCP score was compared with the Karakiewicz nomogram, and a composite (R-CCP) score was developed. Results and limitations A total of 68 patients (12%) recurred and 32 (6%) died of disease within 5 yr of nephrectomy. The CCP score was an independent predictor of recurrence (hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.07–2.09) and DSM (HR 2.49, 95% CI 1.53–4.04) after adjusting for clinical variables using the baseline nomogram. The composite R-CCP score gave a Harrell's concordance index of 0.87 and stratified patients into low- (n = 338) and high-risk (n = 202) categories with 99% and 84% cancer-specific survival probabilities, respectively (p < 0.001). Conclusions The CCP score is a significant, independent predictor of long-term oncologic outcomes in patients who have undergone nephrectomy for RCC. Combining the molecular classifier with baseline clinical variables allows for accurate, patient-specific risk assessment for use in guiding clinical management. Patient summary In this study, we sought to understand how well gene expression information from individual kidney tumors can predict cancer recurrence and death following surgical removal. We found that the combination of the gene expression test and clinical characteristics provides an accurate prognostic assessment to help inform clinical decisions.

  • Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes
    Eur. Urol. (IF 16.265) Pub Date : 2017-12-13
    Matthew D. Galsky, Huan Wang, Noah M. Hahn, Przemyslaw Twardowski, Sumanta K. Pal, Costantine Albany, Mark T. Fleming, Alexander Starodub, Ralph J. Hauke, Menggang Yu, Qianqian Zhao, Guru Sonpavde, Michael J. Donovan, Vaibhav G. Patel, John P. Sfakianos, Josep Domingo-Domenech, William K. Oh, Nicholas Akers, Bojan Losic, Sacha Gnjatic, Eric E. Schadt, Rong Chen, Seunghee Kim-Schulze, Nina Bhardwaj, Andrew V. Uzilov

    Background Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive biomarkers, remain unexplored. Objective To determine the safety, efficacy, and immunomodulatory effects of gemcitabine and cisplatin (GC) plus ipilimumab and explore the impact of somatic DNA damage response gene alterations on antitumor activity. Design, setting, and participants Multicenter single arm phase 2 study enrolling 36 chemotherapy-naïve patients with metastatic urothelial cancer. Peripheral blood flow cytometry was performed serially on all patients and whole exome sequencing of archival tumor tissue was performed on 28/36 patients. Intervention Two cycles of GC followed by four cycles of GC plus ipilimumab. Outcome measurements and statistical analysis The primary endpoint was 1-yr overall survival (OS). Secondary endpoints included safety, objective response rate, and progression-free survival. Results and limitations Grade ≥3 adverse events occurred in 81% of patients, the majority of which were hematologic. The objective response rate was 69% and 1-yr OS was 61% (lower bound 90% confidence interval: 51%). On exploratory analysis, there were no significant changes in the composition and frequency of circulating immune cells after GC alone. However, there was a significant expansion of circulating CD4 cells with the addition of ipilimumab which correlated with improved survival. The response rate was significantly higher in patients with deleterious somatic DNA damage response mutations (sensitivity = 47.6%, specificity = 100%, positive predictive value = 100%, and negative predictive value = 38.9%). Limitations are related to the sample size and single-arm design. Conclusions GC + ipilimumab did not achieve the primary endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%. However, within the context of a small single-arm trial, the results may inform current approaches combining chemotherapy plus immunotherapy from the standpoint of feasibility, appropriate cytotoxic backbones, and potential predictive biomarkers. Trial registration: ClinicalTrials.gov NCT01524991. Patient summary Combining chemotherapy and immune checkpoint blockade in patients with metastatic urothelial cancer is feasible. Further studies are needed to refine optimal combinations and evaluate tests that might identify patients most likely to benefit.

  • Performance of a Prostate Cancer Genomic Classifier in Predicting Metastasis in Men with Prostate-specific Antigen Persistence Postprostatectomy
    Eur. Urol. (IF 16.265) Pub Date : 2017-12-10
    Daniel E. Spratt, Darlene L.Y. Dai, Robert B. Den, Patricia Troncoso, Kasra Yousefi, Ashley E. Ross, Edward M. Schaeffer, Zaid Haddad, Elai Davicioni, Rohit Mehra, Todd M. Morgan, Walter Rayford, Firas Abdollah, Edouard Trabulsi, Mary Achim, Elsa Li Ning Tapia, Mireya Guerrero, Robert Jeffrey Karnes, Adam P. Dicker, Mark A. Hurwitz, Paul L. Nguyen, Felix F.Y. Feng, Stephen J. Freedland, John W. Davis

    Background Prostate cancer patients who have a detectable prostate-specific antigen (PSA) postprostatectomy may harbor pre-existing metastatic disease. To our knowledge, none of the commercially available genomic biomarkers have been investigated in such men. Objective To evaluate if a 22-gene genomic classifier can independently predict development of metastasis in men with PSA persistence postoperatively. Design, setting, and participants A multi-institutional study of 477 men who underwent radical prostatectomy (RP) between 1990 and 2015 from three academic centers. Patients were categorized as detectable PSA (n = 150) or undetectable (n = 327) based on post-RP PSA nadir ≥0.1 ng/ml. Outcome measurements and statisitical analysis Cumulative incidence curves for metastasis were constructed using Fine-Gray competing risks analysis. Penalized Cox univariable and multivariable (MVA) proportional hazards models were performed to evaluate the association of the genomic classifier with metastasis. Results and limitations The median follow-up for censored patients was 57 mo. The median time from RP to first postoperative PSA was 1.4 mo. Detectable PSA patients were more likely to have higher adverse pathologic features compared with undetectable PSA patients. On MVA, only genomic high-risk (hazard ratio [HR]: 5.95, 95% confidence interval [CI]: 2.02–19.41, p = 0.001), detectable PSA (HR: 4.26, 95% CI: 1.16–21.8, p = 0.03), and lymph node invasion (HR: 12.2, 95% CI: 2.46–70.7, p = 0.003) remained prognostic factors for metastasis. Among detectable PSA patients, the 5-yr metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk (p < 0.001). Genomic high risk remained independently prognostic on MVA (HR: 5.61, 95% CI: 1.48–22.7, p = 0.01) among detectable PSA patients. C-index for Cancer of the Prostate Risk Assessment Postsurgical score, Gandaglia nomogram, and the genomic classifier plus either Cancer of the Prostate Risk Assessment Postsurgical score or Gandaglia were 0.69, 0.68, and 0.82 or 0.81, respectively. Sample size was a limitation. Conclusions Despite patients with a detectable PSA harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis. Prospective validation of these findings is warranted and will be collected as part of the ongoing randomized trial NRG GU-002. Patient summary Decipher independently predicted metastasis for patients with detectable prostate-specific antigen after prostatectomy.

  • Use of Concomitant Androgen Deprivation Therapy in Patients Treated with Early Salvage Radiotherapy for Biochemical Recurrence After Radical Prostatectomy: Long-term Results from a Large, Multi-institutional Series
    Eur. Urol. (IF 16.265) Pub Date : 2017-12-08
    Giorgio Gandaglia, Nicola Fossati, R. Jeffrey Karnes, Stephen A. Boorjian, Michele Colicchia, Alberto Bossi, Thomas Seisen, Cesare Cozzarini, Nadia Di Muzio, Barbara Noris Chiorda, Emanuele Zaffuto, Thomas Wiegel, Shahrokh F. Shariat, Gregor Goldner, Steven Joniau, Antonino Battaglia, Karin Haustermans, Gert De Meerleer, Valérie Fonteyne, Piet Ost, Hendrick Van Poppel, Francesco Montorsi, Alberto Briganti

    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.

  • Updated European Association of Urology Guidelines Recommendations for the Treatment of First-line Metastatic Clear Cell Renal Cancer
    Eur. Urol. (IF 16.265) Pub Date : 2017-12-07
    Thomas Powles, Laurence Albiges, Michael Staehler, Karim Bensalah, Saeed Dabestani, Rachel H. Giles, Fabian Hofmann, Milan Hora, Markus A. Kuczyk, Thomas B. Lam, Lorenzo Marconi, Axel S. Merseburger, Sergio Fernández-Pello, Rana Tahbaz, Alessandro Volpe, Börje Ljungberg, Axel Bex

    The randomised phase III clinical trial Checkmate-214 showed a survival superiority for the combination of ipilimumab and nivolumab when compared with the previous standard of care in first-line metastatic/advanced clear cell renal cell carcinoma (RCC) (Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. LBA5, ESMO 2017, 2017). These results change the frontline standard of care for this disease and have implications for the selection of subsequent therapies. For this reason the European Association of Urology RCC guidelines have been updated. Patient summary The European Association of Urology guidelines will be updated based on the results of the phase III Checkmate-214 clinical trial. The trial showed superior survival for a combination of ipilimumab and nivolumab (IN), compared with the previous standard of care, in intermediate- and poor-risk patients with metastatic clear cell renal cell carcinoma. When IN is not safe or feasible, alternative agents such as sunitinib, pazopanib, and cabozantinib should be considered. Furthermore, at present, the data from the trial are immature in favourable-risk patients. Therefore, sunitinib or pazopanib remains the favoured agent for this subgroup of patients.

  • Robot-assisted Retrohepatic Inferior Vena Cava Thrombectomy: First or Second Porta Hepatis as an Important Boundary Landmark
    Eur. Urol. (IF 16.265) Pub Date : 2017-12-07
    Baojun Wang, Hongzhao Li, Qingbo Huang, Kan Liu, Yang Fan, Cheng Peng, Liangyou Gu, Xintao Li, Gang Guo, Rong Liu, Minggen Hu, Guodong Zhao, Hongguang Wang, Fengyong Liu, Jiang Xiong, Xu Zhang, Xin Ma

    Background Robot-assisted retrohepatic inferior vena cava (IVC) thrombectomy (RA-R-IVCTE) has been reported only for limited series. Objective To describe in detail the techniques for RA-R-IVCTE with regard to the relationship of a proximal thrombus to either the first porta hepatis (FPH) or second porta hepatis (SPH). Design, setting, and participants From May 2013 to July 2016, 22 patients with R-IVC tumor thrombi were admitted to our hospital. Surgical procedure RA-R-IVCTE was performed using the Rummel tourniquet technique. For a proximal thrombus inferior to the FPH, we ligated some short hepatic veins (SHVs; typically 1–3). For a thrombus between the FPH and SPH, we mobilized the right lobe of the liver from the IVC by ligating additional SHVs. For a thrombus near or above the SPH but below the diaphragm, we mobilized both the right and left lobes of the liver to obtain high proximal control of the suprahepatic and infradiaphragmatic IVC, and simultaneously clamped the FPH. Measurements Detailed techniques were described for various scenarios and perioperative outcomes were recorded. Results and limitations The median operation time was 285 min (interquartile range [IQR] 191–390). Intraoperative estimated blood loss was 1350 ml (IQR 1000–2075 ml). Some 63.6% of patients required an intraoperative blood transfusion and 68% were transferred to the intensive care unit after surgery. Grade IV complications developed in five cases. Vascular injuries (4 cases) were treated with intraoperative endoscopic sutures. An intestinal fistula was found on postoperative day 7 in one case; treatment with gastrointestinal decompression and drainage resolved the condition by 1 mo. Conclusions Even though the risks involved are high, RA-R-IVCTE is feasible for selected patients. The FPH/SPH is an important boundary landmark for RA-R-IVCTE. The location of proximal IVC tumor thrombi in relation to the FPH or SPH should determine the technique used. Patient summary Robot-assisted thrombectomy for retrohepatic inferior vena cava tumor thrombus is feasible in selected patients.

  • Substitution Urethroplasty with Closure Versus Nonclosure of the Buccal Mucosa Graft Harvest Site: A Randomized Controlled Trial with a Detailed Analysis of Oral Pain and Morbidity
    Eur. Urol. (IF 16.265) Pub Date : 2017-12-01
    Armin Soave, Roland Dahlem, Hans O. Pinnschmidt, Michael Rink, Jessica Langetepe, Oliver Engel, Luis A. Kluth, Birte Loechelt, Philip Reiss, Sascha A. Ahyai, Margit Fisch

    Background Optimal surgical management of the buccal mucosa harvest site in patients with urethral stricture disease during buccal mucosa graft urethroplasty (BMGU) remains controversial. Objective To analyze in detail intensity and quality of pain as well as oral morbidity following closure (C) versus nonclosure (NC) of the donor site. Design, setting, and participants Randomized controlled trial on 135 patients treated with BMGU between October 15, 2014 and December 18, 2015. Intervention Following computer-based randomization, 63 and 72 patients, respectively, received C and NC of the donor site at the inner cheek. Preoperatively, on days 1, 5, and 21 as well as at 3 and 6 mo postoperatively, patients completed standardized questionnaires, including validated questions on intensity and quality of pain as well as oral morbidity. Outcome measurements and statistical analysis The coprimary end points were intensity and quality of oral pain. Secondary end points included oral morbidity and intensity of pain of the perineogenital region. Generalized linear mixed models evaluated the effect of various covariates on intensity and quality of oral pain, oral morbidity, as well as intensity of pain of the perineogenital region. Results and limitations There was noninferiority for NC versus C in intensity and affective quality of oral pain at every time point following BMGU. Oral morbidity and complications included pain, bleeding, swelling, numbness, alteration of salivation and taste, as well as impairment of mouth opening, smiling, whistling, diet, and speech. Time from BMGU had significant effects on intensity (p < 0.001) and quality of oral pain (sensory pain: p < 0.001, affective pain: p < 0.001, total pain: p < 0.001). Length of buccal mucosa graft had significant effects on intensity (p = 0.001) and quality of oral pain (sensory pain: p = 0.020, total pain: p = 0.042). Conclusions NC is noninferior to C of the donor site in intensity and quality of oral pain, and offers a treatment alternative. Time from BMGU and length of the buccal mucosa graft have effects on oral morbidity and complications. Patient summary We investigated pain, morbidity, and complications following closure (C) versus nonclosure (NC) of the buccal mucosa harvest site in patients undergoing buccal mucosa graft urethroplasty (BMGU). We found that NC is not worse than C regarding oral pain. In addition, time from BMGU and length of the buccal mucosa graft have effects on oral morbidity and complications.

  • Multiparametric Magnetic Resonance Imaging Is an Independent Predictor of Salvage Radiotherapy Outcomes After Radical Prostatectomy
    Eur. Urol. (IF 16.265) Pub Date : 2017-11-28
    Vidit Sharma, Avinash Nehra, Michele Colicchia, Mary E. Westerman, Akira Kawashima, Adam T. Froemming, Eugene D. Kwon, Lance A. Mynderse, R. Jeffrey Karnes

    Background The Stephenson nomogram is widely used to estimate the success of salvage radiotherapy (sXRT) for prostate cancer (PCa) recurrence after radical prostatectomy (RP). Objective To determine whether multiparametric pelvic magnetic resonance imaging (mpMRI) performed for biochemical recurrence after RP improves prognostication of sXRT relative to the Stephenson nomogram. Design, setting, and participants Men undergoing RP at our institution from 2003 to 2012 who had biochemical recurrence evaluated by mpMRI within 12 mo of sXRT were retrospectively reviewed. Exclusion criteria included PCa treatment prior to RP, adjuvant XRT after RP, salvage cryotherapy before sXRT, and hormone refractory disease prior to sXRT. Outcome measurements and statistical analysis Multivariable Cox regression analyses (adjusting for Stephenson nomogram covariates) associated mpMRI findings with prostate-specific antigen (PSA) recurrence and metastasis after sXRT. The mpMR images were compared in a binary fashion: no lesion versus vesicourethral/seminal vesical bed/prostate fossa lesions. Results and limitations Among 473 sXRT patients, 57%(204) had lesions on mpMRI: 26%(124) vesicourethral, 28%(135) seminal vesical bed/prostatic fossa, 7%(34) nodal, and 1%(3) bone. Median PSA at mpMRI with lesions was 0.46 versus 0.40 ng/ml without lesions. After excluding nodal/bone lesions, 29% of men developed PSA recurrence and 14% metastasis (median follow-up 45 mo after sXRT). For patients with a pre-sXRT PSA of ≤0.5 ng/ml, negative mpMRI was associated with increased PSA recurrence (39% vs 12%, p < 0.01) and metastasis (16% vs 2%, p < 0.01) at 4 yr after sXRT. For patients with a PSA of ≤0.5 ng/ml, the addition of mpMRI to the propensity score (created using variables from the original Stephenson nomogram) improved the c-statistic from 0.71 to 0.77 for PSA recurrence (hazard ratio [HR] 3.60, p < 0.01) and from 0.66 to 0.77 for metastasis (HR 6.68, p < 0.01). Limitations include evolutions in MRI technique and lack of a cohort of men undergoing mpMRI electing against sXRT. Conclusions Pre-sXRT mpMRI improves clinicopathologic variables to estimate sXRT success, particularly in the early sXRT setting. Patient summary Men who have biochemically recurrent prostate cancer after radical prostatectomy often receive salvage radiotherapy. In our study, multiparametric pelvic magnetic resonance imaging prior to salvage radiotherapy was a significant predictor of prostate-specific antigen failure and metastasis after radiotherapy.

  • Robotic Ureteral Reconstruction Using Buccal Mucosa Grafts: A Multi-institutional Experience
    Eur. Urol. (IF 16.265) Pub Date : 2017-11-26
    Lee C. Zhao, Aaron C. Weinberg, Ziho Lee, Mark J. Ferretti, Harry P. Koo, Michael J. Metro, Daniel D. Eun, Michael D. Stifelman

    Background Minimally invasive treatment of long, multifocal ureteral strictures or failed pyeloplasty is challenging. Robot-assisted buccal mucosa graft ureteroplasty (RBU) is a technique for ureteral reconstruction that avoids the morbidity of bowel interposition or autotransplantation. Objective To evaluate outcomes for RBU in a multi-institutional cohort of patients treated for revision ureteropelvic junction obstruction and long or multifocal ureteral stricture at three tertiary referral centers. Design, setting, and participants This retrospective study involved data for 19 patients treated with RBU at three high-volume centers between October 2013 and July 2016. Surgical procedure RBU was performed using either an onlay graft after incising the stricture or an augmented anastomotic repair in which the ureter was transected and re-anastomosed primarily on one side, and a graft was placed on the other side. Outcome measurements and statistical analysis Preoperative, intraoperative, and postoperative variables and outcomes were assessed. A descriptive statistical analysis was performed. Results and limitations The onlay technique was used for 79%, while repair was carried out using the augmented anastomotic technique for the remaining cases. The reconstruction was reinforced with omentum in 95% of cases. The ureteral stricture location was proximal in 74% and mid in 26% of cases. A prior failed ureteral reconstruction was present in 53% of patients. The median stricture length was 4.0 cm (range 2.0–8.0), operative time was 200 min (range 136–397), estimated blood loss was 95 ml (range 25–420), and length of stay was 2 d (range 1–15). There were no intraoperative complications. At median follow-up of 26 mo, the overall success rate was 90%. Conclusions RBU is a feasible and effective technique for managing complex proximal and mid ureteral strictures. Patient summary We studied robotic surgery for long ureteral strictures using grafts at three referral centers. Our results demonstrate that robotic buccal mucosa graft ureteroplasty is a feasible and effective technique for ureteral reconstruction.

  • A Systematic Review and Meta-analysis Comparing the Efficacy of Nonsteroidal Anti-inflammatory Drugs, Opioids, and Paracetamol in the Treatment of Acute Renal Colic
    Eur. Urol. (IF 16.265) Pub Date : 2017-11-22
    Sameer A. Pathan, Biswadev Mitra, Peter A. Cameron

    Context Renal colic is a common, acute presentation of urolithiasis that requires immediate pain relief. European Association of Urology guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs) as the preferred analgesia. However, the fear of NSAID adverse effects and the uncertainty about superior analgesic effect have maintained the practice of advocating intravenous opioids as the initial analgesia. Objective The objective of this systematic review and meta-analysis was to compare the safety and efficacy of NSAIDs with opioids and paracetamol (acetaminophen) for the management of acute renal colic. Evidence acquisition Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, World Health Organization International Clinical Trials Registry Platform, Google Scholar, and the reference list of retrieved articles were searched up to December 2016 without language restrictions. Two reviewers independently assessed eligible studies using the Cochrane Collaboration tool for assessing and reporting the risk of bias and abstracted data using predefined data fields. Evidence synthesis From 468 potentially relevant studies, 36 randomized controlled trials (RCTs) including 4887 patients, published between 1982 and 2016, were included in this systematic review. The treatment effect observed indicated marginal benefit of NSAIDs over opioids in initial pain reduction at 30 min (11 RCTs, n = 1985, mean difference [MD] –5.58, 95% confidence interval [CI] –10.22 to –0.95; heterogeneity I2 = 81%). In the subgroup analyses by the route of administration, NSAIDs required fewer rescue treatments (seven RCTs, n = 541, number needed to treat [NNT] 11, 95% CI 6–75) and had lower vomiting rates compared with opioids (five RCTs, n = 531, NNT 5, 95% CI 4–8). Comparisons of NSAIDs with paracetamol showed no difference for both drugs at 30 min (four RCTs, n = 1325, MD –5.67, 95% CI –17.52 to 6.18, p = 0.35; I2 = 89%). Patients treated with NSAIDs required fewer rescue treatments (two trials, n = 1145, risk ratio 0.56, 95% CI 0.42–0.74, p < 0.001; I2 = 0%). Conclusions NSAIDs were equivalent to opioids or paracetamol in the relief of acute renal colic pain at 30 min. There was less vomiting and fewer requirements for rescue analgesia with NSAIDs compared with opioids. Patients treated with NSAIDs required less rescue analgesia compared with paracetamol. Despite observed heterogeneity among the included studies and the overall quality of evidence, the findings of a lower need for rescue analgesia and fewer adverse events, in conjunction with the practical advantages of ease of delivery, suggest that NSAIDs should be the preferred analgesic option for patients presenting to the emergency department with renal colic. Patient summary In kidney stone–related acute pain episodes in patients with adequate renal function, treatment with nonsteroidal anti-inflammatory drugs offers effective and most sustained pain relief, with fewer side effects, when compared with opioids or paracetamol.

  • Efficacy and Safety of Tamsulosin in Medical Expulsive Therapy for Distal Ureteral Stones with Renal Colic: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial
    Eur. Urol. (IF 16.265) Pub Date : 2017-11-12
    Zhangqun Ye, Guohua Zeng, Huan Yang, Kun Tang, Xiaochun Zhang, Hong Li, Weibing Li, Zhong Wu, Lingwu Chen, Xingfa Chen, Xiankui Liu, Yaoliang Deng, Tiejun Pan, Jinchun Xing, Shusheng Wang, Yue Cheng, Xiaojian Gu, Wenxi Gao, Jianggen Yang, Yonghai Zhang, Qiwu Mi, Lin Qi, Jiongming Li, Weilie Hu, Peiyu Liang, Zhaolin Sun, Changbao Xu, Yongfu Long, Yongbin Liao, Siping Liu, Guoqing Liu, Xun Xu, Wei He, Zhiqiang Chen, Hua Xu

    Background Recent large high-quality trials have questioned the clinical effectiveness of medical expulsive therapy using tamsulosin for ureteral stones. Objective To evaluate the efficacy and safety of tamsulosin for distal ureteral stones compared with placebo. Design, setting, and participants We conducted a double-blind, placebo-controlled study of 3296 patients with distal ureteral stones, across 30 centers, to evaluate the efficacy and safety of tamsulosin. Intervention Participants were randomly assigned (1:1) into tamsulosin (0.4 mg) or placebo groups for 4 wk. Outcome measurements and statistical analysis The primary end point of analysis was the overall stone expulsion rate, defined as stone expulsion, confirmed by negative findings on computed tomography, over a 28-d surveillance period. Secondary end points included time to stone expulsion, use of analgesics, and incidence of adverse events. Results and limitations Among 3450 patients randomized between September 1, 2011, and August 31, 2013, 3296 (96%) were included in the primary analysis. Tamsulosin benefits from a higher stone expulsion rate than the placebo (86% vs 79%; p < 0.001) for distal ureteral stones. Subgroup analysis identified a specific benefit of tamsulosin for the treatment of large distal ureteral stones (>5 mm). Considering the secondary end points, tamsulosin-treated patients reported a shorter time to expulsion (p < 0.001), required lower use of analgesics compared with placebo (p < 0.001), and significantly relieved renal colic (p < 0.001). No differences in the incidence of adverse events were identified between the two groups. Conclusions Our data suggest that tamsulosin use benefits distal ureteral stones in facilitating stone passage and relieving renal colic. Subgroup analyses find that tamsulosin provides a superior expulsion rate for stones >5 mm, but no effect for stones ≤5 mm. Patient summary In this report, we looked at the efficacy and safety of tamsulosin for the treatment of distal ureteral stones. We find that tamsulosin significantly facilitates the passage of distal ureteral stones and relieves renal colic.

  • Perioperative Morbidity of Lymph Node Dissection for Renal Cell Carcinoma: A Propensity Score–based Analysis
    Eur. Urol. (IF 16.265) Pub Date : 2017-11-11
    Boris Gershman, Daniel M. Moreira, R. Houston Thompson, Stephen A. Boorjian, Christine M. Lohse, Brian A. Costello, John C. Cheville, Bradley C. Leibovich

    Background There are little data regarding the morbidity of lymph node dissection (LND) for renal cell carcinoma (RCC) to assess its risk–benefit ratio. Objective To evaluate the association of LND with 30-d complications among patients undergoing radical nephrectomy (RN) for RCC. Design, setting, and participants A total of 2066 patients underwent RN for M0 or M1 RCC between 1990 and 2010, of whom 774 (37%) underwent LND. Intervention RN with or without LND. Outcome measurements and statistical analysis Associations of LND with 30-d complications were examined using logistic regression with several propensity score techniques. Extended LND, defined as removal of ≥13 lymph nodes, was examined in a sensitivity analysis. Results and limitations A total of 184 (9%) patients were pN1 and 302 (15%) were M1. Thirty-day complications occurred in 194 (9%) patients, including Clavien grade ≥3 complications in 81 (4%) patients. Clinicopathologic features were well balanced after propensity score adjustment. In the overall cohort, LND was not statistically significantly associated with Clavien grade ≥3 complications, although there was an approximately 40% increased risk of any Clavien grade complication that did not reach statistical significance. Likewise, LND was not significantly associated with any Clavien grade or Clavien grade ≥3 complications when separately evaluated among M0 or M1 patients. Extended LND was not significantly associated with any Clavien grade or Clavien grade ≥3 complications. LND was not associated with length of stay or estimated blood loss. Limitations include a retrospective design. Conclusions LND is not significantly associated with an increased risk of Clavien grade ≥3 complications, although it may be associated with a modestly increased risk of minor complications. In the absence of increased morbidity, LND may be justified in a predominantly staging role in the management of RCC. Patient summary Lymph node dissection for renal cell carcinoma is not associated with increased rates of major complications.

  • Systematic Review of Immune Checkpoint Inhibition in Urological Cancers
    Eur. Urol. (IF 16.265) Pub Date : 2017-06-20
    Maud Rijnders, Ronald de Wit, Joost L. Boormans, Martijn P.J. Lolkema, Astrid A.M. van der Veldt

    Context In patients with advanced and metastatic urological cancers, clinical outcome may be improved by immune checkpoint inhibitors (ICIs). Objective To systematically review relevant literature on efficacy and safety of ICIs in patients with advanced and metastatic urothelial cell cancer (UCC), renal cell cancer (RCC), and prostate cancer. Evidence acquisition Relevant databases, including Medline, Embase, and the Cochrane Library, were searched up to March 16, 2017. A narrative review of randomized clinical trials (RCTs) was performed. Evidence synthesis Six RCTs were included for the systematic review. In platinum-pretreated UCC, efficacy of pembrolizumab was superior to chemotherapy, with longer median overall survival (OS; 10.3 vs 7.4 mo), a higher objective response rate (ORR; 21.1% vs 11.4%, p = 0.001), and a lower adverse event rate (60.9% vs 90.2%). Three RCTs assessed the safety and efficacy of nivolumab in advanced RCC. The median OS (25.0 vs 19.6 mo) and the ORR (25% vs 5%) were higher in patients treated with nivolumab compared with second-line everolimus. In all three studies, the safety profile of nivolumab was favorable. In patients with metastatic castration-resistant prostate cancer, two RCTs were identified, which did not show significant benefits for ipilimumab over placebo. In UCC and RCC, there was no conclusive association between programmed cell death receptor ligand 1 (PD-L1) expression in tumor tissue and clinical outcome during pembrolizumab and nivolumab treatment, respectively. Conclusion In metastatic UCC and RCC, pembrolizumab and nivolumab have superior efficacy and safety to second-line chemotherapy and everolimus, respectively. No beneficial effect of ipilimumab was observed in prostate cancer patients. PD-L1 expression status is currently not suitable as a predictive marker for treatment outcome. Patient summary Immune checkpoint inhibitors are able to reactivate the immune system against tumor cells. In second-line setting, pembrolizumab and nivolumab are safe and confer survival benefit in advanced urothelial cell and renal cell cancer, respectively.

  • Genomic Markers in Prostate Cancer Decision Making
    Eur. Urol. (IF 16.265) Pub Date : 2017-11-10
    Vito Cucchiara, Matthew R. Cooperberg, Marc Dall’Era, Daniel W. Lin, Francesco Montorsi, Jack A. Schalken, Christopher P. Evans

    Context Although the widespread use of prostate-specific antigen (PSA) has led to an early detection of prostate cancer (PCa) and a reduction of metastatic disease at diagnosis, PSA remains one of the most controversial biomarkers due to its limited specificity. As part of emerging efforts to improve both detection and management decision making, a number of new genomic tools have recently been developed. Objective This review summarizes the ability of genomic biomarkers to recognize men at high risk of developing PCa, discriminate clinically insignificant and aggressive tumors, and facilitate the selection of therapies in patients with advanced disease. Evidence acquisition A PubMed-based literature search was conducted up to May 2017. We selected the most recent and relevant original articles and clinical trials that have provided indispensable information to guide treatment decisions. Evidence synthesis Genome-wide association studies have identified several genetic polymorphisms and inherited variants associated with PCa susceptibility. Moreover, the urine-based assays SelectMDx, Mi-Prostate Score, and ExoDx have provided new insights into the identification of patients who may benefit from prostate biopsy. In men with previous negative pathological findings, Prostate Cancer Antigen 3 and ConfirmMDx predicted the outcome of subsequent biopsy. Commercially available tools (Decipher, Oncotype DX, and Prolaris) improved PCa risk stratification, identifying men at the highest risk of adverse outcome. Furthermore, other biomarkers could assist in treatment selection in castration-resistant PCa. AR-V7 expression predicts resistance to abiraterone/enzalutamide, while poly(ADP-ribose) polymerase-1 inhibitor and platinum-based chemotherapy could be indicated in metastatic patients who are carriers of mutations in DNA mismatch repair genes. Conclusions Introduction of genomic biomarkers has dramatically improved the detection, prognosis, and risk evaluation of PCa. Despite the progress made in discovering suitable biomarker candidates, few have been used in a clinical setting. Large-scale and multi-institutional studies are required to validate the efficacy and cost utility of these new technologies. Patient summary Prostate cancer is a heterogeneous disease with a wide variability. Genomic biomarkers in combination with clinical and pathological variables are useful tools to reduce the number of unnecessary biopsies, stratify low-risk from high-risk tumors, and guide personalized treatment decisions.

  • Multi-institutional Evaluation of Elective Nodal Irradiation and/or Androgen Deprivation Therapy with Postprostatectomy Salvage Radiotherapy for Prostate Cancer
    Eur. Urol. (IF 16.265) Pub Date : 2017-11-09
    Stephen J. Ramey, Shree Agrawal, Matthew C. Abramowitz, Drew Moghanaki, Thomas M. Pisansky, Jason A. Efstathiou, Jeff M. Michalski, Daniel E. Spratt, Jason W.D. Hearn, Bridget F. Koontz, Stanley L. Liauw, Alan Pollack, Mitchell S. Anscher, Robert B. Den, Kevin L. Stephans, Anthony L. Zietman, W. Robert Lee, Andrew J. Stephenson, Rahul D. Tendulkar

    Background Outcomes with postprostatectomy salvage radiation therapy (SRT) are not ideal. Little evidence exists regarding potential benefits of adding whole pelvic radiation therapy (WPRT) alone or in combination with androgen deprivation therapy (ADT). Objective To explore whether WPRT and/or ADT added to prostate bed radiation therapy (PBRT) improves freedom from biochemical failure (FFBF) or distant metastases (DM). Design, setting, and participants A database was compiled from 10 academic institutions of patients with postprostatectomy prostate-specific antigen (PSA) >0.01 ng/ml; pT1-4, Nx/0, cM0; and Gleason score (GS) ≥7 treated between 1987 and 2013. Median follow-up was 51 mo. Interventions WPRT and/or ADT in addition to PBRT. Outcome measurements and statistical analyses FFBF and DM were calculated using cumulative incidence estimation. Multivariable analysis (MVA) utilized cumulative incidence regression. Results and limitation Median pre-SRT PSA was 0.5 ng/ml for 1861 patients. Median follow-up for patients not experiencing biochemical failure (BF) was 55 mo. MVA showed increased BF for PBRT versus WPRT (hazard ratio [HR] 1.82, p < 0.001) and no ADT versus ADT (HR 1.70, p < 0.001). WPRT was associated with a 5-yr FFBF of 62% versus 49% (p < 0.001) for PBRT. ADT use was associated with improved 5-yr FFBF (55% vs 50%, p = 0.012). No significant differences in DM cumulative incidence were found. Conclusions For patients with GS ≥7 receiving SRT, clinicians should weigh FFBF benefits of WPRT and ADT against toxicities. Future studies should explore the impact of WPRT on quality of life, clinical progression, and overall survival. Patient summary We evaluated patients with prostate cancer treated with radiation after surgery to remove the prostate. Both radiation to the pelvic lymph nodes and suppression of testosterone lowered the chance of increasing prostate-specific antigen (a marker for cancer returning).

  • The Role of Surgery in Metastatic Bladder Cancer: A Systematic Review
    Eur. Urol. (IF 16.265) Pub Date : 2017-11-07
    Mohammad Abufaraj, Guido Dalbagni, Siamak Daneshmand, Simon Horenblas, Ashish M. Kamat, Ryu Kanzaki, Alexandre R. Zlotta, Shahrokh F. Shariat

    Context The role of surgery in metastatic bladder cancer (BCa) is unclear. Objective In this collaborative review article, we reviewed the contemporary literature on the surgical management of metastatic BCa and factors associated with outcomes to support the development of clinical guidelines as well as informed clinical decision-making. Evidence acquisition A systematic search of English language literature using PubMed-Medline and Scopus from 1999 to 2016 was performed. Evidence synthesis The beneficial role of consolidation surgery in metastatic BCa is still unproven. In patients with clinically evident lymph node metastasis, data suggest a survival advantage for patients undergoing postchemotherapy radical cystectomy with lymphadenectomy, especially in those with measurable response to chemotherapy (CHT). Intraoperatively identified enlarged pelvic lymph nodes should be removed. Anecdotal reports of resection of pulmonary metastasis as part of multimodal approach suggest possible improved survival in well-selected patients. Cytoreductive radical cystectomy as local treatment has also been explored in patients with metastatic disease, although its benefits remain to be assessed. Conclusions Consolidative extirpative surgery may be considered in patients with clinically evident pelvic or retroperitoneal lymph nodal metastases but only if they have had a response to CHT. Surgery for limited pulmonary metastases may also be considered in very selected cases. Best candidates are those with resectable disease who demonstrate measurable response to CHT with good performance status. In the absence of data from prospective randomized studies, each patient should be evaluated on an individual basis and decisions made together with the patient and multidisciplinary teams. Patient summary Surgical resection of metastases is technically feasible and can be safely performed. It may help improve cancer control and eventually survival in very selected patients with limited metastatic burden. In a patient who is motivated to receive chemotherapy and to undergo extirpative surgical intervention, surgery should be discussed with the patient among other consolidation therapies in the setting of multidisciplinary teams.

  • Testicular Tumour Size and Rete Testis Invasion as Prognostic Factors for the Risk of Relapse of Clinical Stage I Seminoma Testis Patients Under Surveillance: a Systematic Review by the Testicular Cancer Guidelines Panel
    Eur. Urol. (IF 16.265) Pub Date : 2017-10-31
    Joost L. Boormans, Javier Mayor de Castro, Lorenzo Marconi, Yuhong Yuan, M. Pilar Laguna Pes, Carsten Bokemeyer, Nicola Nicolai, Ferran Algaba, Jan Oldenburg, Peter Albers

    Context Patients with clinical stage I (CS I) seminoma testis with large primary tumours and/or rete testis invasion (RTI) might have an increased risk of relapse. In recent years, these risk factors have frequently been employed to decide on adjuvant treatment. Objective To systematically review the literature on tumour size and RTI as risk factors for relapse in CS I seminoma testis patients under surveillance. Evidence acquisition Relevant databases including Medline, Embase, and the Cochrane Library were searched up to November 2016. Randomised controlled trials (RCTs) or quasi-RCTs, prospective observational studies with controls, retrospective matched-pair studies, and comparative studies from well-defined registries/databases were included. The primary outcome was the rate of relapse and relapse-free survival (RFS). The risk of bias was assessed by the Quality in Prognosis Studies tool. Evidence synthesis After assessing 3068 abstracts and 80 full-text articles, 20 studies met the inclusion criteria. Although evidence to justify a cut-off of 4 cm for size was lacking, it was the most frequently studied. The reported hazard ratio (HR) for the RFS for tumours >4 cm was 1.59–2.8. Accordingly, the reported 5-yr RFS ranged from 86.6% to 95.5% and from 73.0% to 82.6% for patients having tumours ≤4 and >4 cm, respectively. For tumours with RTI present, the reported HR was 1.4–1.7. The 5-yr RFS ranged from 86.0% to 92.0% and 74.9% to 79.5% for patients without versus those with RTI present, respectively. A meta-analysis was considered inappropriate due to data heterogeneity. Conclusions Primary tumour size and RTI are associated with the risk of relapse in CS I seminoma testis patients during surveillance. However, in the presence of either risk factor, the vast majority of patients are cured by orchiectomy alone and will not relapse. Furthermore, the evidence on the prognostic value of size and RTI has significant limitations, so prudency is warranted on their routine use in clinical practice. Patient summary Primary testicular tumour size and rete testis invasion are considered to be important prognostic factors for the risk of relapse in patients with clinical stage I seminoma testis. We systematically reviewed all the literature on the prognostic value of these two postulated risk factors. The outcome is that the prognostic power of these factors in the published literature is too low to advocate their routine use in clinical practice and to drive the choice on adjuvant treatment in clinical stage I seminoma testis patients.

  • Anticancer Activity and Tolerance of Treatments Received Beyond Progression in Men Treated Upfront with Androgen Deprivation Therapy With or Without Docetaxel for Metastatic Castration-naïve Prostate Cancer in the GETUG-AFU 15 Phase 3 Trial
    Eur. Urol. (IF 16.265) Pub Date : 2017-10-23
    Pernelle Lavaud, Gwenaëlle Gravis, Stéphanie Foulon, Florence Joly, Stéphane Oudard, Frank Priou, Igor Latorzeff, Loïc Mourey, Michel Soulié, Remy Delva, Ivan Krakowski, Brigitte Laguerre, Christine Théodore, Jean Marc Ferrero, Philippe Beuzeboc, Muriel Habibian, Frédéric Rolland, Gael Deplanque, Damien Pouessel, Sylvie Zanetta, Jean François Berdah, Jerome Dauba, Marjorie Baciuchka, Christian Platini, Claude Linassier, Nicole Tubiana-Mathieu, Jean Pascal Machiels, Claude El Kouri, Alain Ravaud, Etienne Suc, Jean Christophe Eymard, Ali Hasbini, Guilhem Bousquet, Stéphane Culine, Jean-Marie Boher, Gabrielle Tergemina-Clain, Clémence Legoupil, Karim Fizazi

    Background Androgen deprivation therapy (ADT) plus docetaxel is the standard of care in fit men with metastatic castration-naive prostate cancer (mCNPC) following results from GETUG-AFU 15, CHAARTED, and STAMPEDE. No data are available on the efficacy of treatments used for metastatic castration-resistant prostate cancer (mCRPC) in men treated upfront with ADT plus docetaxel for mCNPC. Objective To investigate the efficacy and tolerance of subsequent treatments in patients treated upfront with chemo-hormonal therapy for mCNPC. Design, setting, and participants Retrospective data from the GETUG-AFU 15 phase 3 trial were collected for treatments received for mCRPC. Outcome measurements and statistical analysis For the first three lines of salvage treatment for mCRPC we investigated the biochemical progression-free survival, maximum prostate-specific antigen (PSA) decline, overall survival, and tolerance. Results and limitations Overall, 245 patients received at least one treatment for mCRPC. For docetaxel used in first-line, a PSA decline ≥50% was observed in 25/66 (38%) and in 4/20 patients (20%) who had received upfront ADT alone and ADT plus docetaxel (p = 0.14). The median biochemical progression-free survival was 6.0 mo (95% confidence interval: 3.6–7.7) and 4.1 mo (95% confidence interval: 1.3–4.9), respectively. For docetaxel used in first- or second-line, a PSA decline ≥50% was observed in 36/80 (45%) and in 4/29 patients (14%) who had received upfront ADT alone and ADT plus docetaxel (p = 0.07). PSA declines ≥50% were observed with bicalutamide in 12/28 (43%) and 4/23 patients (17%) who had received upfront ADT alone and ADT plus docetaxel. Among men treated upfront with ADT plus docetaxel who received abiraterone or enzalutamide for mCRPC, 10/19 patients (53%) achieved a PSA decline ≥50%. Few grade 3–4 events occurred. Study limitations include the observational design and retrospective characteristics of this analysis, without standardized therapeutic salvage protocols, and the limited number of patients in some of the treatment subgroups. Conclusions Docetaxel rechallenge following progression to mCRPC after upfront ADT plus docetaxel for mCNPC was active only in a limited number of patients. Available data on abiraterone and enzalutamide support maintained efficacy in this setting. The lack of standardized therapeutic protocols for men developing mCRPC limits the comparability between patients. Patient summary Rechallenging docetaxel at castration-resistance was active only in a limited number of patients treated upfront with chemo-hormonal therapy for metastatic castration-naive prostate cancer. Anticancer activity was suggested with abiraterone or enzalutamide in this setting.

  • Association Between Lead Time and Prostate Cancer Grade: Evidence of Grade Progression from Long-term Follow-up of Large Population-based Cohorts Not Subject to Prostate-specific Antigen Screening
    Eur. Urol. (IF 16.265) Pub Date : 2017-10-21
    Melissa Assel, Anders Dahlin, David Ulmert, Anders Bergh, Pär Stattin, Hans Lilja, Andrew J. Vickers

    Background Lead time (LT) is of key importance in early detection of cancer, but cannot be directly measured. We have previously provided LT estimates for prostate cancer (PCa) using archived blood samples from cohorts followed for many years without screening. Objective To determine the association between LT and PCa grade at diagnosis to provide an insight into whether grade progresses or is stable over time. Design, setting, and participants The setting was three long-term epidemiologic studies in Sweden including men not subject to prostate-specific antigen (PSA) screening. The cohort included 1041 men with PSA of 3–10 ng/ml at blood draw and subsequently diagnosed with PCa with grade data available. Outcome measurements and statistical analysis Multivariable logistic regression was used to predict high-grade (Gleason grade group ≥2 or World Health Organization grade 3) versus low-grade PCa at diagnosis in terms of LT, defined as the time between the date of elevated PSA and the date of PCa diagnosis with adjustment for cohort and age. Results and limitations The probability that PCa would be high grade at diagnosis increased with LT. Among all men combined, the risk of high-grade disease increased with LT (odds ratio 1.13, 95% confidence interval [CI] 1.10–1.16; p < 0.0001), with no evidence of differences in effect by age group or cohort. Higher PSA predicted shorter LT by 0.46 yr (95% CI 0.28–0.64; p < 0.0001) per 1 ng/ml increase in PSA. However, there was no interaction between PSA and grade, suggesting that the longer LT for high-grade tumors is not simply related to age. Limitations include the assumption that men with elevated PSA and subsequently diagnosed with PCa would have had biopsy-detectable PCa at the time of PSA elevation. Conclusions Our data support grade progression, whereby following a prostate over time would reveal transitions from benign to low-grade and then high-grade PCa. Patient summary Men with a longer lead time between elevated prostate-specific antigen and subsequent prostate cancer diagnosis were more likely to have high-grade cancers at diagnosis.

  • Predicting Response to Intravesical Bacillus Calmette-Guérin Immunotherapy: Are We There Yet? A Systematic Review
    Eur. Urol. (IF 16.265) Pub Date : 2017-10-18
    Ashish M. Kamat, Roger Li, Michael A. O’Donnell, Peter C. Black, Morgan Roupret, James W. Catto, Eva Comperat, Molly A. Ingersoll, Wim P. Witjes, David J. McConkey, J. Alfred Witjes

    Context Bacillus Calmette-Guérin (BCG) is currently the most effective intravesical therapy for nonmuscle invasive bladder cancer, reducing not only recurrence rates but also preventing progression and reducing deaths. However, response rates to BCG vary widely and are dependent on a multitude of factors. Objective To review existing data on clinical, pathologic, immune, and molecular markers that allow prediction of BCG response. Evidence acquisition PubMed and MEDLINE search of English language literature was conducted from its inception to July 2017 using appropriate search terms. Following systematic literature review and analysis of data, consensus voting was used to generate the content of this review. Evidence synthesis As seen in the EORTC and CUETO risk nomograms, clinicopathologic features, especially tumor stage and grade, are the most effective predictors of BCG response. Data are less robust with regards to the association of response with age, female sex, recurrent tumors, multiplicity of tumors, and the presence of carcinoma in situ. Single biomarkers, such as tumor p53 and urinary interleukin-2 expression, have had limited success in predicting BCG response, possibly due to the multifaceted nature of the generated immune response. More comprehensive biomarker panels (eg, urinary cytokines), have a more robust correlation with response, as do patterns of urinary cytologic fluorescent in-situ hybridization examination. Gene expression data correlate with disease progression, but studies examining potential associations with BCG response are limited. Conclusions Currently, the best predictors of BCG response are clinicopathologic features such as tumor grade and stage. Panels of urinary cytokines, as well as fluorescent in-situ hybridization patterns of cytologic anomalies, appear to be promising biomarkers. The complexity of the immune response to BCG and the heterogeneity of bladder cancer suggest that future studies should amalgamate measures reflecting innate immune response and tumor/stromal gene expression before these can be adopted for clinical use. Patient summary Bacillus Calmette-Guérin (BCG) immunotherapy is an effective treatment for many patients with nonmuscle invasive bladder cancer. An individual's response to BCG can be predicted by using various features of the cancer. In the future, predictive markers using molecular measures of the tumor type and the immune response to BCG may allow us to precisely know an individual's likely outcome after BCG treatment.

  • Survival Outcomes of Men with Lymph Node-positive Prostate Cancer After Radical Prostatectomy: A Comparative Analysis of Different Postoperative Management Strategies
    Eur. Urol. (IF 16.265) Pub Date : 2017-10-16
    Karim A. Touijer, Robert Jeffery Karnes, Niccolo Passoni, Daniel D. Sjoberg, Melissa Assel, Nicola Fossati, Giorgio Gandaglia, James A. Eastham, Peter T. Scardino, Andrew Vickers, Cesare Cozzarini, Francesco Montorsi, Alberto Briganti

    Background Optimal management of patients with lymph node metastasis (LNM) after radical prostatectomy (RP) remains undefined. Objective We evaluated the association between three different management strategies and survival in prostate cancer with LNM after RP. Design, setting, and participants We analyzed data of 1338 patients with LNM after RP from three tertiary care centers. Three hundred and eighty-seven patients (28%) were observed, 676 (49%) received lifelong adjuvant androgen deprivation therapy (ADT), and 325 (23%) received adjuvant external beam radiation therapy (EBRT) and ADT. Three hundred and sixty-eight men were followed for more than 10 yr. Outcome measurements and statistical analysis Primary outcome measure was overall survival (OS). Secondary outcomes were cancer-specific survival (CSS) and other-cause mortality. Kaplan-Meier methods were used to visualize OS for the three treatment groups. Cox proportional hazards regression was utilized to compare OS and CSS among the three groups. Results and limitations ADT + EBRT was associated with better OS than ADT alone (hazard ratio [HR]: 0.46, 95% confidence interval [CI]: 0.32–0.66, p < 0.0001) or observation (HR: 0.41, 95% CI: 0.27–0.64, p < 0.0001). Higher-risk patients benefited more from ADT + EBRT than lower-risk patients. Ten-year mortality risk difference between ADT + EBRT, observation, or ADT alone ranged from 5% in low-risk patients to 40% in high-risk patients. Adjuvant ADT + EBRT was also associated with better CSS than observation or ADT alone (p < 0.0001), ADT had better CSS compared to observation (HR: 0.64, 95% CI: 0.43–0.95, p = 0.027). However, ADT was associated with an increased risk of other-cause mortality (HR: 3.05, 95% CI: 1.45–6.40, p = 0.003) compared with observation, resulting in similar OS between ADT and observation (HR: 0.90, 95% CI: 0.65–1.25, p = 0.5). While selection bias might remain, its effect would operate in the opposite direction to our findings. Conclusions In men with LNM after RP, ADT + EBRT improved survival over either observation or adjuvant ADT alone. This survival benefit increases with higher-risk disease. Patient summary Lymph node metastasis following radical prostatectomy is associated with poor survival outcomes. However, we found that adjuvant androgen deprivation therapy with external beam radiation therapy improved survival in these patients.

  • Comparison of Abiraterone Acetate and Docetaxel with Androgen Deprivation Therapy in High-risk and Metastatic Hormone-naïve Prostate Cancer: A Systematic Review and Network Meta-analysis
    Eur. Urol. (IF 16.265) Pub Date : 2017-10-14
    Christopher J.D. Wallis, Zachary Klaassen, Bimal Bhindi, Hanan Goldberg, Thenappan Chandrasekar, Ann M. Farrell, Stephen A. Boorjian, Girish S. Kulkarni, Robert Jeffrey Karnes, Raj Satkunasivam

    Context Randomized clinical trials have recently examined the benefit of adding docetaxel or abiraterone to androgen deprivation therapy (ADT) in hormone-naïve advanced prostate cancer (PCa). Objective To perform a systematic review and network meta-analysis of randomized clinical trials, indirectly evaluating overall survival (OS) for men treated with abiraterone acetate plus prednisone/prednisolone with ADT (Abi-ADT) versus docetaxel with ADT (Doce-ADT) in hormone-naïve high-risk and metastatic PCa. Evidence acquisition Medline, Embase, Web of Science, Scopus, and Clinicaltrials.gov databases were searched in August 2017. We pooled results using the inverse variance technique and random-effects models. The Bucher technique for indirect treatment comparison was used to compare Abi-ADT with Doce-ADT. A priori subgroup and sensitivity analyses were performed. Evidence synthesis Overall, 6067 patients from five trials were included: 1181 (19.5%) patients who received Doce-ADT, 1557 (25.7%) patients who received Abi-ADT, and 3329 (54.9%) patients who received ADT-alone. There was a total of 1921 deaths: 391 in the Doce-ADT group, 353 in the Abi-ADT group, and 1177 in the ADT-only group. The pooled hazard ratio (HR) for OS was 0.75 (95% confidence interval [CI]: 0.63–0.91, I2 = 51%, 3 trials, 2951 patients) for Doce-ADT versus ADT-alone and 0.63 (95% CI: 0.55–0.72, I2 = 0%, 2 trials, 3116 patients) for Abi-ADT versus ADT-alone. The indirect comparison of Abi-ADT to Doce-ADT demonstrated no statistically significant difference in OS between these approaches (HR: 0.84, 95% CI: 0.67–1.06). Findings were similar in various a priori subset analyses, including patients with metastatic disease. Bayesian analyses demonstrated comparable results (HR: 0.83, 95% CI: 0.63–1.16). Despite the lack of statistical significance, Surface Under the Cumulative Ranking Analysis demonstrated an 89% probability that Abi-ADT was preferred. Conclusions We did not identify a significant difference in OS between Abi-ADT and Doce-ADT for men with hormone-naïve high-risk or metastatic PCa, although Bayesian analysis demonstrates a high likelihood that Abi-ADT was preferred. Patient summary We synthesized the evidence available from studies examining the administration of docetaxel or abiraterone in combination with hormonal therapy for patients with newly diagnosed, advanced prostate cancer. While these studies did not directly compare these agents, we used methodological techniques to indirectly compare them and found no significant difference in overall survival.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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