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  • Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression
    Eur. Urol. (IF 16.265) Pub Date : 2017-09-18
    Shancheng Ren, Gong-Hong Wei, Dongbing Liu, Liguo Wang, Yong Hou, Shida Zhu, Lihua Peng, Qin Zhang, Yanbing Cheng, Hong Su, Xiuqing Zhou, Jibin Zhang, Fuqiang Li, Hancheng Zheng, Zhikun Zhao, Changjun Yin, Zengquan He, Xin Gao, Haiyen E. Zhau, Chia-Yi Chu, Jason Boyang Wu, Colin Collins, Stanislav V. Volik, Robert Bell, Jiaoti Huang, Kui Wu, Danfeng Xu, Dingwei Ye, Yongwei Yu, Lianhui Zhu, Meng Qiao, Hang-Mao Lee, Yuehong Yang, Yasheng Zhu, Xiaolei Shi, Rui Chen, Yang Wang, Weidong Xu, Yanqiong Cheng, Chuanliang Xu, Xu Gao, Tie Zhou, Bo Yang, Jianguo Hou, Li Liu, Zhensheng Zhang, Yao Zhu, Chao Qin, Pengfei Shao, Jun Pang

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

  • Perioperative and Oncologic Outcomes of Nephrectomy and Caval Thrombectomy Using Extracorporeal Circulation and Deep Hypothermic Circulatory Arrest for Renal Cell Carcinoma Invading the Supradiaphragmatic Inferior Vena Cava and/or Right Atrium
    Eur. Urol. (IF 16.265) Pub Date : 2017-09-13
    Alessandro Nini, Umberto Capitanio, Alessandro Larcher, Paolo Dell’Oglio, Federico Dehò, Nazareno Suardi, Fabio Muttin, Cristina Carenzi, Massimo Freschi, Roberta Lucianò, Giovanni La Croce, Alberto Briganti, Renzo Colombo, Andrea Salonia, Alessandro Castiglioni, Patrizio Rigatti, Francesco Montorsi, Roberto Bertini

    Background Radical nephrectomy (RN) and caval thrombectomy (CT) for renal cell carcinoma, with extracorporeal circulation (ECC) and deep hypothermic circulatory arrest (DHCA) is a challenging surgical approach. Objective To assess peri-operative and oncologic outcomes of renal cell carcinoma patients treated with RN and CT, using ECC and DHCA. Design, setting, and participants We retrospectively evaluated 46 patients who underwent RN and CT using ECC and DHCA. Surgical procedure After retroperitoneal nodal dissection and RN, a cardiopulmonary bypass was placed and DHCA achieved. A combined approach through the abdomen and the thorax was described. Measurements Perioperative and long-term survival outcomes were reported. Results and limitations Median operative time and length of hospital stay were 545 min and 22 d. Overall, 33 patients (72%) did not require any additional interventional or surgical treatment. Thirty-day and 90-d mortality were 11% (5/46) and 15% (7/46). The 1-yr, 2-yr, and 3-yr cancer specific mortality (CSM)-free survival rates were 77%, 62%, and 56%, respectively. After stratification, according to metastatic status at diagnosis, CSM-free survival rates were significantly lower for cM1 patients compared with cM0 patients (1-yr 46% vs 93%, 2-yr 23% vs 81%, 3-yr 23% vs 73%, p < 0.01). Our study is limited by its retrospective and uncomparative nature. Conclusions RN with CT using ECC and DHCA is a challenging procedure which requires a dedicated multidisciplinary working team to minimise complications and maximise patients’ outcomes. Patient summary Patients with kidney cancer and a thrombus within the inferior vena cava, which reaches above the diaphragm, can be treated with surgery. However, this kind of surgical treatment is challenging and requires a dedicated multidisciplinary team in order to accomplish the task.

  • Response Rate to Chemotherapy After Immune Checkpoint Inhibition in Metastatic Urothelial Cancer
    Eur. Urol. (IF 16.265) Pub Date : 2017-09-13
    Bernadett Szabados, Nick van Dijk, Yen Zhi Tang, Michiel van der Heijden, Akhila Wimalasingham, Alfonso Gomez de Liano, Simon Chowdhury, Simon Hughes, Sarah Rudman, Mark Linch, Thomas Powles

    Immune checkpoint inhibitors (ICIs) are active in metastatic urothelial carcinoma (MUC). They have joined chemotherapy (CT) as a standard of care. Here, we investigate the activity of CT after progression on ICIs. Two cohorts of sequential patients with MUC were described (n = 28). Cohort A received first-line ICIs followed by CT after progression. Cohort B received CT after failure of first-line platinum-based CT followed by ICIs. Response rate (RR) to CT was assessed using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) by a designated radiologist. Best RR for cohort A was 64%. Two patients experienced clinical progression and died before the first radiographic assessment. RR for cohort B was 21%, which was significantly lower than that for cohort A. Progression of disease occurred in 43% of cohort B patients by the end of CT. These data suggest a lack of cross resistance between CT and ICIs in MUC. Therefore, the sequencing of these drugs is likely to be important to maximise outcomes. This is particularly true after first-line ICIs as subsequent CT has significant activity. Patient summary In this report, we studied the effect of chemotherapy in metastatic bladder cancer, which relapsed after immune checkpoint inhibitors. We found that the activity of chemotherapy was maintained despite previous exposure to immune therapy. This underlines the importance of sequencing these agents to maximise outcomes.

  • Key Steps in Conducting Systematic Reviews for Underpinning Clinical Practice Guidelines: Methodology of the European Association of Urology
    Eur. Urol. (IF 16.265) Pub Date : 2017-09-13
    Thomas Knoll, Muhammad Imran Omar, Steven Maclennan, Virginia Hernández, Steven Canfield, Yuhong Yuan, Max Bruins, Lorenzo Marconi, Hein Van Poppel, James N’Dow, Richard Sylvester

    Context The findings of systematic reviews (SRs) and meta-analyses (MAs) are used for clinical decision making. The European Association of Urology has committed increasing resources into the development of high quality clinical guidelines based on such SRs and MAs. Objective In this paper, we have summarised the process of conducting SRs for underpinning clinical practice guidelines under the auspices of the European Association of Urology Guidelines Office. Evidence acquisition The process involves explicit methods and the findings should be reproducible. When conducting a SR, the essential first step is to formulate a clear and answerable research question. An extensive literature search lays the foundation for evidence synthesis. Data are extracted independently by two reviewers and any disagreements are resolved by discussion or arbitration by a third reviewer. Evidence synthesis In SRs, data for particular outcomes in individual randomised controlled trials may be combined statistically in a meta-analysis to increase power when the studies are similar enough. Biases in studies included in a SR/MA can lead to either an over estimation or an under estimation of true intervention effect size, resulting in heterogeneity in outcome between studies. A number of different tools are available such as Cochrane Risk of Bias assessment tool for randomised controlled trials. In circumstances where there is too much heterogeneity, or when a review has included nonrandomised comparative studies, it is more appropriate to conduct a narrative synthesis. The GRADE tool for assessing quality of evidence strives to be a structured and transparent system, which can be applied to all evidence, regardless of quality. A SR not only identifies, evaluates, and summarises the best available evidence, but also the gaps to be targeted by future studies. Conclusions SRs and MAs are integral in developing sound clinical practice guidelines and recommendations. Patient summary Clinical practice guidelines should be evidence based, and systematic reviews and meta-analyses are essential in their production. We have discussed the key steps of conducting systematic reviews and meta-analyses in this paper.

  • Robot-assisted Kidney Transplantation: The European Experience
    Eur. Urol. (IF 16.265) Pub Date : 2017-09-12
    Alberto Breda, Angelo Territo, Luis Gausa, Volkan Tuğcu, Antonio Alcaraz, Mireia Musquera, Karel Decaestecker, Liesbeth Desender, Michael Stockle, Martin Janssen, Paolo Fornara, Nasreldin Mohammed, Giampaolo Siena, Sergio Serni, Luis Guirado, Carma Facundo, Nicolas Doumerc

    Background Robot-assisted kidney transplantation (RAKT) has recently been introduced to reduce the morbidity of open kidney transplantation (KT). Objective To evaluate perioperative and early postoperative RAKT outcomes. Design, setting and participants This was a multicenter prospective observational study of 120 patients who underwent RAKT, predominantly with a living donor kidney, in eight European institutions between July 2015 and May 2017, with minimum follow-up of 1 mo. The robot-assisted surgical steps were transperitoneal dissection of the external iliac vessels, venous/arterial anastomosis, graft retroperitonealization, and ureterovesical anastomosis. Outcome measurements and statistical analysis Descriptive analysis of surgical data and their correlations with functional outcomes. Results and limitations The median operative and vascular suture time was 250 and 38 min, respectively. The median estimated blood loss was 150 ml. No major intraoperative complications occurred, although two patients needed open conversion. The median postoperative estimated glomerular filtration rate was 21.2, 45.0, 52.6, and 58.0 ml/min on postoperative day 1, 3, 7, and 30, respectively. Both early and late graft function were not related to overall operating time or rewarming time. Five cases of delayed graft function (4.2%) were reported. One case (0.8%) of wound infection, three cases (2.5%) of ileus, and four cases of bleeding (3.3%; three of which required blood transfusion), managed conservatively, were observed. One case (0.8%) of deep venous thrombosis, one case (0.8%) of lymphocele, and three cases (2.5%) of transplantectomy due to massive arterial thrombosis were recorded. In five cases (4.2%), surgical exploration was performed for intraperitoneal hematoma. Limitations of the study include selection bias, the lack of an open control group, and failure to report on patient cosmetic satisfaction. Conclusions When performed by surgeons with robotic and KT experience, RAKT is safe and reproducible in selected cases and yields excellent graft function. Patient summary We present the largest reported series on robot-assisted kidney transplantation. Use of a robotic technique can yield low complication rates, rapid recovery, and excellent graft function. Further investigations need to confirm our promising data.

  • Efficacy of Local Treatment in Prostate Cancer Patients with Clinically Pelvic Lymph Node-positive Disease at Initial Diagnosis
    Eur. Urol. (IF 16.265) Pub Date : 2017-09-08
    Thomas Seisen, Malte W. Vetterlein, Patrick Karabon, Tarun Jindal, Akshay Sood, Luigi Nocera, Paul L. Nguyen, Toni K. Choueiri, Quoc-Dien Trinh, Mani Menon, Firas Abdollah

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

  • Erectile Function and Oncologic Outcomes Following Open Retropubic and Robot-assisted Radical Prostatectomy: Results from the LAParoscopic Prostatectomy Robot Open Trial
    Eur. Urol. (IF 16.265) Pub Date : 2017-09-04
    Prasanna Sooriakumaran, Giovanni Pini, Tommy Nyberg, Maryam Derogar, Stefan Carlsson, Johan Stranne, Anders Bjartell, Jonas Hugosson, Gunnar Steineck, Peter N. Wiklund

    Background Whether surgeons perform better utilising a robot-assisted laparoscopic technique compared with an open approach during prostate cancer surgery is debatable. Objective To report erectile function and early oncologic outcomes for both surgical modalities, stratified by prostate cancer risk grouping. Design, setting, and participants In a prospective nonrandomised trial, we recruited 2545 men with prostate cancer from seven open (n = 753) and seven robot-assisted (n = 1792) Swedish centres (2008–2011). Outcome measurements and statistical analysis Clinometrically-validated questionnaire-based patient-reported erectile function was collected before, 3 mo, 12 mo, and 24 mo after surgery. Surgeon-reported degree of neurovascular-bundle preservation, pathologist-reported positive surgical margin (PSM) rates, and 2-yr prostate-specific antigen-relapse rates were measured. Results and limitations Among 1702 preoperatively potent men, we found enhanced erectile function recovery for low/intermediate-risk patients in the robot-assisted group at 3 mo. For patients with high-risk tumours, point estimates for erectile function recovery at 24 mo favoured the open surgery group. The degree of neurovascular bundle preservation and erectile function recovery were greater correlated for robot-assisted surgery. In pT2 tumours, 10% versus 17% PSM rates were observed for open and robot-assisted surgery, respectively; corresponding rates for pT3 tumours were 48% and 33%. These differences were associated with biochemical recurrence in pT3 but not pT2 disease. The study is limited by its nonrandomised design and relatively short follow-up. Conclusions Earlier recovery of erectile function in the robot-assisted surgery group in lower-risk patients is counterbalanced by lower PSM rates for open surgeons in organ-confined disease; thus, both open and robotic surgeons need to consider this trade-off when determining the plane of surgical dissection. Robot-assisted surgery also facilitates easier identification of nerve preservation planes during radical prostatectomy as well as wider dissection for pT3 cases. Patient summary For prostate cancer surgery, an open operation reduces erection problems in high-risk cancers but has higher relapse rates than robotic surgery. Relapse rates appear similar in low/intermediate-risk cancers and the robot appears better at preserving erections in these cases.

  • European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update
    Eur. Urol. (IF 16.265) Pub Date : 2017-09-01
    Morgan Rouprêt, Marko Babjuk, Eva Compérat, Richard Zigeuner, Richard J. Sylvester, Maximilian Burger, Nigel C. Cowan, Paolo Gontero, Bas W.G. Van Rhijn, A. Hugh Mostafid, Joan Palou, Shahrokh F. Shariat

    Context The European Association of Urology (EAU) Guidelines Panel on Upper Urinary Tract Urothelial Carcinoma (UTUC) has prepared updated guidelines to aid clinicians in the current evidence-based management of UTUC and to incorporate recommendations into clinical practice. Objective To provide an overview of the EAU guidelines on UTUC as an aid to clinicians. Evidence acquisition The recommendations provided in the current guidelines are based on a thorough review of available UTUC guidelines and articles identified following a systematic search of Medline. Data on urothelial malignancies and UTUC were searched using the following keywords: urinary tract cancer; urothelial carcinomas; upper urinary tract, carcinoma; renal pelvis; ureter; bladder cancer; chemotherapy; ureteroscopy; nephroureterectomy; adjuvant treatment; instillation; recurrence; risk factors; and survival. References were weighted by a panel of experts. Evidence synthesis Owing to the rarity of UTUC, there are insufficient data to provide strong recommendations (ie, grade A). However, the results of recent multicentre studies are now available, and there is a growing number of retrospective articles in UTUC. The 2017 tumour, node, metastasis (TNM) classification is recommended. Recommendations are given for diagnosis and risk stratification, as well as for radical and conservative treatment; prognostic factors are also discussed. A single postoperative dose of intravesical mitomycin after radical nephroureterectomy reduces the risk of bladder tumour recurrence. Kidney-sparing management should be offered as a primary treatment option to patients with low-risk tumours and two functional kidneys. Conclusions These guidelines contain information on the management of individual patients according to a current standardised approach. Urologists should take into account the specific clinical characteristics of each patient when determining the optimal treatment regimen, based on the proposed risk stratification of these tumours. Patient summary Urothelial carcinoma of the upper urinary tract is rare, but because 60% of these tumours are invasive at diagnosis; appropriate diagnosis and management is most important. We present recommendations based on current evidence for optimal management.

  • Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer
    Eur. Urol. (IF 16.265) Pub Date : 2017-09-01
    Yezi Zhu, Adam Sharp, Courtney M. Anderson, John L. Silberstein, Maritza Taylor, Changxue Lu, Pei Zhao, Angelo M. De Marzo, Emmanuel S. Antonarakis, Mindy Wang, Xingyong Wu, Yuling Luo, Nan Su, Daniel Nava Rodrigues, Ines Figueiredo, Jonathan Welti, Emily Park, Xiao-Jun Ma, Ilsa Coleman, Colm Morrissey, Stephen R. Plymate, Peter S. Nelson, Johann S. de Bono, Jun Luo

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

  • Moving Towards Precision Urologic Oncology: Targeting Enzalutamide-resistant Prostate Cancer and Mutated Forms of the Androgen Receptor Using the Novel Inhibitor Darolutamide (ODM-201)
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-26
    Hendrik Borgmann, Nada Lallous, Deniz Ozistanbullu, Eliana Beraldi, Naman Paul, Kush Dalal, Ladan Fazli, Axel Haferkamp, Pascale Lejeune, Artem Cherkasov, Martin E. Gleave

    Darolutamide (ODM-201) is a novel androgen receptor (AR) antagonist with a chemical structure distinctly different from currently approved AR antagonists that targets both wild-type and mutated ligand binding domain variants to inhibit AR nuclear translocation. Here, we evaluate the activity of darolutamide in enzalutamide-resistant castration resistant prostate cancer (CRPC) as well as in AR mutants detected in patients after treatment with enzalutamide, abiraterone, or bicalutamide. Darolutamide significantly inhibited cell growth and AR transcriptional activity in enzalutamide-resistant MR49F cells in vitro, and led to decreased tumor volume and serum prostate-specific antigen levels in vivo, prolonging survival in mice bearing enzalutamide-resistant MR49F xenografts. Moreover, darolutamide inhibited the transcriptional activity of AR mutants identified in the plasma of CRPC patients progressing on traditional therapies. In particular, darolutamide significantly inhibited the transcriptional activity of the F877L, H875Y/T878A, F877L/T878A, and the previously unreported T878G AR mutants, that transform enzalutamide into a partial agonist. In silico cheminformatics computer modeling provided atomic level insights confirming darolutamide antagonist effect in F877L and T878G AR mutants. In conclusion, our results provide a rationale for further clinical evaluation of darolutamide in enzalutamide-resistant CRPC, in particular in combination with circulating tumor DNA assays that detect AR mutants sensitive to darolutamide, in a precision oncology setting. Patient summary In this study we evaluated the novel drug darolutamide in preclinical models of prostate cancer. We found that darolutamide delays growth of enzalutamide-resistant prostate cancer, in particular in cells with mutated forms of the androgen receptor after previous treatment. Our data supports further evaluation of darolutamide in clinical trials.

  • Long-term Psychological and Quality-of-life Effects of Active Surveillance and Watchful Waiting After Diagnosis of Low-risk Localised Prostate Cancer
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-26
    Sam J. Egger, Ross J. Calopedos, Dianne L. O’Connell, Suzanne K. Chambers, Henry H. Woo, David P. Smith

    Background Long-term psychological well-being and quality-of-life are important considerations when deciding whether to undergo active treatment for low-risk localised prostate cancer. Objective To assess the long-term effects of active surveillance (AS) and/or watchful waiting (WW) on psychological and quality-of-life outcomes for low-risk localised prostate cancer patients. Design, setting, and participants The Prostate Cancer Care and Outcome Study is a population-based prospective cohort study in New South Wales, Australia. Participants for these analyses were low-risk localised prostate cancer patients aged <70 yr at diagnosis and participated in the 10-yr follow-up. Outcome measurements and statistical analysis Validated instruments assessed outcomes relating to six health-related quality-of-life and nine psychological domains relevant to prostate cancer patients. Adjusted mean differences (AMDs) in outcome scores between prostate cancer treatment groups were estimated using linear regression. Results and limitations At 9–11 yr after diagnosis, patients who started AS/WW initially had (1) higher levels of distress and hyperarousal than initial radiation/high-dose-rate brachytherapy patients (AMD = 5.9; 95% confidence interval or CI [0.5, 11.3] and AMD = 5.4; 95% CI [0.2, 10.5], respectively), (2) higher levels of distress and avoidance than initial low-dose-rate brachytherapy patients (AMD = 5.3; 95% CI [0.2, 10.3] and AMD = 7.0; 95% CI [0.5, 13.5], respectively), (3) better urinary incontinence scores than initial radical prostatectomy patients (AMD = –9.1; 95% CI [–16.3, –2.0]), and (4) less bowel bother than initial radiation/high-dose-rate brachytherapy patients (AMD = –16.8; 95% CI [–27.6, –6.0]). No other significant differences were found. Limitations include participant attrition, inability to assess urinary voiding and storage symptoms, and nonrandom treatment allocation. Conclusions Notwithstanding some long-term differences between AS/WW and various active treatment groups in terms of distress, hyperarousal, avoidance, urinary incontinence, and bowel bother, most long-term outcomes were similar between these groups. Patient summary This study assessed the long-term psychological and quality-of-life impacts of initially monitoring rather than actively treating low-risk prostate cancer. The results suggest that initial monitoring rather than active treatment has only a minor impact on subsequent long-term psychological and quality-of-life outcomes.

  • Topography of Prostate Cancer Recurrence After Radiation Therapy: A Detailed Mapping Study of Salvage Radical Prostatectomy Specimens
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-26
    Toshikazu Takeda, Amy L. Tin, Renato B. Corradi, Maha Mamoor, Nicole E. Benfante, Daniel D. Sjoberg, Peter T. Scardino, James A. Eastham, Samson W. Fine, Karim A. Touijer

    In men who do not respond to initial radiation therapy, accurate knowledge of the site of cancer recurrence or persistence is necessary to understand treatment failure. We evaluated the pathologic characteristics of recurrent/persistent prostate cancer with tumor maps from the whole-mount slides of salvage radical prostatectomies performed between 2000 and 2014. Of 216 consecutive patients, detailed tumor maps were available for 77. Sixty-nine patients (90%) were found to have tumor in the apex, of which 46% occurred in the most apical 3 mm. Fifty-three patients (69%) had tumors at a distance of ≤5 mm from the urethra. Five patients had tumor directly involving the urethra, all of whom had urethral invasion at the apex. Seminal vesicle involvement was seen in 32 patients (42%), two of whom had tumor only in the seminal vesicles. Sixty-two patients (81%) had tumors in the distal apex, periurethral area, or seminal vesicles, that is, areas that are not routinely biopsied. Targeting these areas could improve the accuracy of biopsy when cancer recurrence is suspected. Patient summary When recurrence is suspected, clinicians should include biopsy of the distal apex, areas surrounding the urethra, and seminal vesicles. This information will help tailor successful salvage treatments.

  • Improved Recovery of Erectile Function in Younger Men after Radical Prostatectomy: Does it Justify Immediate Surgery in Low-risk Patients?
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-26
    Justin K. Lee, Daniel D. Sjoberg, Mariam Imnadze Miller, Andrew J. Vickers, John P. Mulhall, Behfar Ehdaie

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

  • Antitumour Activity and Safety of Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Plus Prednisone for ≥24 weeks in Europe
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-23
    Johann S. de Bono, Simon Chowdhury, Susan Feyerabend, Tony Elliott, Enrique Grande, Amal Melhem-Bertrandt, Benoit Baron, Mohammad Hirmand, Patrick Werbrouck, Karim Fizazi

    Background Enzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer. Retrospective analyses suggest some cross-resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported. Objective To fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed following abiraterone acetate plus prednisone treatment. Design, setting, and participants Multicentre, single-arm, open-label study, enrolled patients with progressing mCRPC after ≥24 wk of abiraterone acetate plus prednisone treatment. All patients maintained castration therapy during the trial. Prior chemotherapy was allowed but not required. Intervention Patients received enzalutamide 160 mg/d orally. Outcome measurements and statistical analysis The primary endpoint was radiographic progression-free survival. Secondary endpoints were overall survival, prostate-specific antigen (PSA) response, and time-to-PSA progression. Safety data were also assessed. Kaplan-Meier methods were used to descriptively analyse time-to-event endpoints. Results and limitations Overall, 214 patients received enzalutamide treatment, 145 of whom were chemotherapy-naïve. Median radiographic progression-free survival was 8.1 mo (95% confidence interval: 6.1–8.3); median overall survival had not been reached. Unconfirmed PSA response rate was 27% (48 of 181). Median time-to-PSA progression was 5.7 mo (95% confidence interval: 5.6–5.8). The most common treatment-emergent adverse events were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). No seizures were reported. Conclusions Enzalutamide showed antitumour activity in some patients with mCRPC who had previously progressed following ≥24 wk of abiraterone acetate plus prednisone treatment. Patient summary Patients with mCRPC who progressed on previous abiraterone acetate plus prednisone treatment, with or without prior chemotherapy, received enzalutamide. Although cross-resistance between the two agents was observed in a majority of patients, some still benefited from enzalutamide treatment.

  • Active Surveillance Versus Watchful Waiting for Localized Prostate Cancer: A Model to Inform Decisions
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-23
    Stacy Loeb, Qinlian Zhou, Uwe Siebert, Ursula Rochau, Beate Jahn, Nikolai Mühlberger, H. Ballentine Carter, Herbert Lepor, R. Scott Braithwaite

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

  • Urologist Practice Affiliation and Intensity-modulated Radiation Therapy for Prostate Cancer in the Elderly
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-18
    Brent K. Hollenbeck, Samuel R. Kaufman, Phyllis Yan, Lindsey A. Herrel, Tudor Borza, Florian R. Schroeck, Bruce L. Jacobs, Ted A. Skolarus, Vahakn B. Shahinian

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

  • Intravenous Mannitol Versus Placebo During Partial Nephrectomy in Patients with Normal Kidney Function: A Double-blind, Clinically-integrated, Randomized Trial
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-16
    Massimiliano Spaliviero, Nicholas E. Power, Katie S. Murray, Daniel D. Sjoberg, Nicole E. Benfante, Melanie L. Bernstein, James Wren, Paul Russo, Jonathan A. Coleman

    Background Mannitol is currently used as a renal protective agent to mitigate the effects of renal ischemia during nephron-sparing surgery (NSS). This routine practice lacks rigorous methodological study. Objective To assess the effect on renal function outcomes after surgery of mannitol infusion prior to renal ischemia during NSS. Design, setting, participants This prospective, randomized, placebo-controlled, double-blind trial included 199 patients with a preoperative estimated glomerular filtration rate (eGFR) >45 ml/min/1.73m2 scheduled for NSS; the trial was conducted between July 2012 and July 2015. Intervention Patients undergoing NSS were randomized to receive mannitol (12.5 g) or placebo intravenously within 30 min prior to renal vascular clamping. Outcome measurements and statistical analysis The primary outcome was the difference in eGFR (renal function) between the two groups at 6 mo following surgery assessed with an analysis of covariance model using preoperative eGFR, treatment group, and surgical approach as covariates. Results and limitations At baseline, the median age of the patients was 58 yr, and the median eGFR was 88 ml/min/1.73m2. Comparing placebo with mannitol infusion, the adjusted difference of 0.2 eGFR units at 6 mo was not significant (p = 0.9), with the upper bound of the 95% confidence interval (–3.1 to 3.5) excluding a clinically relevant effect of mannitol. Limitations include evaluation of a single mannitol dose and patients all had excellent preoperative renal function. Conclusions Intraoperative 12.5 g mannitol infusion during NSS has no demonstrable clinical benefit when compared with standardized fluid hydration in patients with normal preoperative renal function, and its use in this setting is not warranted. Patient summary In this randomized trial, patients with normal kidney function who received mannitol during surgery to remove part of their kidney had no better kidney function 6 mo after surgery than those who did not receive mannitol. We conclude that this routine practice should be discontinued.

  • AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-14
    Anna Katharina Seitz, Silvia Thoene, Andreas Bietenbeck, Roman Nawroth, Robert Tauber, Mark Thalgott, Sebastian Schmid, Ramona Secci, Margitta Retz, Jürgen E. Gschwend, Jürgen Ruland, Christof Winter, Matthias M. Heck

    Background It has been demonstrated that androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide. Objective To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients. Design, setting, and participants Whole blood samples from a prospective biorepository of 85 mCRPC patients before treatment initiation with abiraterone (n = 56) or enzalutamide (n = 29) were analyzed via droplet digital polymerase chain reaction. Outcome measurements and statistical analysis The association of AR-V7 status with prostate-specific antigen (PSA) response defined by PSA decline ≥50% and with PSA–progression-free survival (PSA-PFS), clinical PFS, and overall survival (OS) was assessed. Results and limitations High AR-V7 expression levels in whole blood were detectable in 18% (15/85) of patients. No patient with high AR-V7 expression achieved a PSA response, and AR-V7 status was an independent predictor of PSA response in multivariable logistic regression analysis (p = 0.03). High AR-V7 expression was associated with shorter PSA-PFS (median 2.4 vs 3.7 mo; p < 0.001), shorter clinical PFS (median 2.7 vs 5.5 mo; p < 0.001), and shorter OS (median 4.0 vs. 13.9 mo; p < 0.001). On multivariable Cox regression analysis, high AR-V7 expression remained an independent predictor of shorter PSA-PFS (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.3–20.7; p < 0.001), shorter clinical PFS (HR 2.3, 95% CI 1.1–4.9; p = 0.02), and shorter OS (HR 3.0, 95% CI 1.4–6.3; p = 0.005). Conclusions Testing of AR-V7 mRNA levels in whole blood is a simple and promising approach to predict poor treatment outcome in mCRPC patients receiving abiraterone or enzalutamide. Patient summary We established a method for determining AR-V7 status in whole blood. This test predicted treatment resistance in patients with metastatic castration-resistant prostate cancer undergoing treatment with abiraterone or enzalutamide. Prospective validation is needed before application to clinical practice.

  • Cost Effectiveness of Nivolumab in Advanced Renal Cell Carcinoma
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-12
    Michal Sarfaty, Moshe Leshno, Noa Gordon, Assaf Moore, Victoria Neiman, Eli Rosenbaum, Daniel A. Goldstein

    Background In recent years, new drugs have been introduced for second-line treatment of advanced renal cell carcinoma (RCC). Nivolumab increases overall survival and is associated with less toxicity compared to everolimus in this setting according to the CheckMate 025 study. However, because of the high cost of nivolumab, there is a need to define its value by considering both efficacy and cost. Objective To estimate the cost effectiveness of nivolumab for second-line treatment of advanced RCC from the US payer perspective. Design, setting, and participants A Markov model was developed to compare the costs and effectiveness of nivolumab with those of everolimus and placebo in second-line treatment of advanced RCC. Health outcomes were measured in life-years (LYs) and quality-adjusted LYs (QALYs). Drug costs were based on 2016 Medicare reimbursement rates. Outcome measurements and statistical analysis Model robustness was assessed in univariable and probabilistic sensitivity analyses. We addressed the issue of the extensive duration of immunotherapy treatment among long-term survivors, which may or may not be approved by payers. Results and limitations The total mean cost per patient was $101 070 for nivolumab and $50 935 for everolimus. Nivolumab generated a gain of 0.24 LYs (0.34 QALYs) compared to everolimus. The incremental cost-effectiveness ratio (ICER) for nivolumab was $146 532/QALY versus everolimus and $226 197/QALY versus placebo. Limiting the maximal treatment duration of nivolumab to 2 yr reduced the ICER to $121 788/QALY versus everolimus. The analysis is limited by data availability and our assumptions. Conclusions Our analysis established that with a willingness-to-pay threshold of $100 000 to $150 000 per QALY, nivolumab is estimated to be cost-effective versus everolimus, but not cost-effective versus placebo. Patient summary We assessed the cost effectiveness of nivolumab in previously treated metastatic kidney cancer. In the USA, it would cost $146 532 to gain one quality-adjusted life-year with nivolumab versus everolimus, or $226 197 versus placebo. Nivolumab is considered cost-effective versus everolimus, but not versus placebo.

  • Variations in the Costs of Radical Cystectomy for Bladder Cancer in the USA
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-10
    Jeffrey J. Leow, Alexander P. Cole, Thomas Seisen, Joaquim Bellmunt, Matthew Mossanen, Mani Menon, Mark A. Preston, Toni K. Choueiri, Adam S. Kibel, Benjamin I. Chung, Maxine Sun, Steven L. Chang, Quoc-Dien Trinh

    Background Radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) has potential for serious complications, prolonged length of stay and readmissions—all of which may increase costs. Although variations in outcomes are well described, less is known about determinants driving variation in costs. Objective To assess surgeon- and hospital-level variations in costs and predictors of high- and low-cost RC. Design, setting, and participants Cohort study of 23 173 patients who underwent RC for BCa in 208 hospitals in the USA from 2003 to 2015 in the Premier Healthcare Database. Outcome measurements and statistical analysis Ninety-day direct hospital costs; multilevel hierarchal linear models were constructed to evaluate contributions of each variable to costs. Results and limitations Mean 90-d direct hospital costs per RC was $39 651 (standard deviation $34 427), of which index hospitalization accounted for 87.8% ($34 803) and postdischarge readmission(s) accounted for 12.2% ($4847). Postoperative complications contributed most to cost variations (84.5%), followed by patient (49.8%; eg, Charlson Comorbidity Index [CCI], 40.5%), surgical (33.2%; eg, year of surgery [25.0%]), and hospital characteristics (8.0%). Patients who suffered minor complications (odds ratio [OR] 2.63, 95% confidence interval [CI]: 2.03–3.40), nonfatal major complications (OR 12.7, 95% CI: 9.63–16.8), and mortality (OR 13.5, 95% CI: 9.35–19.4, all p < 0.001) were significantly associated with high costs. As for low-cost surgery, sicker patients (CCI = 2: OR 0.41, 95% CI: 0.29–0.59; CCI = 1: OR 0.58, 95% CI: 0.46–0.75, both p < 0.001), those who underwent continent diversion (vs incontinent diversion: OR 0.29, 95% CI: 0.16–0.53, p < 0.001), and earlier period of surgery were inversely associated with low costs. Conclusions This study provides insight into the determinants of costs for RC. Postoperative morbidity, patient comorbidities, and year of surgery contributed most to observed variations in costs, while other hospital- and surgical-related characteristics such as volume, use of robot assistance, and type of urinary diversion contribute less to outlier costs. Patient summary Efforts to address high surgical cost must be tailored to specific determinants of high and low costs for each operation. In contrast to robot-assisted radical prostatectomy where surgeon factors predominate, high costs in radical cystectomy were primarily determined by postoperative complication and patient comorbidities.

  • The Risk of Tumour Recurrence in Patients Undergoing Renal Transplantation for End-stage Renal Disease after Previous Treatment for a Urological Cancer: A Systematic Review
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-10
    Romain Boissier, Vital Hevia, Harman Max Bruins, Klemens Budde, Arnaldo Figueiredo, Enrique Lledó-García, Jonathon Olsburgh, Heinz Regele, Claire Fraser Taylor, Rhana Hassan Zakri, Cathy Yuhong Yuan, Alberto Breda

    Context Renal transplantation is the gold standard renal replacement therapy in end-stage renal disease owing to its superior survival and quality of life compared with dialysis. When the potential recipient has a history of cancer, the waiting period before renal transplantation is usually based on the Cincinnati Registry. Objective To systematically review all available evidence on the risk of cancer recurrence in end-stage renal disease patients with a history of urological cancer. Evidence acquisition Medline, Embase, and the Cochrane Library were searched up to March 2017 for all relevant publications reporting oncologic outcomes of urological cancer in patients who subsequently received a transplantation or remained on dialysis. The primary outcome was time to tumour recurrence. Secondary outcomes included cancer-specific and overall survival. Data were narratively synthesised in light of methodological and clinical heterogeneity. The risk of bias of each included study was assessed. Evidence synthesis Thirty-two retrospective studies enrolling 2519 patients (1733 dialysed, 786 renal transplantation) were included. For renal cell carcinomas, the risks of recurrence, cancer-specific, and overall survival were similar between transplantation and dialysis. For prostate cancer, most of the tumours had favourable prognoses consistent with nomograms. Studies dealing with urothelial carcinomas (UCs) mainly included upper urinary tract UC in the context of aristolochic acid nephropathy, for which the risks of synchronous bilateral tumour and recurrence were high. Data on testicular cancer were scarce. Conclusions Immunosuppression after renal transplantation does not affect the outcomes and natural history of low-risk renal cell carcinomas and prostate cancer. Therefore, the waiting time from successful treatment for these cancers to transplantation could be reduced. Except in the particular situation of aristolochic acid nephropathy, more studies are needed to standardise the waiting period after UC owing to the paucity of data. Patient summary Renal transplantation does not appear to increase the risk of recurrence of renal carcinoma or the recurrence of low-risk prostate cancer compared with dialysis. More reliable evidence is required to recommend a standard waiting period especially for urothelial and testicular carcinomas.

  • Prospective Implementation of Enhanced Recovery After Surgery Protocols to Radical Cystectomy
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-08
    Karl H. Pang, Ruth Groves, Suresh Venugopal, Aidan P. Noon, James W.F. Catto

    Background Multimodal enhanced recovery after surgery (ERAS) regimens have improved outcomes from colorectal surgery. Objective We report the application of ERAS to patients undergoing radical cystectomy (RC). Design, setting, and participants Prospective collection of outcomes from consecutive patients undergoing RC at a single institution. Intervention Twenty-six components including prehabilitation exercise, same day admission, carbohydrate fluid loading, targeted intraoperative fluid resuscitation, regional local anaesthesia, cessation of nasogastric tubes, omitting oral bowel preparation, avoiding drain use, early mobilisation, chewing gum use, and audit. Outcome measurements and statistical analysis Primary outcomes were length of stay and readmission rate. Secondary outcomes included intraoperative blood loss, transfusion rates, survival, and histopathological findings. Results and limitations Four hundred and fifty-three consecutive patients underwent RC, including 393 (87%) with ERAS. Length of stay was shorter with ERAS (median [interquartile range]: 8 [6–13] d) than without (18 [13–25], p < 0.001). Patients with ERAS had lower blood loss (ERAS: 600 [383–969] ml vs 1050 [900–1575] ml for non-ERAS, p < 0.001), lower transfusion rates (ERAS: 8.1% vs 25%, chi-square test, p < 0.001), and fewer readmissions (ERAS: 15% vs 25%, chi-square test, p = 0.04) than those without. Histopathological parameters (eg, tumour stage, node count, and margin state) and survival outcomes did not differ with ERAS use (all p > 0.1). Multivariable analysis revealed ERAS use was (p = 0.002) independently associated with length of stay. Conclusions The use of ERAS pathways was associated with lower intraoperative blood loss and faster discharge for patients undergoing RC. These changes did not increase readmission rates or alter oncological outcomes. Patient summary Recovery after major bladder surgery can be improved by using enhanced recovery pathways. Patients managed by these pathways have shorter length of stays, lower blood loss, and lower transfusion rates. Their adoption should be encouraged.

  • Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-07
    Mitchell J. Machiela, Jonathan N. Hofmann, Robert Carreras-Torres, Kevin M. Brown, Mattias Johansson, Zhaoming Wang, Matthieu Foll, Peng Li, Nathaniel Rothman, Sharon A. Savage, Valerie Gaborieau, James D. McKay, Yuanqing Ye, Marc Henrion, Fiona Bruinsma, Susan Jordan, Gianluca Severi, Kristian Hveem, Mark P. Purdue

    Background Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. Objective We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. Design, setting, and participants Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. Outcome measurements and statistical analysis Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. Results and limitations Longer genetically inferred telomere length was associated with an increased risk of RCC (OR = 2.07 per predicted kilobase increase, 95% confidence interval [CI]: = 1.70–2.53, p < 0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2 > 0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR = 1.73, 95% CI = 1.36–2.21, p < 0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N = 5573, OR = 1.93, 95% CI = 1.50–2.49, p < 0.0001), papillary (N = 573, OR = 1.96, 95% CI = 1.01–3.81, p = 0.046), and chromophobe RCC (N = 203, OR = 2.37, 95% CI = 0.78–7.17, p = 0.13). Conclusions Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. Patient summary Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.

  • Impact of Early Salvage Radiation Therapy in Patients with Persistently Elevated or Rising Prostate-specific Antigen After Radical Prostatectomy
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-02
    Nicola Fossati, R. Jeffrey Karnes, Michele Colicchia, Stephen A. Boorjian, Alberto Bossi, Thomas Seisen, Nadia Di Muzio, Cesare Cozzarini, Barbara Noris Chiorda, Claudio Fiorino, Giorgio Gandaglia, Paolo Dell’Oglio, Shahrokh F. Shariat, Gregor Goldner, Steven Joniau, Antonino Battaglia, Karin Haustermans, Gert De Meerleer, Alberto Briganti

    Background Salvage radiation therapy (SRT) is a recommended treatment option for biochemical recurrence after radical prostatectomy (RP). However, its effectiveness may be limited to specific categories of patients. Objective We aimed to identify the optimal candidates for early SRT after RP. Design, setting, and participants The study included 925 node-negative patients treated with SRT after RP at seven institutions. Patients received SRT for either prostate-specific antigen (PSA) rising, or PSA persistence after RP that was defined as PSA level ≥0.1 ng/ml at 1 mo after surgery. All patients received local radiation to the prostate and seminal vesicle bed. Outcome measurements and statistical analysis The primary outcome measured was distant metastasis after SRT. Regression tree analysis was used to develop a risk-stratification tool. Multivariable Cox regression analysis and nonparametric curve fitting methods were used to explore the relationship between PSA level at SRT and the probability of metastasis-free survival at 8 yr. Results and limitations At a median follow-up of 8.0 yr, 130 patients developed distant metastasis. At multivariable analysis, pre-SRT PSA level was significantly associated with distant metastasis (hazard ratio: 1.01, p < 0.0001). However, when patients were stratified into five risk groups using regression tree analysis (area under the curve: 85%), early SRT administration provided better metastasis-free survival in three groups only: (1) low risk: undetectable PSA after RP, Gleason score ≤7, and tumour stage ≥pT3b, (2) intermediate risk: undetectable PSA after RP with Gleason score ≥8, (3) high risk: PSA persistence after RP with Gleason score ≤7. Conclusions We developed an accurate risk stratification tool to facilitate the individualised recommendation for early SRT based on prostate cancer characteristics. Early SRT proved to be beneficial only in selected groups of patients who are more likely to be affected by clinically significant but not yet systemic recurrence at the time of salvage treatment administration. Patient summary In patients affected by prostate cancer recurrence after radical prostatectomy, the early administration of salvage radiation therapy is beneficial only for selected subgroups of patients. In this study, these groups of patients were identified.

  • Racial Disparity in Delivering Definitive Therapy for Intermediate/High-risk Localized Prostate Cancer: The Impact of Facility Features and Socioeconomic Characteristics
    Eur. Urol. (IF 16.265) Pub Date : 2017-08-02
    David F. Friedlander, Quoc-Dien Trinh, Anna Krasnova, Stuart R. Lipsitz, Maxine Sun, Paul L. Nguyen, Adam S. Kibel, Toni K. Choueiri, Joel S. Weissman, Mani Menon, Firas Abdollah

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

  • Determinants of Patient Mobility for Prostate Cancer Surgery: A Population-based Study of Choice and Competition
    Eur. Urol. (IF 16.265) Pub Date : 2017-07-29
    Ajay Aggarwal, Daniel Lewis, Susan C. Charman, Malcolm Mason, Noel Clarke, Richard Sullivan, Jan van der Meulen

    Many countries have introduced policies that enable patients to select a health care provider of their choice with the aim of improving the quality of care. However, there is little information about the drivers or the impact of patient mobility. Using administrative hospital data (n = 19 256) we analysed the mobility of prostate cancer patients who had radical surgery in England between 2010 and 2014. Our analysis, using geographic information systems and multivariable choice modelling, found that 33·5% (n = 6465) of men bypassed their nearest prostate cancer surgical centre. Travel time had a strong impact on where patients moved to but was less of a factor for men who were younger, fitter, and more affluent (p always < 0.001). Men were more likely to move to hospitals that provided robotic prostate cancer surgery (odds ratio: 1.42, p < 0.001) and to hospitals that employed surgeons with a strong media reputation (odds ratio: 2.18, p < 0.001). Patient mobility occurred in the absence of validated measures of the quality of care, instead influenced by the adoption of robotic surgery and the reputation of individual clinicians. National policy based on patient choice and provider competition may have had a negative impact on equality of access, service capacity, and health system efficiency. Patient summary In this study, we assessed the reasons why men would choose to have prostate cancer surgery at a centre other than their nearest. We found that in England men were attracted to centres that carried out robotic surgery and employed surgeons with a national reputation.

  • Quality of Life Outcomes after Primary Treatment for Clinically Localised Prostate Cancer: A Systematic Review
    Eur. Urol. (IF 16.265) Pub Date : 2017-07-27
    Michael Lardas, Matthew Liew, Roderick C. van den Bergh, Maria De Santis, Joaquim Bellmunt, Thomas Van den Broeck, Philip Cornford, Marcus G. Cumberbatch, Nicola Fossati, Tobias Gross, Ann M. Henry, Michel Bolla, Erik Briers, Steven Joniau, Thomas B. Lam, Malcolm D. Mason, Nicolas Mottet, Henk G. van der Poel, Liam Bourke

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

  • Benefits and Harms of Treatment of Asymptomatic Bacteriuria: A Systematic Review and Meta-analysis by the European Association of Urology Urological Infection Guidelines Panel
    Eur. Urol. (IF 16.265) Pub Date : 2017-07-25
    Bela Köves, Tommaso Cai, Rajan Veeratterapillay, Robert Pickard, Thomas Seisen, Thomas B. Lam, Cathy Yuhong Yuan, Franck Bruyere, Florian Wagenlehner, Riccardo Bartoletti, Suzanne E. Geerlings, Adrian Pilatz, Benjamin Pradere, Fabian Hofmann, Gernot Bonkat, Björn Wullt

    People with asymptomatic bacteriuria (ABU) are often unnecessarily treated with antibiotics risking adverse effects and antimicrobial resistance. We performed a systematic review to determine any benefits and harms of treating ABU in particular patient groups. Relevant databases were searched and eligible trials were assessed for risk-of-bias and Grading of Recommendations, Assessment, Development and Education quality. Where possible, a meta-analysis of extracted data was performed or a narrative synthesis of the evidence was presented. After screening 3626 articles, 50 studies involving 7088 patients were included. Overall, quality of evidence ranged from very low to low. There was no evidence of benefit for patients with no risk factors, patients with diabetes mellitus, postmenopausal women, elderly institutionalised patients, patients with renal transplants, or patients prior to joint replacement, and treatment was harmful for patients with recurrent urinary tract infection (UTI). Treatment of ABU resulted in a lower risk of postoperative UTI after transurethral resection surgery. In pregnant women, we found evidence that treatment of ABU decreased risk of symptomatic UTI, low birthweight, and preterm delivery. ABU should be treated prior to transurethral resection surgery. In addition, current evidence also suggests that ABU treatment is required in pregnant women, although the results of a recent trial have challenged this view. Patient summary We reviewed available scientific studies to see if people with bacteria in their urine but without symptoms of urinary tract infection should be treated with antibiotics to eliminate bacteria. For most people, treatment was not beneficial and may be harmful. Antibiotic treatment did appear to benefit women in pregnancy and those about to undergo urological surgery.

  • Emerging Minimally Invasive Treatment Options for Male Lower Urinary Tract Symptoms
    Eur. Urol. (IF 16.265) Pub Date : 2017-07-19
    Giuseppe Magistro, Christopher R. Chapple, Mostafa Elhilali, Peter Gilling, Kevin T. McVary, Claus G. Roehrborn, Christian G. Stief, Henry H. Woo, Christian Gratzke

    Context Lower urinary tract symptoms (LUTS) are one of the most common and troublesome nonmalignant conditions affecting quality of life in aging men. A spectrum of established medical and surgical options is available to provide relief of bothersome LUTS. Both the adverse events of medication and the morbidity with surgical treatment modalities have to be counterbalanced against efficacy. Novel minimally invasive treatment options aim to be effective, ideally to be performed in an ambulatory setting under local anaesthesia and to offer a more favourable safety profile than existing reference techniques. Objective A comprehensive, narrative review of novel minimally invasive treatment modalities for the management of male LUTS due to benign prostatic enlargement is presented. Evidence acquisition Medline, PubMed, Cochrane database, and Embase were screened for randomised controlled trials (RCTs), clinical trials, and reviews on novel minimally invasive treatment options for male LUTS due to benign prostatic enlargement. Evidence synthesis With regard to newly devised intraprostatic injectables (botulinum neurotoxin A, NX1207, PRX302), PRX302 is currently the only substance that was superior to placebo in a phase 3 RCT providing proof of efficacy and safety. The prostatic urethral lift technique has been evaluated in several phase 3 trials showing rapid and durable relief of LUTS without compromising sexual function in carefully selected patients without a prominent median lobe. The first clinical experience of the temporary implantable nitinol device demonstrated that implantation of this novel device is a safe procedure, easy, and fast to perform. Further studies are required to evaluate efficacy, durability, and to define appropriate patient selection. New ablative approaches like the image guided robotic waterjet ablation (AquaBeam) or procedures based on convective water vapour energy (Rezūm) are in the early stages of development. Prostatic artery embolization performed by interventional radiologists at specialised centres shows a high technical success rate in the treatment of bothersome LUTS. However, a substantial clinical failure rate and a particular spectrum of complications not commonly seen after urologic interventions do occur and need to be critically evaluated. Conclusions Initial promising clinical results on novel minimally invasive treatment options indicate efficacy comparable to standard techniques, often associated with a more favourable safety profile, in particular with preservation of sexual function. Many of these techniques are in their infancy and based on experience of new developments in the past. Further RCTs are required to evaluate efficacy, safety, and durability of novel techniques with long-term follow-up and careful evaluation of the selection criteria, which have been applied in clinical trials. The prostatic urethral lift is the only procedure with Level 1 evidence data and that can therefore be recommended for treatment of male LUTS in clinical practice for selected patients. Patient summary Minimally invasive treatment options have been developed to provide relief of lower urinary tract symptoms comparable to standard surgical techniques with a more favourable safety profile. However, long-term clinical evaluation is still needed for most of these innovations before they can be recommended to be an effective replacement for standard surgical treatment.

  • Recommendations for the Management of Rare Kidney Cancers
    Eur. Urol. (IF 16.265) Pub Date : 2017-07-16
    Rachel H. Giles, Toni K. Choueiri, Daniel Y. Heng, Laurence Albiges, James J. Hsieh, W. Marston Linehan, Sumanta Pal, Deborah Maskens, Bill Paseman, Eric Jonasch, Gabriel Malouf, Ana M. Molina, Lisa Pickering, Brian Shuch, Sandy Srinivas, Ramaprasad Srinivasan, Nizar M. Tannir, Axel Bex

    Context The European Association of Urology Renal Cell Carcinoma Guideline Panel recently conducted a systematic review of treatment options for patients with advanced non–clear-cell renal cell carcinomas (RCCs), which showed a substantial lack of evidence for management recommendations. Objective To improve the outcomes of patients with rare kidney cancers (RKCs), we performed a subsequent unstructured review to determine current treatment strategies and druggable pathways, involving key stakeholders with a global perspective to generate recommendations. Evidence acquisition Based on the systematic review, literature was queried in Pubmed, Medline, and abstracts from proceedings of European Society for Medical Oncology and American Society of Clinical Oncology, in addition to consulting key opinion leaders and stakeholders. A conventional narrative review strategy was adopted to summarize the data. Evidence synthesis The systematic review showed an absence of evidence for treating RKCs, with data only supporting sunitinib or MET inhibitors for some specific subtypes. However, a growing body of evidence implicates druggable pathways in specific RKC subtypes. To test hypotheses, the small patient numbers in each subtype require coordinated multicenter efforts. Many RKC patients are currently excluded from studies or are not analyzed using subtype-specific parameters, despite their unmet medical need. Conclusions We recognize the need for additional multicenter studies and subtype-specific analyses; however, we present management recommendations based on the data available. Web-based tools facilitating subtype-specific global registries and shared translational research resources will help generate sufficient data to formulate evidence-based recommendations for guidelines. Patient summary Patients confronted with rare kidney cancers are often treated the same way as clear-cell renal cell carcinoma patients, despite little evidence from randomized trials. Molecular characterization of tumors to stratify patients may improve outcomes. Availability of potential agents and trials remain a problem. Collaboration among medical centers is important to pool scarce data.

  • A Systematic Review and Framework for the Use of Hormone Therapy with Salvage Radiation Therapy for Recurrent Prostate Cancer
    Eur. Urol. (IF 16.265) Pub Date : 2017-07-14
    Daniel E. Spratt, Robert T. Dess, Zachary S. Zumsteg, Daniel W. Lin, Phuoc T. Tran, Todd M. Morgan, Emmanuel S. Antonarakis, Paul L. Nguyen, Charles J. Ryan, Howard M. Sandler, Matthew R. Cooperberg, Edwin Posadas, Felix Y. Feng

    Context Salvage radiotherapy (SRT) is a standard of care for men who recur postprostatectomy, and recent randomized trials have assessed the benefit and toxicity of adding hormone therapy (HT) to SRT with differing results. Objective To perform a systematic review of randomized phase III trials of the use of SRT ± HT and generate a framework for the use of HT with SRT. Evidence acquisition Systematic literature searches were conducted on February 15, 2017 in three databases (MEDLINE [via PubMed], EMBASE, and ClinicalTrials.gov) for human-only randomized clinical trials from January 30, 1990, through January 30, 2017. Only two randomized trials met all inclusion criteria. Evidence synthesis Overall survival benefits from HT were found in one trial, which was limited to when follow-up extended to ≥10 yr, pre-SRT prostate-specific antigen (PSA) ≥0.7 ng/ml, or when higher Gleason grade or positive margins were present. Both trials demonstrated a benefit from HT in men with higher pre-SRT PSAs. Three prognostic factors appeared to discriminate improvements in meaningful clinical endpoints (eg, distant metastasis or survival): pre-SRT PSA, Gleason score, and margin status. Two years of bicalutamide monotherapy resulted in higher rates of gynecomastia with a trend for worse survival when given in favorable risk patients, and 6 mo of luteinizing hormone–releasing hormone agonist therapy resulted in higher rates of hot flashes and long-term hypertension. Conclusions Similar to the selective use of HT with radiotherapy in localized prostate cancer, not all patients appear to derive a meaningful benefit from HT with SRT. Patient, tumor, and treatment factors must be considered when recommending the use of HT with SRT. Knowledge gaps exist in the level 1 data regarding the optimal duration and type of HT, as well as the ability to use predictive biomarkers to personalize the use of HT with SRT. Important clinical trials (RADICALS and NRG GU-006) are aimed to answer these questions. Patient summary In this report, we performed a systematic review of the literature to determine the benefit and harm of adding hormone therapy to salvage radiotherapy (SRT) for recurrent prostate cancer. We found that the benefit of hormone therapy varied by important prognostic factors, including pre-SRT prostate-specific antigen, Gleason grade, and surgical margin status. Our group then developed a framework on how best to utilize hormone therapy with SRT.

  • Recreational Physical Activity in Relation to Prostate Cancer–specific Mortality Among Men with Nonmetastatic Prostate Cancer
    Eur. Urol. (IF 16.265) Pub Date : 2017-07-12
    Ying Wang, Eric J. Jacobs, Susan M. Gapstur, Maret L. Maliniak, Ted Gansler, Marjorie L. McCullough, Victoria L. Stevens, Alpa V. Patel

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

  • Gonadotropin-releasing Hormone Agonists, Orchiectomy, and Risk of Cardiovascular Disease: Semi-ecologic, Nationwide, Population-based Study
    Eur. Urol. (IF 16.265) Pub Date : 2017-07-12
    Frederik Birkebæk Thomsen, Fredrik Sandin, Hans Garmo, Ingela Franck Lissbrant, Göran Ahlgren, Mieke Van Hemelrijck, Jan Adolfsson, David Robinson, Pär Stattin

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

  • Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial
    Eur. Urol. (IF 16.265) Pub Date : 2017-07-11
    Christopher C. Parker, Robert E. Coleman, Oliver Sartor, Nicholas J. Vogelzang, David Bottomley, Daniel Heinrich, Svein I. Helle, Joe M. O'Sullivan, Sophie D. Fosså, Aleš Chodacki, Paweł Wiechno, John Logue, Mihalj Seke, Anders Widmark, Dag Clement Johannessen, Peter Hoskin, Nicholas D. James, Arne Solberg, Sten Nilsson

    Background In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment. Objective To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection. Design, setting, and participants Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr. Outcome measurements and statistical analysis All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs were collected. Additional long-term safety was assessed by development of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and secondary malignancies. Data analysis used descriptive statistics. Results and limitations During treatment to 12 wk following the last injection, 564/600 (94%) radium-223 and 292/301 (97%) placebo patients had treatment-emergent AEs (TEAEs). Myelosuppression incidence was low. Grade 3/4 hematologic TEAEs in radium-223 and placebo groups were anemia (13% vs 13%), neutropenia (2% vs 1%), and thrombocytopenia (7% vs 2%). Ninety-eight of 600 (16%) radium-223 and 68/301 (23%) placebo patients experienced grade 5 TEAEs. Long-term follow-up showed no AML, MDS, or new primary bone cancer; secondary non–treatment-related malignancies occurred in four radium-223 and three placebo patients. One radium-223 patient had aplastic anemia 16 mo after the last injection. No other cases were observed. Limitations include short (3-yr) follow-up. Conclusions Final long-term safety ALSYMPCA analysis shows that radium-223 remained well tolerated, with low myelosuppression incidence and no new safety concerns. Patient summary Updated Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial findings show that radium-223 remained well tolerated during treatment and up to 3 yr after each patient's first injection.

  • Value of an Immediate Intravesical Instillation of Mitomycin C in Patients with Non–muscle-invasive Bladder Cancer: A Prospective Multicentre Randomised Study in 2243 patients
    Eur. Urol. (IF 16.265) Pub Date : 2017-07-10
    Judith Bosschieter, Jakko A. Nieuwenhuijzen, Tessa van Ginkel, André N. Vis, Birgit Witte, Don Newling, Goedele M.A. Beckers, R. Jeroen A. van Moorselaar

    Background The efficacy of an immediate single chemotherapy instillation after transurethral resection of a bladder tumour (TURBT) in patients with non–muscle-invasive bladder cancer (NMIBC) remains a topic of debate. Evidence is even more scarce when an immediate instillation is followed by adjuvant instillations. Objective To compare the effect of a mitomycin C (MMC) instillation within 24 h to an instillation 2 wk after TURBT in patients with NMIBC with or without adjuvant instillations. Design, Setting, and participants Between 1998 and 2003, 2844 NMIBC patients were randomised for immediate versus delayed MMC instillation after TURBT. Patients were categorised in low-risk (LOR), intermediate-risk (IMR), and high-risk (HIR) groups. Total numbers of instillations in these groups were 1, 9, and 15, respectively. Outcome measurements and statistical analysis Primary end point was 3-yr recurrence risk for the IMR and HIR groups and 5-yr risk for the LOR group. Secondary outcomes were time to recurrence and incidence of adverse events. Analyses were performed with the log-rank test, Cox-regression, and χ2 test in SPSS. Results and limitations A total of 2243 patients were eligible on an intention-to-treat basis. Recurrence risks were 43% and 46% in the LOR group (5-yr follow-up, p = 0.11), 20% and 32% in the IMR group (3-yr follow-up, p = 0.037), and 28% and 35% in the HIR group (3-yr follow-up, p = 0.007), for an immediate and a delayed instillation, respectively. For all patients, the recurrence risk was 27% (95% confidence interval [CI], 24–30) in the immediate and 36% (95% CI, 33–39) in the delayed instillation group (p < 0.001) with a 27% reduction in relative recurrence risk (hazard ratio: 0.73, 95% CI, 0.63–0.85, p < 0.001). The incidence of adverse events did not differ significantly between treatment groups (immediate instillation 25%, delayed instillation 22%, p = 0.08). The risk groups in our study differ slightly from the current guidelines, which is a limitation of our study. Conclusions An immediate, single instillation after TURBT reduces the recurrence risk in NMIBC patients, independent of the number of adjuvant installations. Patient summary A single instillation of chemotherapy after the resection of non–muscle-invasive bladder cancer reduces the recurrence risk, even if patients are treated with an adjuvant schedule of instillations.

  • Brachytherapy Boost Utilization and Survival in Unfavorable-risk Prostate Cancer
    Eur. Urol. (IF 16.265) Pub Date : 2017-07-05
    Skyler B. Johnson, Nataniel H. Lester-Coll, Jacqueline R. Kelly, Benjamin H. Kann, James B. Yu, Sameer K. Nath

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

  • Contemporary Treatment Patterns and Outcomes for Clinical Stage IS Testicular Cancer
    Eur. Urol. (IF 16.265) Pub Date : 2017-07-04
    Sophia C. Kamran, Thomas Seisen, Sarah C. Markt, Mark A. Preston, Quoc-Dien Trinh, Lindsay A. Frazier, Toni K. Choueiri, Neil E. Martin, Paul L. Nguyen, Clair J. Beard

    Background Controversy exists regarding the optimal management strategy for clinical stage IS seminomatous (SGCT) and nonseminomatous germ cell tumors (NSGCT) of the testis. Objective To assess contemporary treatment patterns and outcomes for clinical stage IS testicular cancer. Design, setting, and participants Using the National Cancer Data Base (2004–2012), we identified 1362 patients with clinical stage IS SGCT and NSGCT of the testis, treated with either adjuvant treatment (AT) or observation. Outcome measures and statistical analysis We calculated the annual percent change (APC) to assess treatment trends. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and Cox regression analyses were used to compare overall survival (OS) between AT and observation groups. Analyses were stratified by histologic type. Results and limitations Overall, there were 581 (43%) and 781 (57%) men with SGCT and NSGCT, respectively. Among men with SGCT, the use of AT decreased over the study period (APC = –2.7, 95% confidence interval [CI]: –4.4, –1.1, p = 0.001). The 5-yr IPTW-adjusted rates of OS were 99% and 97% in the AT and observation groups, respectively (hazard ratio = 0.36, 95% CI: 0.12, 1.14, p = 0.08). Among men with NSGCT, the use of AT remained stable over the study period (APC = +0.8, 95% CI: –0.7, +2.2, p = 0.29). The 5-yr IPTW-adjusted rates of OS were 97% and 95% in the AT and observation groups, respectively (HR = 0.66, 95% CI: 0.27, 1.61, p = 0.36). Limitations include the lack of full treatment details and cancer-specific survival information. Conclusions Trends in the use of AT significantly decreased over time for SCGT, while it remained stable for NSGCT. Nonetheless, we report 5-yr OS rates of ≥95% for both histologies without any significant benefit with the use of AT. Further studies are warranted to confirm these findings. Patient summary We evaluated treatment trends and outcomes for stage IS testicular cancer. We found that treatment changed over time for seminoma and remained stable for nonseminoma; there was no significant survival benefit in the use of adjuvant treatment versus observation for both seminomatous and nonseminomatous germ cell tumors.

  • Medical Treatment of Nocturia in Men with Lower Urinary Tract Symptoms: Systematic Review by the European Association of Urology Guidelines Panel for Male Lower Urinary Tract Symptoms
    Eur. Urol. (IF 16.265) Pub Date : 2017-06-27
    Vasileios I. Sakalis, Markos Karavitakis, Dina Bedretdinova, Thorsten Bach, J.L.H. Ruud Bosch, Mauro Gacci, Christian Gratzke, Thomas R. Herrmann, Stephan Madersbacher, Charalampos Mamoulakis, Kari A.O. Tikkinen, Stavros Gravas, Marcus J. Drake

    Context The treatment of nocturia is a key challenge due to the multi-factorial pathophysiology of the symptom and the disparate outcome measures used in research. Objective To assess and compare available therapy options for nocturia, in terms of symptom severity and quality of life. Evidence acquisition Medical databases (Embase, Medline, Cochrane Systematic Reviews, Cochrane Central) were searched with no date restriction. Comparative studies were included which studied adult men with nocturia as the primary presentation and lower urinary tract symptoms including nocturia or nocturnal polyuria. Outcomes were symptom severity, quality of life, and harms. Evidence synthesis We identified 44 articles. Antidiuretic therapy using dose titration was more effective than placebo in relation to nocturnal voiding frequency and duration of undisturbed sleep; baseline serum sodium is a key selection criterion. Screening for hyponatremia (< 130 mmol/l) must be undertaken at baseline, after initiation or dose titration, and during treatment. Medications to treat lower urinary tract dysfunction (α-1 adrenergic antagonists, 5-α reductase inhibitors, phosphodiesterase type 5inhibitor, antimuscarinics, beta-3 agonist, and phytotherapy) were generally not significantly better than placebo in short-term use. Benefits with combination therapies were not consistently observed. Other medications (diuretics, agents to promote sleep, nonsteroidal anti-inflammatories) were sometimes associated with response or quality of life improvement. The recommendations of the Guideline Panel are presented. Conclusions Issues of trial design make therapy of nocturia a challenging topic. The range of contributory factors relevant in nocturia makes it desirable to identify predictors of response to guide therapy. Consistent responses were reported for titrated antidiuretic therapy. For other therapies, responses were less certain, and potentially of limited clinical benefit. Patient summary This review provides an overview of the current drug treatments of nocturia, which is the need to wake at night to pass urine. The symptom can be caused by several different medical conditions, and measuring its severity and impact varies in separate research studies. No single treatment deals with the symptom in all contexts, and careful assessment is essential to make suitable treatment selection.

  • Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017
    Eur. Urol. (IF 16.265) Pub Date : 2017-06-24
    Silke Gillessen, Gerhardt Attard, Tomasz M. Beer, Himisha Beltran, Alberto Bossi, Rob Bristow, Brett Carver, Daniel Castellano, Byung Ha Chung, Noel Clarke, Gedske Daugaard, Ian D. Davis, Johann de Bono, Rodolfo Borges dos Reis, Charles G. Drake, Ros Eeles, Eleni Efstathiou, Christopher P. Evans, Aurelius Omlin

    Background In advanced prostate cancer (APC), successful drug development as well as advances in imaging and molecular characterisation have resulted in multiple areas where there is lack of evidence or low level of evidence. The Advanced Prostate Cancer Consensus Conference (APCCC) 2017 addressed some of these topics. Objective To present the report of APCCC 2017. Design, setting, and participants Ten important areas of controversy in APC management were identified: high-risk localised and locally advanced prostate cancer; “oligometastatic” prostate cancer; castration-naïve and castration-resistant prostate cancer; the role of imaging in APC; osteoclast-targeted therapy; molecular characterisation of blood and tissue; genetic counselling/testing; side effects of systemic treatment(s); global access to prostate cancer drugs. A panel of 60 international prostate cancer experts developed the program and the consensus questions. Outcome measurements and statistical analysis The panel voted publicly but anonymously on 150 predefined questions, which have been developed following a modified Delphi process. Results and limitations Voting is based on panellist opinion, and thus is not based on a standard literature review or meta-analysis. The outcomes of the voting had varying degrees of support, as reflected in the wording of this article, as well as in the detailed voting results recorded in Supplementary data. Conclusions The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available, including disease extent and location, prior therapies regardless of type, host factors including comorbidities, as well as patient preferences, current and emerging evidence, and logistical and economic constraints. Inclusion of men with APC in clinical trials should be strongly encouraged. Importantly, APCCC 2017 again identified important areas in need of trials specifically designed to address them. Patient summary The second Advanced Prostate Cancer Consensus Conference APCCC 2017 did provide a forum for discussion and debates on current treatment options for men with advanced prostate cancer. The aim of the conference is to bring the expertise of world experts to care givers around the world who see less patients with prostate cancer. The conference concluded with a discussion and voting of the expert panel on predefined consensus questions, targeting areas of primary clinical relevance. The results of these expert opinion votes are embedded in the clinical context of current treatment of men with advanced prostate cancer and provide a practical guide to clinicians to assist in the discussions with men with prostate cancer as part of a shared and multidisciplinary decision-making process.

  • Characteristics of Prostate Cancer Found at Fifth Screening in the European Randomized Study of Screening for Prostate Cancer Rotterdam: Can We Selectively Detect High-grade Prostate Cancer with Upfront Multivariable Risk Stratification and Magnetic Resonance Imaging?
    Eur. Urol. (IF 16.265) Pub Date : 2017-06-21
    Arnout R. Alberts, Ivo G. Schoots, Leonard P. Bokhorst, Frank-Jan H. Drost, Geert J. van Leenders, Gabriel P. Krestin, Roy S. Dwarkasing, Jelle O. Barentsz, Fritz H. Schröder, Chris H. Bangma, Monique J. Roobol

    Background The harm of screening (unnecessary biopsies and overdiagnosis) generally outweighs the benefit of reducing prostate cancer (PCa) mortality in men aged ≥70 yr. Patient selection for biopsy using risk stratification and magnetic resonance imaging (MRI) may improve this benefit-to-harm ratio. Objective To assess the potential of a risk-based strategy including MRI to selectively identify men aged ≥70 yr with high-grade PCa. Design, setting, and participants Three hundred and thirty-seven men with prostate-specific antigen ≥3.0 ng/ml at a fifth screening (71–75 yr) in the European Randomized study of Screening for Prostate Cancer Rotterdam were biopsied. One hundred and seventy-nine men received six-core transrectal ultrasound biopsy (TRUS-Bx), while 158 men received MRI, 12-core TRUS-Bx, and fusion TBx in case of Prostate Imaging Reporting and Data System ≥3 lesions. Outcome measurements and statistical analysis The primary outcome was the overall, low-grade (Gleason Score 3 + 3) and high-grade (Gleason Score ≥ 3 + 4) PCa rate. Secondary outcome was the low- and high-grade PCa rate detected by six-core TRUS-Bx, 12-core TRUS-Bx, and MRI ± TBx. Tertiary outcome was the reduction of biopsies and low-grade PCa detection by upfront risk stratification with the Rotterdam Prostate Cancer Risk Calculator 4. Results and limitations Fifty-five percent of men were previously biopsied. The overall, low-grade, and high-grade PCa rates in biopsy naïve men were 48%, 27%, and 22%, respectively. In previously biopsied men these PCa rates were 25%, 20%, and 5%. Sextant TRUS-Bx, 12-core TRUS-Bx, and MRI ± TBx had a similar high-grade PCa rate (11%, 12%, and 11%) but a significantly different low-grade PCa rate (17%, 28%, and 7%). Rotterdam Prostate Cancer Risk Calculator 4-based stratification combined with 12-core TRUS-Bx ± MRI-TBx would have avoided 65% of biopsies and 68% of low-grade PCa while detecting an equal percentage of high-grade PCa (83%) compared with a TRUS-Bx all men approach (79%). Conclusions After four repeated screens and ≥1 previous biopsies in half of men, a significant proportion of men aged ≥70 yr still harbor high-grade PCa. Upfront risk stratification and the combination of MRI and TRUS-Bx would have avoided two-thirds of biopsies and low-grade PCa diagnoses in our cohort, while maintaining the high-grade PCa detection of a TRUS-Bx all men approach. Further studies are needed to verify these results. Patient summary Prostate cancer screening reduces mortality but is accompanied by unnecessary biopsies and overdiagnosis of nonaggressive tumors, especially in repeatedly screened elderly men. To tackle these drawbacks screening should consist of an upfront risk-assessment followed by magnetic resonance imaging and transrectal ultrasound-guided biopsy.

  • Impact of Postoperative Radiotherapy in Men with Persistently Elevated Prostate-specific Antigen After Radical Prostatectomy for Prostate Cancer: A Long-term Survival Analysis
    Eur. Urol. (IF 16.265) Pub Date : 2017-06-13
    Giorgio Gandaglia, Stephen A. Boorjian, William P. Parker, Emanuele Zaffuto, Nicola Fossati, Marco Bandini, Paolo Dell’Oglio, Nazareno Suardi, Francesco Montorsi, R. Jeffrey Karnes, Alberto Briganti

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

  • Robot-assisted Laparoscopic Implantation of Brachytherapy Catheters in Bladder Cancer
    Eur. Urol. (IF 16.265) Pub Date : 2017-06-12
    Judith Bosschieter, André N. Vis, Henk G. van der Poel, Luc M. Moonen, Simon Horenblas, Bas W.G. van Rhijn, Bradley R. Pieters, Jakko A. Nieuwenhuijzen, Kees Hendricksen

    Background Robot-assisted laparoscopic (RAL) implantation of brachytherapy catheters (BTCs) can be a minimally invasive alternative to open retropubic implantation. Descriptions of the surgical technique and outcomes are sparse. Objective To describe our technique and perioperative outcomes for RAL BTC implantation in urothelial carcinoma (UC) and urachal carcinoma (UraC). Design, setting and participants Between June 2011 and May 2016, 26 patients with cN0M0 solitary T1G3 or T2G1–3 UC of ≤5 cm or cN0M0 UraC were scheduled for external beam radiotherapy (20 × 2 Gy), RAL BTC implantation, and pulsed-dose (29 × 1.04 Gy) or high-dose rate brachytherapy (10 × 2.50 Gy). Median follow-up was 12 mo (interquartile range 4–20). Surgical procedure RAL BTC implantation with or without pelvic lymph node dissection and/or partial cystectomy. Measurements and statistical analysis Perioperative data, complications, disease-free-survival (DFS), local recurrence-free survival (LRFS), and cystectomy-free survival (CFS) were evaluated as well as the feasibility of the technique. Results and limitations BTC implantation was successful in 92% of the patients. Median hospitalisation was 5 d (interquartile range 4–7) and blood loss <50 ml in all cases. DFS was 74% at 1 yr and 63% at 2 yr. LRFS was 80% at 1 and 2 yr, and CFS was 87% at 1 and 2 yr. Early (≤30 d) high-grade complications (Clavien-Dindo ≥3) occurred in 8% of the patients. The study is limited by the small sample size and short follow-up time. Conclusions RAL BTC implantation is technically feasible and could serve as safe, minimally invasive alternative to open surgery in selected patients. The results of this study should be confirmed in larger studies. Patient summary Brachytherapy catheter (BTC) implantation is traditionally carried out via open retropubic surgery. We describe robot-assisted laparoscopic BTC implantation as a minimally invasive alternative. Perioperative outcomes are described and confirm the safety and feasibility of this procedure.

  • Survival and Complications Following Surgery and Radiation for Localized Prostate Cancer: An International Collaborative Review
    Eur. Urol. (IF 16.265) Pub Date : 2017-06-11
    Christopher J.D. Wallis, Adam Glaser, Jim C. Hu, Hartwig Huland, Nathan Lawrentschuk, Daniel Moon, Declan G. Murphy, Paul L. Nguyen, Matthew J. Resnick, Robert K. Nam

    Background Evaluation of treatment options for localized prostate cancer (PCa) remains among the highest priorities for comparative effectiveness research. Surgery and radiotherapy (RT) are the two interventions most commonly used. Objective To provide a critical narrative review of evidence of the comparative effectiveness and harms of surgery and RT in the treatment of localized PCa. Evidence acquisition A collaborative critical narrative review of the literature was conducted. Evidence synthesis Evidence to clearly guide treatment choice in PCa remains insufficient. Randomized trials are underpowered for clinically meaningful endpoints and have demonstrated no difference in overall or PCa-specific survival. Observational studies have consistently demonstrated an absolute survival benefit for men treated with radical prostatectomy, but are limited by selection bias and residual confounding errors. Surgery and RT are associated with comparable health-related quality of life following treatment in three randomized trials. Randomized data regarding urinary, erectile, and bowel function show few long-term (>5 yr) differences, although short-term continence and erectile function were worse following surgery and short-term urinary bother and bowel function were worse following RT. There has been recent recognition of other complications that may significantly affect the life trajectory of those undergoing PCa treatment. Of these, hospitalization, the need for urologic, rectoanal, and other major surgical procedures, and secondary cancers are more common among men treated with RT. Androgen deprivation therapy, frequently co-administered with RT, may additionally contribute to treatment-related morbidity. Technological innovations in surgery and RT have shown inconsistent oncologic and functional benefits. Conclusions Owing to underpowered randomized control studies and the selection biases inherent in observational studies, the question of which treatment provides better PCa control cannot be definitively answered now or in the near future. Complications following PCa treatment are relatively common regardless of treatment approach. These include the commonly identified issues of urinary incontinence and erectile dysfunction, and others including hospitalization and invasive procedures to manage complications and secondary malignancies. Population-based outcome studies, rather than clinical trial data, will be necessary for a comprehensive understanding of the relative benefits and risks of each therapeutic approach. Patient summary Surgery and radiotherapy are the most common interventions for men diagnosed with prostate cancer. Comparisons of survival after these treatments are limited by various flaws in the relevant studies. Complications are common regardless of the treatment approach.

  • Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma
    Eur. Urol. (IF 16.265) Pub Date : 2017-06-07
    Tyler J. Moss, Yuan Qi, Liu Xi, Bo Peng, Tae-Beom Kim, Nader E. Ezzedine, Maribel E. Mosqueda, Charles C. Guo, Bogdan A. Czerniak, Michael Ittmann, David A. Wheeler, Seth P. Lerner, Surena F. Matin

    Background Upper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer. Objective To characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses. Design, setting, and participants We collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis. Outcome measurements and statistical analysis Adjusting for batch effects, consensus mutation calls from independent pipelines identified DNA mutations, gene expression clusters using unsupervised consensus hierarchical clustering (UCHC), and protein expression levels that were correlated with relevant clinical variables, The Cancer Genome Atlas, and other published data. Results and limitations WES identified mutations in FGFR3 (74.1%; 92% low-grade, 60% high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). APOBEC and CpG were the most common mutational signatures. UCHC of RNAseq data segregated samples into four molecular subtypes with the following characteristics. Cluster 1: no PIK3CA mutations, nonsmokers, high-grade

  • Characterization of Clinical Cases of Advanced Papillary Renal Cell Carcinoma via Comprehensive Genomic Profiling
    Eur. Urol. (IF 16.265) Pub Date : 2017-06-04
    Sumanta K. Pal, Siraj M. Ali, Evgeny Yakirevich, Daniel M. Geynisman, Jose A. Karam, Julia A. Elvin, Garrett M. Frampton, Xuan Huang, Douglas I. Lin, Mark Rosenzweig, Doron Lipson, Philip J. Stephens, Jeffrey S. Ross, Vincent A. Miller, Neeraj Agarwal, Brian Shuch, Toni K. Choueiri, Jon H. Chung

    Background Papillary renal cell carcinoma (PRCC) is a rare subset of RCC. The Cancer Genome Atlas (TCGA) data largely reflect localized disease, and there are limited data for advanced PRCC. Objective To characterize the frequency of genomic alterations (GAs) in patients with advanced PRCC for whom comprehensive genomic profiling (CGP) was performed in the context of routine clinical care. Design, setting, and participants Formalin-fixed, paraffin-embedded tissue was obtained for 169 consecutive patients with confirmed PRCC. DNA was extracted and comprehensive genomic profiling was performed in a certified central laboratory. Measurements Hybrid-capture, adaptor ligation-based libraries of up to 315 genes were sequenced to a median coverage of 648×. All classes of GAs were identified, including substitutions, insertions/deletions, copy number alterations, and rearrangements. Results and limitations From 169 patients, either primary tumor tissue (102 patients, 60%) or metastatic tissue (67 patients, 40%) was collected. In patients with type 1 PRCC, commonly altered genes were MET (33%; 8 activating mutations, 5 amplifications at > 6 copies), TERT (30%), CDKN2A/B (13%), and EGFR (8%). In patients with type 2 PRCC, commonly altered genes were CDKN2A/B (18%), TERT (18%), NF2 (13%), and FH (13%); MET GAs (5 mutations, 3 amplifications) were observed in 7% of type 2 cases. Notable differences from TCGA data include higher frequencies of MET, NF2, and CDKN2A/B GAs, association of alterations in SWI/SNF complex genes with type 2 PRCC, and observation of frequent CDKN2A/B alterations in both type 1 and type 2 disease. Conclusions Both the current study and the TCGA experience represent similarly sized cohorts of patients with PRCC. Key differences in GA frequency probably underscore the marked difference in stage distribution between these data sets. These results may inform planned precision medicine trials for metastatic PRCC. Patient summary Papillary renal cell carcinoma (PRCC) is a rare subtype of kidney cancer, and understanding of the biology of advanced PRCC is limited. This report highlights some of the unique biologic features of PRCC that may inform on future use of targeted therapies for the treatment of metastatic disease.

  • Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets
    Eur. Urol. (IF 16.265) Pub Date : 2017-06-03
    Eugene J. Pietzak, Aditya Bagrodia, Eugene K. Cha, Esther N. Drill, Gopa Iyer, Sumit Isharwal, Irina Ostrovnaya, Priscilla Baez, Qiang Li, Michael F. Berger, Ahmet Zehir, Nikolaus Schultz, Jonathan E. Rosenberg, Dean F. Bajorin, Guido Dalbagni, Hikmat Al-Ahmadie, David B. Solit, Bernard H. Bochner

    Background Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies. Objective To identify genetic alterations with potential clinical implications in NMIBC. Design, setting, and participants Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. Outcome measurements and statistical analysis Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guérin (BCG) were estimated using Kaplan-Meier and Cox regression analyses. Results and limitations TERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes (p < 0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio = 3.14, 95% confidence interval: 1.51–6.51, p = 0.002). Conclusions Next-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation. Patient summary Analysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests.

  • Understanding and Improving Recruitment to Randomised Controlled Trials: Qualitative Research Approaches
    Eur. Urol. (IF 16.265) Pub Date : 2017-06-01
    Daisy Elliott, Samantha Husbands, Freddie C. Hamdy, Lars Holmberg, Jenny L. Donovan

    Context The importance of evidence from randomised trials is now widely recognised, although recruitment is often difficult. Qualitative research has shown promise in identifying the key barriers to recruitment, and interventions have been developed to reduce organisational difficulties and support clinicians undertaking recruitment. Objective This article provides an introduction to qualitative research techniques and explains how this approach can be used to understand—and subsequently improve—recruitment and informed consent within a range of clinical trials. Evidence acquisition A literature search was performed using Medline, Embase, and CINAHL. All studies with qualitative research methods that focused on the recruitment activity of clinicians were included in the review. Evidence synthesis The majority of studies reported that organisational difficulties and lack of time for clinical staff were key barriers to recruitment. However, a synthesis of qualitative studies highlighted the intellectual and emotional challenges that arise when combining research with clinical roles, particularly in relation to equipoise and patient eligibility. To support recruiters to become more comfortable with the design and principles of randomised controlled trials, interventions have been developed, including the QuinteT Recruitment Intervention, which comprises in-depth investigation of recruitment obstacles in real time, followed by implementation of tailored strategies to address these challenges as the trial proceeds. Conclusions Qualitative research can provide important insights into the complexities of recruitment to trials and inform the development of interventions, and provide support and training initiatives as required. Investigators should consider implementing such methods in trials expected to be challenging or recruiting below target. Patient summary Qualitative research is a term used to describe a range of methods that can be implemented to understand participants’ perspectives and behaviours. Data are gathered from interviews, focus groups, or observations. In this review, we demonstrate how this approach can be used to understand—and improve—recruitment to clinical trials. Taken together, our review suggests that healthcare professionals can find recruiting to trials challenging and require support with this process.

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.