Multi-domain quantitative recovery following Radical Cystectomy for patients within the iROC (Robot Assisted Radical Cystectomy with intracorporeal urinary diversion versus Open Radical Cystectomy) Randomised Controlled Trial: The first 30 patients

Many patients develop complications after radical cystectomy (RC) [1]. Reductions in morbidity have occurred through centralisation and technical improvements [2], and perhaps through robot-assisted RC (RARC). Whilst RARC is gaining popularity, there are concerns about oncological safety [3] and extracorporeal reconstruction [4], and randomised controlled trials (RCTs) find little difference [5]. We are conducting a prospective RCT comparing open RC and RARC with mandated intracorporeal reconstruction (Robot-assisted Radical Cystectomy with intracorporeal urinary diversion versus Open Radical Cystectomy [iROC] trial) [6]

Radical cystectomy (bladder removal) against intravesical BCG immunotherapy for high-risk non-muscle invasive bladder cancer (BRAVO): a protocol for a randomised controlled feasibility study

INTRODUCTION: High-risk non-muscle invasive bladder cancer (HRNMIBC) is a heterogeneous disease that can be difficult to predict. While around 25% of cancers progress to invasion and metastases, the remaining majority of tumours remain within the bladder. It is uncertain whether patients with HRNMIBC are better treated with intravesical maintenance BCG (mBCG) immunotherapy or primary radical cystectomy (RC). A definitive randomised controlled trial (RCT) is needed to compare these two different treatments but may be difficult to recruit to and has not been attempted to date. Before undertaking such an RCT, it is important to understand whether such a comparison is possible and how best to achieve it. METHODS AND ANALYSIS: BRAVO is a multi-centre, parallel-group, mixed-methods, individually randomised, controlled, feasibility study for patients with HRNMIBC. Participants will be randomised to receive either mBCG immunotherapy or RC. The primary objective is to assess the feasibility and acceptability of performing the definitive phase III trial via estimation of eligibility and recruitment rates, assessing uptake of allocated treatment and compliance with mBCG, determining quality-of-life questionnaire completion rates and exploring reasons expressed by patients for declining recruitment into the study. We aim to recruit 60 participants from six centres in the UK. Surgical trials with disparate treatment options find recruitment challenging from both the patient and clinician perspective. By building on the experiences of other similar trials through implementing a comprehensive training package aimed at clinicians to address these challenges (qualitative substudy), we hope that we can demonstrate that a phase III trial is feasible. ETHICS AND DISSEMINATION: The study has ethical approval (16/YH/0268). Findings will be made available to patients, clinicians, the funders and the National Health Service through traditional publishing and social media. TRIAL REGISTRATION NUMBER: ISRCTN12509361; Pre results

Health-related quality of life after treatment for bladder cancer in England

Background Little is known about quality of life after bladder cancer treatment. This common cancer is managed using treatments that can affect urinary, sexual and bowel function. Methods To understand quality of life and inform future care, the Department of Health (England) surveyed adults surviving bladder cancer 1–5 years after diagnosis. Questions related to disease status, co-existing conditions, generic health (EQ-5D), cancer-generic (Social Difficulties Inventory) and cancer-specific outcomes (Functional Assessment of Cancer Therapy—Bladder). Results In total, 673 (54%) patients responded; including 500 (74%) men and 539 (80%) with co-existing conditions. Most respondents received endoscopic treatment (60%), while 92 (14%) and 99 (15%) received radical cystectomy or radiotherapy, respectively. Questionnaire completion rates varied (51–97%). Treatment groups reported ≥1 problem using EQ-5D generic domains (59–74%). Usual activities was the most common concern. Urinary frequency was common after endoscopy (34–37%) and radiotherapy (44–50%). Certain populations were more likely to report generic, cancer-generic and cancer-specific problems; notably those with co-existing long-term conditions and those treated with radiotherapy. Conclusion The study demonstrates the importance of assessing patient-reported outcomes in this population. There is a need for larger, more in-depth studies to fully understand the challenges patients with bladder cancer face

Senescence induction in renal carcinoma cells by Nutlin-3: a potential therapeutic strategy based on MDM2 antagonism.

Although the role of p53 as a tumour suppressor in renal cell carcinoma (RCC) is unclear, our recent analysis suggests that increased wild-type p53 protein expression is associated with poor outcome. A growing body of evidence also suggests that p53 expression and increased co-expression of MDM2 are linked with poor prognosis in RCC. We have therefore examined whether an MDM2 antagonist; Nutlin-3, might rescue/increase p53 expression and induce growth inhibition or apoptosis in RCC cells that retain wild-type p53. We show that inhibition of p53 suppression by MDM2 in RCC cells promotes growth arrest and p53-dependent senescence - phenotypes known to mediate p53 tumour suppression in vivo. We propose that future investigations of therapeutic strategies for RCC should incorporate MDM2 antagonism as part of strategies aimed at rescuing/augmenting p53 tumour suppressor function

Hyperthermic intravesical chemotherapy with mitomycin‐C for the treatment of high‐risk non‐muscle‐invasive bladder cancer patients

Abstract Objectives The objectives of the study are to explore tolerability, acceptability and oncological outcomes for patients with high‐risk non‐muscle‐invasive bladder cancer (NMIBC) treated with hyperthermic intravesical chemotherapy (HIVEC) and mitomycin‐C (MMC) at our institution. Patients and Methods Our single‐institution, observational study consists of consecutive high‐risk NMIBC patients treated with HIVEC and MMC. Our HIVEC protocol included six weekly instillations (induction), followed by two further cycles of three instillations (maintenance) (6 + 3 + 3) if there was cystoscopic response. Patient demographics, instillation dates and adverse events (AEs) were collected prospectively in our dedicated HIVEC clinic. Retrospective case‐note review was performed to evaluate oncological outcomes. Primary outcomes were tolerability and acceptability of HIVEC protocol; secondary outcomes were 12‐month recurrence‐free, progression‐free and overall survival. Results In total, 57 patients (median age 80.3 years) received HIVEC and MMC, with a median follow‐up of 18 months. Of these, 40 (70.2%) had recurrent tumours, and 29 (50.9%) had received prior Bacillus Calmette–Guérin (BCG). HIVEC induction was completed by 47 (82.5%) patients, but only 19 (33.3%) completed the full protocol. Disease recurrence (28.9%) and AEs (28.9%) were the most common reasons for incompletion of protocol; five (13.2%) patients stopped treatment due to logistical challenges. AEs occurred in 20 (35.1%) patients; the most frequently documented were rash (10.5%), urinary tract infection (8.8%) and bladder spasm (8.8%). Progression during treatment occurred in 11 (19.3%) patients, 4 (7.0%) of whom had muscle invasion and 5 (8.8%) subsequently required radical treatment. Patients who had received prior BCG were significantly more likely to progress (p = 0.04). 12‐month recurrence‐free, progression‐free and overall survival rates were 67.5%, 82.2%, and 94.7%, respectively. Conclusions Our single‐institution experience suggests that HIVEC and MMC are tolerable and acceptable. Oncological outcomes in this predominantly elderly, pretreated cohort are promising; however, disease progression was higher in patients pretreated with BCG. Further randomised noninferiority trials comparing HIVEC versus BCG in high‐risk NMIBC are required

Urothelial Carcinoma in Bladder Diverticula: A Multicenter Analysis of Characteristics and Clinical Outcomes

BACKGROUND Urothelial carcinoma arising in a bladder diverticulum (UCBD) is uncommon, and data on treatment and outcome are sparse. OBJECTIVE To analyze clinicopathological characteristics of UCBD and to compare outcome after radical cystectomy (RC) and partial cystectomy (PC). DESIGN, SETTING, AND PARTICIPANTS Data of 115 UCBD patients treated with RC (n=81) or PC (n=34) between 2000 and 2016 were collected from 11 institutional databases and were analyzed retrospectively. Median follow-up was 5.0yr (95% confidence interval [CI]: 4.0-6.2). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Upstaging of tumor stage at diagnostic transurethral resection (TUR) to the RC/PC specimen was investigated. Overall survival (OS) and metastasis-free survival (MFS) after RC and PC were analyzed using Kaplan-Meier estimates, and compared using the log-rank test. Intravesical recurrences after PC were reported. A multivariable Cox proportional-hazard model was used to identify factors associated with OS. RESULTS AND LIMITATIONS There were no statistically significant differences in clinicopathological characteristics between RC and PC groups. Fifty-five percent of patients with cTa/is/1 at diagnostic TUR had ≥pT2 tumors at RC/PC. Five-year OS and MFS were, respectively, 62% and 66% for RC and 66% and 55% for PC (p=0.9 and p=0.6). Intravesical tumor recurrence was seen in six of 34 (18%) PC patients. In multivariable analysis, positive surgical margins and extravesical disease (≥pT2) were associated with worse OS, whereas treatment modality was not (RC: reference; PC: hazard ratio 0.94, [95% CI: 0.47-1.90], p=0.9). CONCLUSIONS Upstaging of UCBD was frequent, indicating an inaccuracy in clinical staging. We found no differences in OS or MFS between PC and RC groups; therefore, PC may represent a feasible surgical alternative to RC in selected UCBD patients. PATIENT SUMMARY In this report, we looked at the treatment of urothelial carcinoma arising in a bladder diverticulum (UCBD). We found that bladder-sparing treatment by partial cystectomy may be an alternative to radical cystectomy in carefully selected UCBD patients

Conditional analyses of recurrence and progression in patients with TaG1 non-muscle-invasive bladder cancer.

OBJECTIVE To determine conditional recurrence-free survival (RFS) and progression-free survival (PFS) and improve decision-making toward surveillance protocols and scheduling. Furthermore, evaluating the evolution of predictors for disease recurrence over time, because TaG1 non-muscle-invasive bladder cancer harbors a risk of disease recurrence and progression. MATERIAL AND METHODS The retrospective multicenter design study includes 1,245 TaG1 bladder cancer patients with median follow-up of 62.7 (interquartile range: 34.3-91.1) months. Conditional RFS and PFS estimates were calculated using the Kaplan-Meier method. Multivariable Cox regression model was calculated proportional for the prediction of recurrence and progression (covariables: age, tumor size, multiple tumors, prior recurrence, and immediate postoperative instillation of chemotherapy). RESULTS After 3 months without event, the conditional RFS and PFS (to ≥pT2) rates for 5 additional years without event were 57.5% and 93.4%, respectively. Given a 1-, 2-, 3-, and 5-year survival, the conditional RFS rates for 5 additional years without event improved by +9.8 (67.3%), +5.2 (72.5%), +6.5 (79.0%), +2.0 (81.0%), and +1.0% (82.0%), respectively. In contrast, the 5-year conditional PFS rates were more or less stable with 94.3% after 1 year to 94.1% after 5 years. Multivariable analyses showed decreasing impact of risk parameters on RFS estimates over time. Based on these findings, we suggest a risk stratification to individualize follow-up for intermediate risk TaG1. Main limitation was the retrospective design. CONCLUSIONS Conditional-survival analyses demonstrates that the patient risk profile changes over time. RFS rates rise with increasing survival whereas PFS rates were stable. The impact of prognostic features decreases over time. Our findings can be used for patient counseling and planning of personalized follow-up

Discrepancy Between European Association of Urology Guidelines and Daily Practice in the Management of Non-muscle-invasive Bladder Cancer: Results of a European Survey.

BACKGROUND The European Association of Urology (EAU) non-muscle-invasive bladder cancer (NMIBC) guidelines are meant to help minimise morbidity and improve the care of patients with NMIBC. However, there may be underuse of guideline-recommended care in this potentially curable cohort. OBJECTIVE To assess European physicians' current practice in the management of NMIBC and evaluate its concordance with the EAU 2013 guidelines. DESIGN, SETTING, AND PARTICIPANTS Initial 45-min telephone interviews were conducted with 20 urologists to develop a 26-item questionnaire for a 30-min online quantitative interview. A total of 498 physicians with predefined experience in treatment of NMIBC patients, from nine European countries, completed the online interviews. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Descriptive statistics of absolute numbers and percentages of the use of diagnostic tools, risk group stratification, treatment options chosen, and follow-up regimens were used. RESULTS AND LIMITATIONS Guidelines are used by ≥87% of physicians, with the EAU guidelines being the most used ones (71-100%). Cystoscopy (60-97%) and ultrasonography (42-95%) are the most used diagnostic techniques. Using EAU risk classification, 40-69% and 88-100% of physicians correctly identify all the prognostic factors for low- and high-risk tumours, respectively. Re-transurethral resection of the bladder tumour (re-TURB) is performed in 25-75% of low-risk and 55-98% of high-risk patients. Between 21% and 88% of patients received a single instillation of chemotherapy within 24h after TURB. Adjuvant intravesical treatment is not given to 6-62%, 2-33%, and 1-20% of the patients with low-, intermediate-, and high-risk NMIBC, respectively. Patients with low-risk NMIBC are likely to be overmonitored and those with high-risk NMIBC undermonitored. Our study is limited by the possible recall bias of the selected physicians. CONCLUSIONS Although most European physicians claim to apply the EAU guidelines, adherence to them is low in daily practice. PATIENT SUMMARY Our survey among European physicians investigated discrepancies between guidelines and daily practice in the management of non-muscle-invasive bladder cancer (NMIBC). We conclude that the use of the recommended diagnostic tools, risk-stratification of NMIBC, and performance of re-TURB have been adopted, but adjuvant intravesical treatment and follow-up are not uniformly applied