Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial.

BACKGROUND: The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ. METHODS: KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. FINDINGS: Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred. INTERPRETATION: Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial. FUNDING: Merck Sharp & Dohme.

Predicting non-muscle invasive bladder cancer outcomes using artificial intelligence: a systematic review using APPRAISE-AI.

Accurate prediction of recurrence and progression in non-muscle invasive bladder cancer (NMIBC) is essential to inform management and eligibility for clinical trials. Despite substantial interest in developing artificial intelligence (AI) applications in NMIBC, their clinical readiness remains unclear. This systematic review aimed to critically appraise AI studies predicting NMIBC outcomes, and to identify common methodological and reporting pitfalls. MEDLINE, EMBASE, Web of Science, and Scopus were searched from inception to February 5th, 2024 for AI studies predicting NMIBC recurrence or progression. APPRAISE-AI was used to assess methodological and reporting quality of these studies. Performance between AI and non-AI approaches included within these studies were compared. A total of 15 studies (five on recurrence, four on progression, and six on both) were included. All studies were retrospective, with a median follow-up of 71 months (IQR 32-93) and median cohort size of 125 (IQR 93-309). Most studies were low quality, with only one classified as high quality. While AI models generally outperformed non-AI approaches with respect to accuracy, c-index, sensitivity, and specificity, this margin of benefit varied with study quality (median absolute performance difference was 10 for low, 22 for moderate, and 4 for high quality studies). Common pitfalls included dataset limitations, heterogeneous outcome definitions, methodological flaws, suboptimal model evaluation, and reproducibility issues. Recommendations to address these challenges are proposed. These findings emphasise the need for collaborative efforts between urological and AI communities paired with rigorous methodologies to develop higher quality models, enabling AI to reach its potential in enhancing NMIBC care.

Patients with complete clinical response after neoadjuvant chemoradiotherapy for locally advanced esophageal cancer: A Markov decision analysis of esophagectomy versus active surveillance.

OBJECTIVE: Chemoradiation followed by esophagectomy is a standard treatment option for patients with locally advanced esophageal cancer (LAEC). Esophagectomy is a high-risk procedure, and recent evidence suggests select patients may benefit from omitting or delaying surgery. This study aims to compare surgery versus active surveillance for LAEC patients with complete clinical response (cCR) after neoadjuvant chemoradiotherapy (nCRT). METHODS: Decision analysis with Markov modeling was used. The base case was a 60-year-old man with T3N0M0 esophageal cancer with cCR after nCRT. The decision was modeled for a 5-year time horizon. Primary outcomes were life-years and quality-adjusted life-years (QALY). Probabilities and utilities were derived through the literature. Deterministic sensitivity analyses were performed using ranges from the literature with consideration for clinical plausibility. RESULTS: Surgery was favored for survival with an expected life-years of 2.89 versus 2.64. After incorporating quality of life, active surveillance was favored, with an expected QALY of 1.70 versus 1.56. The model was sensitive to probability of recurrence on active surveillance (threshold value 0.598), probability of recurrence being resectable (0.318), and disutility of previous esophagectomy (-0.091). The model was not sensitive to perioperative morbidity and mortality. CONCLUSIONS: Our study finds that surgery increases life expectancy but decreases QALY. Although the incremental change in QALY for either modality is insufficient to make broad clinical recommendations, our study demonstrates that either approach is acceptable. As probabilities of key factors are further defined in the literature, treatment decisions for patients with LAEC and a cCR after nCRT should consider histology, patient values, and quality of life.

Application of STREAM-URO and APPRAISE-AI reporting standards for artificial intelligence studies in pediatric urology: A case example with pediatric hydronephrosis.

INTRODUCTION: Artificial intelligence (AI) and machine learning (ML) in pediatric urology is gaining increased popularity and credibility. However, the literature lacks standardization in reporting and there are areas for methodological improvement, which incurs difficulty in comparison between studies and may ultimately hurt clinical implementation of these models. The "STandardized REporting of Applications of Machine learning in UROlogy" (STREAM-URO) framework provides methodological instructions to improve transparent reporting in urology and APPRAISE-AI in a critical appraisal tool which provides quantitative measures for the quality of AI studies. The adoption of these will allow urologists and developers to ensure consistency in reporting, improve comparison, develop better models, and hopefully inspire clinical translation. METHODS: In this article, we have applied STREAM-URO framework and APPRAISE-AI tool to the pediatric hydronephrosis literature. By doing this, we aim to describe best practices on ML reporting in urology with STREAM-URO and provide readers with a critical appraisal tool for ML quality with APPRAISE-AI. By applying these to the pediatric hydronephrosis literature, we provide some tutorial for other readers to employ these in developing and appraising ML models. We also present itemized recommendations for adequate reporting, and critically appraise the quality of ML in pediatric hydronephrosis insofar. We provide examples of strong reporting and highlight areas for improvement. RESULTS: There were 8 ML models applied to pediatric hydronephrosis. The 26-item STREAM-URO framework is provided in Appendix A and 24-item APPRAISE-AI tool is provided in Appendix B. Across the 8 studies, the median compliance with STREAM-URO was 67 % and overall study quality was moderate. The highest scoring APPRAISE-AI domains in pediatric hydronephrosis were clinical relevance and reporting quality, while the worst were methodological conduct, robustness of results, and reproducibility. CONCLUSIONS: If properly conducted and reported, ML has the potential to impact the care we provide to patients in pediatric urology. While AI is exciting, the paucity of strong evidence limits our ability to translate models to practice. The first step toward this goal is adequate reporting and ensuring high quality models, and STREAM-URO and APPRAISE-AI can facilitate better reporting and critical appraisal, respectively.

Benefit of Neoadjuvant Cisplatin-based Chemotherapy for Invasive Bladder Cancer Patients Treated with Radiation-based Therapy in a Real-world Setting: An Inverse Probability Treatment Weighted Analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) improves survival for patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. Studies on the potential benefit of NAC before radiation-based therapy (RT) are conflicting. OBJECTIVE: To evaluate the effect of NAC on patients with MIBC treated with curative-intent RT in a real-world setting. DESIGN, SETTING, AND PARTICIPANTS: The study cohort consisted of 785 patients with MIBC (cT2-4aN0-2M0) who underwent RT at academic centers across Canada. Patients were classified into two treatment groups based on the administration of NAC before RT (NAC vs no NAC). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The inverse probability of treatment weighting (IPTW) with absolute standardized differences (ASDs) was used to balance covariates across treatment groups. The impact of NAC on complete response, overall, and cancer-specific survival (CSS) after RT in the weighted cohort was analyzed. RESULTS AND LIMITATIONS: After applying the exclusion criteria, 586 patients were included; 102 (17%) received NAC before RT. Patients in the NAC subgroup were younger (mean age 65 vs 77 yr; ASD 1.20); more likely to have Eastern Cooperative Oncology Group performance status 0-1 (87% vs 78%; ASD 0.28), lymphovascular invasion (32% vs 20%; ASD 0.27), higher cT stage (cT3-4 in 29% vs 20%; ASD 0.21), and higher cN stage (cN1-2 in 32% vs 4%; ASD 0.81); and more commonly treated with concurrent chemotherapy (79% vs 67%; ASD 0.28). After IPTW, NAC versus no NAC cohorts were well balanced (ASD <0.20) for all included covariates. NAC was significantly associated with improved CSS (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.14-0.56; p < 0.001) and overall survival (HR 0.56; 95% CI 0.38-0.84; p = 0.005). This study was limited by potential occult imbalances across treatment groups. CONCLUSIONS: If tolerated, NAC might be associated with improved survival and should be considered for eligible patients with MIBC planning to undergo bladder preservation with RT. Prospective trials are warranted. PATIENT SUMMARY: In this study, we showed that neoadjuvant chemotherapy might be associated with improved survival in patients with muscle-invasive bladder cancer who elect for curative-intent radiation-based therapy.

Comparative real-world survival outcomes of muscle-invasive bladder cancer treated with bladder-only vs. whole-pelvis concurrent chemoradiation.

INTRODUCTION: Elective pelvic nodal irradiation for patients with muscle-invasive bladder cancer (MIBC) undergoing trimodal therapy (TMT ) is controversial. In patients with node-negative (N0) MIBC, the benefit of elective whole-pelvis concurrent chemoradiation (WP-CCR) compared to bladder-only (BO )-CCR has not been demonstrated. Using real-world data from the National Cancer Database (NCDB ), we sought to compare the overall survival (OS ) between BO-CCR and WP-CCR for MIBC. METHODS: Using the 2020 NCDB Participant User File, we identified cases of MIBC diagnosed between 2017 and 2019. We selected patients with clinical T2-T4aN0M0 disease receiving CCR as first-line treatment. CCR was defined as transurethral resection of bladder tumor followed by ≥40 Gy radiation to the bladder with concurrent single- or multiple-agent chemotherapy. Based on elective nodal irradiation status, patients were stratified as having received BO-CCR vs. WP-CCR. OS analysis was performed using summary three-month conditional landmark, inverse probability treatment weighting (IPTW)-adjusted Kaplan-Meier estimates, and Cox regression. RESULTS: A total of 604 patients receiving CCR for MIBC were identified: 367 (60.8%) BO-CCR and 237 (39.2%) WP-CCR. Before IPTW, the groups were imbalanced in terms of baseline characteristics. The median followup of the weighted population was 42.3 months (interquartile range 18.1-49.1 months). In IPTW-adjusted Cox proportional hazards regression analysis, WP-CCR was associated with a significant OS benefit compared to BO-CCR (adjusted hazard ratio 0.72, 95% confidence interval 0.54-0.96, p=0.026). CONCLUSIONS: In the setting of CCR for N0 MIBC, this retrospective NCDB analysis revealed that WP-CCR was associated with a benefit in OS compared to BO-CCR.

Long-term outcomes and cost savings of office fulguration of papillary Ta low-grade bladder cancer.

OBJECTIVES: To assess whether office-based fulguration (OF) under local anaesthesia for small, recurrent, pathological Ta low-grade (LG) non-muscle-invasive bladder cancer (NMIBC) is an effective alternative to transurethral resection of bladder tumour (TURBT), avoiding the costs and risks of procedure, and anesthesia. PATIENTS AND METHODS: Of 521 patients with primary TaLG NMIBC, this retrospective study included 270 patients who underwent OF during follow-up for recurrent, small, papillary LG-appearing tumours at a university centre (University Health Network, University of Toronto, Canada). We assessed the cumulative incidence of cancer-specific mortality (CSM) and disease progression (to MIBC or metastases), as well as possible direct cost savings. RESULTS: In the 270 patients with recurrent TaLG NMIBC treated with OF, the mean (sd) age was 64.9 (13.3) years, 70.8% were men, and 60.3% had single tumours. The mean (sd, range) number of OF procedures per patient was 3.1 (3.2, 1-22). The median (interquartile range) follow-up was 10.1 (5.8-16.2) years. Patients also underwent a mean (sd) of 3.6 (3.0) TURBTs during follow-up in case of numerous or bulkier recurrence. In all, 44.4% of patients never received intravesical therapy. The 10-year incidence of CSM and progression were 0% and 3.1% (95% confidence interval 0.8-5.4%), respectively. Direct cost savings in Ontario were estimated at $6994.14 (Canadian dollars) per patient over the study follow-up. CONCLUSIONS: This study supports that properly selected patients with recurrent, apparent TaLG NMIBC can be safely managed with OF under local anaesthesia with occasional TURBT for larger or numerous recurrent tumours, without compromising long-term oncological outcomes. This approach could generate substantial cost-saving to healthcare systems, is patient-friendly, and could be adopted more widely.

APPRAISE-AI Tool for Quantitative Evaluation of AI Studies for Clinical Decision Support.

Importance: Artificial intelligence (AI) has gained considerable attention in health care, yet concerns have been raised around appropriate methods and fairness. Current AI reporting guidelines do not provide a means of quantifying overall quality of AI research, limiting their ability to compare models addressing the same clinical question. Objective: To develop a tool (APPRAISE-AI) to evaluate the methodological and reporting quality of AI prediction models for clinical decision support. Design, Setting, and Participants: This quality improvement study evaluated AI studies in the model development, silent, and clinical trial phases using the APPRAISE-AI tool, a quantitative method for evaluating quality of AI studies across 6 domains: clinical relevance, data quality, methodological conduct, robustness of results, reporting quality, and reproducibility. These domains included 24 items with a maximum overall score of 100 points. Points were assigned to each item, with higher points indicating stronger methodological or reporting quality. The tool was applied to a systematic review on machine learning to estimate sepsis that included articles published until September 13, 2019. Data analysis was performed from September to December 2022. Main Outcomes and Measures: The primary outcomes were interrater and intrarater reliability and the correlation between APPRAISE-AI scores and expert scores, 3-year citation rate, number of Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) low risk-of-bias domains, and overall adherence to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statement. Results: A total of 28 studies were included. Overall APPRAISE-AI scores ranged from 33 (low quality) to 67 (high quality). Most studies were moderate quality. The 5 lowest scoring items included source of data, sample size calculation, bias assessment, error analysis, and transparency. Overall APPRAISE-AI scores were associated with expert scores (Spearman ρ, 0.82; 95% CI, 0.64-0.91; P < .001), 3-year citation rate (Spearman ρ, 0.69; 95% CI, 0.43-0.85; P < .001), number of QUADAS-2 low risk-of-bias domains (Spearman ρ, 0.56; 95% CI, 0.24-0.77; P = .002), and adherence to the TRIPOD statement (Spearman ρ, 0.87; 95% CI, 0.73-0.94; P < .001). Intraclass correlation coefficient ranges for interrater and intrarater reliability were 0.74 to 1.00 for individual items, 0.81 to 0.99 for individual domains, and 0.91 to 0.98 for overall scores. Conclusions and Relevance: In this quality improvement study, APPRAISE-AI demonstrated strong interrater and intrarater reliability and correlated well with several study quality measures. This tool may provide a quantitative approach for investigators, reviewers, editors, and funding organizations to compare the research quality across AI studies for clinical decision support.

The impact of the early COVID-19 pandemic on healthcare system resource use and costs in two provinces in Canada: An interrupted time series analysis.

INTRODUCTION: The aim of our study was to assess the initial impact of COVID-19 on total publicly-funded direct healthcare costs and health services use in two Canadian provinces, Ontario and British Columbia (BC). METHODS: This retrospective repeated cross-sectional study used population-based administrative datasets, linked within each province, from January 1, 2018 to December 27, 2020. Interrupted time series analysis was used to estimate changes in the level and trends of weekly resource use and costs, with March 16-22, 2020 as the first pandemic week. Also, in each week of 2020, we identified cases with their first positive SARS-CoV-2 test and estimated their healthcare costs until death or December 27, 2020. RESULTS: The resources with the largest level declines (95% confidence interval) in use in the first pandemic week compared to the previous week were physician services [Ontario: -43% (-49%,-37%); BC: -24% (-30%,-19%) (both p<0.001)] and emergency department visits [Ontario: -41% (-47%,-35%); BC: -29% (-35%,-23%) (both p<0.001)]. Hospital admissions declined by 27% (-32%,-23%) in Ontario and 21% (-26%,-16%) in BC (both p<0.001). Resource use subsequently rose but did not return to pre-pandemic levels. Only home care and dialysis clinic visits did not significantly decrease compared to pre-pandemic. Costs for COVID-19 cases represented 1.3% and 0.7% of total direct healthcare costs in 2020 in Ontario and BC, respectively. CONCLUSIONS: Reduced utilization of healthcare services in the overall population outweighed utilization by COVID-19 patients in 2020. Meeting the needs of all patients across all services is essential to maintain resilient healthcare systems.

Existing trends and applications of artificial intelligence in urothelial cancer A scoping review.

INTRODUCTION: The use of artificial intelligence (AI) in urology is gaining significant traction. While previous reviews of AI applications in urology exist, there have been few attempts to synthesize existing literature on urothelial cancer (UC). METHODS: Comprehensive searches based on the concepts of "AI" and "urothelial cancer" were conducted in MEDLINE , EMBASE , Web of Science, and Scopus. Study selection and data abstraction were conducted by two independent reviewers. Two independent raters assessed study quality in a random sample of 25 studies with the prediction model risk of bias assessment tool (PROBAST) and the standardized reporting of machine learning applications in urology (STREAM-URO) framework. RESULTS: From a database search of 4581 studies, 227 were included. By area of research, 33% focused on image analysis, 26% on genomics, 16% on radiomics, and 15% on clinicopathology. Thematic content analysis identified qualitative trends in AI models employed and variables for feature extraction. Only 19% of studies compared performance of AI models to non-AI methods. All selected studies demonstrated high risk of bias for analysis and overall concern with Cohen's kappa (k)=0.68. Selected studies met 66% of STREAM-URO items, with k=0.76. CONCLUSIONS: The use of AI in UC is a topic of increasing importance; however, there is a need for improved standardized reporting, as evidenced by the high risk of bias and low methodologic quality identified in the included studies.

Surgical Site Infections During the Pandemic: The Impact of the "COVID Bundle".

BACKGROUND: A reduction in surgical site infections (SSIs) has been reported in several discrete patient populations during the COVID-19 pandemic. Herein, this study evaluates the impact of the COVID-19 pandemic on SSI in a large patient cohort incorporating multiple surgical disciplines. We hypothesize that enhanced infection control and heightened awareness of such measures is analogous to an SSI care bundle, the hypothetical "COVID bundle", and may impact SSI rates. METHOD: Data collected for the American College of Surgeons National Surgical Quality Improvement Program between January 1, 2015, and April 1, 2021, were retrospectively analyzed. SSI rates were compared among time-dependent patient cohorts: Cohort A (pre-pandemic, N = 24,060, 87%) and Cohort B (pandemic, N = 3698, 13%). Time series and multivariable analyses predicted pre-pandemic and pandemic SSI trends and tested for association with timing of surgery. RESULTS: The overall SSI incidence was reduced in Cohort B versus Cohort A (2.8% vs. 4.5%, p < 0.001). Multivariable analysis indicated a downward SSI trend before pandemic onset (IRR 0.997, 95% CI 0.994, 1). At pandemic onset, the trend reduced by a relative factor of 39% (IRR 0.601, 95% CI 0.338, 1.069). SSI then trended upward during the pandemic (IRR 1.035, 95% CI 0.965, 1.111). SSI rates significantly trended downward in general surgical patients at pandemic onset (IRR 0.572, 95% CI 0.353, 0.928). CONCLUSION: Although overall SSI incidence was reduced during the pandemic, a statistically significant decrease in the predicted SSI rate only occurred in general surgical patients at pandemic onset. This trend may suggest a positive impact of the "COVID bundle" on SSI rates in these patients.

Neoadjuvant Cabazitaxel plus Abiraterone/Leuprolide Acetate in Patients with High-Risk Prostate Cancer: ACDC-RP Phase II Trial.

PURPOSE: Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer. PATIENTS AND METHODS: This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile. RESULTS: The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0-68.0] and 21.9 ng/mL (IQR, 14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078). CONCLUSIONS: Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.

Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis.

BACKGROUND: Previous randomised controlled trials comparing bladder preservation with radical cystectomy for muscle-invasive bladder cancer closed due to insufficient accrual. Given that no further trials are foreseen, we aimed to use propensity scores to compare trimodality therapy (maximal transurethral resection of bladder tumour followed by concurrent chemoradiation) with radical cystectomy. METHODS: This retrospective analysis included 722 patients with clinical stage T2-T4N0M0 muscle-invasive urothelial carcinoma of the bladder (440 underwent radical cystectomy, 282 received trimodality therapy) who would have been eligible for both approaches, treated at three university centres in the USA and Canada between Jan 1, 2005, and Dec 31, 2017. All patients had solitary tumours less than 7 cm, no or unilateral hydronephrosis, and no extensive or multifocal carcinoma in situ. The 440 cases of radical cystectomy represent 29% of all radical cystectomies performed during the study period at the contributing institutions. The primary endpoint was metastasis-free survival. Secondary endpoints included overall survival, cancer-specific survival, and disease-free survival. Differences in survival outcomes by treatment were analysed using propensity scores incorporated in propensity score matching (PSM) using logistic regression and 3:1 matching with replacement and inverse probability treatment weighting (IPTW). FINDINGS: In the PSM analysis, the 3:1 matched cohort comprised 1119 patients (837 radical cystectomy, 282 trimodality therapy). After matching, age (71·4 years [IQR 66·0-77·1] for radical cystectomy vs 71·6 years [64·0-78·9] for trimodality therapy), sex (213 [25%] vs 68 [24%] female; 624 [75%] vs 214 [76%] male), cT2 stage (755 [90%] vs 255 [90%]), presence of hydronephrosis (97 [12%] vs 27 [10%]), and receipt of neoadjuvant or adjuvant chemotherapy (492 [59%] vs 159 [56%]) were similar between groups. Median follow-up was 4·38 years (IQR 1·6-6·7) versus 4·88 years (2·8-7·7), respectively. 5-year metastasis-free survival was 74% (95% CI 70-78) for radical cystectomy and 75% (70-80) for trimodality therapy with IPTW and 74% (70-77) and 74% (68-79) with PSM. There was no difference in metastasis-free survival either with IPTW (subdistribution hazard ratio [SHR] 0·89 [95% CI 0·67-1·20]; p=0·40) or PSM (SHR 0·93 [0·71-1·24]; p=0·64). 5-year cancer-specific survival for radical cystectomy versus trimodality therapy was 81% (95% CI 77-85) versus 84% (79-89) with IPTW and 83% (80-86) versus 85% (80-89) with PSM. 5-year disease-free survival was 73% (95% CI 69-77) versus 74% (69-79) with IPTW and 76% (72-80) versus 76% (71-81) with PSM. There were no differences in cancer-specific survival (IPTW: SHR 0·72 [95% CI 0·50-1·04]; p=0·071; PSM: SHR 0·73 [0·52-1·02]; p=0·057) and disease-free survival (IPTW: SHR 0·87 [0·65-1·16]; p=0·35; PSM: SHR 0·88 [0·67-1·16]; p=0·37) between radical cystectomy and trimodality therapy. Overall survival favoured trimodality therapy (IPTW: 66% [95% CI 61-71] vs 73% [68-78]; hazard ratio [HR] 0·70 [95% CI 0·53-0·92]; p=0·010; PSM: 72% [69-75] vs 77% [72-81]; HR 0·75 [0·58-0·97]; p=0·0078). Outcomes for radical cystectomy and trimodality therapy were not statistically different among centres for cancer-specific survival and metastasis-free survival (p=0·22-0·90). Salvage cystectomy was done in 38 (13%) trimodality therapy patients. Pathological stage in the 440 radical cystectomy patients was pT2 in 124 (28%), pT3-4 in 194 (44%), and 114 (26%) node positive. The median number of nodes removed was 39, the soft tissue positive margin rate was 1% (n=5), and the perioperative mortality rate was 2·5% (n=11). INTERPRETATION: This multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option. FUNDING: Sinai Health Foundation, Princess Margaret Cancer Foundation, Massachusetts General Hospital.

Development, multi-institutional external validation, and algorithmic audit of an artificial intelligence-based Side-specific Extra-Prostatic Extension Risk Assessment tool (SEPERA) for patients undergoing radical prostatectomy: a retrospective cohort study.

BACKGROUND: Accurate prediction of side-specific extraprostatic extension (ssEPE) is essential for performing nerve-sparing surgery to mitigate treatment-related side-effects such as impotence and incontinence in patients with localised prostate cancer. Artificial intelligence (AI) might provide robust and personalised ssEPE predictions to better inform nerve-sparing strategy during radical prostatectomy. We aimed to develop, externally validate, and perform an algorithmic audit of an AI-based Side-specific Extra-Prostatic Extension Risk Assessment tool (SEPERA). METHODS: Each prostatic lobe was treated as an individual case such that each patient contributed two cases to the overall cohort. SEPERA was trained on 1022 cases from a community hospital network (Trillium Health Partners; Mississauga, ON, Canada) between 2010 and 2020. Subsequently, SEPERA was externally validated on 3914 cases across three academic centres: Princess Margaret Cancer Centre (Toronto, ON, Canada) from 2008 to 2020; L'Institut Mutualiste Montsouris (Paris, France) from 2010 to 2020; and Jules Bordet Institute (Brussels, Belgium) from 2015 to 2020. Model performance was characterised by area under the receiver operating characteristic curve (AUROC), area under the precision recall curve (AUPRC), calibration, and net benefit. SEPERA was compared against contemporary nomograms (ie, Sayyid nomogram, Soeterik nomogram [non-MRI and MRI]), as well as a separate logistic regression model using the same variables included in SEPERA. An algorithmic audit was performed to assess model bias and identify common patient characteristics among predictive errors. FINDINGS: Overall, 2468 patients comprising 4936 cases (ie, prostatic lobes) were included in this study. SEPERA was well calibrated and had the best performance across all validation cohorts (pooled AUROC of 0·77 [95% CI 0·75-0·78] and pooled AUPRC of 0·61 [0·58-0·63]). In patients with pathological ssEPE despite benign ipsilateral biopsies, SEPERA correctly predicted ssEPE in 72 (68%) of 106 cases compared with the other models (47 [44%] in the logistic regression model, none in the Sayyid model, 13 [12%] in the Soeterik non-MRI model, and five [5%] in the Soeterik MRI model). SEPERA had higher net benefit than the other models to predict ssEPE, enabling more patients to safely undergo nerve-sparing. In the algorithmic audit, no evidence of model bias was observed, with no significant difference in AUROC when stratified by race, biopsy year, age, biopsy type (systematic only vs systematic and MRI-targeted biopsy), biopsy location (academic vs community), and D'Amico risk group. According to the audit, the most common errors were false positives, particularly for older patients with high-risk disease. No aggressive tumours (ie, grade >2 or high-risk disease) were found among false negatives. INTERPRETATION: We demonstrated the accuracy, safety, and generalisability of using SEPERA to personalise nerve-sparing approaches during radical prostatectomy. FUNDING: None.

Radiation-based Therapy for Muscle-invasive Bladder Cancer: Contemporary Outcomes Across Tertiary Centers.

BACKGROUND: Radiation therapy (RT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). OBJECTIVE: To analyze predictors of complete response (CR) and survival after RT for MIBC. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter retrospective study of 864 patients with nonmetastatic MIBC who underwent curative-intent RT from 2002 to 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Regression models were used to explore prognostic factors associated with CR, cancer-specific survival (CSS), and overall survival (OS). RESULTS AND LIMITATIONS: The median patient age was 77 yr and median follow-up was 34 mo. Disease stage was cT2 in 675 patients (78%) and cN0 in 766 (89%). Neoadjuvant chemotherapy (NAC) was given to 147 patients (17%) and concurrent chemotherapy to 542 (63%). A CR was experienced by 592 patients (78%). cT3-4 stage (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.29-0.63; p < 0.001) and hydronephrosis (OR 0.50, 95% CI 034-0.74; p = 0.001) were significantly associated with lower CR. The 5-yr survival rates were 63% for CSS and 49% for OS. Higher cT stage (HR 1.93, 95% CI 1.46-2.56; p < 0.001), carcinoma in situ (HR 2.10, 95% CI 1.25-3.53; p = 0.005), hydronephrosis (HR 2.36, 95% CI 1.79-3.10; p < 0.001), NAC use (HR 0.66, 95% CI 0.46-0.95; p = 0.025), and whole-pelvis RT (HR 0.66, 95% CI 0.51-0.86; p = 0.002) were independently associated with CSS; advanced age (HR 1.03, 95% CI 1.01-1.05; p = 0.001), worse performance status (HR 1.73, 95% CI 1.34-2.22; p < 0.001), hydronephrosis (HR 1.50, 95% CI 1.17-1.91; p = 0.001), NAC use (HR 0.69, 95% CI 0.49-0.97; p = 0.033), whole-pelvis RT (HR 0.64, 95% CI 0.51-0.80; p < 0.001), and being surgically unfit (HR 1.42, 95% CI 1.12-1.80; p = 0.004) were associated with OS. The study is limited by the heterogeneity of different treatment protocols. CONCLUSIONS: RT for MIBC yields a CR in most patients who elect for curative-intent bladder preservation. The benefit of NAC and whole-pelvis RT require prospective trial validation. PATIENT SUMMARY: We investigated outcomes for patients with muscle-invasive bladder cancer treated with curative-intent radiation therapy as an alternative to surgical removal of the bladder. The benefit of chemotherapy before radiotherapy and whole-pelvis radiation (bladder plus the pelvis lymph nodes) needs further study.

Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline.

PURPOSE: The purpose of this guideline is to provide a useful reference on the effective evidence-based diagnoses and management of non-metastatic upper tract urothelial carcinoma (UTUC). MATERIALS/METHODS: The Pacific Northwest Evidence-based Practice Center of Oregon Health & Science University (OHSU) team conducted searches in Ovid MEDLINE (1946 to March 3rd, 2022), Cochrane Central Register of Controlled Trials (through January 2022), and Cochrane Database of Systematic Reviews (through January 2022). The searches were updated August 2022. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (Table 1).[Table: see text]Results:This Guideline provides updated, evidence-based recommendations regarding diagnosis and management of non-metastatic UTUC including risk stratification, surveillance and survivorship. Treatments discussed include kidney sparing management, surgical management, lymph node dissection (LND), neoadjuvant/adjuvant chemotherapy and immunotherapy. CONCLUSION: This standardized guideline seeks to improve clinicians' ability to evaluate and treat patients with UTUC based on available evidence. Future studies will be essential to further support these statements for improving patient care. Updates will occur as the knowledge regarding disease biology, clinical behavior and new therapeutic options develop.

Cost of Bladder Cancer Care: A Single-center Comparison of Radical Cystectomy and Trimodal Therapy.

INTRODUCTION: Radical cystectomy and trimodal therapy are both accepted options in the management of muscle-invasive bladder cancer. As such, we sought to evaluate the micro-level costs associated with both modalities. METHODS: All patients undergoing trimodal therapy or radical cystectomy for primary treatment of urothelial muscle-invasive bladder cancer at a single academic center between 2008 and 2012 were included. Direct costs associated with each phase of a patient's clinical course were collected from the hospital's financial department, and physician costs were calculated based on the provincial fee schedule. Costs of radiation treatments were derived from previously published literature. RESULTS: A total of 137 patients were included. The mean (±SD) patient age was 69 (±12) years. Overall, 89 (65%) patients underwent radical cystectomy and 48 (35%) were treated with trimodal therapy. The radical cystectomy group had higher rates of cT3/T4 compared to those in the trimodal therapy group (51% vs 26%, P < .001). The median cost in the treatment phase for radical cystectomy was $30,577 (IQR: $23,908-$38,837) vs $18,979 ($17,271-$23,519) for trimodal therapy (P < .001). There was no significant difference between treatment groups with respect to cost of diagnosis or workup. However, the cost of follow-up care was numerically higher for patients undergoing trimodal therapy compared to radical cystectomy ($3,096/y vs $1,974/y, P = .09). CONCLUSIONS: In appropriately selected patients with muscle-invasive bladder cancer trimodal therapy costs are not prohibitive and are lower than in radical cystectomy. With increasing follow-up time after primary treatment, the cost difference between modalities may be mitigated by the need for bladder surveillance and salvage therapy in the trimodal therapy cohort.

Robotic Versus Open Cystectomy for Bladder Cancer: Synthesizing the Data from Current Systematic Reviews and Meta-Analyses.

This is a summary of existing systematic reviews comparing robotic assisted radical cystectomy (RARC) with open radical cystectomy (ORC). Our aim was to compare operative approaches with respect to perioperative, postoperative, oncologic, and health-related quality of life (QOL) outcomes. We performed a systematic review of MEDLINE, Medline-in-Process and Medline Epubs Ahead of Print, and the Cochrane Library on 22 February 2022. We included reviews of adult patients with bladder cancer undergoing RARC or ORC for muscle invasive or high-risk non-muscle invasive bladder cancer. Nonrandomized studies were excluded to minimize confounding and selection bias. The GRADE approach was used to determine the confidence in estimates. We assessed the quality of identified systematic reviews using AMSTAR 2 checklist. Six well-conducted, systematic reviews and meta-analyses were included. RARC was consistently associated with lower estimated blood loss (EBL) and transfusion rates, and longer operative time. There was inconsistent evidence for the impact of RARC on hospital length of stay (LOS). There was no significant difference in overall complication rate or major complication rate, or oncologic outcomes between groups. Comparison of QOL outcomes between studies was limited by statistical and methodological heterogeneity. RARC is associated with improvement in EBL and transfusion risk. There does not appear to be differences in oncologic outcomes or complications between approaches. Prospective studies are needed to assess the impact of diversion type, technique, and recovery pathways on patient outcomes and to assess the impact of operative approach on cost and patient-reported QOL.

Obesity and Complication Risk From Radical Cystectomy: Identifying a Body Mass Index Threshold.

PURPOSE: There are conflicting reports regarding radical cystectomy complication risk from obesity subcategories, and a BMI threshold below which complication risk is notably reduced is undefined. A BMI threshold may be helpful in prehabilitation to aid patient counseling and inform weight loss strategies to potentially mitigate obesity-associated complication risk. This study aims to identify such a threshold and further investigate the association between BMI subcategories and perioperative complications from radical cystectomy. MATERIALS AND METHODS: Data were extracted from the Canadian Bladder Cancer Information System, a prospective registry across 14 academic centers. Five hundred and eighty-nine patients were analyzed. Perioperative (≤90 days) complications were compared between BMI subcategories. Unconditional multivariable logistic regression and cubic spline analysis were performed to determine the association between BMI and complication risk and identify a BMI threshold. RESULTS: Perioperative complications were reported in 51 (30%), 97 (43%), and 85 (43%) normal, overweight, and obese patients (P = .02). BMI was independently associated with developing any complication (OR 1.04 95% CI 1.01, 1.07). Predicted complication risk began to rise consistently above a BMI threshold of 34 kg/m2. Both overweight (OR 2.00 95% CI 1.26-3.17) and obese (OR 1.98 95% CI 1.24-3.18) patients had increased risk of complications compared to normal BMI patients. CONCLUSIONS: Complication risk from radical cystectomy is independently associated with BMI. Both overweight and obese patients are at increased risk compared to normal BMI patients. A BMI threshold of 34 kg/m2 has been identified, which may inform prehabilitation treatment strategies.