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The International Bladder Cancer Group recommends various bladder-sparing therapy (BST) options for patients with bacillus Calmette-Guérin–unresponsive non–muscle-invasive bladder cancer who refuse or are ineligible for radical cystectomy. BST selection should be personalized to each patient, and clinical trial participation is encouraged given the modest efficacy of the BST options available. There has been a recent surge in the development of agents for bacillus Calmette-Guérin–unresponsive (BCG-U) non–muscle-invasive bladder cancer (NMIBC). Critical assessment of these agents and practical recommendations for optimal selection of patients and therapies are urgently needed, especially in the absence of randomized trials on bladder-sparing treatment (BST) options. A global committee of bladder cancer experts was assembled to develop recommendations on BST for BCG-U NMIBC. Working groups reviewed the literature and developed draft recommendations, which were then voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined on the basis of meeting discussions. Final recommendations achieved >75% agreement during the meeting, and some were further refined via web conferences and e-mail discussions. There is currently no single optimal agent for patients with BCG-U disease who seek to avoid radical cystectomy (RC). BST selection should be personalized, taking into account individual patient characteristics and preferences, tumor attributes, and efficacy/toxicity data for the agents available. For patients with BCG-U carcinoma in situ (CIS), gemcitabine/docetaxel (GEM/DOCE), nadofaragene firadenovec (NFF), and nogapendekin alfa inbakicept-pmln (NAI) + BCG are recommended; because of its systemic toxicity, pembrolizumab should only be offered after other options are exhausted. For patients with BCG-U papillary-only tumors, GEM/DOCE, NFF, NAI + BCG, single-agent chemotherapy, hyperthermic mitomycin C, and pembrolizumab are recommended. Given the modest efficacy of available options, clinical trial participation is encouraged. For unapproved agents with reported data, IBCG recommendations await the final results of pivotal trials. The IBCG consensus recommendations provide practical guidance on BST for BCG-U NMIBC. [ABSTRACT FROM AUTHOR]

Objective: To describe patient characteristics and pathological stage at bladder cancer (BCa) diagnosis in a diverse population within a national, equal‐access healthcare system. Methods: This retrospective cohort study identified 15 966 men diagnosed with BCa in the Veterans Affairs (VA) healthcare system from 2000 to 2020. The primary outcome was pathological stage at diagnosis, determined by index transurethral resection of bladder tumour. Logistic regression was used to assess the relationship between race and stage. Competing risk models tested the association between race and BCa‐specific mortality with cumulative incidence estimates. Results: Of 15 966 BCa patients, 12 868 (81%), 1726 (11%), 493 (3%) and 879 (6%) were White, Black, Hispanic and Other race, respectively. Black patients had significantly higher muscle‐invasive bladder cancer (MIBC) rates than White patients (35% vs 32%; P = 0.009). In multivariable analysis, the odds of presenting with MIBC did not differ significantly between Black and White patients (odds ratio [OR] 1.10, 95% confidence interval [CI] 0.98–1.22) or between Hispanic patients (OR 0.82, 95% CI 0.67–1.01) and White patients. Compared to White patients, Black patients had a similar risk of BCa‐specific mortality (hazard ratio [HR] 0.89, 95% CI 0.75–1.06), whereas Hispanic patients had a lower risk (HR 0.56, 95% CI 0.38–0.82). Conclusions: Black patients presented with the highest rates of de novo MIBC. However, in a large, equal‐access healthcare system, this did not result in a difference in BCa‐specific mortality. In contrast, Hispanic patients had lower risks of MIBC and BCa‐specific mortality. [ABSTRACT FROM AUTHOR]

• Up to 50% of patients undergoing cystectomy are clinically understaged. • Identifying responders to neoadjuvant therapy is vital for bladder preservation. • We need precise definitions of clinical response and associated survival outcomes. • DNA damage response gene alterations are promising predictive markers. The morbidity associated with radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) has fueled investigations into the feasibility of bladder preservation strategies after a favorable clinical response to neoadjuvant therapy (NAT). Identifying optimal candidates for bladder preservation is predicated on our ability to identify tumors with inherent cisplatin sensitivity and accurately stage patients before and after NAT. In the present review, we evaluate the accuracy and limitations of contemporary staging modalities and investigate clinical outcomes in patients with MIBC who were managed with bladder preservation after NAT. Lastly, we discuss the predictive role of cisplatin-sensitizing DNA damage response (DDR) gene alterations as a foundational component to current prospective clinical trials evaluating bladder preservation in the setting of MIBC. [ABSTRACT FROM AUTHOR]

Simple Summary: CD47 is a transmembrane protein expressed at a basal level in many cell types but is often overexpressed in tumor cells. CD47 overexpression has been correlated with adverse clinical outcomes in several malignancies. Hence, CD47 could be a promising candidate for target therapy in future cancer treatment. In this retrospective study of 87 patients with muscle invasion bladder cancer (MIBC), we examined CD47 IHC expressions in tumor samples from transurethral resections of bladder tumors (TURBT) and matched radical cystectomy (RC) specimens. We found detectable CD47 expressions in 44% of TURBT samples, but it was not a predictive or prognostic marker for MIBC patients. However, in patients receiving neoadjuvant chemotherapy (NAC), there was a positive trend toward decreased CD47 levels from TURBT to RC. The study suggests that further research is needed to understand the potential role of anti-CD47 therapy in MIBC patients and how NAC may modify immune surveillance mechanisms. Objective: CD47 is an antiphagocytic molecule that plays a critical role in immune surveillance. A variety of malignancies have been shown to evade the immune system by increasing the expression of CD47 on the cell surface. As a result, anti-CD47 therapy is under clinical investigation for a subset of these tumors. Interestingly, CD47 overexpression is associated with negative clinical outcomes in lung and gastric cancers; however, the expression and functional significance of CD47 in bladder cancer is not fully understood. Materials and Methods: We retrospectively studied patients with muscle invasion bladder cancer (MIBC) who underwent a transurethral resection of bladder tumor (TURBT) and subsequently underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC). CD47 expression was examined by IHC in both TURBT and matched RC specimens. The difference in CD47 expression levels between TURBT and RC was also compared. The association of CD47 levels (TURBT) with clinicopathological parameters and survival outcomes was evaluated by Pearson's chi-squared tests and the Kaplan–Meier method, respectively. Results: A total of 87 MIBC patients were included. The median age was 66 (39–84) years. Most patients were Caucasian (95%), male (79%), and aged >60 (63%) and most often (75%) underwent NAC prior to RC. Of those who received NAC, 35.6% were responders and 64.4% were non-responders. The final reported stages as per AJCC for all patients were as follows: stage 0 (32%), stage 1 (1%), stage 2 (20%), stage 3 (43%), and stage 4a (5%). A total of 60% of patients were alive; of those, 30% had disease recurrence and 40% died from bladder cancer at a median follow-up of 3.1 (0.2–14.2) years. CD47 levels were detectable in 38 (44%) TURBT samples. There was no association between CD47 levels and clinicopathological parameters such as age, gender, race, NAC, final stage, disease recurrence, and overall survival (OS). Patients aged >60 (p = 0.006), non-responders (p = 0.002), and at stage ≥ 3 (p < 0.001) were associated with worse OS by a univariate analysis and stage ≥ 3 remained significant even after a multivariate analysis. In patients managed with NAC, there were decreased CD47 levels in RC specimens compared to the TURBT specimens, but this did not reach statistical significance. Conclusion: CD47 expression was not a predictive nor prognostic marker for MIBC patients. However, expression of CD47 was detected in nearly half of MIBCs, and future studies are needed to explore the potential role of anti-CD47 therapy in these patients. Furthermore, there was a slight positive trend in decreased CD47 levels (from TURBT to RC) in patients receiving NAC. As a result, more research is needed to understand how NAC may modify immune surveillance mechanisms in MIBC. [ABSTRACT FROM AUTHOR]

Purpose: We sought to evaluate the impact of repeat transurethral resection of bladder tumor prior to radical cystectomy on oncologic outcomes in a contemporary cohort at a tertiary care center. Materials and Methods: An Institutional Review Board approved review of 657 patients diagnosed with muscle-invasive bladder cancer who underwent radical cystectomy at our institution for clinical stage T2 urothelial carcinoma between 2005 and 2017 was performed. Patients with and without repeat transurethral resection of bladder tumor were matched 1-to-1 by propensity score. Matching was done by age, gender, receipt of neoadjuvant chemotherapy, preoperative hydronephrosis, variant histology, lymphovascular invasion, or carcinoma in situ on index transurethral resection of bladder tumor. Results: A total of 548 patients with muscle-invasive bladder cancer were included after matching (2 groups of 274 patients). Kaplan-Meier estimates of recurrencefree and overall survival demonstrated no significant difference based upon performance of repeat transurethral resection of bladder tumor (P = 1.0 and P = .3, respectively). When outcomes were stratified by pathology of repeat transurethral resection of bladder tumor specimens, those with pT0 had superior recurrence-free and overall survival compared to those with residual muscle invasive disease (P < .001 and P = .001, respectively). Notably, more than 60% of patients who were pT0 on repeat transurethral resection of bladder tumor had residual disease at the time of radical cystectomy. Conclusions: Repeat transurethral resection of bladder tumor prior to radical cystectomy, irrespective of receipt of neoadjuvant chemotherapy, was not associated with improved survival outcomes in this propensity score matched muscle-invasive bladder cancer cohort. The absence of residual tumor on pathological evaluation of repeat transurethral resection of bladder tumor specimen was prognostic and was associated with improved survival outcomes. However, a large percentage of patients with pT0 disease on repeat transurethral resection of bladder tumor had residual disease on radical cystectomy pathology. [ABSTRACT FROM AUTHOR]

Objective: To determine the impact of fibrin clot inhibitor (FCI) use on oncological outcomes in a large contemporary cohort of patients with non‐muscle‐invasive bladder cancer (NMIBC) treated with adequate bacille Calmette–Guérin (BCG). Patients and Methods: We performed an Institutional Review Board‐approved review of patients with NMIBC treated with adequate intravesical BCG, at our institution between 2000 and 2018. FCI use at the time of BCG therapy was recorded for each patient. Patients were stratified according to use of FCI medication. Recurrence‐ and progression‐free survival were analysed using Kaplan–Meier methods and Cox proportional hazard models. Results: Overall, 226 of 526 patients (43.0%) used a FCI: aspirin (205), clopidogrel (38), warfarin (18) and novel oral anticoagulant (NOAC; seven). The use of FCIs did not adversely affect either recurrence‐ or progression‐free survival (P = 0.385 and P = 0.131, respectively). These results did not change when the impact of aspirin, clopidogrel or warfarin/NOAC use on recurrence and progression was evaluated separately. On multivariate analysis, FCI use was neither associated with tumour recurrence nor progression. Conclusion: The use of FCIs was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. Based on these results, FCIs may be safely continued during BCG immunotherapy. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of one‐third‐dose (1/3D) bacillus Calmette‐Guérin (BCG) on oncological outcomes in a large cohort of patients with non‐muscle‐invasive bladder cancer (NMIBC) treated with adequate BCG (as defined by the US Food & Drug Administration (FDA)) in a real‐world setting. Patients and Methods: We performed an institutional review board‐approved review of patients with NMIBC treated with adequate BCG at our institution between 2000 and 2020. Patients were stratified according to whether they had received 1/3D BCG or full‐dose (FD) BCG. Time to recurrence, time to progression and cancer‐specific survival were estimated using Kaplan–Meier methods. Results: Of 563 patients with NMIBC treated with adequate BCG, 150 (26.6%) received 1/3D and 413 (73.4%) received FD. The use of 1/3D BCG did not adversely affect time to recurrence (P = 0.449) or time to progression (P = 0.716), and this remained consistent when patients were stratified by individual 2021 European Association of Urology (EAU) prognostic factor risk groups. Cancer‐specific survival was similar in patients receiving 1/3D and those receiving FD BCG (P = 0.320). Conclusion: The use of 1/3D BCG was not associated with adverse oncological outcomes in a large cohort of patients receiving adequate BCG for intermediate‐ and high‐risk NMIBC. Based on this real‐world experience, risk‐stratified split‐vial dosing may represent a valuable approach for other institutions facing BCG shortages whilst also providing reassurance to patients who may be concerned about suboptimal outcomes. [ABSTRACT FROM AUTHOR]

Objectives: To investigate bacille Calmette–Guérin (BCG) tolerability and response with respect to the timing of BCG administration after transurethral resection of bladder tumour (TURBT) in patients with non‐muscle‐invasive bladder cancer (NMIBC). Patients and Methods: A review of patients with NMIBC at our institution managed with at least 'adequate BCG' (defined by the United States Food and Drug Administration as at least five of six induction instillations, with two additional instillations comprising either maintenance or repeat induction) at our institution from 2000 to 2018 was performed. Time from TURBT to first instillation of induction BCG was stratified by quartile and analysed as a continuous variable. Kaplan–Meier and log‐rank tests analysed differences in recurrence‐free (RFS) and progression‐free survival (PFS). Cox proportional hazards regression models identified associations between risk factors and survival outcomes. Results: A total of 518 patients received adequate BCG at a median (range) of 26 (6–188) days from TURBT. Overall, 45 patients (9%) developed BCG intolerance at a median (range) 12 (7‐33) instillations. When time from TURBT to BCG was stratified into quartiles, there was no difference with respect BCG intolerance (P = 0.966), RFS (P = 0.632) or PFS (P = 0.789). On both uni‐ and multivariate regression analysis for RFS and PFS, time from TURBT to BCG was not a significant predictor when analysed by quartile or as a continuous variable (the hazard ratio for RFS was 1.00, 95% confidence interval [CI] 0.99–1.00, P = 0.449; and for PFS was 0.99, 95% CI 0.98–1.00, P = 0.074). Conclusion: The rates of tolerability and response to adequate BCG are not predicated by the timing of induction BCG instillation after TURBT. Early administration in properly selected patients is safe and delays do not affect therapeutic response. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of upper tract urothelial carcinoma (UTUC) on bacillus Calmette‐Guerin (BCG) response and progression in patients with non‐muscle‐invasive bladder cancer (NMIBC). Patients and Methods: We performed an institutional review board‐approved review of patients with NMIBC treated with adequate intravesical BCG, as defined by the US Food and Drug Administration, at our institution between 2000 and 2018. Patients were stratified by presence of any UTUC and time of UTUC diagnosis (preceding vs synchronous to NMIBC diagnosis or metachronous disease after NMIBC diagnosis). Descriptive statistics were used to summarize the data overall and by groups, and t‐tests or Wilcoxon's rank sum tests and Pearson's chi‐squared or Fisher's exact tests were used to analyse continuous and categorical data, respectively. Results: Of 541 patients with NMIBC treated with adequate BCG, 59 (10.9 %) were diagnosed with UTUC. Of these, 34 had a history of UTUC prior to NMIBC (UTUC‐P; median [interquartile range {IQR}] 13.1 [7.4–27.6] months prior), while 25 developed UTUC after diagnosis of NMIBC (six synchronous and 19 metachronous; median [IQR] 12.1 [1.7–28.1] months after). Compared to the non‐UTUC group, patients with UTUC‐P were more likely to exhibit Tis without papillary tumour in the bladder (20.6% vs 5.0%; P < 0.001), but were less likely to have T1 disease on index transurethral resection (8.8% vs 49.4%; P < 0.001). Patients with UTUC‐P developed more recurrences (55.9% vs 34.0%; P = 0.010), any stage/grade progression (23.5% vs 9.8%; P = 0.012) and progression to muscle‐invasive or metastatic disease (17.6% vs 6.4%; P = 0.014). The presence of high‐grade UTUC‐P compared to low‐grade UTUC‐P was associated with increased NMIBC recurrence (68.2% vs 25.0%; P = 0.049). There was no significant difference in rates of recurrence or progression based on timing of UTUC with respect to the index bladder tumour, although this analysis was limited by small numbers. Conclusions: Presence of UTUC prior to a diagnosis of NMIBC was associated with an almost twofold increased recurrence and progression rates after adequate BCG therapy. This should be considered when counselling patients and designing cohorts for clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Data from the pre-neoadjuvant chemotherapy (NAC) era suggests patients who progress on bacillus Calmette-Guerin (BCG) to muscle-invasive bladder cancer (P-MIBC) exhibit worse outcomes compared to de novo MIBC (D-MIBC). Herein, we investigate whether P-MIBC is an independent poor risk factor in the setting of contemporary NAC use. Materials and Methods: A review of patients who underwent radical cystectomy (RC) for cT2-3 MIBC from 2005 to 2018 was performed. Patients were stratified into high risk (lymphovascular invasion, variant histology, hydronephrosis, cT3b) vs low risk (no risk factors) and P-MIBC (≥pT1 treated with at least induction BCG who progressed to -cT2) vs D-MIBC. Results: Among 801 patients who underwent RC 20.3% had P-MIBC and 79.7% had D-MIBC. In low-risk patients treated without NAC, P-MIBC was associated with pathological upstaging (64.9% vs 42.7%, p[0.004) and worse overall (OS, p[0.006) and cancer-specific survival (CSS, p[0.001) compared to D-MIBC. P-MIBC status conferred uniformly poor survival outcomes to patients who did not receive NAC compared to D-MIBC without NAC (median OS 51.5 months [95% CI 40.0e81.0] vs 85.1 months [95% CI 62.8e96.0], p[0.040; median CSS not reached, p[0.014). However, P-MIBC status did not remain a negative prognostic factor in the setting of NAC (median OS 90.5 months [95% CI 34.0enot estimable] vs 87.8 months [95% CI 68.7enot estimable], p[0.606; median CSS not reached, p[0.448). Conclusions: P-MIBC confers a poor prognosis when managed with RC alone. Treatment with NAC results in equivalent pathological response and survival outcomes compared to D-MIBC. P-MIBC should be included in risk-stratified approaches to NAC selection. [ABSTRACT FROM AUTHOR]

Introduction: Muscle-invasive bladder cancer (BC) often occurs in patients with competing mortality risks, while also being associated with the highest rate of second primary nonurothelial cancers (SNUC) of all solid malignancies. We investigated the incidence, risk factors, and timing of SNUC as a competing mortality risk factor in patients with BC who were treated with curative intent radical cystectomy (RC).Methods: We performed a retrospective cohort study assessing patients who underwent RC for cT2-4 N0M0 BC from January 1, 2005 to December 31, 2018 at a single, high volume tertiary care referral center. The Fine-Gray multivariable regression model was used to evaluate predictive factors for SNUC. Cumulative incidence of mortality (CIM) was estimated with modified Kaplan-Meier analysis.Results: The median follow-up time for the 693 patients who underwent RC was 3.7 years (interquartile range [IQR] 1.9-5.9 years). SNUC developed in 85 (12.3%) patients at a median 3.0 years post-RC (IQR 1.2-5.5 years). On multivariable analysis, the only significant predictor for developing SNUC was freedom from BC recurrence or metastasis (HR 1.54, 95% CI 1.12-1.76, P = 0.019). The most common SNUCs were primary lung cancer (24, 3.2% of cohort) and colon cancer (9, 1.3% of cohort). BC surveillance imaging diagnosed SNUC in 35/52 (67.3%) patients with solid-organ visceral primaries. The overall mortality rate for any SNUC was 38.8%, with the 3 most lethal cancer types being pancreatic, lung, and colon (62.5%, 54.2%, and 44.4% mortality, respectively). The incidence of SNUC uniformly increased postoperatively, with a cumulative incidence of 22.1% (95% CI, 16.8-27.9%) at 12-years post-RC. 163 patients (23.5%) died from BC, 33 patients (4.8%) died from SNUC, and 94 patients (13.6%) died from other causes. While the CIM for BC plateaued around 5-years post-RC at 24%, the incidence of other-cause mortality uniformly rose throughout the postoperative period. By post-RC year 9 there was no significant difference in CIM between BC (CIM 27.2%, 95% CI, 23.5-31.1%) and other-causes (CIM 20.0%, 95% CI, 15.8-24.6%).Conclusions: The cumulative incidence of SNUC at 12-years post-RC was 22%, with the majority identified on BC surveillance imaging. While BC mortality plateaued around 5-years post-RC, mortality related to SNUC or other causes rose steadily in the postoperative period. These data have clinical significance with regards to patient counseling, survivorship and oncologic surveillance in the highly comorbid muscle-invasive BC population. [ABSTRACT FROM AUTHOR]

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive urothelial carcinoma of the bladder confers only a modest survival advantage. Patients with pathologic progression on NAC have poor outcomes related to a delay in definitive surgical management.Objective: To characterize the value of epithelial-mesenchymal transition (EMT) effectors and other novel biomarkers to predict response to NAC.Methods: A tissue microarray was constructed from patients with clinical stage T2 urothelial carcinoma of the bladder using transurethral resection (TUR) specimens (N = 69) and case-matched post-NAC cystectomy specimens (N = 51). Patients were stratified based on pathologic response to NAC and cancer-specific survival. Biomarker expression in TUR specimens was correlated with pathologic response to NAC and clinical outcomes. Phenotypic changes in expression induced by cisplatin-based NAC were characterized in primary TUR and post-NAC cystectomy and lymph node metastasis specimens.Results: Increased expression of mesenchymal markers and actin-cytoskeleton regulators, as well as low apoptosis index, in TUR specimens was associated with pathologic progression on cisplatin-based NAC. Overexpression of N-cadherin and decreased apoptosis was predictive of disease-specific mortality. NAC decreased cofilin phosphorylation and induced a mesenchymal-epithelial transition phenotype.Conclusions: The epithelial-mesenchymal transition phenotype and actin-cytoskeleton remodeling are associated with pathologic progression on NAC. Chemotherapy induced an mesenchymal-epithelial transition phenotype and decreased cofilin phosphorylation, providing new insights into therapeutic resistance mechanisms. Primary tumors with high apoptosis rates exhibited favorable response to NAC and lower mortality rates, indicating that these tumors may be sensitized to therapy. Further validation will establish these novel signatures as predictors of therapeutic response. [ABSTRACT FROM AUTHOR]