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.

Characterizing the Genomic Landscape of the Micropapillary Subtype of Urothelial Carcinoma of the Bladder Harboring Activating Extracellular Mutations of ERBB2.

The micropapillary subtype of urothelial carcinoma (MPUC) of the bladder is a very aggressive histological variant of urothelial bladder cancer (UBC). A high frequency of MPUC contains activating mutations in the extracellular domain (ECD) of ERBB2. We sought to further characterize ERBB2 ECD-mutated MPUC to identify additional genomic alterations that have been associated with tumor progression and therapeutic response. In total, 5,485 cases of archived formalin-fixed, paraffin-embedded UBC underwent comprehensive genomic profiling to identify ERBB2 ECD-mutated MPUC and evaluate the frequencies of genomic co-alterations. We identified 219 cases of UBC with ERBB2 ECD mutations (74% S310F and 26% S310Y), of which 63 (28.8%) were MPUC. Genomic analysis revealed that TERT, TP53, and ARID1A were the most common co-altered genes in ERBB2-mutant MPUC (82.5%, 58.7%, and 39.7%, respectively) and did not differ from ERBB2-mutant non-MPUC (86.5%, 51.9%, and 35.3%). The main differences between ERBB2 ECD-mutated MPUC compared with non-MPUC were KMT2D, RB1, and MTAP alterations. KMT2D and RB1 are tumor-suppressor genes. KMT2D frequency was significantly decreased in ERBB2 ECD-mutated MPUC (6.3%) in contrast to non-MPUC (27.6%; P < .001). RB1 mutations were more frequent in ERBB2 ECD-mutated MPUC (33.3%) than in non-MPUC (17.3%; P = .012). Finally, MTAP loss, an emerging biomarker for new synthetic lethality-based anticancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than in non-MPUC (26.9%; P = .018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.

Long-Term Oncological Outcomes in Patients Diagnosed With Nonmetastatic Plasmacytoid Variant of Bladder Cancer: A 20-Year University of Texas MD Anderson Cancer Center Experience.

PURPOSE: The treated natural history of nonmetastatic plasmacytoid variant of bladder cancer (PV-BCa) is poorly understood owing to its rarity. We sought to examine the disease recurrence and metastasis patterns in this select group of patients in order to identify opportunities for intervention. MATERIALS AND METHODS: We conducted a natural language processing algorithm-augmented retrospective chart review of 56 consecutive patients who were treated with curative intent for nonmetastatic PV-BCa at our institution between 1998 and 2018. Kaplan-Meier and multivariable Cox regression methods were used for survival analyses. RESULTS: The stage at presentation was: ≤ cT2N0 in 22 (39.3%), cT3N0 in 15 (26.8%), cT4N0 in 13 (23.2%), and ≥ cN1 in 6 patients (10.7%). Forty-nine patients (87.5%) received chemotherapy, and 42 (75%) were able to undergo the planned surgery. Notably, only 4 patients (7.2%) had pT0 stage, while 22 (52.4%) had pN+ disease at the time of surgery. At 36-month follow-up, 28.4% of patients (95% CI: 22.1%-34.5%) were alive and 22.2% (95% CI: 16.1%-28.5%) were free of metastatic disease. The benefit of surgical extirpation was stage specific: successful completion of surgery was associated with improved metastasis-free survival (at 36 months 32.4% vs 0%, log-rank P < .001) in patients with localized or locally advanced disease (≤cT2N0/cT3N0); however, in patients with regionally advanced disease (cT4N0/≥cN1), consolidative surgery following chemotherapy was not associated with improved metastasis-free survival (12.5% vs 10% at 36 months, log-rank P = .49). The median time to metastasis from primary treatment end was 6.5 months (IQR: 2.9-14.7). The predominant site of recurrence/metastasis was the peritoneum (76.1%), either in isolation or along with extraperitoneal lesions. Salvage immunotherapy in these patients significantly reduced the risk of death (HR = 0.11, P = .001). CONCLUSIONS: PV-BCa is a disease with high lethality. Despite multimodal treatment, a vast majority of patients develop atypical intraperitoneal metastasis soon after therapy and rapidly succumb to it. Clinical trials evaluating utility of hyperthermic intraperitoneal chemotherapy and/or immunotherapy may be warranted in this high-risk population.

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Impact of age >70 years on oncological outcomes in patients with non-muscle-invasive bladder cancer treated with Bacillus Calmette-Guérin.

OBJECTIVE: To evaluate the impact of age on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate Bacillus Calmette-Guérin (BCG). PATIENTS AND METHODS: We performed an Institutional Review Board-approved retrospective study analysing patients with NMIBC treated with adequate BCG at our institution from 2000 to 2020. Adequate BCG was defined as per United States Food and Drug Administration (FDA) guidelines as being receipt of at least five of six induction BCG instillations with a minimum of two additional doses (of planned maintenance or of re-induction) of BCG instillations within a span of 6 months. The study's primary outcome was to determine if age >70 years was associated with progression to MIBC cancer or distant metastasis. The cumulative incidence method and the competing-risk regression analyses were used to investigate the association of advanced age (>70 years) with progression, high-grade (HG) recurrence and cancer-specific mortality (CSM). RESULTS: Overall, data from 632 patients were analysed: 355 patients (56.2%) were aged ≤70 years and 277 (43.8%) were >70 years. Age >70 years did not adversely affect either cumulative incidence of progression or HG recurrence (P = 0.067 and P = 0.644, respectively). On competing-risk regression analyses, age >70 years did not emerge as an independent predictor of progression or HG recurrence (sub-standardised hazard ratio [SHR] 1.57, 95% confidence interval [CI] 0.87-2.81, P = 0.134; and SHR 1.05, 95% CI 0.77-1.44, P = 0.749). Not unexpectedly, patients in the older group did have higher overall mortality (P < 0.001) but not CSM (P = 0.057). CONCLUSION: Age >70 years was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. BCG should not be withheld from older patients seeking for bladder sparing options.

Influence of lamina propria invasion extension on T1 high-grade non-muscle-invasive bladder cancer in patients undergoing BCG or radical cystectomy.

OBJECTIVE: To evaluate the prognostic value of T1 substaging in patients treated with bacillus Calmette-Guérin (BCG) or immediate radical cystectomy (iRC). MATERIALS AND METHODS: We performed an institutional review board-approved retrospective study analysing non-muscle-invasive bladder cancer (NMIBC) patients with pT1 disease treated with either BCG or iRC between 2000 and 2020. Lamina propria (LP) invasion characteristics were extracted from the pathology report. The Kaplan-Meier method was used to calculate overall survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MFS). Multivariable Cox models were used to determine the association between progression-free survival (PFS) and characteristics in the BCG cohort. A logistic regression model explored the relationship between T1 substaging and upstaging to >pT2 at iRC. RESULTS: A total of 411 T1 high-grade patients were identified. LP invasion characteristics were as follows: not specified: 115 (28%); focal/superficial (F/S): 147 (35.8%); and extensive/multifocal (E/M): 149 (36.2%). Overall, 303 patients (73.7%) received BCG, and 108 patients (26.3%) underwent iRC. The median (interquartile range) follow-up was 53 (32-96) months. Patients with E/M LP invasion were significantly more likely to undergo iRC (34% vs. 19%; P = 0.003). Patients with E/M LP invasion showed poorer MFS and CSS compared to those with F/S LP invasion when treated with BCG but not when treated with iRC. Among BCG-treated patients, progression occurred in 41 patients and E/M LP invasion was independently associated with progression after BCG (hazard ratio 5.3, 95% confidence interval [CI] 2.2-13.1; P < 0.001). T1 substaging was not associated with upstaging at RC (odds ratio 3.15, 95% CI 0.82-12.12; P = 0.095). CONCLUSIONS: Extensive/multifocal LP invasion was associated with poor PFS, MFS and CSS in patients treated with BCG. T1 substaging provides valuable prognostic information and should be reported in pathology reports.

A phase II trial of apalutamide for intermediate-risk prostate cancer and molecular correlates.

OBJECTIVES: To determine whether 6 months of preoperative apalutamide for intermediate-risk prostate cancer (IRPCa) reduces the aggregate postoperative radiotherapy risk and to evaluate associations of molecular perturbations with clinical outcomes in this study cohort. PATIENTS AND METHODS: Between May 2018 and February 2020, eligible patients with IRPCa (Gleason 3 + 4 or 4 + 3 and clinical T2b-c or prostate-specific antigen level of 10-20 ng/mL) were treated with apalutamide 240 mg/day for 6 months followed by radical prostatectomy (RP) in this single-arm, phase II trial. The primary endpoint was presence of any adverse pathological feature at risk of pelvic radiation (pathological T stage after neoadjuvant therapy [yp]T3 or ypN1 or positive surgical margins). Translational studies, including germline and somatic DNA alterations and RNA and protein expression, were performed on post-apalutamide RP specimens, and assessed for associations with clinical outcomes. RESULTS: A total of 40 patients underwent a RP, and only one patient discontinued apalutamide prior to 6 months. In all, 40% had adverse pathological features at time of RP, and the 3-year biochemical recurrence (BCR) rate was 15%, with 27.5% being not evaluable. Genomic alterations frequently seen in metastatic PCas, such as androgen receptor (AR), tumour protein p53 (TP53), phosphatase and tensin homologue (PTEN), or BReast CAncer associated gene (BRCA1/2) were underrepresented in this localised cohort. Adverse pathological features and BCR at 3-years were associated with increased expression of select cell cycle (e.g., E2F targets: adjusted P value [Padj] < 0.001, normalised enrichment score [NES] 2.47) and oxidative phosphorylation (Padj < 0.001, NES 1.62) pathways. CONCLUSIONS: Preoperative apalutamide did not reduce the aggregate postoperative radiation risk to the pre-specified threshold in unselected men with IRPCa. However, transcriptomic analysis identified key dysregulated pathways in tumours associated with adverse pathological outcomes and BCR, which warrant future study. Further investigation of preoperative therapy is underway for men with high-risk PCa.

Current Status and Challenges in Rare Genitourinary Cancer Research and Future Directions.

PURPOSE OF REVIEW: In contemporary urological practice, managing rare genitourinary (GU) malignancies presents significant challenges, necessitating a comprehensive understanding of their unique characteristics and tailored treatment approaches. RECENT FINDINGS: Rare GU malignancies, whether per se, variants of common histologies, or common tumors in uncommon locations, often lack widely available clinical guidelines. Consequently, treatment decisions are frequently based on empirical evidence, risking suboptimal outcomes. However, recent advances in molecular profiling, targeted therapies, and immunotherapy offer promising avenues for improving management strategies and patient outcomes. This review provides a comprehensive overview of some rare GU malignancies encountered in clinical practice, including their distinct pathological features, current management approaches, and ongoing research directions. Understanding the complexities of these rare tumors and implementing multidisciplinary treatment strategies are essential for optimizing patient care and improving survival outcomes.

Current best practice for bladder cancer: a narrative review of diagnostics and treatments.

This Seminar presents the current best practice for the diagnosis and management of bladder cancer. The scope of this Seminar ranges from current challenges in pathology, such as the evolving histological and molecular classification of disease, to advances in personalised medicine and novel imaging approaches. We discuss the current role of radiotherapy, surgical management of non-muscle-invasive and muscle-invasive disease, highlight the challenges of treatment of metastatic bladder cancer, and discuss the latest developments in systemic therapy. This Seminar is intended to provide physicians with knowledge of current issues in bladder cancer.

Evolving systemic management of urothelial cancers.

PURPOSE OF REVIEW: Bladder cancer is the 12th most common cancer worldwide. Historically, the systemic management of urothelial carcinoma has been confined to platinum-based chemotherapy. In this review, we discuss the evolving landscape of systemic treatment for urothelial carcinoma. RECENT FINDINGS: Since 2016, when the Food and Drug Administration approved the first immune checkpoint inhibitor (CPI), programmed cell death 1 and programmed cell death ligand 1 inhibitors have been evaluated in the nonmuscle invasive bladder cancer, localized muscle invasive bladder cancer as well as advanced/metastatic bladder cancer settings. Newer approved treatments such as fibroblast growth factor receptor (FGFR) inhibitors and antibody-drug conjugates (ADCs) represent second-line and third-line options. These novel treatments are now being assessed in combination as well as with older traditional platinum-based chemotherapy. SUMMARY: Novel therapies continue to improve bladder cancer outcomes. Personalized approach with well validated biomarkers are important to predict response to therapy.

International Bladder Cancer Group Intermediate-risk Nonmuscle-invasive Bladder Cancer Scoring System Predicts Outcomes of Patients on Active Surveillance.

PURPOSE: We sought to determine if the International Bladder Cancer Group IR-NMIBC (Intermediate-risk Nonmuscle-invasive Bladder Cancer) scoring system can predict the requirement of delayed transurethral resection of bladder tumor in low-grade nonmuscle-invasive bladder cancer managed by active surveillance. MATERIALS AND METHODS: We prospectively studied recurrent low-grade Ta/T1 nonmuscle-invasive bladder cancer patients managed with active surveillance with the following characteristics: low-grade papillary nonmuscle-invasive bladder cancer, ≤5 apparent low-grade nonmuscle-invasive bladder tumors, tumor diameter ≤1 cm, absence of gross hematuria, and negative urinary cytology. Subsequent transurethral resection of bladder tumor was offered to patients who no longer met the inclusion criteria or patient choice. The ability of the International Bladder Cancer Group IR-NMIBC scoring system to predict receipt of subsequent transurethral resection of bladder tumor was determined. Multivariable Cox proportional hazards analysis was used to determine factors associated with subsequent transurethral resection of bladder tumor. RESULTS: A total of 163 patients with low-grade Ta/T1 nonmuscle-invasive bladder cancer were included for analysis. After a median follow-up of 33 months (IQR: 21-46), transurethral resection of bladder tumor was performed on 109 patients. At landmark time point of 24 months, patients with 0 risk factors were over 2-fold more likely to continue active surveillance compared to patients with ≥3 risk factors (59% vs 24%). Multivariable Cox regression suggested that the International Bladder Cancer Group IR-NMIBC scoring system was associated with subsequent transurethral resection of bladder tumor (1-2 risk factors [HR: 1.66, 95% CI: 0.96-2.90, P = .072], ≥3 risk factors [HR: 3.21, 95% CI: 1.70-6.09, P < .001]) after adjusting for age, T stage, and sex. CONCLUSIONS: The International Bladder Cancer Group IR-NMIBC scoring system can predict the risk of subsequent transurethral resection of bladder tumor in patients with low-grade nonmuscle-invasive bladder cancer on active surveillance.

Repeat Transurethral Resection of Muscle-invasive Bladder Cancer Prior to Radical Cystectomy is Prognostic but Not Therapeutic.

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 recurrence-free 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.

Geographic distribution of racial differences in mortality in muscle-invasive bladder cancer patients: an opportunity for improvement.

OBJECTIVES: To determine the geographic distribution of muscle-invasive bladder cancer mortality according to race in the United States (US). African Americans (AAs) have up to two times the risk of bladder cancer mortality compared to Caucasians. Bladder cancer mortality increases exponentially once it invades the muscle. Geographic heterogeneity in bladder cancer mortality according to race remains to be determined. DESIGN: Analysis of Surveillance, Epidemiology, and End Results (SEER)-Medicare data for 6,044 patients aged 66-85 diagnosed with clinical stage T2-T4 N0M0 bladder cancer from 1 January 2002 to 31 December 2011. Fine and Gray-competing risks regression models were used to assess the association of race with bladder cancer-specific mortality (BCSM) according to tumor registry. RESULTS: Out of 6,044 patients, 5,408 (89.5%) were Caucasian, 352 (5.82%) were non-Hispanic AA, 85 (1.4%) were Hispanic, and 199 (3.29%) were other. Of the 18 registries, AAs with bladder cancer were largely concentrated in Louisiana (19%), New Jersey (17.9%), and Georgia (17.6%). New Jersey was the only registry where AAs had increased risk of BCSM than Caucasians and only for stage T2 disease: (AHR, 1.74; 95% CI 1.22-2.47, p = 0.002). According to treatment, AAs in New Jersey had worse BCSM than Caucasians when they underwent radical cystectomy (AHR, 2.05; 95% CI 1.26-3.35, p = 0.0039) and radiotherapy or chemotherapy alone (AHR, 1.55; 95% CI 1.03-2.35, p = 0.0367). CONCLUSIONS: We observed geographic variation in bladder cancer mortality which impacted only one registry with one of the largest population of AAs. These findings support further investigation into the social determinants of race (i.e., socioeconomic status and distance to healthcare facility) and culturally centered healthcare decision making which may drive these results.

Race reporting and disparities regarding clinical trials in bladder cancer: a systematic review.

PURPOSE: To systematically review the literature to investigate racial disparities among bladder cancer clinical trial enrollees. METHODS: A systematic review was conducted using Ovid, MEDLINE® to identify clinical trials between 1970 and 2020. Articles were reviewed and were included if they assessed race in their outcomes reporting among bladder cancer patients enrolled in clinical trials. The review was conducted in accordance with the PRISMA statement. RESULTS: We identified 544 clinical trials meeting our initial search criteria, with only 24 (4.4%) studies reporting racial demographic data. Enrollees were largely Caucasian (81-98%), with a strikingly small proportion of enrolled patients consisting of African-Americans (2-8%) and Hispanics (2-5%). Only one of the studies reported results on the efficacy and safety/tolerability of the tested treatment separately for racial groups and performed analyses stratified by race. CONCLUSION: Race is poorly studied in bladder cancer clinical trials. Trial cohorts may not reflect multicultural populations. The potential association between race and efficacy, safety or tolerability of the tested interventions is unknown. Given the up to twofold increase in bladder cancer-specific death among African-Americans, further research is needed to address the impact of race in clinical trials, while encompassing socioeconomic factors and disease risk factor exposures.

All High-Grade Ta Tumors Should Be Classified as High Risk: Bacillus Calmette-Guérin Response in High-Grade Ta Tumors.

PURPOSE: There is variation amongst guidelines with respect to risk stratification of Ta tumors, specifically high-grade (HG) Ta tumors. We sought to investigate the response of all Ta tumors to bacillus Calmette-Guérin (BCG) and compare response rates based on European Association of Urology (EAU) classification as intermediate- (IR) or high-risk (HR). MATERIALS AND METHODS: An institutional review of all patients who received adequate BCG from 2000-2018 was conducted. EAU 2021 prognostic risk groups were used to stratify patients including by the newly proposed adverse risk factors. RESULTS: When patient with Ta tumors were stratified into IR and HR, 37 (16%) had IR low-grade (LG) Ta, 92 (40%) had IR HG Ta and 101 (44%) had HR HG Ta tumors. BCG unresponsiveness developed in 13% of HR HG Ta tumors and 14% of IR HG Ta tumors compared to 0.0% of IR LG Ta tumors (p=0.003). While no patients with IR LG Ta tumors progressed, progression rates were similar in HR HG Ta and IR HG Ta tumors (≥T2: 5.9% and 6.5%; [Formula: see text]T1: 13% and 13%, respectively). Rates of recurrence, BCG unresponsiveness and progression were similar, irrespective of number of EAU risk factors present (p=0.9, p=0.8 and p=0.9, respectively). CONCLUSIONS: All HG Ta tumors, regardless of EAU risk stratification, have inferior response to BCG and increased rates of progression compared to IR LG Ta tumors. EAU clinical risk factors did not improve prediction of oncologic outcomes among HG Ta patients who received adequate BCG. These data support consideration of all HG tumors as high risk.

Role of Lymphadenectomy during Radical Cystectomy for Nonmuscle-Invasive Bladder Cancer: Results from a Multi-Institutional Experience.

PURPOSE: While lymph node dissection (LND) at radical cystectomy (RC) for muscle-invasive bladder cancer has been studied extensively, the role of LND for nonmuscle-invasive bladder cancer (NMIBC) remains incompletely defined. Herein, we aim to assess the association between extent of LND during RC for NMIBC and local pelvic recurrence-free survival (LPRS), cancer-specific survival (CSS) and overall survival (OS). MATERIALS AND METHODS: A multi-institutional retrospective review was performed of patients with NMIBC undergoing RC at 3 large tertiary referral centers. To identify a threshold for lymph node yield (LNY) to optimize LPRS, CSS and OS, separate Cox regression models were developed for each possible LNY threshold. Model performance including Q-statistics and hazard ratios (HRs) were used to identify optimal LNY thresholds. RESULTS: A total of 1,647 patients underwent RC for NMIBC, with a median LNY of 15 (quartiles 9,23). Model performance curves suggested LNY of 10 and 20 to optimize LPRS and CSS/OS, respectively. On multivariable regression, LNY >10 was associated with lower risk of LPR compared to LNY ≤10 (HR 0.63, 95% CI 0.42-0.93, p=0.02). Similarly, LNY >20 was associated with improved CSS (HR 0.67, 95% CI 0.52-0.87, p=0.002) and OS (HR 0.75, 95% CI 0.64-0.88, p <0.001) compared to LNY ≤20. Similar results were observed in the cT1 and cTis subgroups. CONCLUSIONS: Greater extent of LND during RC for NMIBC is associated with improved LPRS, CSS and OS, supporting the inclusion of LND during RC for NMIBC, particularly among patients with cTis or cT1 disease. Future prospective studies are warranted to assess the ideal anatomical template of LND in NMIBC.

Reduced-dose bacillus Calmette-Guérin (BCG) in an era of BCG shortage: real-world experience from a tertiary cancer centre.

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.

Should patients with non-muscle-invasive bladder cancer discontinue fibrin clot inhibitors during bacille Calmette-Guérin?

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.

Clinicopathological analysis and outcomes of inflammatory myofibroblastic tumours of the urinary bladder.

OBJECTIVES: To describe clinical, imaging, and histopathological characteristics of inflammatory myofibroblastic tumour (IMT) of the urinary bladder and provide initial management and surveillance recommendations. PATIENTS AND METHODS: We identified patients with IMT of the bladder treated at our facility from 1998 to 2020. Categorical variables were analysed with chi-square and Fisher's exact tests and continuous variables with the Mann-Whitney U-test. Kaplan-Meier analysis was performed for recurrence-free survival. RESULTS: IMT was diagnosed in 35 patients with median (interquartile range [IQR]) follow-up of 20 (11.5-68.5) months. At initial diagnosis 86% were clinically organ-confined, 9% locally advanced, and 5% metastatic. Majority of patients (92%) had residual disease on re-staging transurethral resection (TUR). Of the 15 patients with organ-confined disease managed initially with TUR alone, five (33%) recurred at a median (IQR) of 5 (3.0-5.5) months from initial diagnosis. Presentation with visible haematuria was associated with recurrence (100% in recurrence vs 40% in non-recurrence groups, P = 0.044). There were no patients who developed a recurrence beyond 6 months after diagnosis. Partial or radical cystectomy was required in 23% and 9% of patients, respectively. One patient presented with metastatic disease associated with anaplastic lymphoma kinase (ALK) translocation and achieved a durable complete remission with 7 months of crizotinib therapy. CONCLUSIONS: No patient with IMT treated with aggressive endoscopic management developed recurrences beyond 6 months. There were additionally no recurrences noted after definitive radical or partial cystectomy. These data support organ sparing therapy with aggressive endoscopic management and short-term surveillance in patients with localised IMT, with extirpative surgery reserved for refractory cases.

Critical analysis of quality of life and cost-effectiveness of enhanced recovery after surgery (ERAS) for patient's undergoing urologic oncology surgery: a systematic review.

PURPOSE: Enhanced recovery after surgery (ERAS) protocols have been implemented across a variety of disciplines to improve outcomes. Herein we describe the impact of ERAS on quality of life (QOL) and cost for patients undergoing urologic oncology surgery. METHODS: A systematic literature search using the MEDLINE, Scopus, Clinictrials.gov, and Cochrane Review databases for studies published between 1946 and 2020 was conducted. Articles were reviewed and assigned a risk of bias by two authors and were included if they addressed ERAS and either QOL or cost-effectiveness for patients undergoing urologic oncology surgery. RESULTS: The literature search yielded a total of 682 studies after removing duplicates, of which 10 (1.5%) were included in the review. Nine articles addressed radical cystectomy, while one addressed ERAS and QOL for laparoscopic nephrectomy. Six publications assessed the impact of ERAS on QOL domains. Questionnaires used for assessment of QOL varied across studies, and timing of administration was heterogeneous. Overall, ERAS improved patient QOL during early phases of recovery within the realms of bowel function, physical/social/cognitive functioning, sleep and pain control. Costs were assessed in 4 retrospective studies including 3 conducted in the United States and one from China all addressing radical cystectomy. Studies demonstrated either decreased costs associated with ERAS as a result of decreased length of stay or no change in cost based on ERAS implementation. CONCLUSION: While limited studies are published on the subject, ERAS implementation for radical cystectomy and laparoscopic nephrectomy improved patient-reported QOL during early phases of recovery. For radical cystectomy, there was a decreased or neutral overall financial cost associated with ERAS. Further studies assessing QOL and cost-effectiveness over the entire global period of care in a variety of urologic oncology surgeries are warranted.