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OBJECTIVE: To evaluate the role of pelvic lymph node dissection (PLND) in patients diagnosed with high-risk nonmuscle-invasive bladder cancer (NMIBC) undergoing radical cystectomy (RC) using a national cohort of NMIBC patients. METHODS: A cohort of patients diagnosed with NMIBC cancer with urothelial carcinoma from the National Cancer Database (NCDB) between 2004 and 2019 was utilized. The cohort consists of patients who have not received BCG and underwent upfront radical cystectomy or pelvic exenteration. Kaplan-Meier analysis was utilized to assess overall survival (OS) outcomes. Cox regression was also utilized to identify independent predictors of OS. RESULTS: The cohort of 9399 patients was stratified by clinical T stage and then subdivided by pathological outcome. For patients with cTa, a majority received a lymph node dissection 97.74% (941/1019), amongst the entire cohort, a minority had node positive disease 3.3% (34/1019). For cTis, most patients received a lymph node dissection 94.08% (482/507), and a minority had node positive disease 5.1% (26/507). For cT1, most patients had a lymph node dissection 95.62% (6,060/6,337), and a 13.1% (832/6337) of patients had a positive lymph node. Amongst patients with cT1 disease who underwent PLND, KMA demonstrated better OS compared to patients who did not undergo PLND (P < .001). CONCLUSION: The data suggests an OS benefit in patients with later stage (cT1) NMIBC. Thus, our findings support the existing clinical guidelines of pelvic lymph node dissection in patients with high-risk nonmuscle invasive bladder cancer.

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INTRODUCTION: This study aimed to assess the predictive value of abdominal fat characteristics measured by computed tomography (CT) in identifying early recurrence within one year post-initial transurethral resection of bladder tumor (TURBT) in patients with nonmuscle-invasive bladder cancer (NMIBC). A predictive model integrating fat features and clinical factors was developed to guide individualized treatment. MATERIALS AND METHODS: A retrospective analysis of 203 NMIBC patients from two medical centers was conducted. Abdominal CT images were analyzed using 3D Slicer software. Spearman correlation, logistic regression, and the Lasso algorithm were employed for data analysis. Predictive efficacy was assessed using the area under the curve (AUC) of receiver operating characteristic (ROC) and decision curve analysis (DCA). Calibration was evaluated using the Hosmer-Lemeshow test. RESULTS: Significant differences in abdominal fat characteristics were found between the recurrence and nonrecurrence groups. All fat features positively correlated with body mass index (BMI), with bilateral perirenal fat thickness (PrFT) showing superior predictive performance. Multivariate logistic regression identified independent predictors of early recurrence, including tumor number, early perfusion chemotherapy, left and right PrFT, and visceral fat area (VFA) at umbilical and renal hilum levels. The Lasso-based model achieved an AUC of 0.904, outperforming existing models. CONCLUSION: Abdominal fat characteristics, especially bilateral PrFT, strongly correlate with early recurrence in NMIBC. The Lasso-based model, integrating fat and clinical factors, offers superior predictive efficacy and could improve individualized treatment strategies.

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PURPOSE: Nonmuscle-invasive bladder cancer (NMIBC) has high recurrence rates and is often treated with mitomycin C (MMC) and bacillus Calmette-Guérin (BCG). Their efficacy relies on phase 2 enzyme metabolism and immune response activation, respectively. Dietary isothiocyanates, phytochemicals in cruciferous vegetables, are phase 2 enzyme inducers and immunomodulators, and may impact treatment outcomes. We investigated the modifying effects of cruciferous vegetable and isothiocyanate intake on recurrence risk following MMC or BCG treatment. MATERIALS AND METHODS: Self-reported cruciferous vegetable intake, estimated isothiocyanate intake, and urinary isothiocyanate metabolites were collected from 1158 patients with incident NMIBC in the prospective Be-Well Study. Hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazards regression models for risk of first recurrences, and random effects Cox shared frailty models for multiple recurrences. RESULTS: Over median follow-up of 23 months, 343 (30%) recurrences occurred. Receipt of MMC and BCG was associated with decreased risks of first recurrence (MMC: HR = 0.58; 95% CI: 0.46-0.73; BCG: HR = 0.66; 95% CI: 0.49-0.88) and multiple recurrences (MMC: HR = 0.55; 95% CI: 0.44-0.68; BCG: HR = 0.72; 95% CI: 0.55-0.95). Patients receiving BCG and having high intake (>2.4 servings/mo), but not low intake, of raw cruciferous vegetables had reduced risk of recurrence (HR: 0.56; 95% CI: 0.36-0.86; P for interaction = .02) and multiple recurrences (HR: 0.51; 95% CI: 0.34-0.77; P for interaction < .001). The inverse association between MMC receipt and recurrence risk was not modified. CONCLUSIONS: For NMIBC patients who receive induction BCG, increasing consumption of raw cruciferous vegetables could be a promising strategy to attenuate recurrence risk.

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Vacuna BCG , Isotiocianatos , Mitomicina , Recurrencia Local de Neoplasia , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Mitomicina/uso terapéutico , Vacuna BCG/uso terapéutico , Vacuna BCG/administración & dosificación , Masculino , Femenino , Isotiocianatos/uso terapéutico , Isotiocianatos/farmacología , Estudios Prospectivos , Anciano , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Recurrencia Local de Neoplasia/epidemiología , Resultado del Tratamiento , Antibióticos Antineoplásicos/uso terapéutico , Adyuvantes Inmunológicos/uso terapéutico , Dieta , Invasividad Neoplásica , Estudios de Seguimiento

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Processes for intravesical chemotherapy after transurethral resection of nonmuscle invasive bladder tumors may lack standardization. In 2019, at a large health care system in Los Angeles, California, five incident reports involving chemotherapeutic agent spills from urinary catheters after bladder tumor procedures necessitated a quality improvement project. The project lead determined that a cost-effective alternative device for securing the chemotherapeutic agent in the bladder was needed at four surgical locations of the health care system. In addition, a review of the literature and an observational assessment revealed lack of adherence to standard and recommended processes for using personal protective equipment (PPE) when handling hazardous medications. After revising existing processes, acquiring a cost-effective clamp and recommended chemotherapy PPE, instructing personnel on the clamping process and use of PPE, and implementing use of the clamp, there have been no spills associated with intravesical chemotherapy across the four surgical locations.

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Neoplasias de la Vejiga Urinaria , Humanos , Administración Intravesical , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Equipo de Protección Personal/normas , Los Angeles , Exposición Profesional/prevención & control , Exposición Profesional/normas , Mejoramiento de la Calidad

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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.

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Vacuna BCG , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/mortalidad , Masculino , Femenino , Vacuna BCG/administración & dosificación , Vacuna BCG/uso terapéutico , Administración Intravesical , Estudios de Seguimiento , Anciano , Persona de Mediana Edad , Carcinoma in Situ/patología , Carcinoma in Situ/terapia , Carcinoma in Situ/tratamiento farmacológico , Invasividad Neoplásica , Resultado del Tratamiento , Adenoviridae/genética , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/uso terapéutico , Anciano de 80 o más Años

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PURPOSE: We aimed to compare recurrence-free survival (RFS) and progression-free survival (PFS) of the patients with pure high-grade (HG) vs mixed-grade (MG) nonmuscle-invasive bladder cancer who received adequate bacillus Calmette-Guérin therapy. MATERIALS AND METHODS: We conducted a retrospective cohort analysis using data from an institutional database. The study included patients diagnosed with HG nonmuscle-invasive bladder cancer at the initial transurethral resection specimen between 2010 and 2020. The initial transurethral resection specimens of all patients were reevaluated by a dedicated uropathologist. The percentage of low-grade tumor areas accompanying HG areas was determined for each case. Time-to-event analysis was performed using the Kaplan-Meier method. RFS and PFS rates were compared between groups. RESULTS: Of the 203 patients enrolled in the study, 69 (34%) had MG tumors. Recurrence was observed in 41 out of 134 patients (30.6%) in the HG group and in 19 out of 69 patients (27.5%) in the MG group. The 36-month RFS rates were 69% (CI: 62-77) and 72% (CI: 62-83) for the HG-urothelial carcinoma (UC) and MG-UC groups, respectively. The RFS rates were similar between groups (log-rank, P = .58). Progression was observed in 22 out of 134 patients (16.4%) in the HG group and in 4 out of 69 patients (5.8%) in the MG group. The 36-month PFS rates were 84% (CI: 77-90) and 94% (CI: 89-100) for the HG-UC and MG-UC groups, respectively. The pure HG-UC group had a worse PFS than the MG-UC group (log-rank, P = .042). Multivariate analysis demonstrated that age and tumor grade were significant risk factors for the development of progression. CONCLUSIONS: The indication of MG-UC category separately from pure HG carcinomas in the pathology report seems to be an important issue that can guide patient management. In this way, both more accurate risk classification and more accurate patient counseling can be performed. More importantly, the treatment plan can be made more accurately. For more precise conclusions, our results should be supported by prospective studies with larger sample size.

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Adyuvantes Inmunológicos , Vacuna BCG , Carcinoma de Células Transicionales , Clasificación del Tumor , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/terapia , Vacuna BCG/uso terapéutico , Vacuna BCG/administración & dosificación , Masculino , Estudios Retrospectivos , Femenino , Anciano , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/terapia , Adyuvantes Inmunológicos/uso terapéutico , Persona de Mediana Edad , Administración Intravesical , Invasividad Neoplásica , Anciano de 80 o más Años , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Supervivencia sin Progresión , Tasa de Supervivencia

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BACKGROUND: In patients affected by high-risk nonmuscle invasive bladder cancer (HR-NMIBC) progression to muscle invasive status is considered as the main indicator of local treatment failure. We aimed to investigate the effect of progression and time to progression on overall survival (OS) and to investigate their validity as surrogate endpoints. METHODS: A total of 1,510 patients from 18 different institutions treated for T1 high grade NMIBC, followed by a secondary transurethral resection and BCG intravesical instillation. We relied on random survival forest (RSF) to rank covariates based on OS prediction. Cox's regression models were used to quantify the effect of covariates on mortality. RESULTS: During a median follow-up of 49.0 months, 485 (32.1%) patients progressed to MIBC, while 163 (10.8%) patients died. The median time to progression was 82 (95%CI: 78.0-93.0) months. In RSF time-to-progression and age were the most predictive covariates of OS. The survival tree defined 5 groups of risk. In multivariable Cox's regression models accounting for progression status as time-dependent covariate, shorter time to progression (as continuous covariate) was associated with longer OS (HR: 9.0, 95%CI: 3.0-6.7; P < 0.001). Virtually same results after time to progression stratification (time to progression ≥10.5 months as reference). CONCLUSION: Time to progression is the main predictor of OS in patients with high risk NMIBC treated with BCG and might be considered a coprimary endpoint. In addition, models including time to progression could be considered for patients' stratification in clinical practice and at the time of clinical trials design.

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Neoplasias Vesicales sin Invasión Muscular , Neoplasias de la Vejiga Urinaria , Humanos , Vacuna BCG/uso terapéutico , Recurrencia Local de Neoplasia , Neoplasias de la Vejiga Urinaria/cirugía , Insuficiencia del Tratamiento , Invasividad Neoplásica , Administración Intravesical , Adyuvantes Inmunológicos/uso terapéutico , Estudios Retrospectivos

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BACKGROUND: Photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) for nonmuscle-invasive bladder cancer is superior to conventional white-light TURBT for cancer detection. However, when performing PDD-TURBT, cystoscopy findings vary depending on the quality of the endoscopic equipment. In this study, we compared the effects of different types of endoscopic equipment on postoperative outcomes. METHODS: Patients who underwent their first PDD-TURBT at our clinic were selected. Patients on whom PDD-TURBT was performed using endoscopic equipment A were sorted into Group A, and patients on whom PDD-TURBT was performed using equipment S were sorted into Group S. The characteristics, recurrence-free survival (RFS), and recurrence frequency of these patients were retrospectively investigated and compared. The prognostic factors for RFS were also analyzed. RESULTS: A total of 49 patients were included in Group A and 46 in Group S. In Group S, a higher detection rate (8.2% vs. 30.4 %, p < 0.01) of carcinoma in situ (CIS) was noted. RFS tended to be better in Group S (HR 0.63, p = 0.15). The frequency of recurrence also tended to be lower in Group S (4.92 vs. 3.66 per 10,000 person-days, p = 0.08). Furthermore, CIS (HR 0.30, p = 0.04) and Bacillus Calmette-Guerin therapy (HR: 0.26, p = 0.01) were significant favorable prognostic factors for RFS. CONCLUSION: The quality of the endoscopic equipment may influence postoperative recurrence after PDD-TURBT. Higher-quality endoscopic instruments have superior CIS detection capabilities, which can lead to improvements in postoperative outcomes with the appropriate selection of postoperative adjuvant therapy.

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Cistoscopía , Recurrencia Local de Neoplasia , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/cirugía , Neoplasias de la Vejiga Urinaria/patología , Masculino , Femenino , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Cistoscopía/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Anciano de 80 o más Años , Resección Transuretral de la Vejiga

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OBJECTIVES: To evaluate patient experience, unmet needs, and burden among patients with high-risk nonmuscle-invasive bladder cancer (HR-NMIBC) treated with Bacillus Calmette-Guérin (BCG). METHODS: This cross-sectional study included HR-NMIBC patients who received BCG treatment in the past 3 years. The study, preceded by a focused literature review, was conducted in 2 phases: 1) qualitative interviews with 32 patients in the United States (US), France, Germany, and United Kingdom (UK) and 2) quantitative survey of 150 patients in the US. Both phases of the study assessed patient characteristics, treatment history, experience, and perceptions, as well as side effects, pain, discomfort, and time burden associated with BCG treatment. The quantitative survey included additional items related to BCG treatment satisfaction, health-related quality of life (HRQoL), productivity, and healthcare resource utilization. Descriptive statistics and bivariate subgroup comparisons were reported. RESULTS: All patients in both study phases received transurethral resection of the bladder tumor (TURBT). Nearly all patients reported keeping their bladder/avoiding radical cystectomy (RC) was important (99%). Results from the quantitative survey reported a substantial impact to cancer-specific HRQoL of patients, with lower mean scores on physical (64.7), social (62.8), and role functioning (56.7) as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30). Most patients (69%) were satisfied overall with BCG treatment, although satisfaction declined with increased number of side effects, higher numbers of BCG administrations, and greater discomfort (all P < 0.05). CONCLUSIONS: Most HR-NMIBC patients were satisfied overall with BCG treatment. Approximately half of the patients had stopped BCG treatment, notably, most during the induction phase, suggesting nonadherence to guidelines which recommend maintenance treatment after induction. Future treatments should focus on delaying or avoiding recurrence and cystectomy while reducing patient discomfort and discontinuation prior to completing the recommended course of treatment.

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Neoplasias Vesicales sin Invasión Muscular , Neoplasias de la Vejiga Urinaria , Humanos , Estudios Transversales , Calidad de Vida , Vacuna BCG/uso terapéutico , Estadificación de Neoplasias , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Administración Intravesical , Evaluación del Resultado de la Atención al Paciente , Invasividad Neoplásica/patología , Recurrencia Local de Neoplasia/patología , Adyuvantes Inmunológicos/uso terapéutico

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INTRODUCTION: In the phase 2/3 study QUILT-3.032 (NCT03022825), the ability of the IL-15RαFc superagonist N-803 (nogapendekin alfa inbakicept) plus bacillus Calmette-Guérin (BCG) to elicit durable complete responses in patients with BCG-unresponsive nonmuscle-invasive bladder cancer (NMIBC) was demonstrated. As a secondary end point, patient-reported outcomes (PROs) were assessed. METHODS: Both cohort A patients with carcinoma in situ with or without Ta/T1 disease and cohort B patients with high-grade Ta/T1 papillary disease who received N-803 plus BCG therapy completed the EORTC (European Organization for Research and Treatment of Cancer) Core 30 and Quality of Life NMIBC-Specific 24 questionnaires at baseline and months 6, 12, 18, and 24 on study. Scores were analyzed using descriptive statistics, and multivariable analyses were performed to identify baseline variables associated with PROs. RESULTS: On study, mean physical function (PF) and global health (GH) scores remained relatively stable from baseline for cohorts A (n = 86) and B (n = 78). At month 6, cohort A patients with a complete response reported higher PF scores than those without (P = .0659); at month 12, > 3 as compared with ≤ 3 prior transurethral resections of bladder tumor was associated (P = .0729) with lower GH scores. In cohort B, baseline disease type was associated (P = .0738) with PF and race was significantly associated (P = .0478) with GH at month 6. NMIBC-Specific 24 summary scores also remained stable on study for both cohorts. CONCLUSIONS: The overall stability of PROs scores, taken together with the efficacy findings, indicates a favorable risk-benefit ratio and quality of life following N-803 plus BCG.

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Neoplasias Vesicales sin Invasión Muscular , Proteínas Recombinantes de Fusión , Neoplasias de la Vejiga Urinaria , Humanos , Vacuna BCG/uso terapéutico , Calidad de Vida , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico

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INTRODUCTION: Variant histology (VH) of urothelial carcinoma is uncommon and frequently presents at the muscle-invasive stage. VH is considering a significant risk factor for progression among patients with nonmuscle invasive bladder cancer (NMIBC). While there is some debate, expert opinion is generally that upfront radical cystectomy (RC) should be consider for these patients. Limited data exists to support this position. In this study, we sought to examine the rate of upstaging and overall survival for patients with VH NMIBC against patients with pure urothelial NMIBC who underwent RC, to help clarify the optimal treatment strategy for these patients. METHODS: The institutional REDCap database was utilized to identify all patients with T1 and Ta bladder cancer that underwent RC over the study period (2004-2022). Matched-pair analysis was performed between patients with VH and pure urothelial NMIBC; 42 pairs were matched on prior intravesical therapy, presence of muscularis propria on transurethral resection of bladder tumor (TURBT), any carcinoma in situ presence on prior TURBTs, and final tumor staging on TURBT. The primary outcomes of interest were pathologic tumor upstaging rate at RC and overall survival. Secondary outcomes of interest included association of demographic or pretreatment variables with upstaging, and upstaging rates for specific variant histologies. RESULTS: Patients with VH NMIBC undergoing RC were upstaged at a significantly higher rate than a matched cohort of patients with pure urothelial NMIBC (73.8% vs. 52.4%, P = 0.0244) and among those upstaged, had significantly higher rates of pT3 to pT4 (54.7% vs. 23.8%, P = 0.0088). Rate of node positivity at RC for VH NMIBC was also higher compared to pure urothelial NMIBC (40.5% vs. 21.4%, P = 0.0389). Among histologic variants, patients with plasmacytoid and sarcomatoid subtypes demonstrated the highest rates of upstaging; differences were not statistically significant. The overall median survival was 28.4 months for patients with VH after RC compared to 155.1 months for patients with pure urothelial NMIBC (P = 0.009). CONCLUSION: Patients with VH NMIBC undergoing RC are at significantly higher risk of upstaging at RC when compared to patients with pure urothelial NMIBC and have worse overall survival. While this study supports the concept of an aggressive treatment approach for patients with VH NMIBC, improvements in understanding of the disease are necessary to improve outcomes.

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Carcinoma de Células Transicionales , Neoplasias Vesicales sin Invasión Muscular , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/patología , Carcinoma de Células Transicionales/cirugía , Carcinoma de Células Transicionales/patología , Cistectomía , Vejiga Urinaria/patología , Estadificación de Neoplasias , Estudios Retrospectivos , Invasividad Neoplásica/patología

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INTRODUCTION: The goal of this survey was to evaluate the treatment and practice pattern of patients with high-grade papillary Ta, T1 nonmuscle-invasive bladder cancer (NMIBC), and carcinoma in situ (CIS) in bacillus Calmette-Guérin (BCG)-unresponsive (with adequate BCG exposure = adequate BCG) and those with less than adequate BCG exposure (BCG-exposed). METHODS: An internet-based survey with a target duration of 5 minutes was sent to US urologists who manage patients with NMIBC. Respondents were recruited from the Sesen Bio target list based upon BCG utilization. RESULTS: In 2022, 100 urologists who manage patients with papillary tumors and 159 urologists who manage patients with CIS tumors filled out the survey. Most (78%) were community-based urologists. Study respondents managed an average of 33 (range: 6-158) CIS patients and 44 (range: 10-200) high-grade patients with papillary disease (without CIS) over the past 6 months. Approximately 70% of physicians identified either gemcitabine (∼40%) or mitomycin C (∼30%) as the most often used intravesical chemotherapies for BCG unresponsive and BCG exposed groups. Most physicians reported the use of gemcitabine 2 g or mitomycin C 40 mg in a specific regimen for induction (once a week × 6 weeks) and maintenance (once a month × 12 months). Responses were consistent across groups of BCG therapy (adequate vs BCG-exposed). Physicians were slightly more likely to use a maintenance regimen for the adequate BCG patient. CONCLUSIONS: The most common treatments received by patients with BCG-unresponsive and BCG-exposed NMIBC were intravesical chemotherapy (single-agent gemcitabine or mitomycin C), regardless of whether CIS or papillary disease was present.

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Neoplasias Vesicales sin Invasión Muscular , Neoplasias de la Vejiga Urinaria , Humanos , Mitomicina/uso terapéutico , Vacuna BCG/uso terapéutico , Gemcitabina , Pautas de la Práctica en Medicina , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico

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PURPOSE: There is limited data on oncologic outcomes in nonmuscle invasive bladder cancer (NMIBC) with variant histology (VH) managed with intravesical therapy. We sought to evaluate oncologic outcomes for this cohort at a high-volume center. MATERIALS AND METHODS: A retrospective review of an IRB-approved bladder cancer database was performed. Patients with a history of NMIBC with VH present on transurethral resection of bladder tumor (TURBT) treated with intravesical therapy (BCG or chemotherapy) were identified. Outcomes of interest included recurrence within the bladder, progression to muscle-invasive bladder cancer (MIBC), metastatic progression, cancer-specific, and overall survival. Survival time was computed from the date of initiation of intravesical therapy to the date of event or censoring. For patients who underwent radical cystectomy, recurrence-free, cancer-specific, and overall survival were also computed. The Kaplan-Meier method with log rank was utilized to compare survival time between VH sub-groups. RESULTS: Ninety patients were included in the final cohort with a median follow-up of 38 months. The majority of patients had T1 disease (72%) and received intravesical BCG (83%) as their only form of intravesical therapy. The most commonly represented VH in this series were glandular and squamous differentiation (26%). Forty-eight patients (53%) experienced recurrence within the bladder with a median recurrence-free survival of 24 months (95% Confidence Interval [CI]: 2-46 months). Five-year rates of progression to MIBC and distant metastasis were both 14% respectively. Twenty-six patients (28%) eventually required cystectomy. When stratifying by VH, patients with sarcomatoid, plasmacytoid, and micropapillary had significantly worse oncologic outcomes. CONCLUSION: In this series of highly-selected patients with NMIBC and VH, bladder-sparing treatment with intravesical therapy demonstrated acceptable oncologic outcomes for most VHs. This may be an acceptable treatment option for patients without plasmacytoid, sarcomatoid, or micropapillary features who are not suitable cystectomy candidates or who prioritize bladder-sparing treatment.

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Neoplasias Vesicales sin Invasión Muscular , Neoplasias de la Vejiga Urinaria , Humanos , Vacuna BCG/uso terapéutico , Recurrencia Local de Neoplasia/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/cirugía , Neoplasias de la Vejiga Urinaria/patología , Vejiga Urinaria/patología , Cistectomía , Administración Intravesical , Estudios Retrospectivos , Invasividad Neoplásica , Adyuvantes Inmunológicos/uso terapéutico

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PURPOSE: Bacillus Calmette-Guerin (BCG) is the standard of care for high-risk nonmuscle invasive bladder cancer (NMIBC), but half of patients develop disease recurrence. Intravesical regimens for BCG unresponsive NMIBC are limited. We report the safety, efficacy, and differential response of sequential gemcitabine/docetaxel (gem/doce) depending on BCG failure classification. METHODS: Multi-institutional retrospective analysis of patients treated with induction intravesical gem/doce (≥5/6 instillations) for recurrent high-risk NMIBC after BCG therapy from May 2018 to December 2021. Maintenance therapy was provided to those without high-grade (HG) recurrence on surveillance cystoscopy. Kaplan-Meier curves and Cox regression analyses were utilized to assess survival and risk factors for disease recurrence. RESULTS: Our cohort included 102 patients with BCG-unresponsive NMIBC. Median age was 72 years and median follow-up was 18 months. Six-, 12-, and 24-month high-grade recurrence-free survival was 78%, 65%, and 49%, respectively. Twenty patients underwent radical cystectomy (median 15.5 months from induction). Six patients progressed to muscle invasive disease. Fifty-seven percent of patients experienced mild/moderate adverse effects (AE), but only 6.9% experienced a delay in treatment schedule. Most common AE were urinary frequency/urgency (41%) and dysuria (21%). Patients with BCG refractory disease were more likely to develop HG recurrence when compared to patients with BCG relapsing disease (HR 2.14; 95% CI 1.02-4.49). CONCLUSIONS: In patients with recurrence after BCG therapy, sequential intravesical gem/doce is an effective and well-tolerated alternative to early cystectomy. Patients with BCG relapsing disease are more likely to respond to additional intravesical gem/doce. Further investigation with a prospective trial is imperative.

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Neoplasias Vesicales sin Invasión Muscular , Neoplasias de la Vejiga Urinaria , Humanos , Anciano , Gemcitabina , Docetaxel/uso terapéutico , Vacuna BCG/uso terapéutico , Estudios Retrospectivos , Estudios Prospectivos , Recurrencia Local de Neoplasia/tratamiento farmacológico

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CD40 is a central costimulatory receptor implicated in productive antitumor immune responses across multiple cancers, including bladder cancer. Despite strong preclinical rationale, systemic administration of therapeutic agonistic antibodies targeting the CD40 pathway has demonstrated dose-limiting toxicities with minimal clinical activity, emphasizing an important need for optimized CD40-targeted approaches, including rational combination therapy strategies. Here, we describe a role for the endogenous IL-15 pathway in contributing to the therapeutic activity of CD40 agonism in orthotopic bladder tumors, with upregulation of transpresented IL-15/IL-15Rα surface complexes, particularly by cross-presenting conventional type 1 DCs (Dendritic Cells), and associated enrichment of activated CD8 T cells. In bladder cancer patient samples, we identify DCs as the primary source of IL-15, although they lack high levels of IL-15Rα at baseline. Using humanized immunocompetent orthotopic bladder tumor models, we demonstrate the ability to therapeutically augment this interaction through combined treatment with anti-CD40 agonist antibodies and exogenous IL-15, including the fully-human Fc-optimized antibody 2141-V11 currently in clinical development for the treatment of bladder cancer. Collectively, these data reveal an important role for IL-15 in mediating antitumor CD40 agonist responses in bladder cancer and provide key proof-of-concept for combined use of Fc-optimized anti-CD40 agonist antibodies and agents targeting the IL-15 pathway. These data support expansion of ongoing clinical studies evaluating anti-CD40 agonist antibodies and IL-15-based approaches to develop combinations of these promising therapeutics for the treatment of patients with bladder cancer.

Asunto(s)

Interleucina-15 , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Terapia Combinada , Antígenos CD40 , Fragmentos Fc de Inmunoglobulinas

RESUMEN

PURPOSE: This study compared the efficacy and safety of intravenous chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for high-risk nonmuscle invasive bladder cancer (HRNMIBC) patients after transurethral resection of the bladder tumor (TURBT) surgery. METHODS: A retrospective analysis was performed on 349 HRNMIBC cases admitted to TangDu hospital between January 2014 and June 2019. After TURBT, 262 patients received intravesical chemotherapy alone, whereas 87 patients underwent intravesical chemotherapy in combination with intravenous chemotherapy. The recurrence rate and progression rate were assessed by Chi-square test, the prognostic factors for tumor recurrence were predicted by univariable and multivariable Cox hazards analyses, recurrence-free survival (RFS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. RESULTS: In this study, the recurrence rate was 24.7% (19/77) in the intravenous chemotherapy combined group and 41.6% (102/245) in the intravesical chemotherapy group, while the progression rate was 6.5% (5/77) and 14.3% (35/245) in the two groups respectively. The two groups differed significantly in recurrence rate (p = 0.007) while the progression rate did not show a significant difference (p = 0.071). Multivariable analyses revealed that additional intravenous chemotherapy treatment was an independent prognostic factor for tumor recurrence in the cohort (hazard ratio [HR], 0.495, 95% confidence interval [CI], 0.275-0.892, p = 0.019). Kaplan-Meier curves showed significant differences in RFS and PFS between the two groups, with a log-rank P value of p < 0.005 and p = 0.045, respectively. Grade 3/4 toxicity was reported in 2 of 77 patients in the intravenous chemotherapy combined group, including nausea/vomiting 1.3% (1/77) and hypoleukemia 1.3% (1/77). CONCLUSION: Intravenous chemotherapy of gemcitabine and cisplatin combined with intravesical chemotherapy after TURBT can effectively reduce the postoperative recurrence rate, most toxicities were minor and reversible, and it may be considered as a new choice for HRNMIBC patients.

RESUMEN

Intravesical Bacillus Calmette-Guérin (BCG) therapy for nonmuscle-invasive bladder cancer rarely leads to the development of granulomatous renal masses (renal BCGosis). The management includes nephroureterectomy, antitubercular therapy (ATT), or both. Here, we present a case of a 62-year-old male who was treated with ATT alone for renal masses. Six months after intravesical BCG therapy for transitional cell carcinoma, he developed high-grade fever and night sweat and had multiple renal parenchymal hypodensities on computed tomography (CT) scan. Repeat CT scan 6 months after ATT revealed full resolution of renal hypodensities. This case report highlights the importance of follow-up for early detection of adverse effects of BCG treatment.

RESUMEN

INTRODUCTION: Effective therapies for patients with nonmuscle invasive bladder cancer that recurs or progresses after Bacille Calmette-Guérin (BCG) are lacking. This unmet need is the focus of many drug development efforts, reflected in many completed/ongoing/planned clinical trials for patients with BCG unresponsive bladder cancer. Though BCG unresponsive criteria are well defined, enrollment criteria are variable such that, even at centers with several open trials in this space, a given patient with BCG unresponsive bladder cancer might not qualify for any. To understand the scope of this dilemma, we systematically analyzed enrollment criteria for all BCG unresponsive protocols registered on ClinicalTrials.gov to quantify heterogeneity in enrollment criteria and to determine what proportion of trials were inclusive to patients meeting U.S. Food and Drug Administration (FDA) BCG unresponsive criteria. METHODS: The ClinicalTrials.gov search tool was queried for relevant trials using the terms "bladder cancer" "nonmuscle invasive bladder cancer" and "BCG". Previously published review articles were cross-referenced to ensure that search results were comprehensive. Inclusion and exclusion criteria for the resulting 31 protocols pertaining to distinct categories such as performance status, laboratory parameters, co-morbidities, active medications, and prior therapies were recorded. Based on enrollment criteria, the trial was assessed as fully inclusive or not to patients considered to be BCG unresponsive by the 2018 FDA criteria. RESULTS: Of 31 trials, 15 (48%) had inclusion/exclusion criteria that were fully consistent with (inclusive of patients that met) the BCG unresponsive bladder cancer definition. 18 (58%) of trials excluded patients with a history of prior pelvic radiation therapy. 14 (45%) of trials excluded patients with ECOG performance status >2 (or Karnofsky Performance Status equivalent). The most common disease specific exclusion for patients with BCG unresponsive bladder cancer was a requirement for stage Tis (carcinoma in situ, CIS), which pertained to 7 (23%) of trials. CONCLUSIONS: Enrollment criteria for patients with BCG unresponsive bladder cancer are highly variable. Over half of trials evaluated do not meet stringent criteria for this disease state based upon treatment history and cancer staging requirements. For patients who desire to enroll in clinical trials, this restricts access to novel agents. For bladder cancer treating physicians and regulatory bodies, this also hinders comparisons across agents.

Asunto(s)

Neoplasias de la Vejiga Urinaria , Vejiga Urinaria , Humanos , Administración Intravesical , Vacuna BCG/uso terapéutico , Inmunoterapia/métodos , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Ensayos Clínicos como Asunto

RESUMEN

Background: Transurethral resection of bladder tumors (TURBT) is the standard management for urinary bladder tumors; however, new techniques as Thulium laser en bloc resection of bladder tumors (TmLRBT) have been introduced as a substitute to TURBT. Objectives: In this study safety, efficacy, and tumor recurrence after TmLRBT and TURBT were prospectively compared in patients with primary (<4 cm) bladder tumors. Patients and Methods: Between August 2019 and May 2021, patients with primary (<4 cm) bladder tumors were enrolled. Patients were randomized between the two procedures. All perioperative data were collected prospectively. Pathological specimen findings and recurrence rates were reported during follow-up visits. Results: Sixty patients underwent TURBT, and another 60 had TmLRBT. No significant differences were detected in patient demographics or preoperative tumor characteristics between the two groups. Operation time was less (28.2 vs. 38.9 min, P < 0.001), and rate of bladder perforation was lower with TmLRBT compared to TURBT (3.3% vs. 15.0%, P = 0.027). In the TmLRBT group, higher rate of muscle detection (95.0% vs. 78.3%, P < 0.001) in the pathological specimen, and lower rate of tissue destruction (0.0% vs. 21.6%, P < 0.001) were obtained compared to TURBT. Recurrence rate in cases of nonmuscle invasive bladder cancer was lower with TmLRBT (6.7% vs. 33.0%, P < 0.001). Conclusion: In this study, TmLRBT showed reduced operative time with lower perforation rates. Higher detection of detrusor muscle and less tissue destruction in the pathological specimen were obtained with TmLRBT, as well as lower rates of tumor recurrence. These findings suggest that TmLRBT is a safe and efficacious substitute to TURBT in tumors <4 cm.

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PURPOSE: In nonmuscle invasive bladder cancer (NMIBC) patients who fail standard intravesical treatment and are unfit or unwilling to undergo a radical cystectomy, radiofrequency (RF)-induced hyperthermia combined with intravesical chemotherapy (RF-CHT) has shown promising results. We studied whether higher thermal dose improves clinical NMIBC outcome. METHODS AND MATERIALS: The cohort comprised 108 patients who started with RF-CHT between November 2013 and December 2019. Patients received intravesical mitomycin-C or epirubicin. Bladder hyperthermia was accomplished with an intravesical 915 MHz RF device guided by intravesical thermometry. We assessed the association between thermal dose parameters (including median temperature and Cumulative Equivalent Minutes of T50 at 43 °C [CEM43T50]) and complete response (CR) at six months for patients with (concomitant) carcinoma in situ (CIS), and recurrence-free survival (RFS) for patients with papillary disease. RESULTS: Median temperature and CEM43T50 per treatment were 40.9 (IQR 40.8-41.1) °C and 3.1 (IQR 0.9-2.4) minutes, respectively. Analyses showed no association between any thermal dose parameter and CR or RFS (p > 0.05). Less bladder spasms during treatment sessions was associated with increased median temperature and CEM43T50 (adjusted OR 0.01 and 0.34, both p < 0.001). CONCLUSIONS: No significant association between thermal dose and NMIBC outcome was found. Possibly thermal dose effect in patients of the current cohort exceeds a certain threshold value. On the other hand, occurrence of bladder spasms had a thermal dose limiting effect. We advise to treat patients with temperatures >40.5 °C for at least 45 min while respecting individual tolerability, including occurrence of bladder spasms.

Asunto(s)

Hipertermia Inducida , Neoplasias de la Vejiga Urinaria , Humanos , Hipertermia Inducida/métodos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Mitomicina/uso terapéutico , Epirrubicina/uso terapéutico , Terapia Combinada , Invasividad Neoplásica , Recurrencia Local de Neoplasia/tratamiento farmacológico