Management of BCG failure in non-muscle-invasive bladder cancer the present and the future.

Bladder neoplasms are still among the most common cancer types in the Czech Republic. Even though the majority (more than 90%) of bladder tumours are of urothelial origin, the group is vastly heterogeneous in terms of biological behaviour and thus also progression of the disease. Adequate adjuvant treatment is the cornerstone of the therapy in high-risk patients for disease recurrence, particularly those with a high risk of progression to a muscle-invasive disease (T2 and higher). Intravesical BCG immunotherapy still remains such a therapy. It is a standard therapy with well-established efficacy as regards the recurrence rate and a reduced risk of progression. Nevertheless, radical cystectomy is recommended in patients in whom this therapy fails. Considering the non-negligible morbidity and mortality associated with this type of surgery, intensive research efforts have been put forth to develop new bladder preserving strategies. This article outlines the main bladder preserving strategies that are currently explored.

BCG-unresponsive high-grade non-muscle invasive bladder cancer: what does the practicing urologist need to know?

PURPOSE: Bacille Calmette-Guérin (BCG) is a well-established treatment for preventing or delaying tumour recurrence following high-grade nonmuscle invasive bladder cancer (NMIBC) resection. However, many patients will experience recurrence or progression during or following BCG. This scenario has been one of the most challenging in urologic oncology for several decades since BCG implementation. Finally, significant progress has occurred lately. The aim of this review was to summarize for the practising urologist the current treatment options available in 2020 or expected to be ready for routine use in the near future for patients with high-risk NMIBC who experience BCG failure. METHODS: Narrative review using data through the end of 2020. RESULTS: First, the definition of BCG unresponsive disease which is critical in counseling and managing patients has finally reached a consensus. Second, some promising options other than radical cystectomy are finally available and many other should be in a near future. The options can be categorized as chemotherapy, device-assisted therapy, check-point inhibitors, new intravesical and systemic agents and sequential combinations of these newer modalities with conventional therapy. CONCLUSIONS: Considering the options that are currently under scrutiny, many of which in phase III trials, clinicians should have at their disposal several new treatment options in the next five years.

Guideline adherence for radical cystectomy significantly affects survival outcomes in non-muscle-invasive bladder cancer patients.

BACKGROUND: The relationship between guideline adherence for radical cystectomy of non-muscle-invasive bladder cancer and patient prognoses currently remains unclear. We investigated whether guideline adherence at the time of non-muscle-invasive bladder cancer affects the oncological outcomes of bladder cancer patients who underwent radical cystectomy. METHODS: Among 267 cTa-4N0-2M0 bladder cancer patients, 70 who underwent radical cystectomy under the non-muscle-invasive bladder cancer or muscle-invasive bladder cancer status that progressed from non-muscle-invasive bladder cancer were identified. Patients who followed the guidelines from initial transurethral resection of bladder tumors to radical cystectomy were defined as the guideline adherent group (n = 52), while those who did not were the guideline non-adherent group (n = 18). RESULTS: In the guideline non-adherent group, 8 (44.4%) out of 18 were diagnosed with highest risk non-muscle-invasive bladder cancer for Bacillus Calmette Guérin-naïve patients and 7 (38.9%) had a Bacillus Calmette Guérin unresponsive tumor status. Five-year recurrence-free survival and cancer-specific survival rates for the guideline non-adherent group vs guideline adherent group were 38.9% vs 69.8% (P = 0.018) and 52.7% vs 80.1% (P = 0.006), respectively. A multivariate analysis identified guideline non-adherence as one of independent indicators for disease recurrence (hazard ratio = 2.81, P = 0.008) and cancer-specific death (hazard ratio = 4.04, P = 0.003). In a subgroup analysis of 49 patients with cT1 or less non-muscle-invasive bladder cancer at the time of radical cystectomy, guideline non-adherence remained an independent prognostic factor for cancer-specific survival (hazard ratio = 3.46, P = 0.027). CONCLUSIONS: Guideline adherence during the time course of the non-muscle-invasive bladder cancer stage may result in a favorable prognosis of patients who receive radical cystectomy. Even under non-muscle-invasive bladder cancer status, radical cystectomy needs to be performed with adequate timing under guideline recommendations.

Bladder Cancer: Current Challenges and Future Directions.

Bladder cancer (BCa) is the most common malignancy of the urinary tract and one of the most prevalent cancers worldwide. While the clinical approach to BCa has remained largely unchanged for many years, recent discoveries have paved the way to a new era of diagnosis and management of the disease. BCa-specific mortality started to decrease in the regions with a wide range of activities leading to greater social awareness of the risk factors and the decline in carcinogenic exposure. The urologic community refines the role of transurethral surgery towards more rigorous and high-quality techniques. New agents have been approved for patients with BCG failure who faced radical cystectomy so far. Although radical removal of the bladder is the gold standard for muscle invasive cancer management, the extent and clinical value of lymphadenectomy is currently heavily challenged in randomized trials. Furthermore, alternatives to perioperative chemotherapy have arisen to increase the likelihood of complete treatment delivery and successful oncological outcomes. Finally, improvements in molecular biology and our understanding of tumorigenesis open the era of personalized medicine in bladder cancer. In the present review, the status and future directions in bladder cancer epidemiology, diagnosis and management are thoroughly discussed.

Updates on the use of intravesical therapies for non-muscle invasive bladder cancer: how, when and what.

INTRODUCTION: Intravesical therapy has been an important aspect of the management of non-muscle invasive bladder cancer (NMIBC) for 40 years. Bacillus Calmette-Guerin (BCG) is considered standard of care for intermediate and high-grade non-invasive disease, yet understanding the nuances of subsequent intravesical therapy is important for any provider managing bladder cancer. Herein, we review the literature and describe optimal use of intravesical therapies for NMIBC. METHODS: A comprehensive search of the medical literature was performed and highlighted in this review of intravesical therapy for NMIBC. RESULTS: Post-resection intravesical Mitomycin C therapy for low-risk disease remains an important component of care, and gemcitabine now has level-one evidence demonstrating efficacy in this setting but is not yet a guideline recommendation. BCG intravesical therapy remains the most effective therapy preventing recurrence and progression of intermediate and high-risk NMIBC. Adequately characterizing BCG-failure is critical in determining the next step in management which includes radical cystectomy, additional intravesical immunotherapy, chemotherapy with intravesical gemcitabine ± docetaxel and clinical trials. CONCLUSIONS: Intravesical therapy remains the mainstay of treatment for NMIBC and bladder preservation. Intravesical induction BCG followed by maintenance therapy remains standard of care for intermediate and high-risk patients. Detailing the timing and characteristics of recurrence after intravesical therapy is crucial in determining subsequent treatment recommendations. Current clinical trials focus on systemic immunotherapy and enhancing the intravesical immune response by augmenting the delivery mechanism.

Emerging therapies in the management of high-risk non-muscle invasive bladder cancer (HRNMIBC).

PURPOSE: BCG is the gold standard in management of high-risk non-muscle invasive bladder cancer (HRNMIBC). However, in patients who fail BCG, there are few effective intrasvesical options. This review aims to explore standard and emerging therapies in HRNMIBC. METHODS: A non-systematic literature review was performed using Medline and PubMed. Literature focused on HRNMIBC and BCG failure studies, with particular attention to Phase II and III clinical trials. RESULTS: The only FDA approved therapy for BCG failure patients in Valrubicin. Patients with HRNMIBC and BCG failure patients are at increased risk for progression and death from bladder cancer. There are a variety of clinical trials exploring different therapeutic approaches such as immunotherapy, vaccines, radiotherapy, and gene therapy. These trials are showing some promise in the early reporting phase. CONCLUSION: Despite limited intravesical treatment options in BCG failure patients, there are several promising therapies currently being developed and several with promising early results.

ElectroMotive drug administration (EMDA) of Mitomycin C as first-line salvage therapy in high risk "BCG failure" non muscle invasive bladder cancer: 3 years follow-up outcomes.

BACKGROUND: In case of high grade non-muscle invasive bladder cancer (HG-NMIBC), intravesical BCG represents the first-line treatment; despite the "gold" standard therapy, up to 50% of patients relapse, needing radical cystectomy. Hence, alternative therapeutic strategies have been developed. The aim of the study was to evaluate a first-line salvage treatment with EMDA®-MMC in patients with HGNMIBC unresponsive to BCG. METHODS: We carried out a prospective, single-center, single-arm Phase II study in order to evaluate the efficacy (in terms of recurrence and progression) and the safety of the EMDA®-MMC treatment in 26 (21 male, 5 female) consecutive patients with "BCG refractory" HGNMIBC on a 3 years follow-up. EMDA®-MMC treatment consisted of 40 mg of MMC diluted in 100 ml of sterile water retained in the bladder for 30 min with 20 mA pulsed electric current. EMDA®-MMC regimen consisted of an induction course of 6 weekly instillations followed by a maintenance course of 6 monthly instillations. Follow-up was performed with systematic mapping biopsies of the bladder (with sampling in the prostatic urethra for men), voiding and washing urinary cytology, radiological study of the upper urinary tract. We performed Survival Kaplan-Meier curves and Log-rank test in order to analyze high grade disease-free survival. RESULTS: At the end of follow-up, 16 patients (61.5%) preserved their native bladder; 10 patients (38.4%) underwent radical cystectomy, in 6 patients (23.1%) for recurrent HGNMIBC and in 4 patients (15.4%) for progression to muscle-invasive disease. At the end of follow-up, stratifying patients based on TNM classification (TaG3, T1G3, Cis, TaT1G3 + Cis), disease-free rates were 75, 71.4, 50 and 25%, respectively; survival curves showed statistically significant differences (p value < 0.05). Regarding toxicity, we reported severe adverse systemic event of hypersensitivity to the MMC in 3 patients (11.5%), and local side effects in 6 patients (26.1%). CONCLUSIONS: In the field of alternative strategies to radical cystectomy, the EMDA®-MMC could be considered safe and effective in high-risk NMIBC unresponsive to BCG, as a "bladder sparing" therapy in selected patients. Multicenter studies with a larger number of patients and a longer follow-up might confirm our preliminary results. TRIAL REGISTRATION: EudraCT2017-002585-43. 17 June 2017 (retrospectively registered).

Efficacy and safety of a new device for intravesical thermochemotherapy in non-grade 3 BCG recurrent NMIBC: a phase I-II study.

PURPOSE: We report for the first time the activity and safety of Unithermia(®) (Elmedical Ltd, Hod-Hasharon, Israel), a novel device for administration of MMC-C with hyperthermia (HT), that employs conductive heating, in a series of non-grade 3 non-muscle-invasive bladder cancer (NMIBC) that failed Bacillus Calmette-Guerin (BCG). METHODS: Patients with non-grade 3 NMIBC recurring after at least a full induction course of BCG were eligible for this phase I-II prospective single-arm study. Six weekly instillations with Unithermia(®) were scheduled following complete TUR. Primary end points were treatment safety and response rate (RR), and the latter defined as the absence of any unfavourable outcome at 12 months. Any grade 3 and/or muscle-invasive (T > 1) recurrence was considered disease progression. Kaplan-Meier estimation of the time to recurrence and progression, cancer-specific survival and overall survival was taken as secondary end points. RESULTS: Thirty-four eligible patients entered the study between January 2009 and April 2011. RR was documented in 20/34 (59%). Among the 14/34 (41%) non-responders, four developed G3 disease, one developed carcinoma in situ, and one progressed to muscle-invasive bladder cancer, with an overall 18% progression rate at 1 year. At a median follow-up of 41 months, recurrence and progression rates were 35.3 and 23.5%, respectively. Toxicity did not go beyond grade 2 except in five cases. CONCLUSIONS: Initial experience with MMC-HT with Unithermia(®) showed an interesting activity and safety profile in non-grade 3 NMIBC recurring after BCG, suggesting a role as second-line therapy in this selected subgroup of NMIBC.

Construction of predictive models for cancer-specific survival of patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: results from a multicenter retrospective study.

OBJECTIVE: The aims of this study were to clarify the prognostic factors and to validate the bacillus Calmette-Guérin failure classification advocated by Nieder et al. in patients with non-muscle-invasive bladder cancer who had intravesical recurrence after bacillus Calmette-Guérin therapy. METHODS: Data from 402 patients who received intravesical bacillus Calmette-Guérin therapy between January 1990 and November 2011 were collected from 10 institutes. Among these patients, 187 with bacillus Calmette-Guérin failure were analyzed for this study. RESULTS: Twenty-nine patients (15.5%) were diagnosed with progression at the first recurrence after bacillus Calmette-Guérin therapy. Eighteen (62.1%) of them died of bladder cancer. A total of 158 patients were diagnosed with non-muscle-invasive bladder cancer at the first recurrence after bacillus Calmette-Guérin therapy. Of them, 23 (14.6%) underwent radical cystectomy. No patients who underwent radical cystectomy died of bladder cancer during the follow-up. On multivariate analysis of the 135 patients with bladder preservation, the independent prognostic factors for cancer-specific survival were age (≥70 [P = 0.002]), tumor size (≥3 cm [P = 0.015]) and the Nieder classification (bacillus Calmette-Guérin refractory [P < 0.001]). In a subgroup analysis, the estimated 5-year cancer-specific survival rates in the groups with no positive, one positive and two to three positive factors were 100, 93.4 and 56.8%, respectively (P < 0.001). CONCLUSIONS: Patients with stage progression at the first recurrence after bacillus Calmette-Guérin therapy had poor prognoses. Three prognostic factors for predicting survival were identified and used to categorize patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin into three risk groups based on the number of prognostic factors in each one.

HIVEC as an alternative option in non-muscle-invasive bladder cancer: Experiences from a high-volume center.

BACKGROUND: High risk non-muscle invasive bladder cancer (NMIBC) is usually treated with intravesical BCG-therapy. In case of BCG failure radical cystectomy (RC) is the treatment of choice. Nevertheless, many patients are unfit for or unwilling to undergo RC. Hyperthermic intravesical chemotherapy (HIVEC) is a promising bladder sparing therapy in such cases. It was the purpose of the study to evaluate the efficacy of HIVEC in patients with BCG failure as well as in BCG naïve patients in case of BCG shortage or given contra-indications for BCG. METHODS: We analyzed the first 60 patients who received hyperthermic intravesical chemotherapy (HIVEC) at our department. The therapy regimen consisted of an induction course of 6 weekly sessions, followed by a maintenance course with 6 monthly sessions. Fluorescence cystoscopy with urine cytology and bladder mapping was performed after completion of induction and maintenance therapy at 3 and 12 months. About 68.6 % had received a recurrence after or during BCG treatment, 55% of the subjects were BCG-unresponsive NMIBC according to EAU guidelines. RESULTS: The median follow up was 12 months with 12 cycles of HIVEC therapy being administered on average, representing completion of induction and maintenance therapy with 6 cycles each. The 1- and 2-year recurrence-free-survival (RFS) was 67% and 40% respectively. Only one out of 60 patients developed progression to muscle invasion with progression-free-survival (PFS) of 98% at 2 years. No statistical differences were found in RFS for patients failure to BCG compared to patients that were BCG-naïve (BCG unresponsive vs. BCG-naïve) and patients that carried carcinoma in situ (CIS) compared to patients without CIS (CIS vs. no CIS). CONCLUSION: Chemohyperthermia using HIVEC results in high recurrence-free survival and a 2-year progression-free survival rate of 98% with a bladder preservation rate of almost 80%. Comparing our data, HIVEC shows better oncological results together with better tolerability and safety making HIVEC a good alternative for patients who refuse radical cystectomy or who are ineligible for radical cystectomy.

BCG and Alternative Therapies to BCG Therapy for Non-Muscle-Invasive Bladder Cancer.

Bladder cancer is a heterogeneous disease. Treatment decisions are mostly decided based on disease stage (non-muscle invasive or muscle invasive). Patients with muscle-invasive disease will be offered a radical treatment combined with systemic therapy, while in those with non-muscle-invasive disease, an attempt to resect the tumor endoscopically will usually be followed by different intravesical instillations. The goal of intravesical therapy is to decrease the recurrence and/or progression of the tumor. In the current landscape of bladder cancer treatment, BCG is given intravesically to induce an inflammatory response and recruit immune cells to attack the malignant cells and induce immune memory. While the response to BCG treatment has changed the course of bladder cancer management and spared many "bladders", some patients may develop BCG-unresponsive disease, leaving radical surgery as the best choice of curative treatment. As a result, a lot of effort has been put into identifying novel therapies like systemic pembrolizumab and Nadofaragene-Firadenovac to continue sparing bladders if BCG is ineffective. Moreover, recent logistic issues with BCG production caused a worldwide BCG shortage, re-sparking interest in alternative BCG treatments including mitomycin C, sequential gemcitabine with docetaxel, and others. This review encompasses both the historic and current role of BCG in the treatment of non-muscle-invasive bladder cancer, revisiting BCG alternative therapies and reviewing the novel therapeutics that were approved for the BCG-unresponsive stage or are under active investigation.

Combination intravesical chemotherapy for non-muscle invasive bladder cancer (NMIBC) as first-line or rescue therapy: where do we stand now?

INTRODUCTION: The combination of intravesical gemcitabine (Gem) with docetaxel (Doce) or with mitomycin C (MMC) has been used in the primary setting as an alternative to Bacillus Calmette-Guerin (BCG) to treat high-risk (HR) and intermediate-risk (IR) non-muscle invasive bladder cancer (NMIBC), as well in the rescue setting for patients in whom BCG has failed. AREA COVERED: Efficacy and safety of Gem/Doce and Gem/MMC to treat NMIBC in BCG-naive and failure settings. EXPERT OPINION: In the BCG-naive setting, Gem/Doce was the primary alternative combination therapy reported, with a weighted mean of 12- and 24-month recurrence-free survival (RFS) of 79% and 77% for HR disease and 84% and 76% for IR disease, respectively. In the HR BCG-failure setting, the weighted mean of 12- and 24-month RFS was 60% and 42% for Gem/Doce and 63% and 40% for Gem/MMC. While patients without BCG exposure and papillary disease only benefit the most from Gem/Doce, there is also reasonable efficacy in BCG refractory disease and CIS. Combination therapy is well tolerated, with grade III toxicity reported in less than 1% of patients. Unlike single-agent chemotherapy, intravesical Gem/Doce is considered effective and safe regardless of risk-stratification.

Is CIS a Contraindication to Hyperthermic Intravesical Chemotherapy (HIVEC) after BCG-Failure?

CIS of the bladder is associated with a high risk of progression. In the case of BCG failure, radical cystectomy should be performed. For patients who refuse or are ineligible, bladder-sparing alternatives are evaluated. This study aims to investigate the efficacy of Hyperthermic IntraVesical Chemotherapy (HIVEC) depending on the presence or absence of CIS. This retrospective, multicenter study was conducted between 2016 and 2021. Patients with non-muscle-invasive bladder cancer (NMIBC) with BCG failure received 6-8 adjuvant instillations of HIVEC. The co-primary endpoints were recurrence-free survival (RFS) and progression-free survival (PFS). A total of 116 consecutive patients met our inclusion criteria of whom 36 had concomitant CIS. The 2-year RFS rate was 19.9% and 43.7% in patients with and without CIS, respectively (p = 0.52). Fifteen patients (12.9%) experienced progression to muscle-invasive bladder cancer with no significant difference between patients with and without CIS (2-year PFS rate = 71.8% vs. 88.8%, p = 0.32). In multivariate analysis, CIS was not a significant prognostic factor in terms of recurrence or progression. In conclusion, CIS may not be considered a contraindication to HIVEC, as there is no significant association between CIS and the risk of progression or recurrence after treatment.

Real-world efficacy of adjuvant single-agent intravesical gemcitabine for non-muscle invasive bladder cancer.

INTRODUCTION: Failure, intolerance, or shortage of bacillus Calmette-Guerin (BCG) treatment for patients with high-risk (HR) non-muscle invasive bladder cancer (NMIBC) leave many facing the prospect of radical cystectomy (RC). However, despite the lack of large-scale randomized controlled studies with single-agent intravesical gemcitabine (Gem), it has emerged as a popular salvage agent after BCG failure or even a treatment alternative to BCG. AREAS COVERED: 1. Characterization of treatment regimen details pertaining to single-agent intravesical adjuvant Gem use among disease states of NMIBC characterized by risk and BCG exposure. 2. Comparison of safety and efficacy of Gem according to risk category, type of tumor (papillary vs. carcinoma in situ (CIS)), and tumor grades. EXPERT OPINION: Two randomized studies in early BCG failure disease demonstrate that single-agent Gem has superior efficacy versus repeated BCG therapy or mitomycin C. Studies enrolling patients with predominantly papillary disease without CIS, intermediate-risk (IR) disease, and less BCG exposure appear to derive the highest benefits from adjuvant Gem in terms of recurrence and progression. However, studies with cohorts enriched for a predominance of CIS, HR disease and/or more extensive BCG failure have poorer 2-year recurrence free survival and a somewhat higher risk of progression and RC.

Role of preoperative neutrophil to lymphocyte ratio in prediction of recurrence, progression, and BCG failure in non-muscle invasive bladder cancer: a retrospective study.

Introduction: neutrophil/lymphocyte ratio (NLR), as a biomarker of the systemic inflammatory response, has been studied for diverse tumors. Our study aims to determine whether the NLR can be reliably used as a tool to predict disease course in patients diagnosed with primary non-muscle invasive bladder tumors (NMIBC). Methods: a retrospective study between 2009 to 2014 was conducted on 300 patients newly diagnosed with NMIBC at our institution. The cut-off value of NLR was set at 2.5. Survival curves were compared using the log-rank test. The association between recurrence, progression, and NLR was assessed univariate, and the prognostic significance of high NLR was assessed using multivariate analysis. Results: one hundred and seventy-five patients had an NLR <2.5 and 125 patients had an NLR ≥ 2.5. The survival rate with recurrence at 5 years was higher in the group with an NLR >2.5 (p<0.001, 35 vs 18 months), similarly, the survival rate with progression at 5 years was higher in the group with an NLR > 2.5 (p=0.001, 36 vs. 27 months). The failure rate of immunotherapy using BCG was higher when the NLR was over 2.5. In a multivariate analysis, the factors associated with recurrence were NLR>2.5 (HR=2.03, 95% CI=1.32-3.11, p=0.001), pathologic stage pT1 (HR=2.42, 95% CI=1.52-3.85, p=0.001), high-grade (HR=1.76, 95% CI=1.52-3.92, p=0.01), concomitant CIS lesions (HR=2.31, 95% CI=1.36-3.92, p=0.001), presence of lymphovascular emboli (HR=5.77, 95% CI=1.77-18.78, p=0.004), and BCG immunotherapy failure (HR=5.29, 95% CI=2.88-9.70, p=0.001). With regard to progression, in a multivariate study, the significant factors were NLR>2.5(HR=2.91, 95% CI=1.17-7.23, p=0.01), BCG immunotherapy failure (HR=5.68, 95% CI=3.16-10.22, p=0.001), and the presence of lymphovascular emboli (HR=5.01, 95% CI=1.50-16.05, p=0.001). Conclusion: preoperative NLR value could predict recurrence, progression, and failure of BCG immunotherapy in NMIBC patients.

Prognostic Role of Preoperative Neutrophil-To-Lymphocyte Ratio (NLR) and Recurrence at First Evaluation after Bacillus Calmette-Guérin (BCG) Induction in Non-Muscle-Invasive Bladder Cancer.

We investigated the prognosis of BCG induction-only treatment and non-complete response (CR) at the first 3-month evaluation and examined factors associated with CR. In total, 209 patients with moderate- and high-risk NMIBC who received BCG induction-only treatment between 2008 and 2020 were retrospectively analyzed. Recurrence-free survival (RFS) and progression-free survival (PFS) were assessed based on the initial NMIBC stage. PFS and associated factors of non-CR compared to CR were also assessed. Initial T1 high-grade (HG) (n = 93) had poorer RFS and PFS after BCG induction-only treatment than Ta low-grade (LG) (p = 0.029, p = 0.002). Non-CR (n = 37) had a different neutrophil-to-lymphocyte ratio (NLR) (2.81 ± 1.02 vs. 1.97 ± 0.92) and T staging from CR (p < 0.001, p = 0.008). T1HG recurrence was associated with a worse PFS compared to non-T1HG (13.7 months vs. 101.7 months, p < 0.001). There was no difference in PFS between T1HG and T1LG. T1 and NLR were predictors of response at 3 months in multivariable analysis (p = 0.004, p = 0.029). NLR was also found to be an associated factor with RFS and PFS of bladder cancer (p < 0.001, p < 0.001). BCG induction-only treatment was effective for high-risk TaLG but not for T1HG. T1HG recurrence at 3 months after BCG induction has a poor prognosis for bladder cancer. Preoperative NLR and T1 were predictors of non-CR, and NLR was also associated with the long-term prognosis of bladder cancer.

The Management of Bacillus Calmette-Guérin (BCG) Failure in High-Risk Non-muscle Invasive Bladder Cancer: A Review Article.

Non-muscle invasive bladder cancer (NMIBC) is a common urological malignancy, and bacillus Calmette-Guérin (BCG) therapy is the gold standard treatment in intermediate and high-risk groups. However, BCG failure occurs in a significant proportion of patients, emphasizing the need for effective alternative treatment modalities to address this burden. These treatments include immunotherapy, enhanced drug delivery, targeted therapy, device-assisted chemotherapy, vaccine therapy, and gene therapy, which show varying degrees of safety and efficacy. The objective of this review is to summarize the current evidence and ongoing research on these emerging therapies, offering insight into their potential for improving patient outcomes and quality of life. Although radical cystectomy remains the standard of care for high-risk NMIBC patients unresponsive to BCG, novel treatment modalities hold promise for the future management of this challenging patient population.

Complete response to intravesical gemcitabine in non-muscle invasive bladder cancer patient after BCG failure: A case report and literature review.

Bladder cancer treatment remains a challenge to every oncologist. We report the case of a 57-year-old man with BCG-refractory bladder cancer who had a complete response to intravesical gemcitabine to highlight the role of gemcitabine as a bladder sparing treatment in BCG-failure patients.

Intravesical immunotherapy with a GM-CSF armed oncolytic vesicular stomatitis virus improves outcome in bladder cancer.

A significant proportion of non-muscle invasive bladder cancer cases will progress to muscle invasive disease. Transurethral resection followed by Bacillus Calmette Guerin immunotherapy can reduce this risk, while cystectomy prior to muscle invasion provides the best option for survival. Currently, there are no effective treatments for Bacillus Calmette Guerin refractory disease. A novel oncolytic vesicular stomatitis virus containing the human GM-CSF transgene (VSVd51-hGM-CSF) was rescued and tested as a potential bladder-sparing therapy for aggressive bladder cancer. The existing variant expressing mouse GM-CSF was also used. Measurement of gene expression and protein level alterations of canonical immunogenic cell death associated events on mouse and human bladder cancer cell lines and spheroids showed enhanced release of danger signals and immunogenic factors following infection with VSVd51-m/hGM-CSF. Intravesical instillation of VSVd51-mGM-CSF into MB49 bladder cancer bearing C57Bl/6 mice demonstrated enhanced activation of peripheral and bladder infiltrating effector immune cells, along with improved survival and reduced tumor volume. Importantly, virus-mediated anti-tumor immunity was recapitulated in bladder cancer patient-derived organoids. These results suggest that VSVd51-hGM-CSF is a promising viro/immunotherapy that could benefit bladder cancer patients.

Current Therapy and Emerging Intravesical Agents to Treat Non-Muscle Invasive Bladder Cancer.

Transurethral resection of bladder tumor remains the cornerstone of non-muscle invasive bladder cancer management, proper risk stratification, and appropriate selection of adjuvant therapy. A single, postoperative dose of intravesical chemotherapy is used for low-risk patients; patients with high-grade, high-risk disease should receive intravesical bacillus Calmette-Guérin (BCG) induction and maintenance therapy. For patients who develop BCG-unresponsive disease, cystectomy remains the standard of care. Pembrolizumab and valrubicin are approved in the BCG failure setting and as alternative treatments to cystectomy. Nadofaragene firadenovec, vicinium, hyperthermic chemotherapy, and various combination therapies are under investigation as treatment options for patients in the salvage setting.