Treatment patterns and prognosis in patients with Bacillus Calmette-Guérin-exposed high-risk non-muscle invasive bladder cancer: a real-world data analysis.

PURPOSE: The International Bladder Cancer Group designated the subgroup that is resistant to Bacillus Calmette-Guérin (BCG) but does not meet the criteria for BCG-unresponsive NMIBC as "BCG-exposed high-risk NMIBC" to guide optimal trial design. We aimed to investigate the treatment patterns and prognoses of patients with BCG-exposed NMIBC. METHODS: We conducted a retrospective chart review of 3283 patients who received intravesical BCG therapy for NMIBC at 14 participating institutions between January 2000 and December 2019. Patients meeting the criteria for BCG-exposed and BCG-unresponsive NMIBC, as defined by the Food and Drug Administration and International Bladder Cancer Group, were selected. To compare treatment patterns and outcomes, high-risk recurrence occurring more than 24 months after the last dose of BCG was defined as "BCG-treated NMIBC." In addition, we compared prognoses between BCG rechallenge and early cystectomy in patients with BCG-exposed NMIBC. RESULTS: Of 3283 patients, 108 (3.3%), 150 (4.6%), and 391 (11.9%) were classified as having BCG-exposed, unresponsive, and treated NMIBC, respectively. BCG-exposed NMIBC demonstrated intermediate survival curves for intravesical recurrence-free and progression-free survival, falling between those of BCG-unresponsive and treated NMIBC. Among patients with BCG-exposed NMIBC, 48 (44.4%) received BCG rechallenge, which was the most commonly performed treatment, and 19 (17.6%) underwent early cystectomy. No significant differences were observed between BCG rechallenge and early cystectomy in patients with BCG-exposed NMIBC. CONCLUSIONS: The newly proposed definition of BCG-exposed NMIBC may serve as a valuable disease subgroup for distinguishing significant gray areas, except in cases of BCG-unresponsive NMIBC.

Circulating Basophils as a Prognostic Marker for Response to Bacillus Calmette-Guérin.

PURPOSE: To predict recurrence and progression in non-muscle-invasive bladder cancer (NMIBC) patients receiving bacillus Calmette-Guérin (BCG), we evaluated circulating basophils as a biomarker that could be detected from the complete blood count. PATIENTS AND METHODS: We use a pooled cohort of patients from the Centre Hospitalier Universitaire de Québec-Université Laval (2016-2020) and the Vancouver General Hospital (2010-2018) where a complete blood count was available before transurethral resection of bladder tumor (TURBT) of a high-grade NMIBC and subsequent BCG. Descriptive statistics described the cohort based on the dichotomous presence or absence of basophils on the complete blood count. Kaplan-Meier estimates and a log-rank test compared recurrence-free survival (RFS) and progression-free survival (PFS), with multivariable cox regression analysis used to estimate proportional hazard ratios. RESULTS: The study cohort included 261 patients, with a median follow-up of 31.5 months (interquartile range 18.1-45.0 months). The median age was 74.0 years and 16.8% were female. Circulating basophils were detectable in 49 (18.9%) patients. Both RFS and PFS were significantly lower in patients with detectable basophils. Multivariable analysis demonstrated detectable basophils were an independent predictor of both recurrence (HR = 1.85; 95% confidence interval [CI] 1.20-2.85; P = .01) and progression (HR = 2.29; 95% CI 1.14-4.60; P = .02). CONCLUSION: Our results confirm that baseline levels of circulating basophils are an immunological biomarker to predict recurrence and progression of NMIBC.

Granulomatous myocarditis arising from intravesical Bacillus Calmette-Guérin therapy leading to death diagnosed by postmortem examination: a case report.

BACKGROUND: Intravesical Bacillus Calmette-Guérin (BCG) is used as a standard adjuvant therapy for non-muscle invasive urothelial cancer. Most patients tolerate the treatment well, with mild side effects. Systemic complications are extremely rare, occur due to BCG dissemination and are associated with immunocompromised state and urothelial breach. CASE PRESENTATION: We present a case of a 78-year-old male, a former smoker, with history of non-muscle invasive urothelial carcinoma status post partial resection followed by intravesical BCG therapy. An autopsy was performed due to the sudden nature of his death. Autopsy showed multiple necrotizing granulomas in the brain, atrium, ventricles, lungs, kidneys, and urinary bladder. Stains for acid-fast bacilli and fungi were negative. In addition, bilateral lungs showed evidence of bronchopneumonia secondary to cytomegalovirus. CONCLUSION: Granulomatous myocarditis arising from BCG therapy is extremely rare. Our patient with urothelial cancer treated with BCG developed multiorgan granulomas, most likely due to a hypersensitivity reaction to intravesical BCG. Arrhythmia induced by granulomatous myocarditis was the cause of his death. Although there have been few cases of systemic BCG-osis causing fatal sepsis leading to death, a cardiac cause of death is unique.

Efficacy and safety of photodynamic therapy for non-muscle-invasive bladder cancer: a systematic review and meta-analysis.

Background: Photodynamic therapy (PDT) is a promising treatment for non-muscle-invasive bladder cancer (NMIBC), we conducted this systematic review to comprehensively assess its efficacy and safety. Methods: A comprehensive literature research was conducted using PubMed, Web of Science, and Scopus, and studies reporting the safety and efficacy of PDT in NMIBC were included. Complete response (CR) rates, recurrence-free survival (RFS) at different time points, and complication incidences were extracted and synthesized. Pooled results were presented as rates with a 95% confidence interval (95% CI). Results: Overall, 28 single arm studies were included in the meta-analysis. For unresectable NMIBC, therapeutic PDT achieved CR in 68% (95% CI: 59%-77%) of patients. Among these CR cases, 71% (95% CI: 56%-85%) and 38% (95% CI: 12%-64%) have a RFS longer than 12 and 24 months, respectively. For Tis patients, the CR rate was 68% (95% CI: 56%-80%), and 84% (95% CI: 48%-100%) and 13% (95% CI: 1%-32%) have a RFS longer than 12 and 24 months. For patients with resectable tumors, post-resection adjuvant PDT could provide a 12 and 24 months RFS in 81% (95% CI:76%-87%) and 56% (95% CI:41%-71%) of them. Especially, for NMIBC patients who failed BCG therapy, adjuvant PDT could still achieve a 1-year and 2-year RFS in 68% (95% CI:51%-86%) and 56% (95% CI:32%-81%) patients. The complications were mostly mild and transient, including lower urinary tract symptoms and photosensitivity. Conclusion: Both therapeutic and adjuvant PDT present satisfying safety and efficacy for NMIBC, including these cases that are resistant to the standard of care. As a promising option for NMIBC, PDT deserves further exploration by future high-quality research. Systematic review registration: https://inplasy.com/inplasy-2022-11-0043/, INPLASY2022110043.

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.

The Urinary Microbiome and Bladder Cancer.

Bladder cancer is the 10th most common cancer worldwide. Approximately 75% of patients with bladder cancer will present with non-muscle invasive disease. Patients are usually treated with transurethral resection of bladder tumor (TURBT), in addition to adjuvant intravesical therapy (chemotherapy or anti-cancer immunotherapy with Bacillus Calmette Guerin- BCG) for those at intermediate-risk and high-risk of recurrence and progression. For many years, urine has been thought to be "sterile"; however, advanced microbiological and molecular techniques, including 16S ribosomal RNA (16S rRNA) sequencing, have negated that previous paradigm and confirmed the presence of a urinary microbiome. The urinary microbiome has been associated with several urological diseases, including interstitial cystitis, urgency urinary incontinence, neurogenic bladder dysfunction, and others. More recently, many reports are emerging about the role of the urinary microbiome in urothelial carcinogenesis, including gender disparity in bladder cancer and responses to treatments. The urinary microbiome may serve as a biomarker that can help with risk stratification as well as prediction of the response to intravesical therapies. However, the microbiome literature has been hampered by the lack of a unified standardized methodology for sample collection, type, preservation, processing, as well as bioinformatics analysis. Herein we describe and critique the literature on the association between urinary microbiome and bladder cancer and highlight some of the future directions.

C-reactive protein as a prognostic predictor for non-muscle invasive bladder cancer after intravesical bacillus Calmette-Guérin therapy: A Japan Urological Oncology Group study analysis.

OBJECTIVE: To investigate the involvement of pretreatment C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) in the prognosis of patients who underwent intravesical bacillus Calmette-Guérin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC). METHODS: The clinicopathological data of 1709 patients with NMIBC who underwent initial intravesical BCG therapy after transurethral resection of bladder tumor were retrospectively analyzed to evaluate the outcome of intravesical BCG therapy in a multicenter study conducted by the Japan Urological Oncology Group. The prognoses of these patients were analyzed to determine whether the biomarkers (CRP and NLR) could predict the efficacy of intravesical BCG therapy. Patients were divided into two groups according to the pretreatment CRP and NLR, with cutoff values defined as CRP ≥ 0.5 mg/dl and NLR ≥ 2.5, based on several previous reports. RESULTS: In the univariable analysis, CRP ≥ 0.5 mg/dl was significantly associated with intravesical recurrence, cancer-specific survival, and bladder cancer (BC) progression, while NLR ≥ 2.5 was not significantly associated with patient prognosis. In the multivariable analysis, CRP ≥ 0.5 mg/dl was significantly associated with intravesical recurrence and BC progression. The concordance index was used to examine the accuracy in predicting recurrence and progression events. While CRP was slightly, though not statistically significant, inferior to the European Association of Urology risk classification, the combination of them showed improved predictive accuracy. CONCLUSION: This study suggests that CRP can be a prognostic factor after intravesical BCG therapy and may provide useful data for determining treatment and follow-up strategies for patients with NMIBC.

The use of natural killer cell activity and PPD test in the prediction of results in intravesical BCG treatment of patients with nonmuscle-invasive bladder cancer.

PURPOSE: To predict the efficacy of intravesical BCG therapy in patients with nonmuscle-invasive bladder tumors (NIBC) by using components of the cellular immune response such as the tuberculin skin test (PPD) and natural killer (NK) activity measurement. METHODS: Ninety-nine patients who were started on intravesical BCG therapy for NIBC were evaluated prospectively. Patients who were included in the intermediate, high, and very high-risk groups according to the EAU NMIBC Scoring System and who had never received intravesical BCG therapy previously were included. The clinical and demographic characteristics of the patients (age, gender, EAU NMBIC risk group, EORTC progression and recurrence scores, CUETO progression and recurrence scores, presence and types of comorbidity) were recorded. NK activity was measured and the PPD test was applied 3 days before the start of intravesical BCG therapy. The results of PPD were measured in millimeters 72 h after the test. RESULTS: PPD values measured before BCG treatment, as an independent variable, were found to be significantly lower in patients with recurrence. A significant correlation was detected between NK activity results obtained before BCG treatment and recurrence after treatment, when the cutoff was 200-500 pg/dl. There was no significant relationship between the time to recurrence and PPD and NKA measurements. CONCLUSION: We conclude that the results of PPD test and NK activity measurement performed before starting intravesical BCG therapy in NIBC may be a marker that can be used to predict the risk of recurrence under treatment.

Mycobacterium Bovis Spondylodiscitis: A Rare Complication of Intravesical Bacillus Calmette-Guérin Therapy.

Teaching point: Mycobacterium bovis spondylodiscitis is a rare, often delayed, complication of intravesical Bacillus Calmette-Guérin therapy for bladder cancer.

Granulomatous Prostatitis Mimicking Invasive Prostate Cancer.

Teaching Point: Benign granulomatous prostatitis mimics prostate cancer on MRI. Peculiar urological history of a patient undergoing prostate MRI helps sorting out that differential, such as a treatment with topic Bacilli Calmette-Guerin instillations.

[Guidelines from the cancer (CC-AFU) and infection disease (CI-AFU) committees of the French Association of Urology for the management of adverse events and complications of BCG]. / Recommandations des Comités de cancérologie (CC-AFU) et d'infectiologie (CI-AFU) de l'Association française d'urologie pour la prise en charge effets indésirables et complications du BCG.

INTRODUCTION: Intravesical instillations of BCG are recommended for the treatment of high-risk non-muscle-invasive bladder cancer. However, their prolonged use remains limited by the associated potentially serious adverse effects or complications. The purpose of this article was to provide updated recommendations for the diagnosis and management of adverse events (AEs) or complications of intravesical BCG instillations. MATERIALS AND METHODS: Review of the literature in Medline (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using the following MeSH keywords or a combination of these keywords: "bladder," "BCG," "complication," "toxicity," "adverse events," "prevention," and "treatment". RESULTS: AEs or complications of BCG included genitourinary and systemic symptoms. The most common complications (cystitis, moderate fever) should be treated symptomatically and may require adjustment to allow patients to have the most complete BCG treatment possible. Serious complications are rare but must be identified promptly because of the life-threatening nature of the disease. Their management is based on the combination of anti-tuberculosis treatments, anti-inflammatory drugs and the definitive discontinuation of BCG. CONCLUSION: The management of BCG AEs requires early identification, rational and effective treatment if necessary, and discussion of the continuation of treatment for each situation.

Role of PD-1/PD-L1-mediated tumour immune escape mechanism and microsatellite instability in the BCG failure of high-grade urothelial carcinomas.

BACKGROUND: Intravesical BCG treatment fails inexplicably in 30%-45% of patients for high-grade nonmuscle-invasive bladder cancer (NMIBC). We aimed to investigate the role of PD-1/PD-L1 interaction on BCG failure of high-grade NMIBC and to identify biomarkers for predicting BCG responsive cases. METHODS: Thirty BCG responsive and 29 nonresponsive NMIBCs were included in the study. Expressions of PDL1(SP-263), MSH2, MSH6, PMS2, and MLH1 were evaluated on pre- and post-BCG transurethral resection (TUR-B) specimens by immunohistochemistry. PD-L1(SP-263) expression was categorised as negative/low, high. DNA mismatch repair protein (MMR) expressions were classified as "reduced" if ≤30% of nuclei stained, "preserved" if >30% of nuclei stained. Microsatellite instability (MSI) testing was performed by PCR using five mononucleotide markers. RESULTS: Reduced DNA MMR protein expression was found to be significantly higher in the pretreatment biopsies of BCG-responsive group than the BCG nonresponsive tumour group (p = 0.022). PD-L1 expression did not show any significant difference between the pre- and posttreatment TUR-B specimens of the BCG nonresponsive tumour group or between the pretreatment TUR-B specimens of BCG nonresponsive and the BCG responsive groups (p = 0.508, p = 0.708, respectively). DISCUSSION: Immune escape of tumour cells by PD-1/PD-L1 interaction does not seem to have any role in BCG failure of NMIBCs. Reduced MMR expression may help to determine cases that will respond well to BCG therapy. A better antitumour activity of BCG in NMIBCs with reduced MMR expression may be related to the ongoing accumulation of cancer neoantigens in correlation with increased tumour mutation load as a result of DNA repair defects.

Siglec-6 as a New Potential Immune Checkpoint for Bladder Cancer Patients.

Among the growing family of inhibitory receptors regulating immunity, sialic acid-binding immunoglobulin domain-containing lectins (Siglecs) have recently emerged as immunoregulatory receptors recognizing sialylated ligands on tumor cell surface. However, their role in the immunoregulation of bladder cancer (BCa) remains unknown. Here, we determined the presence of eight Siglec ligands (SLs) on bladder nontumor and tumor cell lines. S2L, S3L, and S6L were not expressed, and few bladder tumor cell lines expressed S5L and S14L. In contrast, S7L and S10L were upregulated on all bladder tumor cell lines. We found a discrepency in S9L expression by nontumor cell lines, which is however highly expressed by bladder tumor cell lines. Notably, expression of S5L, S6L, and S14L was increased upon bacillus Calmette-Guérin (BCG) infection. Furthermore, we analyzed the expression of Siglecs on T cells from healthy donors and BCa patients. Circulating T cells only expressed Siglec-6, which is upregulated in non-muscle-invasive BCa patients. In addition, BCG therapy induced the overexpression of Siglec-6 by urinary CD8+ T cells. In vitro functional assays suggested that Siglecs may decrease cytotoxic functions of effector CD8+ T cells. Finally, analyses from two BCa datasets (The Cancer Genome Atlas and UROMOL cohorts) showed that Siglec-6 is associated with tumor progression and poor survival. Our findings indicate that Siglec-6 might be a new target for BCa treatments. PATIENT SUMMARY: We investigated the expression of Siglecs, a family of immunoregulatory receptors, in bladder cancer patients. We observed that the expression of Siglec-6 is increased on circulating and urinary T cells of non-muscle-invasive bladder cancer patients. We also showed that Siglec-6 is associated with lower survival in bladder cancer patients and might contribute to bladder cancer recurrence.

Impact of bacillus Calmette-Guerin intravesical therapy on the diagnostic efficacy of The Paris System for Reporting Urinary Cytology in patients with high-grade bladder cancer.

BACKGROUND: In high-grade urothelial carcinoma (UC) of the bladder, bacillus Calmette-Guerin (BCG) therapy is a therapeutic mainstay, and urinary cytology is recommended to detect recurrences. However, intravesical BCG instillations can induce morphologic changes in urothelial cells. The authors investigated the impact of BCG therapy on the efficacy of urinary cytology. METHODS: Matched pathology and cytology samples from patients undergoing transurethral resection of the bladder after BCG therapy were assessed. Cytology samples were graded according to The Paris System for Reporting Urinary Cytology. Diagnostic quality criteria were tested for different cutoff definitions, and the results were compared between those obtained <100 versus ≥100 days after the last BCG instillation. In addition, the oncologic outcome of false-positive results was assessed. RESULTS: In total, 389 matched cases from 197 patients who had a history of high-grade UC (HGUC) were identified. Sixty cases (15.7%) were diagnosed as high-grade urothelial bladder cancer. The cytology diagnoses were as follows: non-HGUC, 191 cases (49.1%); atypical urothelial cells, 80 cases (20.6%); suspicious for HGUC, 56 cases (14.4%); and HGUC, 56 cases (14.4%). Interrater reliability was substantial (κ = 0.660). Sensitivity increased from 45% to 75% when cases diagnosed as suspicious for HGUC were also counted as positive. Notably, sensitivity was reduced within the first 100 days after BCG therapy (61.9%) compared with sensitivity at longer intervals (82.1%). Reactive atypia (odds ratio, 4.155; 95% confidence interval, 2.136-8.085; P < .001) and cellular degeneration (odds ratio, 5.050; 95% CI, 2.094-12.175; P < .001) of urothelial cells were associated with false-positive rates, and 44.7% of patients who had a false-positive cytology classification presented with HGUC during follow-up. CONCLUSIONS: BCG therapy has a short-term adverse impact on the efficacy of urinary cytology. After BCG therapy, cases classified as suspicious for HGUC should be considered positive. Importantly, patients with false-positive cytology findings should be closely monitored.

A possible protective role for Bacillus Calmette-Guérin therapy in urinary bladder cancer in the era of COVID-19: a brief report.

Given the systemic immunogenic effects of Bacillus Calmette-Guérin (BCG) therapy in patients with bladder cancer and its non-specific immunogenic effects in viral respiratory diseases, we aimed to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in bladder cancer patients with a history of BCG therapy. In the present study, all bladder cancer survivors with a history of BCG therapy were identified and included in the study according to the data recovered from the UORC (Uro-Oncology Research Center) registry database. These patients were followed up in terms of acquiring coronavirus disease 2019 (COVID-19). Among the studied patients, 102 eligible bladder cancer patients with a history of BCG therapy entered the study. The males constituted the majority of the patients (86.3%), and more than half of the study population (55.9%) were above 65 years old. Among the understudy patients, 12.7% were confirmed for COVID-19. The study results did not show a statistically significant association between the time and number of BCG therapy courses and SARS-CoV-2 infection. Although no statistically significant association was observed between receiving BCG therapy and developing COVID-19, the infection rate in patients who had recently received BCG therapy was lower than those who had received therapy more than a year ago.

Oncological outcomes of high-grade T1 non-muscle-invasive bladder cancer treatment in octogenarians.

PURPOSE: To evaluate the outcomes of high-grade T1 non-muscle-invasive bladder cancer treatment (NMIBC) in elderly patients over 80 years of age. METHODS: This is a retrospective single tertiary-centre study. Medical records of patients with T1 high-grade NMIBC treated with transurethral resection of the bladder tumour (TURBT) were reviewed. Among 269 patients with high-grade T1 NMIBC, 74 individuals were over 80 years of age at the time of surgery. Finally, 67 patients met the inclusion criteria. RESULTS: Only 47.8% of patients (N = 32) received at least five of the six instillations of the BCG immunotherapy induction course. Oncological outcomes were compared between patients who received at least the induction course of BCG and non-BCG-treated patients matched to each other based on age and Charlson comorbidity index. Thirty case-control pairs were included in the final analysis. Rates of disease recurrence (80% vs. 53%) and cancer-specific mortality (40% vs. 10%) were significantly higher in the group of patients who did not receive BCG. BCG therapy, Charlson comorbidity index, haemoglobin concentration and the number of tumours > 3 in TURBT constituted independent prognostic factors for cancer-specific survival (CSS). CONCLUSION: BCG should be strongly recommended to patients with T1HG NMIBC despite advanced age and comorbidities. Already BCG induction improves CSS and reduces the recurrence rate in octogenarians with T1HG bladder cancer.

Prosthetic hip joint infection by Bacillus Calmette-Guerin therapy following intravesical instillation for bladder cancer identified using whole-genome sequencing: a case report.

BACKGROUND: Joint replacement is an effective intervention and prosthetic joint infection (PJI) is one of the most serious complications of such surgery. Diagnosis of PJI is often complex and requires multiple modalities of investigation. We describe a rare cause of PJI which highlights these challenges and the role of whole-genome sequencing to achieve a rapid microbiological diagnosis to facilitate prompt and appropriate management. CASE PRESENTATION: A 79-year-old man developed chronic hip pain associated with a soft-tissue mass, fluid collection and sinus adjacent to his eight-year-old hip prosthesis. His symptoms started after intravesical Bacillus Calmette-Guerin (BCG) therapy for bladder cancer. Synovasure™ and 16S polymerase chain reaction (PCR) tests were negative, but culture of the periarticular mass and genome sequencing diagnosed BCG infection. He underwent a two-stage joint revision and a prolonged duration of antibiotic therapy which was curative. CONCLUSIONS: BCG PJI after therapeutic exposure can have serious consequences, and awareness of this potential complication, identified from patient history, is essential. In addition, requesting appropriate testing is required, together with recognition that traditional diagnostics may be negative in non-pyogenic PJI. Advanced molecular techniques have a role to enhance the timely management of these infections.

Novel anticancer therapy in BCG unresponsive non-muscle-invasive bladder cancer.

INTRODUCTION: Many patients with non-muscle-invasive bladder cancer (NMIBC) failed intravesical BCG therapy. Currently, radical cystectomy is the recommended standard of care for those patients. There is unfortunately no effective other second-line therapy recommended. AREAS COVERED: In this review, we present the topics of BCG unresponsive NMIBC; definition, prognosis, and further treatment options: immunotherapy, intravesical chemotherapy, gene therapy, and targeted individualized therapy. EXPERT OPINION: There are major challenges of the management of NMIBC who failed BCG therapy as many patients refuse or are unfit for radical cystectomy. Multiple new modalities currently under investigation in ongoing clinical trials to better treat this category of patients. Immunotherapy, especially PD-1/PD-L1 inhibitors, offers exciting and potentially effective strategies for the treatment of BCG unresponsive NMIBC. As the data expands, it is sure that soon there will be established new guidelines for NMIBC.