Predictors of BCG Therapy Complications in Non-Muscle-Invasive Bladder Cancer: A Clavien-Dindo-Based Study.

MAINTENANCE BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY FOR RECURRENT TA, T1 AND CARCINOMA IN SITU TRANSITIONAL CELL CARCINOMA OF THE BLADDER: A RANDOMIZED SOUTHWEST ONCOLOGY GROUP STUDY

Loss of Heterozygosis on IFN-α Locus is a Prognostic Indicator of Bacillus Calmette-Guerin Response for Nonmuscle Invasive Bladder Cancer

EFFECTS OF ACETYLIC SALICYLIC ACID AND PENTOXIFYLLINE ON THE EFFICACY OF INTRAVESICAL BCG THERAPY IN ORTHOTOPIC MURINE BLADDER CANCER (MB49)

Simple SummaryThis retrospective cohort study aimed to understand the incidence, clinical impact, and risk factors associated with upper urinary tract urothelial carcinoma (UTUC) after intravesical Bacillus Calmette-Guerin (BCG) therapy. The study included 3226 patients diagnosed with non-muscle-invasive bladder cancer (NMIBC) and treated with intravesical BCG therapy between January 2000 and December 2019. Of these patients, 6.1% were diagnosed with UTUC during the follow-up period, and those with UTUC had worse survival rates compared to those without UTUC. Tumor multiplicity, treatment for Connaught strain, and intravesical recurrence after BCG therapy were associated with subsequent UTUC diagnosis. The study suggests that patients with these risk factors may require closer monitoring for UTUC after BCG therapy.Upper urinary tract urothelial carcinoma (UTUC) after intravesical bacillus Calmette-Guerin (BCG) therapy is rare, and its incidence, clinical impact, and risk factors are not fully understood. To elucidate the clinical implications of UTUC after intravesical BCG therapy, this retrospective cohort study used data collected between January 2000 and December 2019. A total of 3226 patients diagnosed with non-muscle-invasive bladder cancer (NMIBC) and treated with intravesical BCG therapy were enrolled (JUOG-UC 1901). UTUC impact was evaluated by comparing intravesical recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) rates. The predictors of UTUC after BCG treatment were assessed. Of these patients, 2873 with a medical history that checked UTUC were analyzed. UTUC was detected in 175 patients (6.1%) during the follow-up period. Patients with UTUC had worse survival rates than those without UTUC. Multivariate analyses revealed that tumor multiplicity (odds ratio [OR], 1.681; 95% confidence interval [CI], 1.005–2.812; p = 0.048), Connaught strain (OR, 2.211; 95% CI, 1.380–3.543; p = 0.001), and intravesical recurrence (OR, 5.097; 95% CI, 3.225–8.056; p < 0.001) were associated with UTUC after BCG therapy. In conclusion, patients with subsequent UTUC had worse RFS, CSS, and OS than those without UTUC. Multiple bladder tumors, treatment for Connaught strain, and intravesical recurrence after BCG therapy may be predictive factors for subsequent UTUC diagnosis.

Management of high-risk non-muscle-invasive bladder cancer (NMIBC) represents a clinical challenge due to high failure rates despite prior bacillus Calmette-Guérin (BCG) therapy. To describe real-world patient characteristics, long-term outcomes, and the economic burden in a population with high-risk NMIBC treated with BCG therapy. This retrospective cohort study identified 412 patients with high-risk NMIBC from 63 139 patients diagnosed with bladder cancer who received at least 1 dose of BCG within Department of Veterans Affairs (VA) centers across the US from January 1, 2000, to December 31, 2015. Adequate induction BCG therapy was defined as at least 5 installations, and adequate maintenance BCG therapy was defined as at least 7 installations. Data were analyzed from January 2, 2020, to January 20, 2021. Intravesical BCG therapy, including adequate induction BCG therapy, was defined as at least 5 intravesical instillations of BCG within 70 days from BCG therapy start date. Adequate maintenance BCG therapy was defined as at least 7 installations of BCG within 274 days of the start (the first instillation) of adequate induction BCG therapy (ie, adequate induction BCG plus some form of additional BCG). The Kaplan-Meier method was used to estimate outcomes, including event-free survival. All-cause expenditures were summarized as medians with corresponding interquartile ranges (IQRs) and adjusted to 2019 USD. Of the 412 patients who met inclusion criteria, 335 (81%) were male and 77 (19%) were female, with a median age of 67 (IQR, 61-74) years. Follow-up was 2694 person-years. A total of 392 patients (95%) received adequate induction BCG therapy, and 152 (37%) received adequate BCG therapy. For all patients with high-risk NMIBC, the 10-year progression-free survival rate and disease-specific death rate were 78% and 92%, respectively. Patients with carcinoma in situ (Cis) had worse disease-free survival than those without Cis (hazard ratio [HR], 1.85; 95% CI, 1.34-2.56). Total median costs at 1 year were $29 459 (IQR, $14 991-$52 060); at 2 years, $55 267 (IQR, $28 667-$99 846); and at 5 years, $117 361 (IQR, $59 680-$211 298). Patients with progressive disease had significantly higher median 5-year costs ($232 729 [IQR, $151 321-$341 195] vs $94 879 [IQR, $52 498-$172 631]; P < .001), with outpatient care, pharmacy, and surgery-related costs contributing. Despite adequate induction BCG therapy, only 37% of patients received adequate BCG therapy. Patients with Cis had increased risk of progression, and progression regardless of Cis was associated with significantly increased costs relative to patients without progression. Extrapolating cost figures, regardless of progression, resulted in nationwide costs at 1 year of $373 million for patients diagnosed with high-risk NMIBC in 2019.

Factors Affecting Response to Bacillus Calmette-Guérin Plus Interferon for Urothelial Carcinoma in Situ

The bladder microbiota is not significantly altered by intravesical BCG therapy

Intravesical bacillus Calmette-Guérin (BCG) therapy is the standard adjuvant treatment for high-risk non-muscle-invasive bladder cancer (NMIBC). However, the impact of advanced age, particularly ≥80 years, on oncological outcomes of BCG therapy remains controversial. This study evaluated age-stratified outcomes and real-world BCG delivery in patients with NMIBC. We retrospectively reviewed 120 consecutive patients with NMIBC who initiated intravesical BCG therapy between June 2019 and May 2025 at a single center. Patients were stratified by age at BCG initiation into <80 years (n=91) and ≥80 years (n=29). High-risk recurrence-free survival (HR-RFS), progression-free survival (PFS), metastasis-free survival (MFS), and overall survival (OS) were assessed. HR-RFS was defined as the time from BCG initiation to recurrence of high-risk NMIBC or disease progression. Survival outcomes were estimated using the Kaplan-Meier method and compared between groups. Baseline clinicopathological characteristics and the rate of achieving the institution-defined minimum BCG exposure were similar between the two age groups. During a median follow-up of 33.5 months, there were no significant differences in HR-RFS (p=0.803), PFS (p=0.700), MFS (p=0.750), or OS (p=0.065) between the groups. Although HR-RFS was numerically lower in the ≥80 years group, progression to muscle-invasive disease and distant metastasis remained infrequent and comparable between groups. In this real-world cohort, intravesical BCG therapy achieved comparable oncological outcomes in patients aged ≥80 years and younger patients with NMIBC. Chronological age alone was not associated with inferior clinically meaningful disease control, supporting BCG use in older patients when clinically indicated, with treatment decisions guided by tolerability and patient preference.

Urinary bladder cancer includes non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). While patients with NMIBC have a better prognosis, NMIBC often recurs, requiring long-term surveillance and repeated treatments. Intravesical Bacillus Calmette-Guérin (BCG) therapy is standard for high-grade or recurrent NMIBC; however, 30%-50% of patients failed to respond, and the mechanisms of resistance remain unclear. To identify predictive biomarkers for response to intravesical BCG therapy, we analyzed NANOG and Histone deacetylase 1 (HDAC1) expression in 90 bladder cancer specimens from NMIBC patients treated with BCG therapy using immunohistochemistry. The correlation between NANOG and HDAC1 expression and clinical outcomes, including response to BCG therapy, was assessed. High-grade NMIBC cases showed significantly higher expression of NANOG and HDAC1 compared to low-grade cases (p < 0.05). Additionally, elevated NANOG expression in combination with HDAC1, was associated with poor response to BCG therapy and decreased lymphocyte infiltration in the tumor-microenvironment. NANOG is suggested to directly increases HDAC1 expression, which could suppress lymphocyte infiltration in the tumor microenvironment by altering immune-related gene expression. These findings suggest that the NANOG/HDAC1 axis plays a key role in predicting resistance to intravesical BCG therapy in NMIBC.

Introduction. Transurethral resection of bladder tumor (TURBT) is the gold standard treatment for patients with non-muscle invasive bladder cancer (NMIBC). However, the high recurrence rate after TURBT makes necessary not only regular following to reveal recurrence disease timely, but it also talks about a necessity of adjuvant antitumor therapy in some cases, that allows to prevent disease recurrence and progression. In this regard, patients belonging to high- and sometimes intermediate- risk progression groups are shown to undergo postoperative adjuvant intravesical Bacillus Calmette–Guérin (BCG) therapy. Despite the long experience of using BCG therapy for NMIBC treatment the question of the existence of possible prognostic markers and response predictors to intravesical BCG therapy remains open.Objective. To review cutting-edge data on different markers that can be used as predictive response markers to ongoing intravesical BCG therapy in NMIBC-patients.Materials and methods. A literature search was conducted using PubMed/ Medline and Google Scholar databases. We used terms 'bladder cancer', 'non-muscle-invasive bladder cancer' in conjunction with 'recurrence', 'progression', 'BCG', 'intravesical therapy', 'immune response', 'molecular markers' to choose relevant articles published between 2000 and 2022.Results. Clinical and pathological characteristics of the tumor and the patient himself remain leading in predicting the response to intravesical BCG therapy in NMIBC-patients. However, to improve the effectiveness of assessing the risk of developing adverse BC outcomes and choosing the most appropriate strategy for monitoring and treatment in each case, it is necessary to introduce additional assessment parameters. Molecular and genetic markers could be considered as such parameters, make it possible to reveal differences between tumors at a deeper level.Conclusion. Currently, there are no markers that have high-evidence in predicting response to intravesical BCG therapy in NMIBC-patients compared with the cliniсal and pathological characteristics of the tumor and the patient himself. The clearer awareness of molecular genetic pathways of BC pathogenesis, the mechanism of BCG antitumor effect will make it possible to competently select markers that have the highest specificity for BC, which will increase the predictive ability of currently existing tools to assess the risks of BC recurrence and progression.

MP08-09 Down-STAGING IN AUA RISK STRATIFICATION AFTER INTRAVESICAL BACILLUS CALMETTE-GUERIN THERAPY HAS FAVORABLE EFFECT ON RECURRENCE FREE SURVIVAL AFTER 2ND LINE INTRAVESICAL GEMCITABINE CHEMOTHERAPY

This study investigated the clinical impact of carcinoma in situ (CIS) in intravesical Bacillus Calmette-Guérin (BCG) therapy for patients with non-muscle-invasive bladder cancer (NMIBC). This study retrospectively evaluated 3035 patients who were diagnosed with NMIBC and treated by intravesical BCG therapy between 2000 and 2019 at 31 institutions. Patients were divided into six groups according to the presence of CIS as follows: low-grade Ta without concomitant CIS, high-grade Ta without concomitant CIS, high-grade Ta with concomitant CIS, high-grade T1 without concomitant CIS, high-grade T1 with concomitant CIS, and pure CIS (without any papillary lesion). The endpoints were recurrence- and progression-free survival after the initiation of BCG therapy. We analyzed to identify factors associated with recurrence and progression. At a median follow-up of 44.4months, recurrence and progression were observed in 955 (31.5%) and 316 (10.4%) patients, respectively. Comparison of six groups using univariate and multivariate analysis showed no significant association of CIS. However, CIS in the prostatic urethra was an independent factors associated with progression. Concomitant CIS did not show a significant impact in the analysis of Ta and T1 tumors which were treated using intravesical BCG. Concomitant CIS in the prostatic urethra was associated with high risk of progression. Alternative treatment approaches such as radical cystectomy should be considered for patients with NMIBC who have a risk of progression.

Since the first report in 1976, accumulated clinical evidence has supported intravesical Bacillus Calmette-Guerin (BCG) therapy as one of the standard methods of management of intermediate- and high-risk non-muscle invasive bladder cancer. Despite its efficacy, intravesical BCG therapy is associated with a variety of adverse events (AEs), most of which are tolerable or controllable with supportive care. However, some patients receiving intravesical BCG therapy may experience uncommon but severe AEs, leading to cessation of BCG therapy. Not all, but most severe AEs result from either local or systemic infection with live BCG. Intravesical instillation of BCG elicits multiple immune reactions, although the precise immunological mechanism of BCG therapy is not clear. It is convenient to separate the complex reactions into the following three categories: infection of urothelial cells or bladder cancer cells, induction of immune reactions, and induction of antitumor effects. Recently, our knowledge about each category has increased. Based on this understanding, predictors of the efficacy of intravesical BCG therapy, such as urinary cytokine measurement and cytokine gene polymorphism, have been investigated. Recently, preclinical studies using a novel engineered mycobacterium vaccine have been conducted to overcome the limitations of BCG therapy. One approach is Th1 cytokine-expressing recombinant forms of BCG; another approach is development of non-live bacterial agents to avoid AEs due to live BCG infection. We also briefly describe our approach using an octaarginine-modified liposome-incorporating BCG cell wall component to develop future substitutes for live BCG.

Background: Although retreatment with BCG is considered standard of care for patients with BCG-exposed high-grade (HG) non-muscle invasive bladder cancer (NMIBC), less than 50% of patients are expected to respond. As such, the ability to augment the efficacy of BCG in this population remains a critical unmet need. Preclinical studies suggest that intravesical gemcitabine (Gem) may demonstrate synergistic efficacy with BCG by favorably altering the tumor microenvironment. We therefore sought to evaluate the safety, tolerability, and preliminary clinical efficacy of GemBCG in patients with BCG-exposed HG NMIBC through an IRB-approved Phase I/II clinical trial. Methods: Patients with BCG-exposed papillary HG NMIBC (Ta/T1) with or without carcinoma in situ (CIS) that recurred within 24 months of BCG therapy were eligible for this trial. Exclusion criteria included BCG-unresponsive disease, contraindication to BCG therapy, or ureteral/urethral urothelial disease. Consenting patients underwent complete transurethral resection of bladder tumors followed by intravesical Gem twice weekly (weeks 1, 4, 7, 10) for a total of 8 doses. Dose escalation of Gem was performed from 50-2000 mg using a Bayesian modified continual reassessment method. Intravesical Gem instillations alternated with weekly intravesical TICE BCG therapy (weeks 2, 3, 5, 6, 8, 9) for a total of 6 doses fixed at 50 mg followed by maintenance BCG in responders. Complete response (CR) rates and progression to muscle-invasive bladder cancer (MIBC) or cystectomy were evaluated at 12 months of follow up in the Phase I cohort. Results: A total of 25 patients was enrolled (median age 70 years [IQR 64-75]), all of which have at least 12 months of follow up. Of these, 88% (22/25) were male. Median duration of bladder cancer treatment prior to enrollment was 385 days (IQR 173-634), and 28% (7/25) previously received either maintenance therapy (3/25) or &amp;gt;1 induction courses of BCG (4/25). Based on centralized pathology review, a total of 68% had CIS ± papillary disease (8 HGTa, 5 HGT1, and 4 Tis), while 32% had papillary-only disease (4 HGTa and 4 HGT1). No dose limiting toxicities were observed, and 14/25 patients were treated at the maximum tolerated dose. The treatment was well tolerated with no patient experiencing treatment-related Grade 3-5 toxicity. CR rates at 6 months and 12 months were 96% (24/25) and 92% (23/25), respectively. No progression to MIBC or radical cystectomy was observed. Conclusion: Combination GemBCG in BCG-exposed HG NMIBC is well tolerated and appears to provide excellent cancer control. Based on these encouraging findings and the ongoing phase II portion (NCT04179162), a prospective randomized controlled trial comparing GemBCG to BCG alone for BCG-exposed NMIBC is planned through the National Clinical Trial Network (Alliance A032303). Citation Format: Syed M. Alam, Christopher D. Gaffney, Jessica Lavery, Merve Basar, Neeta D'Souza, Christian Hernandez, Melissa McCarter, Patricia Moran, Kristen Stasi, Kara Worth, Daniel Sjoberg, Guido Dalbagni, Timothy Donahue, Sherri Donat, Dean Bajorin, Bernard H. Bochner, Alvin Goh, Judy Sarungbam, Hikmat Al-Ahmadie, Eugene J. Pietzak. Final results from a Phase I trial of intravesical chemoimmunotherapy with gemcitabine and Bacillus Calmette-Guérin (BCG) for patients with BCG-exposed high-grade non-muscle invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr PR005.

Bacillus Calmette-Guerin (BCG) therapy is safe and effective in non-muscle invasive bladder cancer (NMIBC) patients with immunomodulating conditions