Bacillus Calmette-Guérin Failure Research Articles

Systemic Immune-Inflammation Index (SII) as Prognostic Indicator for BCG Therapy in Bladder Cancer: A Systematic Review and Meta-analysis

Background: Bacillus Calmette-Guérin (BCG) immunotherapy is a standard treatment for high-risk non-muscle invasive bladder cancer (NMIBC) after tumor resection. However, not all patients respond to BCG therapy. Reliable prognostic markers are needed to predict treatment outcomes. Objectives: This study reviewed the prognostic value of systemic immune-inflammation index (SII) and related markers in BCG response. Methods: A systematic literature search was conducted in PubMed, Web of Science, and Scopus databases from inception to October 2023 for studies on SII index, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) in bladder cancer patients receiving BCG therapy. Four retrospective studies involving 1124 patients met the inclusion criteria and were included in qualitative synthesis. Three studies were included in the meta-analysis of progression-free survival (PFS) and recurrence-free survival (RFS). Data on study characteristics and demographics, follow-up duration, cancer stage/grade, and pre-treatment marker levels were extracted. Hazard ratios (HRs) were pooled using a random effects model. Results: Elevated pre-treatment SII was associated with significantly worse PFS (HR: 3.72, 95% CI: 1.74-7.98, P<0.001) and RFS (HR: 3.72, 95% CI: 1.42-9.77, P=0.007). However, significant heterogeneity was found among trials in the overall survival (OS) (I2 =83.49, P=0.002) and RFS (I2 =89.69%, P=0.002). In multivariate analysis, SII>672.75 was an independent predictor of BCG failure (OR: 2.229, 95% CI: 1.172-4.238, P=0.015). NLR, PLR, and MLR also showed potential prognostic value with area under the curve (AUC) values ranging from 0.592 to 0.663 for predicting non-response to BCG therapy. Specifically, NLR>3.0435, PLR>123.4398, and MLR>0.1995 were significantly associated with non-response to BCG (P<0.001 for all). In univariate analysis, BCG non-response was associated with high pre-treatment levels of PLR, NLR, and MLR (P<0.001). Conclusion: Pre-treatment SII and other inflammatory markers may predict poor outcomes after BCG immunotherapy in bladder cancer patients. SII holds promise as an accessible prognostic biomarker that can guide treatment decisions. Further large prospective studies are warranted to validate these preliminary findings.

Multiple genetic loci influence vaccine-induced protection against Mycobacterium tuberculosis in genetically diverse mice.

Mycobacterium tuberculosis (M.tb.) infection leads to over 1.5 million deaths annually, despite widespread vaccination with BCG at birth. Causes for the ongoing tuberculosis endemic are complex and include the failure of BCG to protect many against progressive pulmonary disease. Host genetics is one of the known factors implicated in susceptibility to primary tuberculosis, but less is known about the role that host genetics plays in controlling host responses to vaccination against M.tb. Here, we addressed this gap by utilizing Diversity Outbred (DO) mice as a small animal model to query genetic drivers of vaccine-induced protection against M.tb. DO mice are a highly genetically and phenotypically diverse outbred population that is well suited for fine genetic mapping. Similar to outcomes in people, our previous studies demonstrated that DO mice have a wide range of disease outcomes following BCG vaccination and M.tb. challenge. In the current study, we used a large population of BCG-vaccinated/M.tb.-challenged mice to perform quantitative trait loci mapping of complex infection traits; these included lung and spleen M.tb. burdens, as well as lung cytokines measured at necropsy. We found sixteen chromosomal loci associated with complex infection traits and cytokine production. QTL associated with bacterial burdens included a region encoding major histocompatibility antigens that are known to affect susceptibility to tuberculosis, supporting validity of the approach. Most of the other QTL represent novel associations with immune responses to M.tb. and novel pathways of cytokine regulation. Most importantly, we discovered that protection induced by BCG is a multigenic trait, in which genetic loci harboring functionally-distinct candidate genes influence different aspects of immune responses that are crucial collectively for successful protection. These data provide exciting new avenues to explore and exploit in developing new vaccines against M.tb.

Documento multidisciplinar de consenso sobre el tratamiento actual del tumor vesical no-músculo invasor que no responde al tratamiento con bacilo Calmette-Guérin

Radical cystectomy is the current treatment of choice for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). However, the high comorbidity of this surgery and its effects on the quality of life of patients require the investigation and implementation of bladder-sparing treatment options. These must be evaluated individually by the uro-oncology committee based on the characteristics of the BCG failure, type of tumor, patient preferences and treatment options available in each center. Based on FDA-required oncologic outcomes (6-month complete response rate for CIS: 50%; duration of response in responders for CIS and papillary: 30% at 12 months and 25% at 18 months), there is not currently a strong preference for one treatment over another, although the intravesical route seems to offer less toxicity. This work summarizes the evidence on the management of BCG-unresponsive NMIBC based on current scientific evidence and provides consensus recommendations on the most appropriate treatment.

Salvage therapy for BCG failure with intravesical sequential gemcitabine and docetaxel in patients with recurrent NMIBC.

Bacillus Calmette-Guérin (BCG) failure occurs in approximately 40% of patients with non-muscle-invasive bladder cancer (NMIBC) within two years. We describe our institutional experience with sequential intravesical gemcitabine and docetaxel (gem/doce) as salvage therapy post-BCG failure in patients who were not candidates for or declined radical cystectomy (RC). We retrospectively reviewed NMIBC patients with BCG failure who received gem/doce from April 2019 through October 2022 at the CHU de Québec-Université Laval. Patients received at least five weekly intravesical instillations according to published protocols. Patients who responded to gem/doce had maintenance instillations monthly for up to two years. Primary outcome was progression-free survival (PFS). Secondary outcomes included recurrence-free survival (RFS), cystectomy-free survival (CFS), cancer-specific survival (CSS), overall survival (OS), and treatment adverse events. Survival probabilities were estimated using the Kaplan-Meier method from the first gem/doce instillation. Thirty-five patients with a median age of 78 years old were included in the study. The median followup time was 21 months (interquartile range 10-29). More than 25% of patients received two or more prior BCG induction treatments. Overall and MIBC PFS estimates at one year were 85% and 88%, and at two years, 60% and 70%, respectively. Adverse events occurred in 37% of the patients, but only two patients didn't complete the treatment due to intolerance. Three patients underwent RC due to cancer progression. OS was 94% at two years. With 60% of PFS at two years, gem/doce appears to be a safe and well-tolerated option for BCG failure patients. Further studies are needed to justify widespread use.

Value of Immunological Biomarkers in Early Prediction of Bacillus Calmette-Guerin Failure in High-Risk Non-muscle-invasive Bladder Cancer

Objectives To investigate the predictive value of different immunological markers on treatment outcomes after bacillus Calmette-Guerin (BCG) induction in high-risk non-muscle-invasive bladder cancer (NMIBC). Patients and Methods Patients who underwent transurethral resection of bladder tumors for NMIBC were assessed for study eligibility. Urine and blood samples were taken from patients at baseline (immediately before the first dose of induction). Urine samples were evaluated for interleukin (IL)-6, IL-8, IL-10, IL-11, and interferon- γ by solid-phase enzyme-linked immunosorbent assay (ELISA). Blood samples were evaluated for epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) using quantitative reverse transcriptase-polymerase chain reaction analysis. Each marker was assessed in relation to tumor recurrence. Results Between June 2016 and December 2019, 160 patients were included. Tumor recurrence occurred in 47 (29.38%) patients over a median (IQR) follow-up of 24 (12: 49) months. Using univariate analysis, the following urinary cytokines were associated with higher recurrence: urinary IL-6, 8, 10, 11, and interferon-γ. Also, serum EGFR and HER2 were associated with higher recurrence. On multivariate Cox regression analysis, significant variables include HER2 [HR (95%CI): 2.675 (1.367-5.233), p= 0.004], and IL-11 [HR (95%CI): 0.889 (0.825-0.957), p= 0.002]. Conclusions Serum HER2 and urinary IL-11 could be applied in clinical practice to predict BCG failure in patients with high-risk NMIBC, so those patients could be offered other modalities (radical cystectomy) early with better survival. Further studies are recommended to establish their exact role.

Sequential intravesical gemcitabine/docetaxel provides a durable remission in recurrent high-risk NMIBC following BCG therapy

PurposeBacillus 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. MethodsMulti-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. ResultsOur 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). ConclusionsIn 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.

Recent advancements in the diagnosis and treatment of non-muscle invasive bladder cancer: Evidence update of surgical concept, risk stratification, and BCG-treated disease.

In the management of non-muscle invasive bladder cancer (NMIBC), disease progression and long-term control are determined by the intensity of delivered treatment and surveillance and the cancer cells' biological nature. This requires risk stratification-based postoperative management, such as intravesical instillation of chemotherapy drugs, Bacillus Calmette-Guérin (BCG), and radical cystectomy. Advancements in mechanical engineering, molecular biology, and surgical skills have evolved the clinical management of NMIBC. In this review, we describe the updated evidence and perspectives regarding the following aspects: (1) advancements in surgical concepts, techniques, and devices for transurethral resection of the bladder tumor; (2) advancements in risk stratification tools for NMIBC; and (3) advancements in treatment strategies for BCG-treated NMIBC. Repeat transurethral resection, en-bloc transurethral resection, and enhanced tumor visualization, including photodynamic diagnosis and narrow-band imaging, help reduce residual cancer cells, provide accurate diagnosis and staging, and sensitive detection, which are the first essential steps for cancer cure. Risk stratification should always be updated and improved because the treatment strategy changes over time. The BCG-treated disease concept has recently diversified to include BCG failure, resistance, refractory, unresponsiveness, exposure, and intolerance. A BCG-unresponsive disease is an extremely aggressive subset unlikely to respond to a rechallenge with BCG. Numerous ongoing clinical trials aim to develop a future bladder-sparing approach for very high-risk BCG-naïve NMIBC and BCG-unresponsive NMIBC. The key to improving the quality of patient care lies in the continuous efforts to overcome the clinical limitations of bedside management.

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.

Effectiveness of BCG in recurrent non-muscle invasive bladder tumor: A 10 year retrospective study from a tertiary care centre

Abstract Introduction: Cancer-a term a word used to be so rare five decades back that people didn’t even know about this but now it has become so common and rampant and interestingly can be compared to a devil whose size seems to be increasing progressively. Even after so much advancement in medical science we have not been able to catch its tail. Urinary Bladder one of the very common cancer in our urological domain with its subtype non-muscle invasive bladder cancer (NMIBC) having high recurrence and progression rates has become very interesting subject for research. Such features led investigators to study the use of drugs to prevent this, out of which Bacillus Calmette–Guerin (BCG) has been successfully used as an intra vesical therapy to prevent recurrence and progression in NMIBC for more than four decades. Materials and Methods: In our study we have analyzed 111 patients retrospectively with only recurrent urinary bladder tumor irrespective of treatment received in the past. After completion Trans Urethral resection of bladder tumor (TURBT) and re-staging TURBT to substantiate the stage, induction and maintenance course of intravesical BCG was given according to Lamm protocol & the impact of this therapy was studied in regards to recurrence free, progression free, cystectomy free & overall survival rates. Result: Out of 111 patients, sixty percent of patient remained disease free, 19 patients had stage progression, nine patients underwent radical cystectomy and there was three cancer specific death. Conclusion: Despite BCG being the gold standard treatment for NMIBC, still intense research is required as there is a wide dark area of BCG failure.

Long-term follow-up of sequential intravesical gemcitabine and docetaxel salvage therapy for non-muscle invasive bladder cancer.

Intravesical gemcitabine and docetaxel (Gem/Doce) has been established as a safe and efficacious salvage treatment for recurrent NMIBC since 2015. Despite widespread adoption of this regimen, long-term outcomes have not been described. We report our experience with intravesical Gem/Doce following BCG failure in a large cohort of patients with extended follow-up. We retrospectively identified 97 patients at our institution treated with Gem/Doce for high-risk NMIBC after BCG failure between 2009 and 2017. Patients received six weekly intravesical Gem/Doce instillations. Monthly maintenance for 2 years was initiated if disease free at first follow-up. Outcomes included recurrence-free survival (RFS), high-grade recurrence-free survival (HG-RFS), progression-free survival (PFS), cystectomy-free survival (CFS), cancer-specific survival (CSS), and overall survival (OS). Survival probabilities were estimated using the Kaplan-Meier method. Median follow-up was 49 months. Median age was 73 years, and 71% of the cohort had CIS containing disease. Thirty five percent of the cohort had BCG-unresponsive disease. Complete response at 3-month surveillance was 74% and median duration of response was 25 months. At 1, 2, and 5 years, HG-RFS was 60%, 50%, and 30%, respectively. HG-RFS was similar among BCG-unresponsive patients and the overall cohort. During follow-up, 20 patients underwent cystectomy and 15 patients experienced disease progression. Five-year PFS, CFS, CSS, and OS were 82%, 75%, 91%, and 64%, respectively. In this long-term analysis, intravesical Gem/Doce for high-risk NMIBC after BCG failure yielded a 75% 5-year bladder preservation rate and a 91% 5-year cancer-specific survival rate. Further prospective trials are warranted.

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.

Intravesical administration of durvalumab to patients with high risk non muscle invasive bladder cancer after BCG failure. A phase II trial by the Hellenic GU Cancer Group

Intravesical administration of durvalumab to patients with high risk non muscle invasive bladder cancer after BCG failure. A phase II trial by the Hellenic GU Cancer Group

Do current definitions of BCG failure/ BCG unresponsive NMIBCs correlate with disease progression? Results of an individual patient data validation international multi-center retrospective study

Do current definitions of BCG failure/ BCG unresponsive NMIBCs correlate with disease progression? Results of an individual patient data validation international multi-center retrospective study

Patient Preferences for Treatment of Bacillus Calmette-Guérin–unresponsive Non–muscle-invasive Bladder Cancer: A Cross-country Choice Experiment

BackgroundPatients with non–muscle-invasive bladder cancer (NMIBC) that is unresponsive to bacillus Calmette-Guérin (BCG) immunotherapy face a difficult choice. Immediate radical cystectomy (RC) is effective but might represent overtreatment. Continuing bladder preservation with medical therapy is an alternative, but it risks progression to muscle-invasive bladder cancer (MIBC) and a reduction in survival. ObjectiveTo understand the trade-offs patients are willing to make in selecting treatments for BCG-unresponsive NMIBC. Design, setting, and participantsAdults with NMIBC from the UK, France, Germany, and Canada who reported current receipt of BCG, disease unresponsive to BCG, or receipt of RC in the previous 12 mo after failure of BCG were recruited to participate in an online choice experiment. Patients were asked to make repeated choices between two hypothetical medical treatments and the option to undergo immediate RC. The medical treatments required trade-offs between the time to RC, the mode and frequency of administration, the risk of experiencing serious side effects, and the risk of disease progression. Outcome measurements and statistical analysisError component logit models were used to calculate relative attribute importance (RAI) scores as the maximum percentage contribution to a preference and acceptable benefit-risk trade-offs. Results and limitationsMost of the 107 participants (average age 63 yr) never selected RC (89%) as their preferred option in the choice experiment. Preferences were most affected by time to RC (RAI 55%), followed by risk of progressing to MIBC (RAI 25%), medication administration (RAI 12%), and the risk of serious side effects (RAI 8%). To increase the time to RC from 1 yr to 6 yr, patients accepted a 43.8% increase in the risk of progression and a 66.1% increase in the risk of serious side effects. ConclusionsPatients with BCG-treated NMIBC valued bladder-sparing treatments and were willing to make substantial benefit-risk trade-offs to delay RC. Patient summaryAdults with bladder cancer not invading the bladder muscle completed an online experiment in which they chose between hypothetical medications and bladder removal. The results show that patients would be willing to accept different risks associated with medications to delay bladder removal. Patients considered disease progression the most important risk of medicinal treatment.

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

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). 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. 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). preoperative NLR value could predict recurrence, progression, and failure of BCG immunotherapy in NMIBC patients.

A Multicenter Study of 2-year Outcomes Following Hyperthermia Therapy with Mitomycin C in Treating Non-Muscle Invasive Bladder Cancer: HIVEC-E.

High grade, non-muscle invasive bladder cancer (NMIBC) is usually treated with intravesical Bacillus Calmette-Guérin. Chemohyperthermia therapy (CHT) may be a novel alternative therapy for the treatment of NMIBC. To evaluate the recurrence-free survival (RFS) of patients treated with CHT using the Combat bladder recirculation system (BRS) for NMIBC. This was a prospective multi-institutional study of 1,028 consecutive patients with NMIBC undergoing CHT between 2012 and 2020. A total of 835 patients were treated with CHT with Mitomycin C (MMC). Disease was confirmed on transurethral resection of bladder tumor (TURBT) prior to starting CHT. Follow-up included cystoscopy and subsequent TURBT if recurrence/progression was suspected. The primary endpoint was RFS. Secondary endpoints were progression-free survival (PFS) and adverse events from CHT. Median follow up was 22.4 months (Interquartile range (IQR): 12.8 -35.8). Median age was 70.4 years (IQR: 62.1 -78.6). A total of 557 (66.7%), 172 (20.6) and 74 (8.9%) of patients were classified to BCG naïve, BCG unresponsive and BCG failure, respectively. The RFS at 12 months and 24 months for BCG naïve was 87.6% (95% CI 85.0% - 90.4%) and 75.0% (95% CI 71.3% - 78.8%), respectively. The RFS at 12 months and 24 months for BCG unresponsive cohort was 78.1% (95% CI 72.0% - 84.7%) and 57.4% (95% CI 49.7% - 66.3%), respectively. The RFS at 24 months for the BCG unresponsive cohort for CIS with/without papillary disease and papillary only disease were 43.6% (95% CI 31.4% -60.4%) and 64.5% (95% CI 55.4% - 75.1%), respectively. Minor adverse events occurred in 216 (25.6%) patients and severe events occurred in 17 (2.0%) patients. CHT with MMC using the Combat BRS is effective in the medium term and has a favorable adverse event profile.

FACTORS PREDICTING THE OUTCOME OF BCG (BACILLUS CALMETTE-GUERIN) THERAPY

Background: Bacillus Calmette-Guerin is currently con­sidered to be the gold standard in conservative treatment for intermediate and high risk non-muscle invasive blad­der cancer (NMIBC). However, up to 40% of the patients, treated with adjuvant BCG therapy, experience failure. As the new methods of treatment after BCG failure ap­pear, there is a need to assess efficacy of this therapy in order to improve appropriate treatment during or before BCG therapy. Aim: To review the latest studies on factors, predicting BCG efficacy, and provide summarized information re­garding treatment outcomes in current practice. Methodology: The search was conducted in MEDLINE (Pubmed) and ScienceDirect databases using predeter­mined keywords: Bacillus Calmette-Guerin (BCG), fai­lure, intravesical therapy, outcome, response, predicting factors, immunological markers, efficacy. 10 articles pu­blished since 2017 were included in this literature review. Results: Prognostic factors such as the use of antibiotics prior to the therapy, body mass index (BMI), lympho­vascular invasion (LVI), endothelin-1 (ET-1), tumor substaging, CD4/CD8, GATA3/T-bet, CD163/CD68, neu­trophil-to-lymphocyte (NLR) ratios are promising factors for estimating the possible response of BCG therapy be­fore undergoing treatment. Blood eosinophil count and percentage, FISH test following 3 months after first BCG instillation and a Cytokine Panel for Response to Intrave­sical Therapy (CyPRIT) nomogram showed huge poten­tial for predicting BCG outcome during BCG treatment. Conclusion: There are quite many possible clinicopatho­logic, immunological, immunohistochemical and anam­nestical factors that could predict the success of BCG therapy. However, in order to include prognostic fac­tors in treatment guidelines, further studies should be performed to determine which of these factors have the greatest clinical value.

Abstract 1282: Elevated T cell exhaustion and immune cell infiltration is associated with BCG failure in patients with non-muscle invasive bladder cancer

Abstract Introduction: Gold standard treatment in patients with high-risk non-muscle invasive bladder cancer (NMIBC) includes Bacillus Calmette-Guérin (BCG), which activates the immune cells to kill remaining cancerous cells after surgical removal of the tumors. However, 40% of patients do not have a clinical benefit of BCG. The presence of immune cells, their functional state, as well as genomic alterations in the tumor and the normal appearing urothelial tissue, defined as field effect, may have significant impact on therapeutic outcome. Materials and methods: To investigate this, we analyzed samples from 156 patients diagnosed with NMIBC, including 237 tumors, 569 urine samples, and 305 biopsies of adjacent normal appearing urothelium. Patients had a median follow-up time of 8 years. 70 patients (45%) progressed to muscle-invasive bladder cancer or experienced early high grade recurrence within two years after ended BCG treatment, defined as BCG failure. Urinary levels of 92 immune-oncology related proteins were measured in pre- and post-treatment samples using the Olink proteomics platform. Total RNA- and whole exome sequencing (WES) data was generated from tumors before and after BCG. Clonal patient-specific mutations were selected for deep-targeted sequencing of the adjacent normal appearing biopsies. The level of field effect was defined as the mean of the variant allele frequency for mutations observed in normal biopsies. Results: We found that treatment with BCG activated the immune system regardless of clinical outcome. However, patients differed in urinary protein profile after BCG depending on their clinical response. Transcriptomic analysis of tumors showed that UROMOL2021 subtypes were significantly associated with outcome and clinical response (p=0.018). Paired tumors showed a shift in subtype to an immune infiltrated subtype (class 2b) after treatment in 36% of cases. Patients with BCG failure showed signs of immune exhaustion after treatment indicated by higher expression of the T cell exhaustion marker genes CTLA4 (p=0.0067), LAG3 (p=0.00012), TIM-3 (p=0.022), KLRG1 (p=0.028), and PD-1 (p=0.047), and higher immune cell infiltration (p=0.011). Genomic features such as mutational signatures and mutational load were not predictive of clinical response. Interestingly, BCG-responsive patients had a high level of field effect before BCG (p=0.0026), suggesting that field effect could lead to increased BCG efficacy. Conclusion: BCG treatment was associated with immune system activation reflected in both urine and tissue samples. In patients with BCG failure, we observed an immune exhausted phenotype after treatment, and we observed a high level of field effect before treatment in responsive patients. Collectively, this could indicate that increased immunogenicity and prolonged immune activation are key factors in BCG treatment responsiveness. Citation Format: Trine Strandgaard, Iver Nordentoft, Emil Christensen, Sia Lindskrog, Philippe Lamy, Karin Birkenkamp-Demtröder, Torben Steiniche, Jørgen Bjerggaard Jensen, Lars Dyrskjøt. Elevated T cell exhaustion and immune cell infiltration is associated with BCG failure in patients with non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1282.

MP54-14 SEQUENTIAL INTRAVESICAL GEMCITABINE/DOCETAXEL PROVIDES A DURABLE REMISSION IN RECURRENT HIGH RISK NMIBC FOLLOWING BCG THERAPY

You have accessJournal of UrologyCME1 May 2022MP54-14 SEQUENTIAL INTRAVESICAL GEMCITABINE/DOCETAXEL PROVIDES A DURABLE REMISSION IN RECURRENT HIGH RISK NMIBC FOLLOWING BCG THERAPY Kendrick Yim, Kevin Melnick, Sarah L. Mott, Vani Gupta, Timothy N. Clinton, Filipe L.F. Carvalho, Matthew Mossanen, Graeme S. Steele, Kent Mouw, Michael A. O'Donnell, and Mark A. Preston Kendrick YimKendrick Yim More articles by this author , Kevin MelnickKevin Melnick More articles by this author , Sarah L. MottSarah L. Mott More articles by this author , Vani GuptaVani Gupta More articles by this author , Timothy N. ClintonTimothy N. Clinton More articles by this author , Filipe L.F. CarvalhoFilipe L.F. Carvalho More articles by this author , Matthew MossanenMatthew Mossanen More articles by this author , Graeme S. SteeleGraeme S. Steele More articles by this author , Kent MouwKent Mouw More articles by this author , Michael A. O'DonnellMichael A. O'Donnell More articles by this author , and Mark A. PrestonMark A. Preston More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002633.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Bacillus Calmette-Guerin (BCG) is the standard of care for high risk non-muscle invasive bladder cancer (NMIBC), but half of patients eventually fail BCG and radical cystectomy (RC) remains the alternative with best oncologic outcomes. However, RC is morbid surgery; many patients are poor surgical candidates and desire bladder-sparing alternatives. Intravesical regimens for BCG unresponsive NMIBC are limited. We report the safety and durable efficacy of sequential gemcitabine/docetaxel (gem/doce) in high risk NMIBC after BCG failure. METHODS: Single institution retrospective analysis of patients treated with induction intravesical gem/doce (≥5/6 instillations) for high risk NMIBC from May 2018 to May 2021. BCG failures were grouped as BCG unresponsive, intolerant or early relapsing. Maintenance therapy was provided to patients without evidence of high grade (HG) recurrence on surveillance cystoscopy per physician preference. Kaplan-Meier curves were generated to estimate survival probabilities. RESULTS: Seventy-four patients were included in this study (median age 72.0, median follow-up 18 months). Six-, 12, and 24-month HG recurrence free survival rates (RFS) were 81%, 67%, and 49% respectively (Figure 1A). Four patients experienced disease progression on transurethral resection. Fourteen patients underwent radical cystectomy (median 22 months from induction) (Figure 1B), with only 4 patients progressing to muscle invasion. Forty-eight (65%) patients experienced mild to moderate grade adverse effects (AE), but only 7% experienced a delay in treatment schedule. Most common AE were urinary frequency/urgency in 36 (49%) and dysuria in 12 (16%). CONCLUSIONS: In an independent study of high-risk BCG failures, sequential intravesical gem/doce appears to be an effective and well tolerated alternative to early cystectomy, validating prior reports of its utility. A prospective trial is warranted to better characterize efficacy and compare to other intravesical therapies. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e932 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kendrick Yim More articles by this author Kevin Melnick More articles by this author Sarah L. Mott More articles by this author Vani Gupta More articles by this author Timothy N. Clinton More articles by this author Filipe L.F. Carvalho More articles by this author Matthew Mossanen More articles by this author Graeme S. Steele More articles by this author Kent Mouw More articles by this author Michael A. O'Donnell More articles by this author Mark A. Preston More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP54-17 TIMING OF RADICAL CYSTECTOMY FOR BCG FAILURE

You have accessJournal of UrologyCME1 May 2022MP54-17 TIMING OF RADICAL CYSTECTOMY FOR BCG FAILURE Patrick Hensley, Niyati Lobo, Kelly Bree, Akshay Sood, Neema Navai, Colin Dinney, and Ashish Kamat Patrick HensleyPatrick Hensley More articles by this author , Niyati LoboNiyati Lobo More articles by this author , Kelly BreeKelly Bree More articles by this author , Akshay SoodAkshay Sood More articles by this author , Neema NavaiNeema Navai More articles by this author , Colin DinneyColin Dinney More articles by this author , and Ashish KamatAshish Kamat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002633.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We examine how the timing of radical cystectomy (RC) in a cohort of uniformly treated patients who recur despite intravesical bacillus Calmette-Guérin (BCG) therapy impacts oncologic outcomes. METHODS: An institutional review of patients who underwent radical cystectomy (RC) for ≤cT3N0 urothelial carcinoma of the bladder from 2005-2020 was performed. Patients received at least induction BCG and were categorized as either BCG-nonmuscle-invasive bladder cancer (BCG-NMIBC; ≤cT1 after BCG) vs. BCG-muscle-invasive bladder cancer (BCG-MIBC; progression to ≥cT2 disease after BCG) based on clinical stage prior to RC. Patients who underwent RC for de novo MIBC (D-MIBC) were included as a comparator. Kaplan-Meier analysis estimated median overall survival (OS) and cancer-specific survival (CSS). Comparison of time-to-event endpoints was done using the log-rank test. RESULTS: 78 patients with BCG-NMIBC, 167 with BCG-MIBC, and 637 with D-MIBC were included. Median follow-up after RC was 2.8 years. 446 (55%) MIBC patients received neoadjuvant chemotherapy according to our institutional risk-stratified approach. 69 (88%) NMIBC patients met the FDA definition of ‘BCG unresponsive disease’. Rates of ≥(y)pT3 disease at RC were 12%; 46%; 39% (p <0.001) and for (y)N+ disease were 5%; 27%; 20% (p <0.001) for BCG-NMIBC; BCG-MIBC; D-MIBC, respectively. Median OS was 9.5 years (95% CI 5.3-13.7), 4.1 years (95% CI 2.1-6.2), and 6.9 years (95% CI 5.6-8.3) for BCG-NMIBC; BCG-MIBC; D-MIBC, respectively (Figure). There were no survival differences following RC between patients meeting the following criteria for BCG unresponsive NMIBC: (1) residual/recurrent CIS, (2) recurrent HG Ta/1, or (3) persistent/new HG T1 disease. CONCLUSIONS: Patients who undergo RC for recurrent NMIBC after BCG failure, but prior to progression to MIBC, exhibit favorable pathologic stage and survival outcomes relative to those who progress to MIBC on BCG. Our data emphasize the importance of vigilance, accurate clinical staging and timely intervention in patients who exhibit BCG failure. Source of Funding: This research was supported by the Wayne B. Duddlesten Professorship in Cancer Research, the Raymond and Maria Floyd Bladder Cancer Research Foundation Grant, NIH/NCI UTMD Anderson SPORE in Genitourinary Cancer (P50CA091846), the Cancer Center Support Grant (NCI Grant P30 CA016672), and a Urology Care Foundation Research Scholars Award (IRG 85-001-25) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e933 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Patrick Hensley More articles by this author Niyati Lobo More articles by this author Kelly Bree More articles by this author Akshay Sood More articles by this author Neema Navai More articles by this author Colin Dinney More articles by this author Ashish Kamat More articles by this author Expand All Advertisement PDF DownloadLoading ...