Adjuvant Bacillus Calmette-Guérin Research Articles

A Systematic Review and Meta-analysis of the Clinical Impact of Prophylactic Quinolones with Adjuvant Bacillus Calmette-Guérin Instillation for Non-muscle-invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) reduces disease recurrence and progression in intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC). BCG-associated adverse events during instillations are common, leading to treatment cessation. Prophylactic use of quinolones in conjunction with BCG instillations is one approach for reducing BCG-associated adverse events. Our aim was to delineate the clinical impact of quinolone prophylaxis (QP) in patients receiving adjuvant BCG instillations for NMIBC. In October 2024, a systematic search of MEDLINE, Embase, and the Cochrane Central Register of controlled trials was performed. Prospective and retrospective studies reporting comparative outcomes for patients with and without QP during BCG instillations were included. Outcomes were reported in a binary fashion. Random-effects meta-analysis using the weighted mean difference was conducted. Primary outcomes for pooled analyses included BCG-associated toxicities, the completion rate for BCG induction, the likelihood of antituberculosis treatment, and disease recurrence and progression at 12 mo. The systematic review included five studies. Four randomised controlled trials were included in the meta-analysis, and one nonrandomised study was also included in the narrative review. The studies involved 445 patients, of whom 194 received QP + BCG and 251 received BCG alone. QP use was associated with lower incidence of class ≥2 (40.8% vs 54.7%; relative risk [RR] 0.79, 95% confidence interval [CI] 0.67-0.94; p=0.006), and class ≥3 BCG-associated toxicities (25.3% vs 36.4%; RR 0.70, 95% CI 0.50-0.98; p=0.04) and a higher completion rate for BCG induction (83.0% vs 70.6%; RR 1.16, 95% CI 1.01-1.34; p=0.04). The 12-mo recurrence rates (14.7% vs 19.4%; RR 0.76, 95% CI 0.46-1.27; p=0.3) and progression rates (4.5% vs 6.4%; RR 0.86, 95% CI 0.09-8.25; p=0.9) did not significantly differ for QP + BCG versus BCG alone. The use of QP with adjuvant BCG for NMIBC mitigated debilitating BCG-associated toxicities and improved the completion rate for BCG induction therapy.

Consensus document on the implications of standardization of BCG supply in the management of patients with non-muscle-invasive bladder cancer

Patients with non-muscle-invasive bladder cancer (NMIBC) in the intermediate and high-risk groups must receive adjuvant treatment with intravesical Bacillus Calmette–Guérin (BCG) following transurethral resection (TUR), as it reduces the risk of recurrence and presumably the risk of progression as well. Optimization of BCG efficacy is achieved by administering maintenance therapy. However, since many immunological aspects of the mechanism of action of BCG in the bladder remain unknown, the implementation of the optimal dose, number of instillations, strains and adequate maintenance regimen over the last decades has been heterogeneous. Additionally, this has hindered the interpretation of efficacy in terms of oncologic outcomes. This, together with the shortages of BCG in recent years, have forced scientific societies to adapt their clinical practice guidelines and modify their protocols of adjuvant treatment with BCG. This includes changes to strains, doses, and maintenance during this period of time. This consensus document evaluates the current status of adjuvant BCG treatment and the implications of BCG supply availability in the treatment of patients with NMIBC. It also addresses the implementation of novel therapies that will improve cancer prognosis and the quality of life of patients with NMIBC in the future.

Documento de consenso sobre las implicaciones de la normalización del suministro del Bacillus Calmette-Guérin en el manejo del paciente con tumor vesical no-músculo invasivo (TVNMI)

Patients with non-muscle-invasive bladder cancer (NMIBC) in the intermediate and high-risk groups must receive adjuvant treatment with intravesical Bacillus Calmette-Guerin (BCG) following transurethral resection (TUR), as it reduces the risk of recurrence and presumably the risk of progression as well. Optimization of BCG efficacy is achieved by administering maintenance therapy. However, since many immunological aspects of the mechanism of action of BCG in the bladder remain unknown, the implementation of the optimal dose, number of instillations, strains and adequate maintenance regimen over the last decades has been heterogeneous. Additionally, this has hindered the interpretation of efficacy in terms of oncologic outcomes. This, together with the shortages of BCG in recent years, have forced scientific societies to adapt their clinical practice guidelines and modify their protocols of adjuvant treatment with BCG. This includes changes to strains, doses, and maintenance during this period of time. This consensus document evaluates the current status of adjuvant BCG treatment and the implications of BCG supply availability in the treatment of patients with NMIBC. It also addresses the implementation of novel therapies that will improve cancer prognosis and the quality of life of patients with NMIBC in the future.

Cumulative incidence of and risk factors for BCG infection after adjuvant BCG instillations.

To investigate the cumulative incidence proportion of disseminated or local Bacillus Calmette-Guérin (BCG) infections after adjuvant BCG instillations in patients with non-muscle-invasive bladder cancer (NMIBC). We analysed the timing and occurrence of BCG infections and absolute and relative risk in relation to patient characteristics available in the Swedish nationwide database 'BladderBaSe 2.0'. The cumulative incidence proportion of a BCG infection was indicated by a reported diagnosis of tuberculosis (TB) in the patient registry or filing a prescription for tuberculostatic drugs. The cumulative incidence proportion was 1.1% at the 5-year follow-up in 5033 patients exposed to adjuvant BCG instillations. The incidence rate was highest during the first 2 years after start of BCG instillations. Women had a lower risk than men (hazard ratio 0.23, 95% confidence interval 0.07-0.74). Age and calendar time at diagnosis, comorbidity, tumour risk group, previous medication with corticosteroids, immunosuppressive drugs, or time between transurethral resection of the bladder tumour and commencing the adjuvant BCG instillation were not associated with risk. These data further supports that the overall risk of a BCG infection after BCG-instillation treatment for NMIBC is low. The great majority of infections occur in the first 2 years, calling for an awareness of the diverse symptoms of BCG infection during this period. We provide evidence for male sex as a risk factor; however, the statistical precision is low and with a risk of selection bias, making it difficult to rule out the other suggested risk factors without further studies with different approaches.

Repeat Transurethral Resection (TUR) + Bacillus Calmette-Guérin (BCG) Versus Upfront Induction BCG After TUR in High-risk Non–muscle-invasive Bladder Cancer: Feasibility Phase of a Randomized Controlled Study

BackgroundHigh-level evidence supporting the role of repeat transurethral resection (reTUR) in non–muscle-invasive bladder cancer (NMIBC) is lacking. A randomized controlled trial (RCT) assessing whether immediate reTUR has an impact on patient prognosis is essential. However, since such a RCT will require enrollment of a high number of patients, a preliminary feasibility study is appropriate. ObjectiveTo assess the feasibility of an RCT investigating the impact of immediate reTUR + adjuvant bacillus Calmette-Guérin (BCG) versus upfront induction BCG after initial TUR in NMIBC. Design, setting, and participantsEligible patients were randomly assigned to receive either reTUR + adjuvant BCG or upfront induction BCG after TUR. Patients with macroscopically completely resected high-grade T1 NMIBC, with or without concomitant carcinoma in situ, and with detrusor muscle (DM) present in the initial TUR specimen were considered eligible for inclusion. Exclusion criteria included lymphovascular invasion (LVI), histological subtypes, hydronephrosis, concomitant upper tract urothelial carcinoma (UTUC), or urothelial carcinoma within the prostatic urethra. The aim was to enroll 30 patients in this feasibility study. Outcome measurements and statistical analysisThe patient recruitment rate was the primary outcome. Oncological outcomes (recurrence-free and progression-free survival) were secondary endpoints. Results and limitationsOverall, 30 patients (15 per arm) were randomized over a period of 14 mo (August 2020–October 2021). Two eligible patients refused the randomization, resulting in a patient compliance rate of 93.3% for the study protocol. We excluded 49 ineligible patients before randomization because of histological subtypes (n = 16, 33%), LVI (n = 9, 18%), DM absence in the TUR specimen (n = 12, 24%), metastatic disease (n = 5, 10%), concomitant UTUC (n = 3, 6%), or hydronephrosis (n = 4, 8%). At reTUR, persistent disease was found in four patients (29%) and upstaging to muscle-invasive disease in one (7%). Over median follow-up of 17 mo, disease recurrence was detected in three patients (23%) in the reTUR arm and six patients (40%) in the upfront BCG arm. Progression to muscle-invasive disease was observed in one patient treated with upfront BCG. ConclusionsThe feasibility of conducting an RCT comparing upfront BCG versus reTUR + BCG in high-grade T1 NMIBC has been demonstrated. Our results underline the need to screen a large number of patients owing to characteristics meeting the exclusion criteria in a high percentage of cases. Patient summaryWe found that a clinical trial of the role of a repeat surgical procedure to remove bladder tumors through the urethra would be feasible among patients with high-grade non–muscle-invasive bladder cancer. These preliminary results may help in refining the role of this repeat procedure for patients in this category.

Comparison of hyperthermic intravesical chemotherapy and Bacillus Calmette-Guerin therapy in high-risk non-muscle invasive bladder cancer: a matched-pair analysis.

To compare adjuvant hyperthermic intravesical chemotherapy (HIVEC) with mitomycin C and standard Bacillus Calmette-Guerin (BCG) therapy in terms of oncological outcomes and adverse events in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). The data of patients with high-risk papillary NMIBC treated with adjuvant intravesical BCG instillations or HIVEC in our institution between June 2017 and August 2022 were analyzed retrospectively. Twenty-four patients who received HIVEC were matched 1:1 with patients receiving BCG therapy based on tumor characteristics (tumor stage and grade), age, gender, smoking status, and the number of tumors (single or multiple). HIVEC and standard BCG treatments were compared in terms of recurrence-free survival (RFS), progression-free survival (PFS), and adverse events. Forty-eight patients (24 in the BCG group and 24 in the HIVEC group) were included in the study. The median follow-up times of the BCG and HIVEC groups were 32 [interquartile range (IQR): 28.0-47.8] and 28 (IQR: 16.7-41.8) months, respectively (p = 0.11). There was no significant difference between the groups in terms of the 24-month RFS (BCG 83% vs HIVEC 88%, p = 0.64) and the 24-month PFS (BCG 100% vs HIVEC 94%, p = 0.61). Regarding the safety profile, at least one adverse event occurred in 13 (54%) of the patients in the BCG group and 12 (50.0%) of those in the HIVEC group (p = 0.77). This study demonstrated that HIVEC with mitomycin C has a similar oncological efficacy and safety profile to standard BCG therapy in high-risk NMIBC.

Adding mitomycin (MM) to bacillus Calmette-Guérin (BCG) as adjuvant intravesical therapy for high-risk, non–muscle-invasive urothelial bladder cancer (NMIBC): BCGMM; ANZUP 1301.

TPS4617 Background: Adjuvant intravesical BCG decreases disease recurrence and progression in high-risk, NMIBC, however recurrence occurs in 30% of those affected, despite optimal therapy. Meta-analyses evaluating addition of intravesical MM to BCG showed lower rates of recurrence and cancer-specific mortality in people with NMIBC who received combination regimens. Phase 3 randomized trials to definitively test this combination are lacking. The BCGMM trial (NCT02948543) will determine the effects of adding MM to the standard BCG after resection of high-risk NMBIC. This is the largest study evaluating this approach in high-risk NMIBC, is of particular relevance given the current BCG shortage, and has the potential to change global practice. Methods: This open-label phase 3 trial is randomizing 500 participants stratified by stage, site of disease, and presence of carcinoma in-situ, in a 1:1 ratio to Arm A (BCG induction weekly x6 then monthly x10) or Arm B (BCG weeks 1, 2, 4, 5, 7, 8; months 4, 5, 7, 8 + MM weeks 3, 6, 9; months 3, 6, 9, see figure below). This provides 85% power to detect an absolute improvement of 10% in 2-year disease free survival (DFS) at 2p = 0.05. Stage 1 (n = 130) was to determine rates of treatment completion, activity reflected by cystoscopic findings at 3 months, adverse events, resource use, and health related quality of life, established feasibility. Stage 2, including an additional 370 participants, will provide information on DFS, time to recurrence and progression, overall survival, and identification of potential predictive biomarkers, is estimated to complete accrual by Q2 2023. Progress As of Jan 2023, 484 of 500 planned participants have been recruited from 16 Australian and 1 UK site. In stage 1, successful treatment completion, defined as 75% or more of planned treatment doses, was achieved by 76% in the experimental group (BCGMM) versus 60% in the control group (BCG alone). Clinical trial information: NCT02948543 .

HER2/neu expression status of post BCG recurrent non-muscle-invasive bladder urothelial carcinomas in relation to their primary ones.

Transurethral resection (TUR) followed by adjuvant therapy is still the treatment of choice of Non-Muscle-Invasive Bladder Urothelial Carcinoma (NMIBUC). However, recurrence is one of the most troublesome features of these lesions. Early second resection and adjuvant BCG therapy has been shown to improve the outcome. To evaluate the prognostic value of C-erbB-2 (HER2/neu) expression status in Non-Muscle-Invasive Bladder Urothelial Carcinoma cases, before and after intravesical Bacillus Calmette Guerin (BCG immunotherapy). HER2/neu expression was studied in 120 (Ta-T1) Non-Muscle-Invasive Urothelial Carcinoma cases. The expression was evaluated and compared to the expression after Bacillus Calmette Guerin (BCG) immunotherapy. HER2/neu expression in low and high grade of the Non- Muscle-Invasive Urothelial Carcinoma was (38%) and (83%) respectively. The difference of the expression rates by tumor grade was statistically significant. In recurring lesions post BCG therapy, C-erbB-2 expression was markedly decreased (31.6%) when compared to its expression before therapy (65%). The HER2/neu expression increased as the tumor grade rose. The reduction in expression following BCG treatment in Non-Invasive transitional cell carcinoma cases could reflect a reduction of the potential malignancy of the tumor.

MP08-17 BACILLUS CALMETTE–GUÉRIN STRAINS DON’T MATTER: RESULTS FROM A TERRITORY-WIDE RETROSPECTIVE COHORT STUDY

You have accessJournal of UrologyCME1 Apr 2023MP08-17 BACILLUS CALMETTE–GUÉRIN STRAINS DON’T MATTER: RESULTS FROM A TERRITORY-WIDE RETROSPECTIVE COHORT STUDY Kang Liu, Hongda Zhao, Xuan Chen, Peter Ka-Fung Chiu, Chi-Fai Ng, and Jeremy Yuen-Chun Teoh Kang LiuKang Liu More articles by this author , Hongda ZhaoHongda Zhao More articles by this author , Xuan ChenXuan Chen More articles by this author , Peter Ka-Fung ChiuPeter Ka-Fung Chiu More articles by this author , Chi-Fai NgChi-Fai Ng More articles by this author , and Jeremy Yuen-Chun TeohJeremy Yuen-Chun Teoh More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Adjuvant intravesical Bacillus Calmette–Guérin (BCG) immunotherapy is recommended for non-muscle-invasive bladder cancer (NMIBC), except those low-risk patients. However, whether different strains of BCG have different efficacy on survival outcomes in the long term remains controversial. The current study tries to provide further evidence with a territory-wide retrospective cohort. METHODS: We retrospectively included 2,602 NMIBC patients with adjuvant intravesical BCG immunotherapy around Hong Kong from 2001 to 2020. Kaplan–Meier plotter with the log-rank test was used to explore overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and progression-free survival (PFS). Multivariable Cox regression analysis was used to balance clinical characteristics and to estimate hazard ratios (HRs) with a 95% confidence interval (CI). Adequate BCG treatment subgroup analysis was performed. RESULTS: Of 2,602 patients, 1291 (49.6%) received Connaught strain 81mg, 199 (7.6%) received Connaught strain 27mg, 1014 (49.2%) received Tokyo strain, and 98 (3.8%) received Danish strain. Although the Connaught strain 27mg group were inferior to the Connaught strain 81mg group in OS (HRs: 1.256, 95% CI: 1.047-1.507), CSS (HRs: 1.693, 95% CI: 1.079-2.657) and PFS (HRs: 1.857, 95% CI: 1.198-2.876) in the whole cohort, the differences were eliminated upon subgroup analysis focusing on patients who received adequate BCG treatment (Table 1, Figure 1). The other two strains, i.e. Tokyo and Danish strains, had similar survival outcomes with the Connaught strain 81mg group in both the whole cohort and the adequate BCG treatment subgroup. CONCLUSIONS: In this large BCG cohort, no significant differences in survival outcomes were observed between Connaught, Tokyo, and Danish strains as soon as adequate BCG treatment was given. Source of Funding: UGC Research Matching Fund 8601521 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e101 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kang Liu More articles by this author Hongda Zhao More articles by this author Xuan Chen More articles by this author Peter Ka-Fung Chiu More articles by this author Chi-Fai Ng More articles by this author Jeremy Yuen-Chun Teoh More articles by this author Expand All Advertisement PDF downloadLoading ...

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.

Modified Glasgow Prognostic Score as a Predictor of Recurrence in Patients with High Grade Non-Muscle Invasive Bladder Cancer Undergoing Intravesical Bacillus Calmette-Guerin Immunotherapy.

Background: A systemic inflammatory marker, the modified Glasgow prognostic score (mGPS), could predict outcomes in non-muscle-invasive bladder cancer (NIMBC). We aimed to investigate the predictive power of mGPS in oncological outcomes in HG/G3 T1 NMIBC patients undergoing Bacillus Calmette–Guérin (BCG) therapy. Methods: We retrospectively reviewed patient’s medical data from multicenter institutions. A total of 1382 patients with HG/G3 T1 NMIBC have been administered adjuvant intravesical BCG therapy, every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months. The analysis of mGPS for recurrence and progression was performed using multivariable and univariable Cox regression models. Results: During follow-up, 659 patients (47.68%) suffered recurrence, 441 (31.91%) suffered progression, 156 (11.28%) died of all causes, and 67 (4.84%) died of bladder cancer. At multivariable analysis, neutrophil to lymphocyte ratio [hazard ratio (HR): 7.471; p = 0.0001] and erythrocyte sedimentation rate (ESR) (HR: 0.706; p = 0.006 were significantly associated with recurrence. mGPS has no statistical significance for progression (p = 0.076). Kaplan–Meier survival analysis showed a significant difference in survival among patients from different mGPS subgroups. Five-year OS was 93% (CI 95% 92–94), in patients with mGPS 0, 82.2% (CI 95% 78.9–85.5) in patients with mGPS 1 and 78.1% (CI 95% 60.4–70) in mGPS 2 patients. Five-year CSS was 98% (CI 95% 97–99) in patients with mGPS 0, 90% (CI 95% 87–94) in patients with mGPS 1, and 100% in mGPS 2 patients. Limitations are applicable to a retrospective study. Conclusions: mGPS may have the potential to predict recurrence in HG/G3 T1 NMIBC patients, but more prospective, with large cohorts, studies are needed to study the influence of systemic inflammatory markers in prediction of outcomes in NMIBC for a definitive conclusion.

Comparing adverse effects, short term outcomes, and cost implications of hyperthermic intravesical chemotherapy with Mitomycin-C and intravesical bacillus Calmette-Guerin instillation (Moscow-I strain) in the management of intermediate and high-risk nonmuscle invasive bladder cancer.

Introduction:The recommended treatment for intermediate and high-risk nonmuscle invasive bladder cancer (NMIBC) is adjuvant intravesical bacillus Calmette–Guerin (BCG) instillation. However, up to 50% experience tumor recurrences even after adjuvant BCG, and many patients develop local or systemic adverse effects. Our study compared adverse effects, short-term recurrence rates, and cost-implications of BCG therapy to Hyperthermic Intra-VEsical Chemotherapy (HIVEC) with Mitomycin-C (MMC) in these patients.Materials and Methods:Retrospective analysis of intermediate and high-risk NMIBC patients who received either intravesical BCG or HIVEC® after transurethral resection of bladder tumor in our institute (January 2017 to March 2020) was done. Twenty-two patients who received HIVEC and 29 who received BCG were analyzed. We used SPSS Statistics v20.0 (IBM Corp., Armonk, NY, USA) software for the statistical analysis.Results:Nineteen (86.4%) patients in the HIVEC group had no adverse effects. Two (9.1%) patients had Grade I lower urinary tract symptoms (LUTS) treated symptomatically. One patient developed UTI after HIVEC, and further cycles were stopped (Grade II). BCG group had a higher rate of Grade III adverse effects in six (20.7%) patients. Median follow-up was 10.5 and 22 months. The tumor recurred in one (4.5%) and six (20.7%) patients in HIVEC and BCG groups, respectively. There was no difference in recurrence-free survival at 18 months and the cost for the HIVEC therapy was more.Conclusions:HIVEC with MMC is a reasonable adjuvant treatment option in NMIBC, which is well tolerated, albeit increased cost of the treatment. Randomized trials with more follow-up are required for further conclusion.

Endothelin-1 indicates unfavorable prognosis in primary high-grade non-muscle-invasive urothelial bladder cancer.

To conduct a prospective study of the potential prognostic role of endothelin-1 (ET-1) in a cohort of primary high-grade non-muscle-invasive urothelial bladder cancer patients, who were treated with adjuvant intravesical Bacillus Calmette-Guérin (BCG). Patients with primary high-grade nonmuscle- invasive urothelial bladder cancer, who received postoperatively induction and maintenance BCG therapy, were prospectively included. Recurrence and progression were histologically proven. Immunohistochemical staining for ET-1 was assessed. Epidemiological, pathological and clinical parameters as well as the expression of ET-1 in tumor specimens were statistically analyzed for recurrence, progression, recurrence-free survival (RFS) and progression-free survival (PFS). ET-1 associates significantly with recurrence (p = 0.000), progression (p = 0.000), RFS (p = 0.000) and PFS (p = 0.000). The patient's age is also significant for recurrence (p = 0.003, OR = 1.273 95% CI: 1.086-1.492) and RFS (p = 0.013). ET-1 seems to deteriorate prognosis in patients suffering from primary high-grade non-muscle-invasive urothelial bladder cancer, who are treated with adjuvant BCG instillations. Furthermore, the patient's age associates with an increased likelihood for recurrence.

Genetic Variants in Immune Related Genes as Predictors of Responsiveness to BCG Immunotherapy in Metastatic Melanoma Patients.

Simple SummaryThe study objective was to determine if an SNP (single nucleotide polymorphism)-based immune multi-gene panel has the ability to predict adjuvant BCG (Bacillus Calmette–Guérin) immunotherapy responsiveness post-tumor resection in AJCC (American Joint Committee on Cancer) stages III and IV metastatic melanoma patients. A pilot study followed by further verification and control melanoma patient cohorts involving three phase III multicenter clinical trials was used to verify if an immune gene SNP panel could identify if adjuvant BCG therapy correlates with disease outcomes. We found a specific immune gene SNP panel that could identify which patients would respond to adjuvant BCG immunotherapy, but it was not applicable in the control non-immunotherapy treated patients. These studies provide evidence that SNP immune-gene assessment has utility in predicting melanoma patient’s immunotherapy responses to adjuvant BCG immunotherapy.Adjuvant immunotherapy in melanoma patients improves clinical outcomes. However, success is unpredictable due to inherited heterogeneity of immune responses. Inherent immune genes associated with single nucleotide polymorphisms (SNPs) may influence anti-tumor immune responses. We assessed the predictive ability of 26 immune-gene SNPs genomic panels for a clinical response to adjuvant BCG (Bacillus Calmette-Guérin) immunotherapy, using melanoma patient cohorts derived from three phase III multicenter clinical trials: AJCC (American Joint Committee on Cancer) stage IV patients given adjuvant BCG (pilot cohort; n = 92), AJCC stage III patients given adjuvant BCG (verification cohort; n = 269), and AJCC stage III patients that are sentinel lymph node (SLN) positive receiving no immunotherapy (control cohort; n = 80). The SNP panel analysis demonstrated that the responder patient group had an improved disease-free survival (DFS) (hazard ratio [HR] 1.84, 95% CI 1.09–3.13, p = 0.021) in the pilot cohort. In the verification cohort, an improved overall survival (OS) (HR 1.67, 95% CI 1.07–2.67, p = 0.025) was observed. No significant differences of SNPs were observed in DFS or OS in the control patient cohort. This study demonstrates that SNP immune genes can be utilized as a predictive tool for identifying melanoma patients that are inherently responsive to BCG and potentially other immunotherapies in the future.

Impact of chronic kidney disease on oncological outcomes in patients with high-risk non-muscle-invasive bladder cancer who underwent adjuvant bacillus Calmette-Guérin therapy

ObjectivesTo investigate the impact of chronic kidney disease (CKD) on oncological outcomes in patients with high-risk non-muscle invasive bladder cancer (NMIBC) who underwent adjuvant induction bacillus Calmette-Guérin (BCG) therapy after transurethral resection of bladder tumor (TURBT). Materials and MethodsWe conducted a multi-institutional retrospective study assessing 209 patients with high-risk NMIBC who underwent TURBT and subsequent adjuvant induction BCG therapy from December 1998 to April 2019. Patients were divided into 2 groups: those with preoperative estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m2 (non-CKD group), and those with eGFR < 60 ml/min/1.73 m2 (CKD group). Primary endpoints were intravesical recurrence-free survival (RFS) and muscle-invasive bladder cancer (MIBC)-free survival. Background-adjusted multivariate analyses with the inverse probability of treatment weighting (IPTW) method using the propensity score were performed to evaluate the impact of CKD on intravesical RFS, MIBC-free survival, metastasis-free survival, cancer-specific survival, and overall survival. Moreover, multivariable analyses were performed to assess the impact of CKD on intravesical recurrence and MIBC progression, adjusting for the competing risk of death using the Fine-Gray competing risk regression model. ResultsMedian age and follow-up period after TURBT were 72 years and 45 months, respectively. Of 209 patients, 71 (34%) were diagnosed with CKD before TURBT. Background-adjusted multivariate analyses with the IPTW method indicated that CKD was significantly associated with shorter intravesical RFS, MIBC-free survival, metastasis-free survival, cancer-specific survival, and overall survival. In the Fine-Gray competing risk regression model, CKD showed significantly higher probabilities of intravesical recurrence and MIBC progression, with an adjusted subdistribution hazard ratio of 1.886 (95% confidence interval 1.069–3.330, P = 0.028) and 3.740 (95% confidence interval 1.060–13.20, P = 0.040), respectively. ConclusionsCKD presents a risk factor of poor oncological outcomes in patients with high-risk NMIBC who underwent adjuvant induction BCG therapy after TURBT.

Association of the commensal urinary microbiome with response to Bacillus Calmette-Guérin (BCG) immunotherapy in nonmuscle invasive bladder cancer.

423 Background: Standard therapy for high-risk non-muscle invasive bladder cancer (NMIBC) is intravesical BCG. Despite its established efficacy, up to 50% of patients may recur. The development of predictive biomarkers for BCG immunotherapy would enhance treatment algorithms and potentially uncover mechanisms of resistance. Recent data have characterized the presence of a commensal urine microbiome, but its role in BCG-treated NMIBC patients remains unexplored. We assessed the composition of the urine microbiome in NMIBC patients and evaluated associations with response to therapy. Methods: Patients with a newly diagnosed bladder tumor were enrolled prior to TURBT on an institutional review board-approved study at a single institution. Adjuvant BCG instillation was administrated to high-risk patients according to the surgical histology. Urine samples for microbiome assessment were collected by catheterization to eliminate urethral contamination before the TURBT and up to 8 additional timepoints. 16S sequencing and analysis was performed on baseline specimens prior to BCG. Results: Among 31 patients enrolled, 10 (32%) recurred and 21 (68%) had no recurrence with a median follow up of 6 months. Median age was 69 years (range 46-87), and 9 (29%) patients were female and 22 patients (71%) were male. The most abundant phyla observed were Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Tenericutes. Together these accounted for &gt; 99% of the phyla detected in the cohort. Global analysis of distances by operational taxonomic units (OTUs) indicated a significant difference between patients with and without recurrence (Bonferroni-corrected P = 0.017). The abundance of Proteobacteria was higher in patients with recurrence (P = 0.035), with stronger differences observed for specific classes such as Gammaproteobacteria (P = 0.0025). Firmicutes such as Lactobacillales were more abundant in patients without recurrence (P = 0.049). Conclusions: In this study we detected variation in the composition of the urine microbiome in NMIBC patients, which may predict response to BCG immunotherapy. Further studies to confirm these results are ongoing.

Outcomes of subsequent non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin after radical nephroureterectomy for upper urinary tract urothelial carcinoma.

To describe the clinicopathological characteristics and prognosis of subsequent non-muscle-invasive bladder cancer (NMIBC) after radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC), and particularly its response to intravesical Bacillus Calmette-Guérin (BCG). An observational study was conducted in 1463 patients with UTUC who had undergone RNU and in 1555 patients with primary NMIBC. Of the 1463 patients with UTUC, 256 (17%) subsequently developed NMIBC (UTUC-NMIBC group) and were available for the analysis. The clinicopathological background and outcomes, including intravesical recurrence-free survival and bladder progression-free survival, were compared between the patients with UTUC-NMIBC and the patients with primary NMIBC treated with intravesical BCG. Propensity score matching was performed to adjust for the potential differences in the backgrounds of the two groups. To validate the utility of the CUETO scoring model in the UTUC-NMIBC group, risk scores were calculated and compared with the published probabilities for recurrence and progression. Compared with the unadjusted primary NMIBC group (n = 352), the UTUC-NMIBC group (n = 75) were found to have a worse prognosis for intravesical recurrence and progression, before propensity score matching. After propensity score matching for potential confounding factors, however, a worse prognosis was observed only for intravesical recurrence. The validation test of the CUETO scoring model for the UTUC-NMIBC group showed a significant difference in the rate of intravesical recurrence and progression for the 0-4 and 5-6 score groups between the UTUC-NMIBC group and the CUETO risk table reference data. Compared with the primary NMIBC group, the UTUC-NMIBC group had a worse prognosis after intravesical BCG, especially with regard to intravesical recurrence. This suggests that patients with UTUC-NMIBC are inherently poor responders to BCG exposure. An optimal treatment strategy and risk scoring model to select patients for adjuvant intravesical BCG, chemotherapy or immediate radical cystectomy should be established.

NONMUSCLE INVASIVE TRANSITIONAL CELL CARCINOMA OF URINARY BLADDER – ADJUVANT INTRAVESICAL THERAPIES AFTER TRANSURETHRAL TUMOR RESECTION

Introduction. More than 70% of all bladder cancers are nonmuscle invasive involving only the mucosa and the submucosa. A large percentage of patients present local recurrence after endoscopic surgery, and many of them progress to muscle invasive disease necessitating radical cystectomy. The high recurrence and progression rate is the reason to use intravesical therapy to prevent recurrences. The aim of this study is to compare the efficacity and safety of intravesical immunotherapy with Bacillus Calmette Guerin (BCG) vs. chemotherapy (Pharmoribicin) after TUR-B for NMIBC. Material and methods. Following TURB and pathological analysis, NMIBC was stratified into low, intermediate and high-risk groups depending on the probability of recurrence and progression to muscle-invasive disease. Patients were treated with adjuvant intravesical therapies, BCG or Pharmorubicin. Results. Between 2008 and 2012, a total of 125 patients with NMIBC were diagnosed in the Urology Department Sibiu. Histopathological data show: pT1 G1 – 48 patients (38.4%), pT1 G2 – 69 patients (55.2%), pT1G3 and or Tis – 8 patients (6.4%). Adjuvant intravesical therapies with Pharmorubicin was administered to 83 patients (66.4%) and with BCG 42 patients (33.6%). Pharmorubicin, the recurrence rate was 22.8% in the first year and at 5 years there was a recurrence of 36.1%. For the group of patients treated with BCG recurrent rate was 14.2% in the first year and 33,3% at 5 years. For the whole group of patients tumor progression was 2.4% in the first year and 9.6% at 5 years. For the Pharmorubicin group, in the first year, the progression was 2.4% compared with 2.3% tumor progression in the BCG-treated group. Conclusions. Intravesical instillation treatment after TURB reduce the recurrence rate and tumor progression. In our series there are no major differences between efficacity of intravesical immunotherapy (BCG) vs. chemotherapy (Pharmoribicin). Disease-free survival and progression-free survival are comparable to the two studied lots.

Characterizing intermediate-risk non–muscle-invasive bladder cancer: Implications for the definition of intermediate risk and treatment strategy

PurposePatients with intermediate-risk non–muscle-invasive bladder cancer have traditionally been defined as those not included in the low- or high-risk groups. Therefore, the intermediate-risk group consists of heterogeneous patients. Materials and methodsWe reviewed 326 patients diagnosed with intermediate-risk tumors. We subclassified these patients into 3 groups according to their clinical courses. Group A included patients with initial and multiple low-grade tumors (N = 170). Group B consisted of patients with a low-grade tumor that recurred after a low-risk tumor (N = 97), and Group C consisted of patients with a low-grade tumor that recurred after a high-risk tumor (N = 59). ResultsThe 2-year recurrence-free survival rate was significantly lower in Group C (42%) than in Groups A (69%, P<0.01) and B (70%, P<0.01). Regarding progression-free survival, no significant differences were observed among the groups. In total, 167 patients received adjuvant bacillus Calmette-Guérin (BCG), and 39 received adjuvant chemotherapy instillations. In Groups A and B, there were no significant differences in efficiency against tumor recurrence between BCG and chemotherapy. In Group C, the 5-year recurrence-free survival rate was 65% in patients receiving BCG, which was significantly higher when compared with patients receiving chemotherapy (P = 0.01). Furthermore, Group C included 11 BCG refractory cases, 5 of whom later experienced stage progression during follow-up. ConclusionOur subclassification analysis suggested that intermediate-risk tumors that recurred after a high-risk tumor (Group C) should be treated with adjuvant BCG therapy, owing to the high probability of subsequent recurrence. Furthermore, the definition of intermediate risk may include some BCG refractory cases.

Impact of Adjuvant Intravesical Bacillus Calmette-Guérin Treatment on Patients with High-Grade T1 Bladder Cancer

Purpose: To evaluate the impact of adjuvant intravesical bacillus Calmette-Guérin (BCG) treatment in patients with high-grade transitional cell carcinoma of bladder. Patients and Methods: A total of 207 consecutive patients who underwent transurethral resection for high-grade T1 transitional cell carcinoma of bladder at our institution between January 1, 2005 and December 31, 2012. Of those patients, 77 underwent early cystectomy without BCG instillation and were excluded from the analysis. The overall survival and cancer-specific mortality were compared in 2 different therapy options groups (group of patients who received adjuvant BCG instillation vs. the group of patients who did not receive BCG therapy). Overall mortality was estimated by the Kaplan-Meier method, univariate comparisons were made with the log rank test. The cumulative incidence of deaths from bladder cancer (BC) was determined by univariate and multivariate competing risk analysis. Cox proportional hazard models for competing risks were used to study the combined effects of the variables on BC-specific mortality. Results: The 5-year overall survival in patients with BCG instillation vs. patients who did not receive BCG therapy was 74 vs. 28% (p = 0.0016). In the univariate analysis, the adjuvant intravesical BCG treatment was associated with decreased cancer-specific mortality (p = 0.0062). In the multivariable analysis, the age and the BCG instillation were independent factors of overall survival (hazard ratio 0.26, 95% CI 0.15-0.46, p < 0.0001) and cancer-specific mortality (hazard ratio 0.29, 95% CI 0.12-0.71, p = 0.0067). Conclusion: Dispensing from adjuvant intravesical BCG treatment is associated with increased overall- and disease-specific mortality in patients with T1 high-grade transitional cell carcinoma of bladder. This observation confirms that adjuvant BCG instillation is a crucial part of treatment in this patient population.