Course Of Bacillus Calmette-Guerin Research Articles

Abstract PR005: 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 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 >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.

Abstract B007: Urinary cytokine profiles reflect rationale for treatment with gemcitabine and Bacillus Calmette-Guérin (BCG) in BCG-exposed high-risk non-muscle invasive bladder cancer (NMIBC)

Abstract Background: Bacillus Calmette-Guérin (BCG) remains the most efficacious and widely studied intravesical therapy for NMIBC, but less than 50% of BCG-exposed patients will respond to a second course of BCG. One mechanism of resistance to BCG is an immunosuppressive tumor microenvironment with myeloid-derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), and Tregs that abrogate the anti-tumor immune response. IL-6 is associated with MDSCs and BCG resistance. Gemcitabine (Gem), however, has been shown to selectively inhibit MDSCs, TAMs, and Tregs. This observation served as the biologic rationale for our recently completed Phase I trial of combination chemoimmunotherapy with intravesical Gem and BCG for BCG-exposed high-grade (HG) NMIBC (NCT04179162) that demonstrated excellent tolerability and preliminary efficacy (96% complete response at 6-month follow-up). We sought to evaluate immune modulation with the addition of Gem to BCG as determined by changes in urinary cytokine/chemokine levels. Methods: Patients with BCG-exposed papillary HG NMIBC (Ta/T1) +/- carcinoma in situ recurring within 24 months of BCG therapy were treated with intravesical Gem twice weekly (weeks 1,4,7,10; 8 total doses) and intravesical TICE BCG weekly (weeks 2,3,5,6,8,9; 6 total doses) followed by SWOG maintenance BCG for responders. Urine specimens were collected prior to treatment and on weeks 4, 8, 12, 24, and 52 weeks after on-trial treatment initiation. Urinary cytokines present in the supernatant were evaluated using a 96-plex immuno-oncology proximity extension assay (Olink®). Cytokines with < 75% of values below the lower limit of detection of the assay were not evaluated. We performed an exploratory analysis of select pre-specified cytokines using a linear mixed model. Mean changes and 95% confidence intervals (CI) are presented with global p-values testing for a change in cytokine levels at any timepoint. Results: Urine samples were available for all 25 patients in the Phase I study. A total of 25 proteins on the panel were excluded due to low detection. Chemokines associated with T-cell trafficking (CXCL9, CXCL10, CXCL11) increased during induction treatment through 3 months of follow up and then returned to baseline after the completion of treatment (p<0.001 for each cytokine). IL-6 decreased after initiation of treatment and remained low through 12 months of follow up (-2.7, 95% CI -3.8, -1.7; p<0.001). Notably, the one patient who had a recurrence also had a rise in IL-6 after an initial decline while on treatment. Conclusion: We found evidence that the addition of intravesical gemcitabine to BCG favorably augments the tumor microenvironment based on changes in urinary cytokine/chemokine profiles. Additional tumor and urinary correlatives are ongoing. Based on the the robust preliminary efficacy demonstrated in the ongoing phase I/II trial (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: Christopher D. Gaffney, Syed M. Alam, Jessica A. 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. Urinary cytokine profiles reflect rationale for treatment with gemcitabine and Bacillus Calmette-Guérin (BCG) in BCG-exposed high-risk non-muscle invasive bladder cancer (NMIBC) [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 B007.

Topical instillation of BCG immunotherapy for biopsy-proven primary upper urinary tract carcinoma in situ: A single institution series and systematic review.

Primary upper tract carcinoma in situ (UTcis) is a rare disease whose diagnosis and natural history are poorly understood. Radical nephroureterectomy is the standard of care but in imperatives or selected cases, topical instillations of Bacillus Calmette-Guérin (BCG) may represent a good alternative. The aim of this study was to report the histologic response to BCG instillations for the treatment of biopsy-proven UTcis and to systematically assess the current evidence on topical BCG instillation for the treatment of UTcis. This is a retrospective analysis of patients with biopsy-proven UTcis treated with BCG instillation between 1995 and 2020 in an expert center. The initial diagnosis was performed by a standardized random biopsy scheme during ureterorenoscopy (URS) in patients with positive cytology but negative CT and bladder biopsies. BCG course consisted of 6 weekly instillation of 81 mg Immucyst (Sanofi Pasteur MSD AG, Baar, Switzerland). Administration techniques were single-J, double-J and nephrostomy tube. The primary outcome was the rate of complete histological response at the 3-month 2nd-look-URS. Kaplan-Meier analysis curves assessed recurrence- and progression-free survival. A total of 22 patients (23 renal units) were included. Twenty-one (91.3%) patients completed the planned 6-week instillation cycle. Only one major complication was recorded (renal tuberculosis). Twenty patients had a 3-month 2nd-look-URS, with a complete histological response achieved in 17/20 cases (85%). After a median time of follow-up of 40 months (30-62), 8/20 patients harbored disease recurrence, including 5 cases of disease progression (≥pT2). The main limitations are the retrospective and non-comparative design of the study. Our systematic review (CRD42022324876) identified 15 studies (289 renal units). UTcis suffers from the lack of a standardized definition, and considerable heterogeneity has been found in making the diagnosis and assessing the response to treatment. Our study is the first to propose a histological diagnosis of UTcis as well as a histological re-evaluation of the response to treatment. Topical instillations of BCG appear to be a promising alternative, avoiding radical treatment in the majority of cases.

MP54-14 MENTAL HEALTH ILLNESS IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER. DOES BCG PLAY A ROLE?

You have accessJournal of UrologyCME1 Apr 2023MP54-14 MENTAL HEALTH ILLNESS IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER. DOES BCG PLAY A ROLE? Valentina Grajales, Zhigang Duan, Wei Shen Tan, Roberto Contieri, Hui Zhao, Sharon Giordano, Stephen B. Williams, and Ashish M. Kamat Valentina GrajalesValentina Grajales More articles by this author , Zhigang DuanZhigang Duan More articles by this author , Wei Shen TanWei Shen Tan More articles by this author , Roberto ContieriRoberto Contieri More articles by this author , Hui ZhaoHui Zhao More articles by this author , Sharon GiordanoSharon Giordano More articles by this author , Stephen B. WilliamsStephen B. Williams More articles by this author , and Ashish M. KamatAshish M. Kamat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003307.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Up to a third of cancer patients experience a mental health condition during their cancer treatment; Bacillus Calmette-Guerin (BCG) has been shown to be neuroprotective. Herein, we assess the incidence of mental health illness (MHI) in non-muscle invasive bladder cancer (NMIBC) patients and the impact of intravesical BCG on the development of non-neurodegenerative MHI. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data set, we identified 30,991 patients diagnosed with NMIBC between 2005-2017. MHI diagnosis and BCG treatment were identified using ICD9/ICD10 diagnosis codes and HCPCS codes from Medicare inpatient, outpatient, and physician claims. We excluded developmental, organic, and neurodegenerative MHI. Descriptive statistics were done using the Pearson’s chi-square test for categorical variables. RESULTS: A total of 27.0% of patients (N=8,367) received at least an induction course of BCG. Pre-existing MHI was present in 15.9% (N=4,928) of patients 1 year prior to bladder cancer diagnosis. These patients had lower rates of induction BCG (23.0% VS 27.8%, p<0.001). Excluding pre-existing MHI, 43.7% (N=11,377) of patients developed MHI after their bladder cancer diagnosis. Both female and older patients had higher rates of developing MHI (p<0.001), Table 1. Patients without pre-existing MHI treated with at least an induction course of BCG (N=7,233) had a lower MHI development rate than those who did not receive BCG (41.5% VS 44.5%, p<0.001). CONCLUSIONS: Patients with NMIBC are at high risk of developing MHI after diagnosis especially elderly and female patients. Patients who received at least induction BCG treatment had lower rates of developing de novo MHI, however, those with pre-existing MHI were less likely to receive BCG. Source of Funding: This research was supported by the Wayne B. Duddlesten Professorship in Cancer Research © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e759 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Valentina Grajales More articles by this author Zhigang Duan More articles by this author Wei Shen Tan More articles by this author Roberto Contieri More articles by this author Hui Zhao More articles by this author Sharon Giordano More articles by this author Stephen B. Williams More articles by this author Ashish M. Kamat More articles by this author Expand All Advertisement PDF downloadLoading ...

Variation in Statewide Intravesical Treatment Rates for Non-Muscle Invasive Bladder Cancer During the Bacillus Calmette-Guerin Drug Shortage

To measure the changes in treatment patterns for non-muscle invasive bladder cancer before and during the Bacillus Calmette-Guerin (BCG) drug shortage. We used a 5% random sample of Medicare beneficiaries and identified 7971 bladder cancer patients (2648 pre-BCG shortage and 5323 during the shortage) ≥66 years of age who received intravesical treatment within 1 year of diagnosis between 2010 and 2017. The BCG shortage period was defined from July 2012 ongoing. Full induction treatment with BCG, mitomycin C, gemcitabine, or other intravesical agents was defined as receiving ≥5 of 6 treatments within 60 days. State-level BCG use before and during the drug shortage was compared in US states reporting at least 50 patients in each period. Independent variables included year of index date, age, sex, race, rurality, and region of residence. BCG utilization rates decreased 5.9%-33.0% in the shortage period (95% CI (-8.2%)-(-3.7%)). The proportion of patients that completed a full induction course of BCG decreased from 31.0% in the pre-shortage period to 27.6% in the shortage period (P = .002). 84% of reporting states (16 of 19) had decreased BCG utilization ranging between 5% and 36% compared to pre-shortage rates. During the BCG drug shortage, eligible bladder cancer patients were less likely to receive gold standard intravesical BCG with a large variation in treatment patterns between US states.

Study EV-104: Phase 1 study of intravesical enfortumab vedotin for treatment of patients with non-muscle invasive bladder cancer (NMIBC)—Trial in progress.

TPS582 Background: The majority of patients with bladder cancer present with non-muscle invasive disease (Chang 2016; Woldu 2017; Kates 2020; Li 2020). The standard of care for treatment of high risk NMIBC involves transurethral resection of the bladder tumor (TURBT) followed by intravesical Bacillus Calmette-Guerin (BCG) or chemotherapy. Although the response rate to BCG therapy is high, many patients recur within 1–5 years (Matulay JU 2021). For patients who have BCG unresponsive disease after adequate course of BCG, there are limited options. While radical cystectomy (RC) is still considered the standard of care, most patients are reluctant to undergo RC and their options are limited to intravesical chemotherapy or pembrolizumab. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder tumors. In EV-301, a phase 3 study, EV showed an OS benefit vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). Based on its demonstrated benefit in la/mUC, EV is currently being evaluated in earlier UC settings. The purpose of this study is to investigate the intravesical administration of EV for patients with NMIBC. Methods: EV-104 (NCT05014139) is a phase 1, open-label, multicenter, dose-escalation and dose-expansion study designed to evaluate the safety, tolerability, PK, and antitumor activity of intravesical EV in adults with high-risk BCG-unresponsive NMIBC (carcinoma in situ with or without papillary disease) who are ineligible for or refuse RC. The dose escalation part of the trial aims to identify the maximum tolerated dose (MTD) and/or recommended dose of intravesical EV. The dose expansion part will evaluate patients at the MTD or recommended dose and further characterize safety and antitumor activity of intravesical EV. The study treatment regimen will include an induction phase, where patients will receive intravesical EV weekly for 6 weeks followed by monthly maintenance for a total of 9 additional EV doses. Patients will be assessed for response every 3 months by cystoscopy and urine cytology, while on study. Safety and antitumor activity endpoints will be summarized using descriptive statistics. The study is currently enrolling in the US with additional sites planned in Canada and the EU. Clinical trial information: NCT05014139 .

Sex Remains Negative Prognostic Factor in Contemporary Cohort of High-Risk Non-Muscle-Invasive Bladder Cancer.

Sex-specific differences in outcomes of patients diagnosed with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have been reported with controversial findings. This study aims to investigate sex-specific diversities in the treatment and oncologic outcomes of primary HR-NMIBC in a multicenter setting. A multicenter retrospective analysis of 519 patients (388 men and 131 women) treated with transurethral resection (TUR) for primary HR-NMIBC was performed. Univariable and multivariable Cox regression models were used to investigate the association of clinico-pathologic features and generate hazard ratios (HRs). Second-look TUR (reTUR) was performed in 406 (78%) patients. A total of 218 (42%) of patients were subjected to an induction course of intravesical BCG (Bacillus Calmette-Guérin) plus maintenance therapy. The median follow-up was 44 months. Among the entire cohort, 238 (46%) and 86 patients (17%) had recurred and progressed to muscle-invasive disease (MIBC), respectively. Female sex was associated with increased risk of disease recurrence in the entire cohort: HR = 1.94, 95% CI = 1.48-2.55, p &lt; 0.001 and HR = 1.91, 95% CI = 1.39-2.60, p &lt; 0.001 in univariate and multivariate analysis, respectively. In patients subjected to reTUR and treated additionally with BCG, female sex was associated with increased risk of disease recurrence in univariate analysis (HR 1.81, 95% CI 1.07-3.06, p = 0.03), but not in multivariate analysis (HR 1.99, 95% CI 0.98-4.02, p = 0.06). There was no difference between sexes with regard to disease progression. HR-NMIBC diagnosed in females is associated with higher risk of disease recurrence when compared to males.

Treatment and disease management patterns for bacillus Calmette-Guérin unresponsive nonmuscle invasive bladder cancer in North America, Europe and Asia: A real-world data analysis.

BackgroundThis study examined real-world treatment and management of bacillus Calmette-Guérin (BCG)-unresponsive patients across 3 continents, including patients unable or unwilling to undergo cystectomy.Materials and methodsPhysicians actively involved in managing patients with nonmuscle invasive bladder cancer completed online case report forms for their 5 consecutive patients from the broad BCG-unresponsive population and a further 5 consecutive BCG-unresponsive patients who did not undergo cystectomy (in Japan, physicians provided a total of 5 patients across both cohorts).ResultsMost patients had received 1 (37%) or 2 (24%) maintenance courses of BCG. Five or more maintenance BCG courses were received by patients in Japan (59%) and China (31%), while in Germany 76% of patients received only 1 course. Most patients became BCG-unresponsive during their first (44%) or second (22%) treatment course; in Germany, 77% became BCG-unresponsive during their first treatment course. Most countries did not provide another course of BCG after a patient first became unresponsive, whereas unresponsive patients in Japan and China were most likely to be retreated with BCG. “Untreated - on watch and wait” was the main treatment/management approach received post-BCG treatment for 42% or more of patients in most countries except China (39%) and the United States (36%). “Following treatment guidelines” was consistently the top reason for post-BCG treatment selection across all treatment options.ConclusionsThis study confirmed the global unmet need for patients with nonmuscle invasive bladder cancer, and found that many patients experienced periods of no treatment after not responding to BCG therapy.

Intravesical docetaxel for high-risk non-muscle invasive bladder cancer after Bacillus Calmette-Guérin failure.

Background:There are limited bladder-preserving therapeutic options for patients with high-risk non-muscle invasive bladder cancer (NMIBC) after failed Bacillus Calmette-Guérin (BCG) therapy. Salvage intravesical docetaxel therapy was described in 2006 but has not been validated outside of the original institution. In this study, we presented the first external report on the oncologic outcomes of intravesical docetaxel.Materials and methods:We identified 13 patients with high-risk NMIBC treated with ≥1 course of intravesical BCG who received salvage intravesical docetaxel. Recurrence-free survival (RFS) was estimated using the Kaplan–Meier method. Associations of clinicopathologic features with RFS were evaluated using Cox regression.Results:Median age was 75.2 years, and 46.2% of patients were male. Of the patients 92.3% had a prior diagnosis of high-grade T1 disease, 38.5% had a prior diagnosis of carcinoma in situ, and 46.2% had received ≥2 courses of BCG. Only 1 (7.7%) patient experienced docetaxel-related toxicity. Nine (69.2%) patients had a complete response at initial post-docetaxel cystoscopy. During a median follow-up of 12.0 (interquartile range 5.0–18.1) months, a total of 7 (53.8%) patients developed recurrence. Median time to recurrence was 10.1 (interquartile range 4.8–11.6) months. Estimated RFS at 6-, 12-, 18-, and 24-months was 75%, 50%, 50%, and 25%. Three (23.1%) patients ultimately underwent cystectomy. On univariable analysis, multiple courses of induction BCG were associated with decreased RFS, although this did not reach statistical significance (hazard ratio 4.69, p = 0.08).Conclusions:In this first external validation study, intravesical docetaxel was associated with excellent response rates and intermediate-term RFS among patients with high-risk NMIBC after failed BCG therapy.

The association of salvage intravesical therapy following BCG with pathologic outcomes and survival after radical cystectomy for patients with high-grade non-muscle invasive bladder cancer: A multi-institution analysis

IntroductionWhile numerous current clinical trials are testing novel salvage therapies (ST) for patients with recurrent nonmuscle invasive bladder cancer (NMIBC) after bacillus Calmette-Guérin (BCG), the natural history of this disease state has been poorly defined to date. Herein, we evaluated oncologic outcomes in patients previously treated with BCG and ST who subsequently underwent radical cystectomy (RC). MethodsWe identified 378 patients with high-grade NMIBC who received at least one complete induction course of BCG (n = 378) with (n = 62) or without (n = 316) additional ST and who then underwent RC between 2000 and 2018. Oncologic outcomes were compared using the Kaplan-Meier method and Cox proportional hazards models. Sensitivity analyses were conducted stratifying by presenting tumor stage, matched 1:3 for receipt vs. no receipt of ST. ResultsPatients receiving ST were more likely to initially present with CIS (26% vs. 17%) and less likely with T1 disease (34% vs. 50%, P = 0.06) compared to patients not treated with ST. Receipt of ST was not associated with increased risk of adverse pathology (≥pT2 or pN+) at RC (31% vs. 41%, P = 0.14). Likewise, 5-year cancer-specific survival did not significantly differ between groups on univariable Kaplan-Meier analysis (73% for ST and 74% for no ST, P = 0.7). Moreover, on multivariable analysis, receipt of ST was not significantly associated the risk of death from bladder cancer (HR 1.12; 95% CI 0.60–2.09, P = 0.7). Results were unchanged on sensitivity analysis. ConclusionsThese data suggest that, in carefully selected patients, ST following BCG for high grade NMIBC does not compromise oncologic outcomes for patients who ultimately undergo RC.

Robotic cystectomy histopathology outcomes in patients who have ‘failed’ Bacillus Calmette–Guérin: A case series

Objective: Robot-assisted radical cystectomy (RARC) is considered the gold-standard for patients who fail Bacillus Calmette–Guérin (BCG) treatment for high-grade non-muscle-invasive bladder cancer. We reviewed our histopathological outcomes to assess whether we are proceeding to cystectomy at an appropriate time. Methods: A retrospective analysis of the RARC database (2015–2020) was performed to identify patients who received intravesical BCG before cystectomy. Data regarding demographics, number of BCG instillations and staging were collected. Histopathological stage at cystectomy was compared between patients who received an induction course of BCG only (group A), and those who had continued maintenance doses (group B). Results: A total of 73 patients (57 males and 16 females) met the final inclusion criteria, with 24 patients in group A and 49 patients in group B. At cystectomy, 19 patients had ⩾T2 disease (group A: 7; group B: 12). There was no significant difference between groups ( p=0.78). Pelvic lymph node dissection was performed in 68 patients, with six patients found to have lymph node metastases. Conclusion: RARC plays a key role in managing BCG failure, considering the number of patients with muscle-invasive disease at final staging. However, prolonged BCG treatment was not associated with more advanced disease in our case series. Thus, persistence with intravesical treatment warrants consideration for selected patients. Level of evidence: Level 4.

The obesity paradox: defining the impact of body mass index and diabetes mellitus for patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin.

To evaluate if the obesity paradox, wherein obesity portends worse overall prognosis for a disease but improved outcomes for patients receiving immunotherapy, exists for patients receiving bacillus Calmette-Guérin (BCG) in a contemporary cohort. We performed an Institutional Review Board-approved database review to identify patients with non-muscle-invasive bladder cancer (NMIBC) completing at least an induction course of BCG. Clinicopathological variables collected included: body mass index (BMI), medications, and diabetes mellitus (DM). Outcomes of interest included: recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Univariate and multivariate modelling were used to evaluate the association between outcomes and clinical factors. A total of 579 patients (median follow-up 4.6years) received BCG induction for NMIBC; 90% had high-grade disease (47.2% clinical stage T1). In all, 75.7% of patients were overweight or obese and 18% had DM. Aspirin, statins, metformin and β-blockers were used in 34%, 42%, 11%, and 29% of patients, respectively. Overweight and obese patients had improved PFS, CSS and OS. DM was associated with worse RFS. Medications of interest had no association with outcomes. Elevated BMI is associated with improved outcomes in patients with NMIBC treated with BCG immunotherapy. Patients with DM are at increased risk of recurrence. These findings support a potential obesity paradox in bladder cancer. Evaluation of the underlying mechanism and the role of global patient assessment, counselling, and risk factor modification are warranted.

PCN349 Healthcare Resource Use (HCRU) of NON-Muscle Invasive Bladder Cancer (NMIBC) Patients Post Bacillus Calmette-Guérin (BCG)-Unresponsive Status in Multiple Countries

BCG is the standard-of-care treatment for NMIBC patients. However, many patients become BCG unresponsive with few options for subsequent treatment other than cystectomy. We evaluated HCRU in these patients, as little evidence is available. A retrospective chart review was conducted in five European countries, US, China, and Japan from January to May 2019. Urologists and medical/clinical oncologists abstracted data for BCG-unresponsive patients. BCG-unresponsive status was defined as having at least one of: persistent or recurrent carcinoma in situ (CIS) alone or with recurrent Ta/T1 disease within 12 months of completion of adequate BCG therapy; recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy; T1 high-grade disease at the first evaluation following an induction BCG course. HCRU data included physician visits, tests, procedures, and hospitalisations from the time patients were classified as BCG-unresponsive. 508 physicians abstracted data for 2,554 patients. Mean patient age was 72 years and 77% were male. 60% had a current ECOG of 0-1, and staging at diagnosis were CIS alone (34%), papillary disease only (34%), and papillary with CIS (32%). Since BCG-unresponsive status, patients visited their treating physician and PCP most frequently (mean 4.6 and 1.6 visits, respectively) and most patients (92%) underwent tests/procedures related to NMIBC. Most commonly, 75% of patients received CT scans, 50% underwent urine cytology tests and 41% TURBT. 43% were hospitalised, with 59% of these requiring ≥3 nights in hospital. The most common reasons for hospitalisation were standard procedure (49%), intractable gross haematuria (23%) and treating a complication (22%). 34% of patients were admitted through ER. Current management approaches resulted in considerable HCRU demand post BCG-unresponsive status. Most patients required multiple tests/procedures and a high proportion required overnight hospitalisations, which highlights the need for effective treatment and management strategies.

Quality of life and adverse events in patients with nonmuscle invasive bladder cancer receiving adjuvant treatment with BCG, MMC, or chemohyperthermia

IntroductionChemohyperthermia (CHT) with mitomycin C (MMC) is together with Bacillus Calmette-Guérin (BCG), and passive MMC, a treatment option for patients with non muscle-invasive bladder cancer. There are no data published about the impact of CHT in quality of life (QoL). We evaluated QoL and adverse events (AE) in this 3-arm observational study. Patients and MethodsProspective observational study from September 2016 to March 2017, we recruited consecutive patients that received adjuvant treatment after transurethral resection of bladder tumor. Patients received induction courses of either BCG, CHT, or passive MMC. Patients filled the questionnaires Functional assessment of cancer therapy for bladder cancer patients (FACT-Bl) and International prostate symptom score (IPSS) before, during, and after the induction course. A urologist documented AE using Common Terminology Criteria for AE (CTCAE criteria). ResultsA total of 56 patients, receiving a total of 296 bladder instillations (BCG n = 27, CHT n = 14 and MMC n = 15). FACT-Bl showed statistically significant differences in the fourth week in favor of CHT versus BCG, IPSS did not show statistically significant differences before, during, and after induction course in all 3 arms. All patients recovered their baseline QoL at the end of the induction treatment. Overall 55.5%, 50% and 20% of patients presented any grade of AE in the BCG, CHT and MMC groups respectively. About 7% of patients in BCG and CHT arms had to discontinue treatment due to AE. BCG and CHT showed a similar rate of AE but in CHT were mostly grade I and BCG had grade I, II, and IV. Passive MMC had the safest profile. ConclusionThere are no clinically significant differences between BCG, CHT, and passive MMC regarding QoL and lower urinary tract symptoms during the induction course. CHT has a more favorable AE profile when compared with BCG.

Short-changed during the bacillus Calmette–Guérin shortages?

Objective: Intravesical bacillus Calmette–Guérin (BCG) is the first-line treatment of choice for high-risk non-muscle-invasive bladder cancer (NMIBC). Our aim was to evaluate the long-term impact of BCG shortages on oncological outcomes. Methods: All patients undertaking an initial course of intravesical BCG for intermediate or high risk NMIBC at a single UK cancer centre between August 2012 and August 2014 were evaluated. Compliance was defined as completing 12 doses of BCG within the first year following diagnosis. Results: Due to BCG shortages, 25/114 (22%) patients were compliant with planned maintenance treatment. Compared to the compliant cohort, the non-compliant due to BCG shortages cohort had a higher rate of disease recurrence (35.3% vs. 24%), required more additional intravesical treatments (14.7% vs. 12%) and had a higher rate of radical cystectomy (11.8% vs. 4%). Disease-free survival was superior in the compliant cohort at two years (88% vs. 79.5%) and at 4.5 years (72% vs. 56.1%). There was no statistically significant difference, likely due to the sample size. Conclusions: The consequences of undertreatment due to BCG shortages can impact long-term cancer outcomes. Increased vigilance, robust long-term surveillance and alternative treatment strategies are required for NMIBC patients affected by shortages in BCG supplies. Level of evidence: Level 2b

Phase Ib study: APL-1202 (APL) in combination with Bacillus Calmette-Guerin (BCG) in recurrent non-muscle invasive bladder cancer (NMIBC).

e17039 Background: APL is a selective human methionine aminopeptidases II (MetAP2) inhibitor. In preclinical studies, APL has demonstrated both anti-angiogenic and anti-tumor activities as well as a potential synergistic effect with BCG or PD-1. A. This phase 1b study assesses the tolerability and pharmacokinetics (PK) characteristics of oral APL and intravesical BCG combination in HR NMIBC pts. Methods: Pts who had received a prior induction course of BCG within 12 weeks (wks) of enrollment and were scheduled to receive either maintenance or another induction course of BCG were given 750 mg/day APL (2x125 mg tablet, TID) for 12 wks. The tolerability and PK of APL was evaluated one wk prior to first BCG instillation and during combination use with BCG. AEs were evaluated to assess safety and tolerability. Wilcoxon matched-pair signed-rank test was used for PK analysis. Results: Six pts (4M, 2F) with a median age of 72.5 yrs (range 58-81 yrs) were enrolled; 4 pts had grade 3 Ta and 2 pts had Tis. Four and 2 pts received induction and maintenance course of BCG, respectively. Six AEs of grade 1 or 2 were reported by 3 pts, and they were respiratory and head congestion, acid reflux, rash, bronchitis, nausea, and cystitis. None of these AEs were judged to be related to APL. Five pts completed the study and 1 pt dropped out due to a grade 1 cystitis after receiving 4 wks of APL and 2 doses of BCG. The PK results suggested similar PK characteristics (plasma AUCtau, Cmax and t1/2, and urinary excreted faction Ae%). Conclusions: APL was well tolerated when given for 12 wks to NMIBC pts who also received induction or maintenance BCG. Further study of APL in combination with BCG is warranted. Clinical trial information: NCT03672240.

PD03-06 EFFECTS OF LEVOFLOXACIN ON BACILLUS CALMETTE-GUERIN-INDUCED TOXICITY IN PATIENTS WITH NONMUSCLE INVASIVE BLADDER CANCER: RESULTS OF A RANDOMIZED, PROSPECTIVE, MULTICENTER STUDY

You have accessJournal of UrologyBladder Cancer: Non-invasive I (PD03)1 Apr 2020PD03-06 EFFECTS OF LEVOFLOXACIN ON BACILLUS CALMETTE-GUERIN-INDUCED TOXICITY IN PATIENTS WITH NONMUSCLE INVASIVE BLADDER CANCER: RESULTS OF A RANDOMIZED, PROSPECTIVE, MULTICENTER STUDY Kazuyuki Numakura*, Mizuki Kobayashi, Toshiya Ishida, Katsumi Okane, Kazumasa Suzuki, Naotake Shimoda, Takehiro Suzuki, Teruaki Kumazawa, Ryusei Sasaki, Hisami Fukuda, Taketoshi Nara, Sohei Kanda, Huang Mingguo, Mitsuru Saito, Shintaro Narita, Takamitsu Inoue, Norihiko Tsuchiya, and Tomonori Habuchi Kazuyuki Numakura*Kazuyuki Numakura* More articles by this author , Mizuki KobayashiMizuki Kobayashi More articles by this author , Toshiya IshidaToshiya Ishida More articles by this author , Katsumi OkaneKatsumi Okane More articles by this author , Kazumasa SuzukiKazumasa Suzuki More articles by this author , Naotake ShimodaNaotake Shimoda More articles by this author , Takehiro SuzukiTakehiro Suzuki More articles by this author , Teruaki KumazawaTeruaki Kumazawa More articles by this author , Ryusei SasakiRyusei Sasaki More articles by this author , Hisami Fukuda Hisami Fukuda More articles by this author , Taketoshi Nara Taketoshi Nara More articles by this author , Sohei KandaSohei Kanda More articles by this author , Huang MingguoHuang Mingguo More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Norihiko Tsuchiya Norihiko Tsuchiya More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000823.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although bacillus Calmette-Guerin (BCG) is a standard of care for especially high-risk nonmuscle-invasive bladder cancer (NMIBC), a high rate of adverse events (AEs) remains a major problem. In this randomized, prospective, multicenter study, we examined whether levofloxacin (LVFX) given after each intravesical instillation of BCG could improve its tolerance in patients with intermediate- to high-risk urothelial carcinoma of the bladder. We also investigated the impact of LVFX on the antitumor efficacy of BCG. METHODS: In this study, 100 patients with primary or recurrent NMIBC (Ta/T1, CIS, G1-G3) were randomized to induction treatment with intravesical BCG plus LVFX in group 1 (n=52) or BCG alone in group 2 (n=48). AEs were assessed using a National Cancer Institute-Common Toxicity Criteria Version 3.0. The median patient ages were 69.5 years (46 – 80) and the median follow up period was 36 months (12 – 128). All patients were Japanese, consisting of 80 men and 20 women. RESULTS: There was no significant difference in baseline characteristics and symptoms between the groups. Overall, there were no significant differences decreases in the rate of patients having with pollakisuria, miction pain, gross hematuria, fever elevation, and others between the group 1 and group 2. The rate of BCG discontinuation was not different between the groups (24.5% vs 13.7%, p = 0.207). However, the incidence of AEs with grade II or more pollakisuria and fever elevation was significantly lower (5.9% vs 28.2%, p = 0.016; 0% vs 8.2%, p=0.034) in the group 1 (Table 1). The 5-year progression-free and cancer-specific survival rates were better in the group I (HR 0.26, 95%CI 0.57-0.81, p = 0.011; 1 HR 0.13, 95%CI 0.01-0.74, p = 0.006) (Figure 1). CONCLUSIONS: Prophylactic LVFX may reduce the severity of AEs and can contribute to better outcomes from BCG intravesical therapy in patients with NMIBC, improving compliance with the BCG course. Source of Funding: none © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e74-e74 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kazuyuki Numakura* More articles by this author Mizuki Kobayashi More articles by this author Toshiya Ishida More articles by this author Katsumi Okane More articles by this author Kazumasa Suzuki More articles by this author Naotake Shimoda More articles by this author Takehiro Suzuki More articles by this author Teruaki Kumazawa More articles by this author Ryusei Sasaki More articles by this author Hisami Fukuda More articles by this author Taketoshi Nara More articles by this author Sohei Kanda More articles by this author Huang Mingguo More articles by this author Mitsuru Saito More articles by this author Shintaro Narita More articles by this author Takamitsu Inoue More articles by this author Norihiko Tsuchiya More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement PDF downloadLoading ...

An evaluation of monthly maintenance therapy among patients receiving intravesical combination gemcitabine/docetaxel for nonmuscle-invasive bladder cancer

PurposeTo report our experience with sequential maintenance intravesical gemcitabine/docetaxel (GEM/DOCE) for patients with nonmuscle-invasive bladder cancer. Materials and methodsFifty-nine patients who received full GEM/DOCE for nonmuscle-invasive bladder cancer between 2013 and 2018, per the protocol adapted from University of Iowa, were identified and characterized. Patients were treated with 6 weekly instillations of GEM/DOCE and subsequent monthly maintenance installations for those with no evidence of disease at the first surveillance. Student's t test and χ2 test were used to compare continuous and categorical variables as appropriate. For survival analyses, Kaplan-Meier (KM) curves were created to assess disease-free survival (DFS). Overall comparisons of KM survival analysis were conducted using the Wilcoxon test. ResultsAmong all patients, median follow-up was 24 months. Sixty-six percent of patients received ≥2 intravesical induction therapies prior to receiving GEM/DOCE. Thirty-one patients (63%) failed ≥2 induction courses of Bacillus Calmette-Guérin (BCG) before receiving GEM/DOCE. Overall DFS was 49% at 1 year and 29% at 2 years. For patients who failed ≥1 induction courses of BCG, overall DFS was 48% at 1 year and 32% at 2 years. GEM/DOCE appears to be effective for therapy naïve and patients who have failed previous intravesical therapies (P = 0.39). There were 41 (69.5%) patients who had no evidence of disease at the first surveillance and were eligible for maintenance therapy. Among these patients, 24 were managed with observation alone and 17 with monthly maintenance. Median follow-up for observed patients was 36 months and 26 months for patients with maintenance. DFS at 1 year was 42% for observed patients and 81% for patients receiving maintenance (P = 0.04). DFS at 2 years was 32% for observed patients and 59% for patients receiving maintenance therapy (P = 0.45). For maintenance eligible patients who received ≥1 induction courses of BCG, DFS was 42% for observed patients and 81% for patients receiving maintenance therapy at 1 year and 34% for observed patients and 59% for patients receiving maintenance therapy at 2 years. Pathologic stage at recurrence was similar between observed patients and those receiving maintenance (P = 0.83). KM analyses showed greater DFS for patients receiving maintenance therapy compared to observed patients (P = 0.04). ConclusionPatients who demonstrate initial complete response to GEM/DOCE may benefit from maintenance GEM/DOCE.

Abstract CT047: Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous Pembrolizumab in high grade nonmuscle invasive bladder cancer

Abstract PURPOSE: A phase I trial of intravesical bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab was conducted in patients with high grade non-muscle invasive bladder cancer who had persistent or recurrent disease after failing treatment with at least 2 courses of intravesical therapy (one of which had to contain BCG) or BCG followed by maintenance BCG. The primary objective was to determine the safety of this combination. Secondary end points included response to treatment at 19 weeks (end of treatment) and 3 months post treatment. MATERIALS AND METHODS: A total of 9 patients with recurrent/persistent high-grade non-muscle invasive bladder cancer after at least two courses of intravesical therapy or one course of BCG treatment followed by one course of maintenance BCG were enrolled in the study. Six doses of pembrolizumab were given every 3 weeks over 16 weeks given concurrently with 6 weekly doses of BCG beginning at week 7. Patient safety was evaluated during and for 30 days following pembrolizumab treatment. Preliminary combination efficacy was determined at 19 weeks using cystoscopy. Bladder biopsy was performed in patients with suspicious lesions. RESULTS: The combination of BCG and pembrolizumab was well tolerated at both 100mg and 200mg fixed doses. Fatigue and cystitis-type symptoms (burning, spasm, urgency, sensitivity, and frequency) were the most common adverse events and all cases were either grade 1 or 2. Two patients died during the trial period. One patient died due to progression of low grade upper urinary tract transitional cell carcinoma. The other patient died after cystectomy (for progressive disease) due to causes unrelated to the trial treatment. Of the 9 patients treated, 6 (78%) had no evidence of disease in the bladder and 1 had a mixed response (progression in the upper urinary tract only) at 19 weeks (end of treatment) while 5 (56%) remained disease-free at the 3 month follow up. CONCLUSIONS: The combination of BCG and pembrolizumab was well tolerated with subjects exhibiting the expected adverse effects associated with the use of both medications. Intravesical BCG and pembrolizumab may have clinical activity in non-muscle invasive bladder cancer recurring after repeated intravesical therapy. .A phase III trial is now open and enrolling in the United States and other countries (NCT03711032). Citation Format: Shaheen Alanee, Ahmed El Zawahry, Sherjeel Sana, Kevin McVary, Kathy Robinson, Krishna A. Rao. Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous Pembrolizumab in high grade nonmuscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT047.

Contemporary oncologic outcomes of second induction course BCG in patients with nonmuscle invasive bladder cancer

PurposeAccording to the 2016 American Urological Association (AUA) guidelines for nonmuscle invasive bladder cancer (NMIBC), clinicians should offer a 2nd intravesical induction course of Bacillus Calmette-Guérin (BCG) to patients with persistent or recurrent Ta or CIS disease after a 1st BCG induction course. However, evidence for a 2nd course is limited, and some patients forego a 2nd induction of BCG in favor of a clinical trial or alternate intravesical therapy. We sought to investigate contemporary oncologic outcomes of a 2nd induction course of BCG in a multi-institutional cohort. Materials and methodsThree hundred fifty-three patients who received full induction BCG for NMIBC since 2001 at 2 institutions were identified. Patients were categorized as receiving primary 6-week induction therapy or subsequent 2nd 6-week induction therapy for patients who recurred or persisted. The baseline differences in demographic and tumor characteristics were compared between the 2 groups, and Kaplan-Meier curves were constructed to assess high-grade recurrence free survival (HgRFS) among both groups. Univariable logistic regression was used to determine factors associated with recurrence after 2nd course BCG ResultsA total of 353 patients received 1st induction BCG (BCG1) and 116 patients received a 2nd induction course (BCG2). Maintenance therapy was given to 117 (33.1%) patients after BCG1 and 43 (37.1%) patients after BCG2. Both cohorts were similar in demographics including age, sex, and race. Pathologic stage before treatment differed as BCG1 patients were more likely to have T1 (40.8% vs. 25%) and less likely to have CIS (13.9% vs. 33.6%) (P < 0.001). Complete response (CR) 3 months after BCG1 was observed in 276 patients (78.2%) and 104 patients (89.7%) after BCG2. Responses remained durable, with 36-month CR of 54.7% in BCG1 and 65.6% in BCG2. Progression to MIBC was identified in 1.4% of BCG1 patients vs. 3.4% in BCG2 patients (P = 0.17). Pathologic stage before BCG2 does not predict progression to MIBC (P = 0.21) after BCG2. The time interval between the 1st and 2nd induction of BCG was not significantly associated with response to 2nd induction BCG (P = 0.47). Maintenance therapy after BCG2 was associated with decreased recurrence after 2nd induction course of BCG. ConclusionA 2nd course of BCG is efficacious with a durable HgRFS, validating the recommendations of the 2016 AUA guidelines.