High-grade Non-muscle Invasive Bladder Cancer 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 B024: Development of HM-001 as a therapeutic drug for non-muscle invasive bladder cancer

Abstract HM-001 is a drug containing sodium chlorite as the active ingredient that is being developed as a drug for non-muscle invasive bladder cancer (NMIBC), and is currently undergoing physician-led clinical trials. It has been discovered that sodium chlorite generates radicals in an acidic environment, and phosphatidylserine on the surface of tumor cells acts as a Lewis acid to generate radicals. HM-001, like other anticancer drugs and BCG, is intended to be injected into the bladder, retained, and then excreted. GLP studies using the same administration method has been completed, and no toxic changes have been observed in human trial doses. The efficacy of HM-001 against NMIBC was evaluated using an orthotopic transplantation model of UM-UC-3, a bladder cancer cell line. In the model, cells were transplanted into the bladder of SCID mouse after epithelial removal with trypsin, 600, 800, 1,600, and 3,200 ppm of HM-001 were administered once a week, and the weight of the excised bladder was calculated. After 4 weeks, the tumor weight was calculated and the tumor weight suppression rate in the control group was evaluated. As a result, the medicinal efficacy was confirmed at concentrations of 800ppm or higher. On the other hand, the UM-UC-3 model is a commonly used model, but it mimics CIS (carcinoma in situ) and can only partially mimic NMIBC. That is, other models are needed to evaluate efficacy for low- and high-grade NMIBC other than CIS. Therefore, we established high-grade and low-grade PDX and evaluated the effectiveness of HM-001 against low- and high-grade PDX through ex vivo testing. First, patient-derived tissue was transplanted into SCID mice, allowed to grow, and then removed. After extraction, they were cut into 2 mm3 pieces, exposed to HM-001 at 800, 1600, and 3200 ppm for 2 hours, and then transplanted into SCID mice. As a result of comparing the tumor size after transplantation with the control group, a dose-dependent tumor regression effect was confirmed in high-grade and low-grade PDX. NMIBC is divided into low-, medium-, and high-risk categories, with different treatment methods and drugs used for each. In particular, low-grade forms are restricted to low- and intermediate-risk groups. The results of this study show that HM-001 is effective not only for high-risk (including CIS) NMIBC but also for low- and intermediate-risk (low-grade) NMIBC. Citation Format: Shinji Mima, Monta Sakaki, Noriaki Kiya, Atsunari Kawashima, Norio Nonomura, Chihaya Kakinuma. Development of HM-001 as a therapeutic drug for 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 B024.

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.

Abstract IA012: Novel approaches to the management of non-muscle invasive bladder cancer

Abstract Non-muscle invasive bladder cancer (NMIBC) is a prevalent disease with a high recurrence rate and the potential to progress to muscle-invasive stages. While transurethral resection and bacillus Calmette-Guerin (BCG) immunotherapy remain the mainstay of treatment, limitations exist, particularly for high-grade and BCG-unresponsive NMIBC. This necessitates the exploration of novel therapeutic strategies. This talk will explore promising avenues in NMIBC management, including combination intravesical therapies, enhanced delivery methods for existing treatments, and emerging fields like gene therapy, targeted therapy, immunotherapy variants, and photodynamic therapy. These approaches hold the potential to improve bladder preservation rates, reduce recurrence, and ultimately enhance patient outcomes across the entire spectrum of NMIBC disease. Citation Format: Ashish M. Kamat. Novel approaches to the management of 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 IA012.

Grade Heterogeneity in High-Grade Urothelial Carcinomas: Does It Have an Impact on the Survival of Patients With Intermediate/High-Risk Nonmuscle-Invasive Bladder Cancer Who Received Adequate Adjuvant Bacillus Calmette-Guérin Therapy?

We aimed to compare recurrence-free survival (RFS) and progression-free survival (PFS) of the patients with pure high-grade (HG) vs mixed-grade (MG) nonmuscle-invasive bladder cancer who received adequate bacillus Calmette-Guérin therapy. We conducted a retrospective cohort analysis using data from an institutional database. The study included patients diagnosed with HG nonmuscle-invasive bladder cancer at the initial transurethral resection specimen between 2010 and 2020. The initial transurethral resection specimens of all patients were reevaluated by a dedicated uropathologist. The percentage of low-grade tumor areas accompanying HG areas was determined for each case. Time-to-event analysis was performed using the Kaplan-Meier method. RFS and PFS rates were compared between groups. Of the 203 patients enrolled in the study, 69 (34%) had MG tumors. Recurrence was observed in 41 out of 134 patients (30.6%) in the HG group and in 19 out of 69 patients (27.5%) in the MG group. The 36-month RFS rates were 69% (CI: 62-77) and 72% (CI: 62-83) for the HG-urothelial carcinoma (UC) and MG-UC groups, respectively. The RFS rates were similar between groups (log-rank, P = .58). Progression was observed in 22 out of 134 patients (16.4%) in the HG group and in 4 out of 69 patients (5.8%) in the MG group. The 36-month PFS rates were 84% (CI: 77-90) and 94% (CI: 89-100) for the HG-UC and MG-UC groups, respectively. The pure HG-UC group had a worse PFS than the MG-UC group (log-rank, P = .042). Multivariate analysis demonstrated that age and tumor grade were significant risk factors for the development of progression. The indication of MG-UC category separately from pure HG carcinomas in the pathology report seems to be an important issue that can guide patient management. In this way, both more accurate risk classification and more accurate patient counseling can be performed. More importantly, the treatment plan can be made more accurately. For more precise conclusions, our results should be supported by prospective studies with larger sample size.

Assessing the Predictive Accuracy of EORTC, CUETO and EAU Risk Stratification Models for High-Grade Recurrence and Progression after Bacillus Calmette-Guérin Therapy in Non-Muscle-Invasive Bladder Cancer.

The currently available EORTC, CUETO and EAU2021 risk stratifications were originally developed to predict recurrence and progression in non-muscle-invasive bladder cancer (NMIBC). However, they have not been validated to differentiate between high-grade (HG) and low-grade (LG) recurrence-free survival (RFS), which are distinct events with specific implications. We aimed to evaluate the accuracy of available risk models and identify additional risk factors for HG RFS and PFS among NMIBC patients treated with Bacillus Calmette-Guérin (BCG). We retrospectively included 171 patients who underwent transurethral resection of the bladder tumor (TURBT), of whom 73 patients (42.7%) experienced recurrence and 29 (17%) developed progression. Initially, there were 21 low-grade and 52 high-grade recurrences. EORTC2006, EORTC2016 and CUETO recurrence scoring systems lacked accuracy in the prediction of HG RFS (C-index 0.63/0.55/0.59, respectively). EAU2021 risk stratification, EORTC2006, EORTC2016, and CUETO progression scoring systems demonstrated low to moderate accuracy (C-index 0.59/0.68/0.65/0.65) in the prediction of PFS. In the multivariable analysis, T1HG at repeat TURBT (HR = 3.17 p < 0.01), tumor multiplicity (HR = 2.07 p < 0.05), previous history of HG NMIBC (HR = 2.37 p = 0.06) and EORTC2006 progression risk score (HR = 1.1 p < 0.01) were independent predictors for HG RFS. To conclude, available risk models lack accuracy in predicting HG RFS and PFS in -NMIBC patients treated with BCG.

Experimental and New Approaches for Bladder Preservation in Intermediate and High-Risk Non-Muscle-Invasive Bladder Cancer (NMIBC).

About 75% of bladder cancers are detected as non-muscle invasive. High-risk patients have high progression risk. Although the standard is transurethral resection of bladder tumor plus full dose intravesical BCG for one to 3 years, due to the high risk of progression, radical cystectomy may be considered in specific cases. Although radical cystectomy is still the best approach for high-grade NMIBC from an oncological perspective, its high morbidity and impact on quality of life motivate studies of new strategies that may reduce the need for cystectomy. We carried out a mini-review whose objectives were: 1 - to identify bladder-sparing alternatives that are being studied as possible treatment for patients with intermediate and high-risk NMIBC; 2 - understand the evidence that exists regarding success rate, follow-up, and side effects of different strategies. Several studies have sought alternatives for bladder preservation, including immunotherapy, intravesical chemotherapy, chemo-hyperthermia, antibody-drug conjugates, viral genetic therapy, and others with promising results. The selection of an optimal therapy for high-risk NMIBC that can reduce the need for cystectomy, with low toxicity and high efficacy, is of paramount importance and remains an issue, however, several known medications are being tested as bladder-preserving alternatives in this scenario and have shown promise in studies.

Abstract 3329: Development of HM-001 as a therapeutic drug for non-muscle invasive bladder cancer

Abstract HM-001 is a drug containing sodium chlorite as the active ingredient that is being developed as a drug for non-muscle invasive bladder cancer (NMIBC), and is currently undergoing physician-led clinical trials. It has been discovered that sodium chlorite generates radicals in an acidic environment, and phosphatidylserine on the surface of tumor cells acts as a Lewis acid to generate radicals. HM-001, like other anticancer drugs and BCG, is intended to be injected into the bladder, retained, and then excreted. GLP studies using the same administration method has been completed, and no toxic changes have been observed in human trial doses. The efficacy of HM-001 against NMIBC was evaluated using an orthotopic transplantation model of UM-UC-3, a bladder cancer cell line. In the model, cells were transplanted into the bladder of SCID mouse after epithelial removal with trypsin, 600, 800, 1,600, and 3,200 ppm of HM-001 were administered once a week, and the weight of the excised bladder was calculated. After 4 weeks, the tumor weight was calculated and the tumor weight suppression rate in the control group was evaluated. As a result, the medicinal efficacy was confirmed at concentrations of 800ppm or higher. On the other hand, the UM-UC-3 model is a commonly used model, but it mimics CIS (carcinoma in situ) and can only partially mimic NMIBC. That is, other models are needed to evaluate efficacy for low- and high-grade NMIBC other than CIS. Therefore, we established high-grade and low-grade PDX and evaluated the effectiveness of HM-001 against low- and high-grade PDX through ex vivo testing. First, patient-derived tissue was transplanted into SCID mice, allowed to grow, and then removed. After extraction, they were cut into 2 mm3 pieces, exposed to HM-001 at 800, 1600, and 3200 ppm for 2 hours, and then transplanted into SCID mice. As a result of comparing the tumor size after transplantation with the control group, a dose-dependent tumor regression effect was confirmed in high-grade and low-grade PDX. NMIBC is divided into low-, medium-, and high-risk categories, with different treatment methods and drugs used for each. In particular, low-grade forms are restricted to low- and intermediate-risk groups. The results of this study show that HM-001 is effective not only for high-risk (including CIS) NMIBC but also for low- and intermediate-risk (low-grade) NMIBC. Citation Format: Shinji Mima, Monta Sakaki, Noriaki Kiya, Atsunari Kawashima, Norio Nonomura, Chihaya Kakinuma. Development of HM-001 as a therapeutic drug for non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3329.

Urinary bother, Urinalysis, and Two-Year Efficacy Follow-Up Results of Phase I Trial of Intravesical Bacillus Calmette-Guérin Combined with Intravenous Pembrolizumab in Recurrent or Persistent High-Grade Non-Muscle-Invasive Bladder Cancer after Previous Bacillus Calmette-Guérin Treatment

ObjectiveTo report urinary bother, urinalysis changes, disease-free survival (DFS), and overall survival (OS) over 2 years for subjects enrolled in a phase I dose-escalation trial (NCT02324582) of intravesical Bacillus Calmette-Guérin (BCG) in combination with systemic pembrolizumab for recurrent or persistent high-grade non-muscle invasive bladder cancer (HGNMIBC). MethodsEighteen patients consented to the study. Five were screen failures. Clinical activity was determined using cystoscopy and cytology with a biopsy of suspicious lesions. Urinalysis and International Prostate symptom score were assessed at pre-treatment, Week 10 (during combined BCG and pembrolizumab treatment), and 3 and 6 months from treatment completion. IPSS was analyzed using a mixed-model repeated measures analysis. A Chi-square test was used to compare urinalysis results at each interval. ResultsThe pathologic disease stage after restaging transurethral resection and before treatment was pTa in 6 (46.2%), CIS in 6 (46.2%), and pT1 in 1 (7.7%). There was no increase in reported urinary bother throughout treatment. Quality of life measurements demonstrated no change in subjective burden. On urinalysis, we did not observe significant differences at 3 months compared to baseline evaluation. At 12 months, the DFS and OS were 69.23% and 92.31%, respectively. At 24 months, the DFS and OS were 38.46% and 92.31%, respectively. ConclusionsTreatment with BCG combined with intravenous pembrolizumab is not showing increased urinary bother or adverse urinalysis changes. Two-year response data is promising and await confirmation in the phase III study (Keynote 676)

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

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

Protocol of the Comparison of Intravesical Therapy and Surgery as Treatment Options (CISTO) study: a pragmatic, prospective multicenter observational cohort study of recurrent high-grade non-muscle invasive bladder cancer

BackgroundBladder cancer poses a significant public health burden, with high recurrence and progression rates in patients with non-muscle-invasive bladder cancer (NMIBC). Current treatment options include bladder-sparing therapies (BST) and radical cystectomy, both with associated risks and benefits. However, evidence supporting optimal management decisions for patients with recurrent high-grade NMIBC remains limited, leading to uncertainty for patients and clinicians. The CISTO (Comparison of Intravesical Therapy and Surgery as Treatment Options) Study aims to address this critical knowledge gap by comparing outcomes between patients undergoing BST and radical cystectomy.MethodsThe CISTO Study is a pragmatic, prospective observational cohort trial across 36 academic and community urology practices in the US. The study will enroll 572 patients with a diagnosis of recurrent high-grade NMIBC who select management with either BST or radical cystectomy. The primary outcome is health-related quality of life (QOL) at 12 months as measured with the EORTC-QLQ-C30. Secondary outcomes include bladder cancer-specific QOL, progression-free survival, cancer-specific survival, and financial toxicity. The study will also assess patient preferences for treatment outcomes. Statistical analyses will employ targeted maximum likelihood estimation (TMLE) to address treatment selection bias and confounding by indication.DiscussionThe CISTO Study is powered to detect clinically important differences in QOL and cancer-specific survival between the two treatment approaches. By including a diverse patient population, the study also aims to assess outcomes across the following patient characteristics: age, gender, race, burden of comorbid health conditions, cancer severity, caregiver status, social determinants of health, and rurality. Treatment outcomes may also vary by patient preferences, health literacy, and baseline QOL. The CISTO Study will fill a crucial evidence gap in the management of recurrent high-grade NMIBC, providing evidence-based guidance for patients and clinicians in choosing between BST and radical cystectomy. The CISTO study will provide an evidence-based approach to identifying the right treatment for the right patient at the right time in the challenging clinical setting of recurrent high-grade NMIBC.Trial registrationClinicalTrials.gov, NCT03933826. Registered on May 1, 2019.

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.

Effect of neoadjuvant chemotherapy on survival in patients with T1 high-grade non-muscle-invasive bladder cancer who underwent radical cystectomy.

Patients with non-muscle-invasive bladder cancer (NMIBC) who are at high and very high risk of disease progression are recommended for radical cystectomy (RC). However, the impact of neoadjuvant chemotherapy (NAC) on survival outcomes in NMIBC patients undergoing RC remains unclear. Patients diagnosed with T1 high-grade NMIBC who underwent RC were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) was assessed using the Kaplan-Meier technique, and multivariable Cox regression analysis was conducted to determine the independent factors of OS. A total of 1268 T1 high-grade NMIBC patients who underwent RC between 2004 and 2015 were included in the study. NAC was administered to 76 (6.0%) patients. At a median follow-up of 75 months, there was no significant difference in the OS between the NAC and non-NAC groups (HR = 0.89, 95% CI 0.61-1.30, P = .539). However, in the multivariate Cox regression model, NAC demonstrated a more pronounced improvement in OS approaching statistical significance (HR = 0.7, 95% CI 0.47-1.05, P = .088). Subgroup analysis revealed a survival benefit of NAC in patients with lymph node metastasis. In summary, the results of this study suggest that NAC has the potential to confer a survival advantage in patients diagnosed with T1 high-grade NMIBC who undergo RC, but additional studies are needed. Nonetheless, the survival benefits of NAC in patients with lymph node involvement are apparent.

Clinical and pathological predictors of persistent T1 HG at second resection.

T1 high-grade (HG) non-muscle invasive bladder cancer (NMIBC) has a significant risk of recurrence and progression, and the European Association of Urology recommends a second transurethral resection of the bladder (ReTUR). Stage at ReTUR has been shown to be a reliable predictor of survival, therefore, we sought to assess clinical and pathological predictors associated with the persistence of T1 at ReTUR in our retrospective multicentric cohort. This is a retrospective multicentric study of T1 HG patients at transurethral resection of the bladder (TURB) who underwent subsequent ReTUR. All histological samples were sub-classified according to Rete Oncologica Lombarda (ROL) T1 sub-staging system. One hundred and sixty-six patients were enrolled. Forty-four (26.5%) had T1 HG tumor at ReTUR while 93 (56%) had residual tumor of any stage. Lesion size was significantly greater in T1 HG patients at ReTUR, as well as the prevalence of multifocality. The multivariable logistic regression model showed lesion dimension and multifocality as predictors of T1 HG at ReTUR, after adjusting for significant covariables (CIS and detrusor muscle presence). ROL sub-staging system was not a significant predictor, but ROL2 prevalence was higher in the T1 HG at ReTUR group. Lesion size and multifocality were independent predictors of T1 HG persistence at ReTUR, and patients at risk should be promptly identified and treated accordingly. Our results could help physicians make patient-tailored decisions by identifying those most likely to benefit from a second resection.

Implications of the COVID19 pandemic on the need and timing of second transurethral bladder tumour resection in high-grade non-muscle invasive bladder cancer.

Due to the COVID19 pandemic, the EAU has recommended to, if needed, postpone second transurethral resection of bladder tumour (TURBT) after BCG induction in selected patients. We aimed to evaluate the oncological outcomes of postponed TURBT and the potential to replace second TURBT by routine cystoscopy and cytology. A single-center, retrospective analysis of patients with TaG3/high grade (HG) or T1HG urothelial bladder cancer was performed. All patients underwent a complete TURBT between 2000 and 2013 with presence of detrusor muscle, full BCG induction and routine cystoscopy and cytology, followed by a second TURBT. Results of the cystoscopy, cytology and pathology reports of the TURBT were analyzed by descriptive characteristics, sensitivity, specificity, negative and positive predictive values, as well as survival analyses. 112 patients were included. Residual tumour was present at second TURBT in 21.4%. Upstaging rate from pTaHG to pT1HG and pT1HG to pT2 was 0% and 2.7%, respectively. pT0 was confirmed in 79% of patients, but in 98% of patients with combined negative cytology and cystoscopy after BCG. With a median follow-up of 109months, the 3-year OS was 85%, RFS 74% and PFS 89%. Sensitivity, specificity, negative predictive value and positive predictive value of cystoscopy and urinary cytology for the presence of residual tumour were 92%, 97%, 98% and 85%, respectively. This study underpins the recommendation of the EAU NMIBC guideline panel that, if needed and in selected patients, second TURBT may be postponed until after BCG induction treatment in pT1HG disease. Also, routine second TURBT can be omitted in pTaHG disease. Data on replacing second TURBT after BCG treatment by routine cystoscopy and cytology appear promising but require further confirmation in prospective studies.

Underutilization of intravesical chemotherapy and immunotherapy for high grade non-muscle invasive bladder cancer in California between 2006–2018: Effect of race, age and socioeconomic status on treatment disparities

ObjectiveAmong patients diagnosed with non-muscle invasive bladder cancer (NMIBC), those with high risk disease have the greatest risk of recurrence and disease progression. The underutilization of intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) has been a longstanding concern in clinical practice. This study aimed to determine the disparities present in receipt of adjuvant intravesical chemotherapy and immunotherapy in treatment of patients with high grade NMIBC following initial transurethral resection of a bladder tumor (TURBT). MethodsThe California Cancer Registry data was used to identify 19,237 patients diagnosed with high grade NMIBC who underwent TURBT. Treatment variables include re-TURBT, re-TURBT and intravesical chemotherapy (IVC) and/or BCG. Independent variables include age, sex, race/ethnicity, neighborhood socioeconomic status (nSES), primary insurance payer and marital status at diagnosis. Multiple logistic regression and multinomial regression models were used to examine variation in the treatments received following TURBT. ResultsThe proportion of patients receiving TURBT followed by BCG was similar across all racial and ethnic groups (28%–32%). BCG therapy was higher in patients belonging to the highest nSES quintile (37% for highest vs. 23%–26% for the 2 lowest quintiles). In multiple variable analyses, receipt of any intravesical therapy (IVT) was influenced by nSES, age, marital status, race/ethnicity, and insurance type. Patients in the lowest nSES quintile had a 45% less likelihood of receiving IVT compared to the highest nSES group (OR [95%CI]: 0.55[0.49, 0.61]). Race/ethnicity differences in receipt of any adjuvant therapy were noted in the middle to lowest nSES quintile for Hispanic and Asian/Pacific Islander patients when compared to non-Hispanic White patients. When comparing variation in treatment by insurance type at diagnosis, those with Medicare or other insurance were 24% and 30% less likely to receive BCG after TURBT compared to those with private insurance, (OR [95%CI]: 0.76 [0.70, 0.82] and 0.70[0.62, 0.79]) respectively. ConclusionIn patients with a diagnosis of high risk NMIBC, disparities in utilization of BCG are seen based on SES, age, and insurance type.

Phase 1b/2 dose expansion, open-label study to evaluate safety and anti-tumor activity of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer.

TPS4618 Background: Bladder cancer is the most common malignancy involving the urinary system, with over 700,000 individuals living with bladder cancer in the US in 2019. In the US, approximately 80,000 new cases and 18,000 deaths occur each year due to bladder cancer. Approximately 70% of new urothelial bladder cancer cases are classified as non-muscle invasive bladder cancer (NMIBC). With the current Bacillus Calmette-Guerin (BCG) shortage and limited effective alternate therapies, there continues to be a significant unmet need for treatment options for patients with NMIBC. TARA-002 is being developed for intravesical instillation for the treatment of high-grade (HG) NMIBC. TARA-002 is a lyophilized biological preparation for instillation containing cells of Streptococcus pyogenes (Group A, type 3) Su strain treated with benzylpenicillin. The chemical characteristics of TARA-002 are intended to be comparable to OK-432. Therefore, nonclinical and clinical evidence with OK-432 and TARA-002 support the ADVANCED-1 study (dose escalation Phase 1a [NCT05085977] and dose expansion Phase 1b/2 [NCT05085990]). The dose for the planned Phase 1b/2 study (ADVANCED-1-Ph1b/2) will be based on the recommended Phase 2 dose (RP2D) established in the Phase 1a study. Methods: ADVANCED-1-Ph1b/2 is a Phase 1b/2, dose expansion, open-label study of intravesical instillation of TARA-002 in adults with HG carcinoma in situ (CIS) NMIBC. The purpose of this study is to evaluate the safety and anti-tumor activity of TARA-002 administered intravesically for the treatment of subjects with CIS NMIBC (± Ta/T1) with active disease. The study includes approximately 102 eligible male and female subjects ≥ 18 years of age enrolled in 2 cohorts based on their prior BCG experience. Cohort A includes subjects unable to obtain BCG or subjects who have not received BCG in the last 24 months prior to CIS diagnosis, and Cohort B includes subjects with CIS who are BCG unresponsive after completion of adequate BCG therapy (at least 5 of 6 doses of an initial induction course plus either at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course). Those with current or a history of penicillin allergy or current evidence of any condition, therapy, or laboratory abnormality that might confound the results are excluded. The overall study duration is 6 months/24 weeks per subject for Ph1b/2-Cohort A (includes induction, reinduction [if applicable]), and 24 months/96 weeks per subject for Ph1b/2-Cohort B (includes induction, reinduction [if applicable], maintenance until 18 months). The ADVANCED-1 study started in March 2022. Phase 1a is open for enrollment. Phase 1b/2 is expected to begin enrollment in May 2023. Clinical trial information: NCT05085977 ; NCT05085990 .

Clinical performance of Bladder EpiCheck methylation test for active surveillance of non-muscle invasive bladder cancer: Systematic review and meta-analysis.

e16597 Background: Non-muscle invasive bladder cancer (NMIBC) has a favorable 5-year survival, but up to 60% of patients experience cancer recurrence within the first year of diagnosis. The current gold standard for active surveillance is periodic cystoscopy, but this is expensive and invasive. An alternative non-invasive method involves urine cytology, but it has poor sensitivity. Recently developed urine-based molecular diagnostics such as the EpiCheck (Nucleix, Rehovot, Israel) test offers non-invasive and quick testing for active surveillance. In this systematic review and meta-analysis, we aimed to evaluate the diagnostic value of Bladder EpiCheck in active surveillance of NMIBC. Methods: We searched PubMed, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials for relevant studies published between 1 January 2010 and 31 December 2022. The primary outcome was the sensitivity / negative predictive value (NPV) and specificity (PPV) of Bladder EpiCheck in active surveillance of NMIBC. We also performed a subgroup analysis to evaluate the performance of EpiCheck in detecting the recurrence of high-grade and low-grade NMIBC. Results: Our systematic search identified 110 articles, from which 6 studies were included in the final analysis. Compared with urine cytology, EpiCheck had a higher pooled sensitivity (73% [95% CI: 59-83] vs. 51% [95% CI: 30-72]) and NPV (90% [95% CI: 79.5-95.2] vs. 84% [95 % CI: 69-92]. However, EpiCheck had a lower pooled specificity (63% [95% CI: 48-76] vs. 97% [95% CI: 89-99]) and PPV (63% [95% CI: 48-76] vs. 85% [95 % CI: 69-94] than urine cytology. Similarly in subgroup analysis, EpiCheck had a higher pooled sensitivity than urine cytology in detecting both high-grade (86% [95% CI: 78-91] vs. 63% [95% CI: 43-80]) and low-grade (44% [95% CI: 34-55] vs. 13% [95% CI: 7-23]) NMIBC. Conclusions: The Bladder EpiCheck test has a better sensitivity than urine cytology and may be utilized as a part of the active surveillance strategy for NIMBC recurrence.

Gemcitabine as first-line therapy for high-grade non-muscle invasive bladder cancer: results from a tertiary center in the contemporary BCG-shortage era.

To evaluate the safety profile and efficacy of intravesical gemcitabine as first-line adjuvant therapy for non-muscle invasive bladder cancer (NMIBC) in the setting of ongoing Bacillus Calmette-Guérin (BCG) shortage. We performed an institutional, retrospective review of patients treated with intravesical gemcitabine induction and maintenance therapy from March 2019 to October 2021. Patients with intermediate or high-risk NMIBC who were BCG-naïve or experienced a high-grade (HG) recurrence after 12 months since the last dose of BCG were included in the analysis. The primary endpoint was complete response (CR) rate at the 3-month visit. Secondary endpoints were recurrence-free survival (RFS) and assessment of adverse events. A total of 33 patients were included. All had HG disease and 28 (84.8%) were BCG-naive. The median follow-up was 21.4 months (range, 4.1-39.4). Tumor stages were cTa in 39.4%, cT1 in 54.5%, and cTis in 6.1% of patients. Most patients (90.9%) were in the AUA high-risk category. The 3-month CR was 84.8%. Among patients who achieved CR with adequate follow-up, 86.9% (20/23) remained disease-free at 6 months. The 6-month and 12-month RFS were 87.2% and 76.5%, respectively. The estimated median RFS was not reached. Approximately 78.8% of patients were able to complete full induction. Common adverse events (incidence ≥10%) included dysuria and fatigue/myalgia. Intravesical gemcitabine for intermediate and high-risk NMIBC in areas where BCG supply is limited was safe and feasible at short-term follow-up. Larger prospective studies are needed to better ascertain the oncologic efficacy of gemcitabine.

A Restaging Transurethral Resection of Bladder Tumor Is Always Necessary For High-grade T1 Non–muscle-invasive Bladder Cancer

Patients with high-grade T1 non-muscle-invasive bladder cancer (NMIBC) have a high risk of recurrence and upstaging. Restaging transurethral resection of bladder tumor allows better staging so that patients can proceed to the appropriate treatment in a timely manner. This should be done in all patients with high-grade T1 NMIBC.