Treatment Of Non-muscle Invasive Bladder Cancer Research Articles

Clinical Efficacy of Neoadjuvant Intravesical Mitomycin-C Therapy Immediately Before Transurethral Resection of Bladder Tumor in Patients With Nonmuscle-invasive Bladder Cancer: Preliminary Results of a Prospective, Randomized Phase II Study. Letter.

You have accessJournal of UrologyLetters to the Editor1 Apr 2023Clinical Efficacy of Neoadjuvant Intravesical Mitomycin-C Therapy Immediately Before Transurethral Resection of Bladder Tumor in Patients With Nonmuscle-invasive Bladder Cancer: Preliminary Results of a Prospective, Randomized Phase II Study. Letter. Ashish Ranjan, Ankit Misra, Sanjoy Kumar Sureka, and Uday Pratap Singh Ashish RanjanAshish Ranjan Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India More articles by this author , Ankit MisraAnkit Misra * E-mail Address: [email protected] Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India More articles by this author , Sanjoy Kumar SurekaSanjoy Kumar Sureka Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India More articles by this author , and Uday Pratap SinghUday Pratap Singh Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003363AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail J Urol. 2023;209(1):131-139. To the Editor: We read with great interest the study investigating the novel role of intravesical mitomycin-C (MMC) in nonmuscle-invasive bladder cancer (NMIBC) in a neoadjuvant setting.1 Single, immediate, post-transurethral resection of bladder tumor (TURBT) instillation of MMC is the standard protocol in NMIBC.2 It primarily reduces the recurrence risk by eliminating viable residual tumors and preventing reseeding of the free-floating cancer cells.3 However, fear of extravasation and its associated serious complications has led to its low practical compliance worldwide.4 This study has demonstrated the use of neoadjuvant intravesical MMC for NMIBC with promising therapeutic efficacy, better tolerability, and low significant adverse effects. Although the dose and schedule of neoadjuvant MCC followed in the study were convenient for the patient, we would like to know the scientific basis for using 2 doses at a specific interval. The writers mention a preliminary study for deciding on 2 doses of neoadjuvant MMC, but no reference has been given. Do the authors feel that the control group should have received a single immediate post-TURBT MMC per the standard? Were any morphological or radiological criteria considered before administering the neoadjuvant therapy? The rationale of giving MMC post-TURBT is only to give it to patients with superficial disease on resection. Would it not be an overtreatment and waste of resources on those that eventually come out as muscle invasive? MMC concentration in tumor and normal tissue was measured to know about uptake, but is there any standard concentration in the postoperative instillation setting to which it was matched? Moreover, it would be interesting to know the method used to detect the concentration of MMC in the tissue. Would continuous saline irrigation used during the TURBT have diluted the effect of MMC on the tissue? Multifocal tumors were more in the control arm (24, 63%) than in the intervention arm (15, 46%). Was this difference statistically significant? This could have a bearing on better recurrence-free survival in the intervention arm and more progression in control. Lastly, we appreciate the authors' focus on an important area in NMIBC treatment. REFERENCES 1. . Clinical efficacy of neoadjuvant intravesical mitomycin-C therapy immediately before transurethral resection of bladder tumor in patients with nonmuscle-invasive bladder cancer: preliminary results of a prospective, randomized phase II study. J Urol. 2023; 209(1):131-139. Link, Google Scholar 2. . Trial-based cost-effectiveness analysis of an immediate postoperative mitomycin C instillation in patients with non–muscle-invasive bladder cancer. Eur Urol Open Sci. 2022; 37:7-13. Crossref, Medline, Google Scholar 3. . Continuous saline bladder irrigation in reducing recurrence and progression when compared to immediate mitomycin-C instillation post-resection of bladder tumor: a short communication. Asian Pac J Cancer Prev. 2022; 23(1):171-175. Crossref, Medline, Google Scholar 4. . Systematic review and individual patient data meta-analysis of randomized trials comparing a single immediate instillation of chemotherapy after transurethral resection with transurethral resection alone in patients with stage pTa-pT1 urothelial carcinoma of the bladder: which patients benefit from the instillation?Eur Urol. 2016; 69(2):231-244. Crossref, Medline, Google Scholar Submitted December 19, 2022; accepted February 2, 2023; published 000. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue 4April 2023Page: 677-678 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ashish Ranjan Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India More articles by this author Ankit Misra Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India * E-mail Address: [email protected] More articles by this author Sanjoy Kumar Sureka Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India More articles by this author Uday Pratap Singh Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India More articles by this author Expand All Submitted December 19, 2022; accepted February 2, 2023; published 000. 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MP63-13 TRIALS IN PROGRESS: A PHASE I/II TRIAL OF INTRAVESICAL CHEMOIMMUNOTHERAPY WITH GEMCITABINE AND BACILLUS CALMETTE-GUÉRIN (BCG) FOR PATIENTS WITH BCG-EXPOSED HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC)

You have accessJournal of UrologyCME1 Apr 2023MP63-13 TRIALS IN PROGRESS: A PHASE I/II TRIAL OF INTRAVESICAL CHEMOIMMUNOTHERAPY WITH GEMCITABINE AND BACILLUS CALMETTE-GUÉRIN (BCG) FOR PATIENTS WITH BCG-EXPOSED HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) Christopher Gaffney, NEETA D'Souza, Christian Hernandez, Melissa McCarter, Patricia Moran, Kristen Staci, Kara Worth, Guido Dalbagni, Timothy Donahue, Sherri Donat, Bernard Bochner, Judy Sarungbam, Dean Bajorin, Hikmat AL-Ahmadie, Daniel Sjoberg, Alvin Goh, and Eugene Pietzak Christopher GaffneyChristopher Gaffney More articles by this author , NEETA D'SouzaNEETA D'Souza More articles by this author , Christian HernandezChristian Hernandez More articles by this author , Melissa McCarterMelissa McCarter More articles by this author , Patricia MoranPatricia Moran More articles by this author , Kristen StaciKristen Staci More articles by this author , Kara WorthKara Worth More articles by this author , Guido DalbagniGuido Dalbagni More articles by this author , Timothy DonahueTimothy Donahue More articles by this author , Sherri DonatSherri Donat More articles by this author , Bernard BochnerBernard Bochner More articles by this author , Judy SarungbamJudy Sarungbam More articles by this author , Dean BajorinDean Bajorin More articles by this author , Hikmat AL-AhmadieHikmat AL-Ahmadie More articles by this author , Daniel SjobergDaniel Sjoberg More articles by this author , Alvin GohAlvin Goh More articles by this author , and Eugene PietzakEugene Pietzak More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003321.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The standard of care for high-risk NMIBC after exposure to induction only BCG or relapse >12 months after “adequate” BCG is retreatment with BCG. However, ∼50% will relapse within 6 months. Intravesical Gemcitabine (GEM) is a well-tolerated, common treatment for NMIBC with better efficacy after BCG than mitomycin C which may synergistically enhance the efficacy of BCG by augmenting the immune tumor microenvironment. We are evaluating gemcitabine and BCG (GemBCG) intravesical chemoimmunotherapy to address the need for more effective and less toxic bladder preserving treatments by enhancing BCG efficacy. METHODS: This is an investigator-initiated Phase I/II trial of GemBCG for BCG-exposed NMIBC enrolling patients with BCG-exposed carcinoma in-situ (CIS±Ta/T1) that recurred within 24 months of last BCG (BCG-exposed/BCG-relapsing NMIBC, Figure 1). Patients with BCG-unresponsive disease, contraindication to BCG, or prostatic/ureteral urothelial disease are excluded. The primary endpoint for Phase I was safety and dose tolerability. The primary endpoint for Phase II is clinical complete response (CR) at 6 months (absence of high-grade disease on cystoscopy/TURBT and negative cytology). Using a Simon’s optimal 2-stage design testing the null hypothesis of a true CR of 55% at 6 months (based on historical outcomes of BCG alone) we plan to enroll 19 and 24 patients in the first and second stage, respectively. Phase I patients treated at the maximum tolerated dose (MTD) are included in phase II. Secondary outcomes include recurrence progression, and cystectomy-free survival. Correlative studies explore immune and molecular predictors of response and resistance to chemoimmunotherapy in tumor tissue, urine, and blood. RESULTS: Of the 25 patients who completed Phase I, 14/25 were treated at the MTD and processed to Phase II. Treatment was well-tolerated (no treatment related grade ≥3 adverse events) and demonstrated promising early efficacy (95% [19/20] CR at 6-months). CONCLUSIONS: A combination of intravesical GEM and BCG appears safe and well tolerated in patients with BCG-relapsed/BCG-exposed NMIBC. Promising early efficacy data requires completion of Phase II for confirmation (NCT04179162). Source of Funding: N/A © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e876 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher Gaffney More articles by this author NEETA D'Souza More articles by this author Christian Hernandez More articles by this author Melissa McCarter More articles by this author Patricia Moran More articles by this author Kristen Staci More articles by this author Kara Worth More articles by this author Guido Dalbagni More articles by this author Timothy Donahue More articles by this author Sherri Donat More articles by this author Bernard Bochner More articles by this author Judy Sarungbam More articles by this author Dean Bajorin More articles by this author Hikmat AL-Ahmadie More articles by this author Daniel Sjoberg More articles by this author Alvin Goh More articles by this author Eugene Pietzak More articles by this author Expand All Advertisement PDF downloadLoading ...

Conservative treatment for high-risk NMIBC failing BCG treatment: who benefits from adding electromotive drug administration (EMDA) of mitomycin C (MMC) to a second BCG induction cycle?

PurposeRadical cystectomy (RC) is the standard treatment for high-risk non muscle-invasive bladder cancer (NMIBC) failing first BCG treatment. A second BCG course is an option for those patients who refuse RC or are not eligible for it, but its success rate is quite low. Aim of the present study was to determine whether the addition of intravesical electromotive drug administration of mytomicin-C (EMDA-MMC) improved the efficacy of second BCG course.MethodsPatients with high-risk NMIBC having failed first BCG treatment and having refused RC were offered a second BCG induction course either alone (group A) or combined with EMDA-MMC (group B). Recurrence-free survival (RFS), progression-free survival (PFS) and cancer-specific survival (CSS) were tested.ResultsOf the 80 evaluable patients, 44 were in group A and 36 in group B; median follow-up was 38 months. RFS was significantly worse in group A whereas there was no difference in PFS and CSS between the two groups. Stratifying by disease stage, Ta patients receiving combined treatment had statistically better RFS and PFS survival than those receiving BCG only; this difference did not apply to T1 patients. Multivariable analysis confirmed that combined treatment was a significant predictor of recurrence and was close to predict progression. No tested variable was predictive of recurrence or progression in T1 tumours. Among those who underwent RC, CSS was 61.5% in those who had progression and 100% in those who remained with NMIBC.ConclusionCombined treatment improved RFS and PFS only in patients with Ta disease.

A phase II trial of intravesical chemoimmunotherapy with gemcitabine and bacillus Calmette-Guérin (BCG) for patients with BCG-exposed, high-grade, non-muscle–invasive bladder cancer.

TPS579 Background: The standard of care for high-risk non-muscle invasive bladder cancer (NMIBC) after exposure to induction only BCG or relapse >12 months after “adequate” BCG is retreatment with BCG. However, ~50% of patients will relapse within 6 months. Thus, there is a critical need to develop novel combination therapies to improve BCG immunotherapy efficacy. Combination BCG with immune checkpoint inhibition is associated with a ~12-18% risk of serious treatment-related adverse events and BCG combined with Mitomycin C (MMC) has unacceptable urinary toxicity. Intravesical Gemcitabine (GEM) is a common treatment for NMIBC, is well tolerated, has better efficacy after BCG than MMC, and, based on preclinical data, may synergistically enhance the efficacy of BCG by augmenting the immune tumor microenvironment. We completed a prospective Phase I trial of chemoimmunotherapy with gemcitabine and BCG in BCG-relapsed/BCG-exposed NMIBC that was well-tolerated (no treatment related grade ≥3 adverse events) with promising early efficacy (95% [19/20] 6-month complete response rate). No dose limiting toxicities were seen. The maximum tolerated dose (MTD) was 2000 mg gemcitabine and 50 mg TICE BCG. Methods: To address the need for more effective and less toxic bladder preserving treatment options by enhancing the effectiveness of BCG, we launched an investigator-initiated phase I/II trial of combination intravesical gemcitabine with BCG in patients with BCG-exposed NMIBC (NCT04179162). The Phase II portion is currently enrolling patients with BCG-exposed carcinoma in-situ (CIS ±Ta/T1) that recurred within 24 months of last BCG (BCG-exposed/BCG-relapsing NMIBC). Patients with BCG-unresponsive disease, contraindication to BCG, or prostatic/ureteral urothelial disease are excluded. Induction intravesical GEM (2000mg, twice weekly) is given weeks 1, 4, 7, and 10 and intravesical BCG (40mg, Tice strain, weekly) is given weeks 2, 3, 5, 6, 8, and 9. Responders receive SWOG maintenance BCG. The primary endpoint is clinical complete response (CR) at 6 months (absence of high-grade disease on cystoscopy/TURBT and negative cytology) using a Simon’s optimal 2-stage design testing the null hypothesis of a true CR of 55% at 6 months (based on historical outcomes of BCG alone) against a 1-sided alternative. In the first stage, the study would stop if ≤ 9/15 patients had a CR. In the second stage, the null hypothesis will be rejected if ≥ 29 CRs are observed in 43 total patients (type I error rate 5% and power of 80% if the true CR rate is 75%). Phase I patients treated at the MTD (14/25) are included in Phase II. Secondary outcomes include recurrence-free, progression-free, and cystectomy-free survival. Correlative studies explore immune and molecular predictors of response and resistance to chemoimmunotherapy in tumor tissue, urine, and blood. Clinical trial information: NCT04179162 .

A phase 1, open-label trial to evaluate feasibility and safety of intramural injection of belzupacap sarotalocan (AU-011) in non-muscle–invasive bladder cancer (NMIBC).

TPS596 Background: A high unmet medical need exists for new therapies in NMIBC to reduce common risks of recurrence, progression and, ultimately, cystectomy. Belzupacap sarotalocan, a novel investigational virus-like drug conjugate (VDC), has a dual mechanism of action designed to provide 1) selective binding to malignant cells, causing acute necrosis upon light activation, and 2) long-term anti-tumor immunity as demonstrated in pre-clinical models. This Phase 1 trial is designed to evaluate the feasibility and safety of intramural injection with or without intratumoral injection of belzupacap sarotalocan for treatment of NMIBC. The hypothesis is that after near infrared light activation, targeted distribution of belzupacap sarotalocan at high concentrations at the tumor base could necrose the tumor where it is most likely to be invasive. In turn, the tumor targeted pro-immunogenic cell death could potentially lead to an anti-tumor immune response preventing the risk for recurrence, progression and metastasis. Methods: This is an actively enrolling “window of opportunity” trial (NCT05483868) in low, medium or high risk NMIBC subjects scheduled to undergo TURBT or cystectomy per standard of care. A pre-treatment biopsy will be performed in up to 23 adult subjects enrolled in 4 cohorts, who will be given belzupacap sarotalocan +/- laser as shown in the table. The primary endpoint is incidence and severity of treatment-related adverse events, serious adverse events regardless of attribution, and incidence of dose-limiting toxicities. Each cohort will have a safety review for the injection procedure and laser (as needed), after 3 subjects have been treated and followed for 28 days. Secondary endpoints are based on histopathology and include assessment of local biodistribution of belzupacap sarotalocan measured via immunohistochemical staining, tumor necrosis, and evidence of an immune response via comparison of pre-treatment biopsy to TURBT/cystectomy samples after treatment. Statistical analysis plan includes descriptive statistics for the above endpoints. Clinical trial information: NCT05483868 . [Table: see text]

Elicitation of Health State Utilities Associated with Progression from Bacillus Calmette-Guerin (BCG) Unresponsive Non-muscle Invasive Bladder Cancer (NMIBC).

The treatments for high-grade non-muscle invasive bladder cancer (NMIBC) vary between bladder preserving intravesical approaches and radical cystectomy. The impact of these treatments on health-related quality of life may vary widely. The purpose of this study was to elicit the general public's perspective on quality of life, measured as utility scores associated with treatment for Bacillus Calmette-Guerin (BCG)-unresponsive NMIBC and disease progression, for supporting economic evaluation of newly developed treatments for NMIBC. Part I involved the development and testing of health states describing NMIBC, which was informed by a rapid review, expert input and a patient advisor. Part II involved elicitation of societal utility values for the different health states. Time trade-off (TTO) interviews were conducted with members of the UK general public. Five health states described different NMIBC scenarios including disease recurrence and progression. Participants ranked each health state, followed by the TTO valuation exercise. Descriptors included NMIBC symptom severity, impact and treatment characteristics. In total, 202 members of the general public participated. The mean age was 46 (standard deviation [SD] 14.6) years. Sample mean (SD) EQ-5D-5L visual analogue scale (VAS) and index scores were 83.2 (12.3) and 0.89 (0.18), respectively. Mean utilities were 0.781 for No High-Grade Recurrence, 0.586 for High-Grade Recurrence, 0.572 for >1-Year Post-cystectomy and 0.283 for metastatic disease. The First Year Post-cystectomy path health state had a mean utility of 0.288. Pairwise comparisons found statistically significant differences between utilities (p < 0.001), except between High-Grade Recurrence and > 1-Year Post-cystectomy (p = 0.524). There were significant differences in utility scores by age and employment status. This study provides utility scores for health states describing living with NMIBC, which is associated with a significant health-related quality-of-life burden. These values address an existing gap in available data and have the potential to be used in models evaluating the cost-effectiveness of both current and newly developed treatments for bladder cancer.

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

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

The Progress of Chitosan-Based Nanoparticles for Intravesical Bladder Cancer Treatment

Bladder cancer (BC) is the most frequently occurring cancer of the urinary system, with non-muscle-invasive bladder cancer (NMIBC) accounting for 75-85% of all the bladder cancers. Patients with NMIBC have a good survival rate but are at high risk for tumor recurrence and disease progression. Intravesical instillation of antitumor agents is the standard treatment for NMIBC following transurethral resection of bladder tumors. Chemotherapeutic drugs are broadly employed for bladder cancer treatment, but have limited efficacy due to chemo-resistance and systemic toxicity. Additionally, the periodic voiding of bladder and low permeability of the bladder urothelium impair the retention of drugs, resulting in a weak antitumoral response. Chitosan is a non-toxic and biocompatible polymer which enables better penetration of specific drugs to the deeper cell layers of the bladder as a consequence of temporarily abolishing the barrier function of urothelium, thus offering multifaceted biomedical applications in urinary bladder epithelial. Nowadays, the rapid development of nanoparticles significantly improves the tumor therapy with enhanced drug transport. This review presents an overview on the state of chitosan-based nanoparticles in the field of intravesical bladder cancer treatment.

Novel Therapies for High-Risk Non-Muscle Invasive Bladder Cancer.

The treatment options for high-risk non-muscle invasive bladder cancer (NMIBC), particularly following BCG, remain limited. We highlight recent, promising therapies for high-risk NMIBC. Several therapies utilizing different mechanisms of action have demonstrated favorable results in the BCG-naïve and BCG-unresponsive settings. These treatments include intravenous and intravesical immunotherapy, viral- and bacterial-based intravesical therapies, combination intravesical chemotherapy regimens, and novel intravesical chemotherapy administration. Overall, the efficacy and tolerability of emerging treatments for NMIBC appear promising and provide potential alternatives to radical cystectomy. As the landscape of managing BCG-unresponsive disease evolves, clinical trials will explore future options and determine effective alternatives.

Laboratory predictors to intravesical BCG therapy response in patients with non-muscle invasive bladder cancer

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

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

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

New synthetic nano-immunotherapy (OncoTherad®) for non-muscle invasive bladder cancer: Its synthesis, characterization and anticancer property

Bacillus Calmette-Guérin (BCG)-based intravesical immunotherapy has been applied as gold standard treatment for high-risk non-muscle invasive bladder cancer (NMIBC) for almost half a century. However, several patients with high-risk disease experience relapse, including those whose condition has worsened and who failed to respond to BCG. Non-significant therapeutic options have been developed for these at-risk patients, for many years. Immunotherapies have shown promising outcomes for bladder cancer treatment. Accordingly, our research group developed the OncoTherad® (MRB-CFI-1) immunotherapy, which has shown positive outcomes in NMIBC treatment. The aim of the current study is to describe, in details, the physicochemical features and potential action mechanisms of OncoTherad® nano-immunotherapy, based on toll-like receptor 4 (TLR4)-mediated interferon and on RANK/RANKL signaling pathways, in animal model with NMIBC. Based on the current findings, OncoTherad® nano-immunotherapy did not have genotoxic effect on the investigated model and did not show signs of limiting local and/or systemic toxicity at therapeutic doses. OncoTherad® nano-immunotherapy was more effective than the BCG treatment, since it reduced by 70% the malignancy rate. Furthermore, it was possible identifying an important action mechanism of OncoTherad®, which was based on the modulation of TLR4-mediated interferon and RANK/RANKL signaling pathways that, altogether, were essential to reduce malignancy rate. OncoTherad® mechanisms in these pathways helped preventing tumor recurrence.

BCG Administration after Prior Radiation Treatment for Prostate Cancer.

Prostate radiotherapy is associated with worse oncologic outcomes in patients with bladder cancer. The underlying mechanism is incompletely understood but is thought to be related to an altered microenvironment promoting tumorigenesis. However, there is a gap in the literature regarding how the effect of BCG varies according to prior radiotherapy in patients with non-muscle invasive bladder cancer (NMIBC). In this context, we sought to evaluate oncologic outcomes in NMIBC patients who have previously undergone prostate radiotherapy compared to patients with no prior history of pelvic radiotherapy. This is a retrospective cohort study that includes all patients who received intravesical for NMIBC at our institution from 2001 to 2019. Patients were stratified into 3 cohorts: prior radiotherapy (RT), radical prostatectomy (RP), and no prostate cancer (No PCa). The outcomes of interest were recurrence at 1-year, progression to muscle-invasive bladder cancer (MIBC), and progression to metastatic disease. Comparisons were also made between cohorts with respect to elapsed time from radiation therapy. Wilcoxon rank-sum test was used for comparing continuous variables, while χ2 and Fischer's exact tests were used to examine categorical variables. In 199 total patients who underwent BCG for NMIBC, 23 had a prior history of prostate radiotherapy treatment, while 17 underwent prior radical prostatectomy. Overall, 41.2% of patients had recurrence at 1 year. There was no difference in the number of induction or maintenance BCG administrations received between the cohorts within the first year. There was no significant difference in recurrence at 1 year between the 3 cohorts (P=.56). There was also no difference in progression to MIBC or progression to metastatic disease with P=.50 and 0.89, respectively. The risk of recurrence after induction BCG treatment for high-grade NMIBC does not vary according to prior radiation treatment for prostate cancer.

ALT-803 in the treatment of non-muscle-invasive bladder cancer: Preclinical and clinical evidence and translational potential.

Bladder cancer (BCa) is one of the most common malignant tumors that cause death. Approximately 75%-85% of BCa develop into non-muscle-invasive bladder cancer (NMIBC). Bacillus Calmette-Guérin (BCG) is the gold standard for avoiding cystectomy in the treatment of NMIBC. Unfortunately, up to 30% of patients do not respond to BCG treatment, and up to 70% of BCG responders relapse. The United States Food and Drug Administration (FDA) approved valrubicin (1998) and pembrolizumab (2020) for the treatment of BCG-unresponsive (BCGu) NMBIC. However, the complete remission rate for valrubicin and pembrolizumab was only 16% and 40.6%, respectively. ALT-803 (N-803) is an IL-15 superagonist and reduces tumor burden by promoting the proliferation and activation of NK cells and CD8+ T cells. The FDA received (23 May 2022) and accepted to review (28 July 2022) the marketing submission of ALT-803 plus BCG for the treatment of BCGu NMIBC. However, the FDA previously rejected the application for oportuzumab monatox (OM) due to a lack of data comparing it with pembrolizumab on August 20, 2021. Interestingly, the clinical efficacy and safety of ALT-803 were higher than that of pembrolizumab and OM, suggesting that ALT-803 may be approved by FDA. This review aims to further knowledge of the preclinical and clinical evidence of ALT-803 in the treatment of NMIBC and discuss its translational potential.

Positive Predictive Values of Procedure Codes on the Treatment of Non-Muscle Invasive Bladder Cancer in the Danish National Patient Registry.

Globally non-muscle invasive bladder cancer (NMIBC) is a high-incidence disease. There is a large heterogeneity within NMIBC regarding recurrence- and progression risks, and large-scale studies of treatment patterns and prognoses in an everyday setting could result in NMIBC-subgroup treatment optimization, benefiting both patients and the economy. The Danish national registries provide such an opportunity if the registered procedure codes are valid. Therefore, the aim of the study was to validate the International Classification of Diseases, 10th Edition (ICD-10) codes of NMIBC treatment used in the Danish National Patient Registry (DNPR). From the DNPR, we randomly selected 200 NMIBC treatment courses identified by the dates of the course and the codes of transurethral resection of the bladder ((TURB), n = 125), photodynamic diagnosis ((PDD), n = 25), bladder instillation with Bacillus Calmette vaccine ((BCG), n = 25), or bladder instillation with chemotherapy/Mitomycin C ((MMC), n = 25). We used medical record reviews as the reference standard and estimated positive predictive values (PPVs) of all procedure codes and negative predictive values (NPVs) of PDD- and the perioperative single-shot MMC codes. We identified the medical records in 150 (75%) of the 200 treatment courses (149 individual patients). The overall PPVs were TURB: 98.9% (95% confidence interval: 93.8; 100.0%), PDD: 95.8% (78.9; 99.9%), adjuvant BCG: 90.0% (68.3; 98.8%), perioperative single-shot MMC 1/5, and adjuvant MMC: 69.2% (38.6; 90.9%). The overall NPVs were PDD: 64.8% (54.4; 73.9%) and perioperative single-shot MMC: 97.7% (92.1; 99.4%). The ICD-10 NMIBC procedure codes recorded in the DNPR are generally valid with high PPVs. The NPV of the PPD code is acceptable. However, the code for perioperative single-shot MMC is uncertain with low PPV, but a high NPV.

Efficacy of compound aluminum sulfate injection as a monotherapeutic regimen in non-muscle invasive bladder cancer patients: a retrospective single-arm cohort study.

BackgroundCompound aluminum sulfate injection (CASI) originated from a Chinese traditional medicine, “Kuzhiye”, and has been used in treating non-muscle invasive bladder cancer (NMIBC). Previous studies suggested that CASI was a potential monotherapeutic drug for NMIBC. However, the efficacy and safety of CASI in the treatment of NMIBC, as well as the long-term recurrence after treatment, need to be further evaluated.MethodsA multicenter retrospective single-arm cohort study was conducted. From 2006 to 2009, 101 patients (74 men and 27 women, aged 58.9±11.9 years) with T1 or benign NMIBC were enrolled. Each patient was directly injected with CASI through catheter needle into the root of NMIBC. Vital signs, electrocardiography, blood count, blood biochemistry, and urine analysis were re-examined on day 2 and day 14 after CASI injection, together with a cystoscopic examination 4 weeks after CASI treatment was performed for all patients to assess the clinical activity and safety of CASI. To study long-term efficacy, patients in center 2 were followed up for recurrence with a median follow-up time of 13.8 years.ResultsFor the 101 patients enrolled in this study, demographic characteristics in the 3 centers showed no significant differences. After CASI, 2 patients showed administration site-dependent, but not dose-dependent, increase in their aluminum concentration in 24 hours without obvious abnormality in blood biochemistry. The overall effective rate was 97.03%, including complete tumor necrosis in 94 patients. Treatment-related adverse events occurred in 20 patients (19.80%), including 9 drug-related and 11 cystoscopy-related adverse events (AEs). All AEs were endurable and disappeared within 2 weeks without any treatment. The maximum tolerated single dose of CASI was 21 mL. Among the 43 patients at center 2, 3 patients were excluded because they changed to other treatment regimen. As of April 2022, of the 40 patients enrolled, 22 had no recurrence and 7 relapsed. The follow-up time was 2–16.2 years. The other 11 patients were lost to follow up.ConclusionsCASI may be an effective and safe option for the treatment of NMIBC and is expected to be a potential monotherapy regimen for NMIBC.

Treatment and surveillance for non-muscle-invasive bladder cancer: a clinical practice guideline (2021 edition)

Non-muscle invasive bladder cancer (NMIBC) is a major type of bladder cancer with a high incidence worldwide, resulting in a great disease burden. Treatment and surveillance are the most important part of NIMBC management. In 2018, we issued “Treatment and surveillance for non-muscle-invasive bladder cancer in China: an evidence-based clinical practice guideline”. Since then, various studies on the treatment and surveillance of NMIBC have been published. There is a need to incorporate these materials and also to take into account the relatively limited medical resources in primary medical institutions in China. Developing a version of guideline which takes these two issues into account to promote the management of NMIBC is therefore indicated. We formed a working group of clinical experts and methodologists. Through questionnaire investigation of clinicians including primary medical institutions, 24 clinically concerned issues, involving transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and intravesical immunotherapy of NMIBC, and follow-up and surveillance of the NMIBC patients, were determined for this guideline. Researches and recommendations on the management of NMIBC in databases, guideline development professional societies and monographs were referred to, and the European Association of Urology was used to assess the certainty of generated recommendations. Finally, we issued 29 statements, among which 22 were strong recommendations, and 7 were weak recommendations. These recommendations cover the topics of TURBT, postoperative chemotherapy after TURBT, Bacillus Calmette–Guérin (BCG) immunotherapy after TURBT, combination treatment of BCG and chemotherapy after TURBT, treatment of carcinoma in situ, radical cystectomy, treatment of NMIBC recurrence, and follow-up and surveillance. We hope these recommendations can help promote the treatment and surveillance of NMIBC in China, especially for the primary medical institutions.

Identification of Long Non-Coding RNA MIR4435-2HG as a Prognostic Biomarker in Bladder Cancer.

The abnormal expression of long non-coding RNAs(lncRNAs) is closely related to the prognosis of patients. This finding may indicate a new target for the treatment of malignant tumors. Non-muscle invasive bladder cancer (NMIBC) is the most common subtype of bladder cancer, and BCG intravesical therapy is the first-line treatment for NMIBC, but about half of NMIBC patients relapse within two years after BCG treatment. Therefore, it is necessary to screen out lncRNAs related to the prognosis and treatment of BGC-resistant patients. Here, we performed differential expression analysis of lncRNAs in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, and screened MIR4435-2HG as the only BCG-response-related lncRNA. Then, the prognosis value of MIR4435-2HG was validated in several publicly available cohorts, and confirmed its prognostic value in bladder cancer of different stages. In addition, we also analyzed its genetic alterations, clinical relevance, function enrichment, and association with other biomarkers. Further validation of the expression of MIR4435-2HG might be helpful to instruct NMIBC prognosis and treatment.

Mitomycin C allergy after passive and device-assisted hyperthermia for non-muscle invasive bladder cancer treatment: A retrospective cohort from a high-volume center.

Mitomycin C (MMC) is one of the most frequently utilized intravesical chemotherapy drugs for the management of non-muscle-invasive bladder cancer (NMIBC). Allergic reactions (Type 4 delayed hypersensitivity) are seldomly reported in the literature but not so infrequent in daily practice, its incidence has been increasing with the use of device-assisted hyperthermia. This study aims to identify the incidence, risk factors, and clinical characteristics of patients with allergic reactions to MMC. Single-center retrospective cohort from June 2014 to August 2018. Patients with intermediate or high-risk NMIBC were included. Patients received passive MMC (4 weekly and eleven monthly instillations of 40mg of MMC) or Chemohyperthermia (CHT) with MMC (6 weekly and 6-monthly instillations, heated at 43°C [+/- 0.5°C] using Combat BRS). We included 258 patients (MMC = 157, CHT = 101) and found 7 (4.4%) suspected and 4 confirmed (2.4%) allergies in the passive MMC group and 11 suspected (10.9%) and 7 confirmed (6.9%) in the CHT group. The mean number of instillations received before developing the allergy was 6 in the passive MMC and 5 in the CHT group. Seven out of 18 suspected allergy cases were pseudo-allergic reactions with negative allergy tests. Early postoperative MMC instillation was associated with an increased risk of allergy (OR 2.47 [CI 1.39-4.36], P = 0.001), while neither history of atopy nor history of other medications allergy was found to increase the risk. MMC allergy risk is increased with the use of device-assisted hyperthermia with an incidence of 2.4% for passive MMC and 6.9% for CHT. History of prior allergies does not seem to increase the risk of developing MMC allergy. In this series 38% of suspected cases were found to be pseudo-allergic reactions, highlighting the need to confirm the diagnosis before definitively stopping the treatment.

Abstract CT036: CORE1: Phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG)

Abstract Introduction: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. IV pembrolizumab, was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ~20%.This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. Methods:35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravescical CG0070 (1x1012 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Pts with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24 m. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence. The primary endpoint of the study is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety of the combination. Correlate assessments will include changes in the tumor immune microenvironment, systemic immune induction, viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-Ad5 Ab titer will be correlated with tumor response. Results: Thus far, 10 patients are evaluable at the 3 m timepoint for efficacy. Assessment of these 10 pts demonstrates 100% CR at 3 mos. Six of the 10 pts have also reached the 6 m hallmark in a CR as well as 2 at the 12 mos timepoint. Treatment related AE have been limited to transient grade 1-2 local-regional genitourinary adverse events with no grade 3 or 4 treatment related AE reported date. Conclusions: This initial data on the efficacy and safety of CG0070 plus pembrolizumab for the treatment of BCG unresponsive NMIBC is encouraging. An update on the study will be provided at the time of presentation. Citation Format: Roger Li, Gary Steinberg, Paras Shah, Ed Uchio, Donald Lamm, Trinity Bivalacqua, Vignesh Packiam, Ashish Kamat, Michael Chisamore, John McAdory, Paola Grandi, Jee-Hyun Kim, James Burke. CORE1: Phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT036.