Bladder-sparing Therapy Research Articles

Outcomes of Patients with Bacillus Calmette-Guérin (BCG)-Unresponsive Non-Muscle Invasive Bladder Cancer as Defined by the U.S. Food and Drug Administration.

Limited data are available on the outcomes of patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to intravesical bacillus Calmette-Guérin (BCG), as defined by the United States Food and Drug Administration. To define the outcomes of patients with BCG-unresponsive NMIBC. This was a retrospective, single-institution observational cohort study. Records of patients managed at our institution for BCG-unresponsive NMIBC between 2005 and 2020 were reviewed and clinical outcomes evaluated. The study included 149 patients. Management was with initial radical cystectomy in 60 patients (40%) and initial bladder-sparing therapy (BST) in 89 patients (60%). Overall survival was greater among patients undergoing RC than BST (HR 1.83, 95% CI 1.04-3.22, p = 0.036), potentially due to patient selection, as no significant difference was noted for metastasis-free or cancer-specific survival. Patients opting for initial BST had high rates of treatment failure, with estimated 5-year cystectomy-free survival of only 42%. Patients who received additional lines of BST after a subsequent failure were at increased risk of having ≥pT3 or pN+ disease at cystectomy (42% for ≥2 lines BST, versus 18% for 1 line BST and 15% for initial cystectomy, p = 0.038). Among patients who underwent initial BST for BCG-unresponsive NMIBC, rates of treatment failure were very high. Patients who underwent delayed cystectomy after ≥2 lines of BST had elevated rates of extravesical disease. Our observations emphasize the importance of recent and ongoing clinical trials in this clinical space.

Abstract 2060: Treatment combination strategies to improve radiation efficacy in immunologically cold tumors in vivo

Abstract Introduction: Radiation therapy (RT) is a promising bladder-sparing therapy in muscle-invasive bladder cancer (MIBC). However, 30% of patients exhibit radioresistant tumors requiring salvage surgery. Combining RT with immune checkpoint inhibitor was reported to have synergic effects on anti-tumor immunity. Yet, it is also met with treatment resistance. In addition, activation of the STING pathway was shown to induce cell death, cancer cell antigens release and presentation, and promote the priming, activation and trafficking of T cells into tumors. Previous in vivo results from our team using the MB49 murine bladder cancer cell line - and immunologically ‘hot’ tumor model - demonstrated significant improvement of survival and immune cell infiltration upon STING agonist treatment, when combined with RT and anti-PDL1 treatment. Oppositely, treating the ‘cold’ tumor model UPPL with a combination of RT and anti-PDL1 treatment did not improve survival compared to RT alone. Consistently, UPPL tumors present low T cell and high neutrophil infiltration in vivo. Thus, the main objective of the present study is to evaluate whether combining RT, anti-PDL-1 and STING agonist treatments can improve the immunogenicity of UPPL tumors. Methods: Seven-week-old male C57BL/6 mice were subcutaneously injected with 5.106 UPPL tumor cells. Once tumors reached 0.1-0.15 cm3, mice were randomized into the following treatment groups : 1) Untreated; 2) PDL-1; 3) STING; 4) PDL-1 + STING; 5) RT; 6) RT + PDL-1; 7) RT + STING; 8) RT + STING + PDL-1. Midpoint (~0.6-0.8 cm3, n=5) and endpoint (2 cm3, n=8) tumors, spleens and draining lymph nodes (dLN) were harvested and dissociated for flow cytometry analysis of TME composition and cytokine production. Results: We report that RT and RT-combined treatments delayed tumor growth and prolonged survival in vivo compared to untreated. Additionally, our combination approaches shifted immune infiltration : compared to untreated, each strategy changed myeloid and T cells infiltrating cells in tumors. Combination of RT with anti-PDL-1 and STING agonist favored macrophages infiltration as well as increased MHC-II expression in dendritic cells (DC). Furthermore, we observed increased infiltration of cytotoxic CD8+ T cells (Granzyme B+ and IFN-γ+ CD8+) in these groups. Conclusions: Our results suggest RT and RT combination treatments in cold tumor affect antigen presentation potency in DCs, fine-tune the functionality of infiltrating CD8+ T cells. This preliminary study shows immunologically cold tumors can be modulated through treatment combination, which has relevance in human treatment-resistant tumors. It adds to the very small body of literature taking a deep dive into the immune modulation of a conventionally used ‘cold’ tumor cell line. Citation Format: Eva Michaud, Gautier Marcq, Sabina Fehric, JiaMin Huang, Jose Joao Mansure, Ciriaco Piccirillo, Wassim Kassouf. Treatment combination strategies to improve radiation efficacy in immunologically cold tumors in vivo [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 2060.

Abstract 2524: Investigating the role of neutrophils in muscle-invasive bladder cancer and response to radiation therapy

Abstract Background: Radiation therapy (RT) is an increasingly used bladder-sparing therapy for patients with muscle-invasive bladder cancer (MIBC). However, 20-30% of patients do not respond to RT. Neutrophils have previously been linked to radioresistance, but the specific mechanism is still unknown. Previous work by our team has shown that neutrophil extracellular trap (NET) formation plays a role in RT resistance in an immunologically hot tumor, with high T cell infiltration, using the MB49 murine bladder cancer cell line, in a vivo model. In MIBC, a recently developed cell line can be used to study cold, luminal-like tumors. However, work on this cell line and its response to RT is still in its initial stages. Immune checkpoint inhibitors such as anti-PD-L1 have been tested by our team in these cold tumors of MIBC and have not shown to be effective in treating or radiosensitizing the tumor. Consequently, we aim to determine how neutrophil migration and neutrophil extracellular traps (NET) impact tumor growth in a cold, luminal-like tumor model. Furthermore, we aim to understand how neutrophil migration and NETs impact immunological changes in the tumor microenvironment (TME). Methods: To determine the response to RT in these cold tumors, mice were injected with 5M cells on the right flank of our luminal-like cancer model (UPPL cell line). Once tumors reached 0.1-0.15 cm3, mice were randomized into the different treatment groups: 1) Control; 2) RT; 3) Anti-PDL1 4) DNAse I; 5) RT + Anti-PDL1; 6) RT + DNAse I; 7) Anti-PDL1 + DNAse I; 8) RT + Anti-PDL1 + DNAse I. Size of the tumor was monitored. 8 mice tumors per group were collected at the primary endpoint set at 1.5 cm3 and 5 mice tumors per group were collected after 21 days (midpoint). Tumors were collected analyzed by flow cytometry and immunohistochemistry (IHC). Preliminary Results: Prolonged survival was observed in the mice treated with the triple combination when compared to the other groups. Tumor growth in this group also showed delay early on. So far, the frequency of pro-tumorigenic neutrophils infiltration in tumors seems to happen early on (midpoints) in mice treated with RT, whereas the infiltration happens later (endpoint) in the mice treated with the triple combination. Currently, we are also evaluating the NET production in these tumors through IHC. Conclusion: This ongoing experiment using RT on the UPPL cell line will allow us to understand what happens in patients who are resistant to RT. Understanding the role of neutrophils and NETs, along with the changes in the TME caused by the manipulation of these is key to understanding radiation resistance. This knowledge will bring us one step closer to developing new bladder-sparring treatments and improving patient care in the clinic. Citation Format: Sabina Fehric, Eva Michaud, Surashri Shinde-Jadhav, JiaMin Huang, Jose J. Mansure, Roni Rayes, Jonathan Spicer, Wassim Kassouf. Investigating the role of neutrophils in muscle-invasive bladder cancer and response to radiation therapy [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 2524.

Assessment of erectile and ejaculatory functions after bladder-sparing therapy against muscle-invasive bladder cancer

ABSTRACT Introduction Radical cystectomy (RC) is still gold standard for muscle invasive bladder cancer (MIBC). Whereas, bladder-sparing therapy with transurethral resection of bladder tumor (TUR) and chemoradiation therapy (CRT) has been recognized as an alternative treatment to RC for selected patients with MIBC. We have developed and implemented tetra-modality bladder-sparing therapy (TeMT) incorporating partial cystectomy (PC) in addition to maximal TUR and induction CRT to overcome local recurrence after bladder-sparing therapy (Kageyama et al. Am J Clin Oncol 2003, Koga et al. BJU Int 2012, Kijima et al. BJU Int 2019). There are few studies on erectile and ejaculatory functions after bladder-sparing therapy. Objective To cross-sectionally survey erectile and ejaculatory functions after TeMT in patients with MIBC. Methods Of the total 117 male patients with MIBC who completed TeMT between 2006 and 2019, 70 patients were set as the target to distribute the questionnaires after excluding patients lost to follow up as of February 2020, patients with local recurrence of MIBC or additional prostate cancer treatment. Erectile function was assessed using the International Index of Erectile Function short form (IIEF-5), and ejaculatory function using Male Sexual Health Questionnaire Ejaculatory Dysfunction short form (MSHQ-EjD-SF). Attending physicians handed the questionnaires to the patients at the first regular outpatient visit after February 2020 and had the patients complete them outside the office. Results Of 44 patients received the questionnaires between February and August 2020, 35 completed the questionnaires. The median age (range) of the eligible patients was 70 (50-87) years old, and the median time from the date of PC to the date of response was 5.2 (0.35-14) years. The results of IIEF-5 showed that 3 (9%) had no erectile dysfunction (ED) (22-25 points), 9 (26%) had mild ED (17-21 points), 4 (11%) had mild to moderate ED (12-16 points), 4 (11%) had moderate ED (8-11 points), and 15 (43%) had severe ED (5-7 points). Based on the results of MSHQ-EjD-SF, 23 patients (66%) responded that they could ejaculate. Of those, 5 patients (14%) scored 4 or higher on all questions 1-3 of MSHQ-EjD-SF, suggesting that they did not have ejaculatory dysfunction. Conclusions Preservation of erectile and ejaculatory functions was observed in MIBC patients treated with bladder-sparing therapy. Along with that of lower urinary tract function, preservation of male sexual function in bladder-sparing therapy, especially ejaculatory function which is inevitably lost by RC, is considered to be an advantage over RC. Disclosure Work supported by industry: no.

PD12-01 BLADDER TUMOR MICROBIOME MAY AUGMENT RESPONSE TO BCG IN NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 May 2022PD12-01 BLADDER TUMOR MICROBIOME MAY AUGMENT RESPONSE TO BCG IN NON-MUSCLE INVASIVE BLADDER CANCER Jacob Knorr, Glenn Werneburg, Ava Adler, Jose Agudelo, Prithvi Murthy, Rebecca Campbell, Petar Bajic, Nima Almassi, Christopher Weight, Georges-Pascal Haber, Aaron Miller, and Byron Lee Jacob KnorrJacob Knorr More articles by this author , Glenn WerneburgGlenn Werneburg More articles by this author , Ava AdlerAva Adler More articles by this author , Jose AgudeloJose Agudelo More articles by this author , Prithvi MurthyPrithvi Murthy More articles by this author , Rebecca CampbellRebecca Campbell More articles by this author , Petar BajicPetar Bajic More articles by this author , Nima AlmassiNima Almassi More articles by this author , Christopher WeightChristopher Weight More articles by this author , Georges-Pascal HaberGeorges-Pascal Haber More articles by this author , Aaron MillerAaron Miller More articles by this author , and Byron LeeByron Lee More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002538.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Despite proven efficacy and longstanding use of Mycobacterium bovis Bacillus Calmette-Guerin (BCG) for non-muscle invasive bladder cancer, it remains unclear which patients respond to treatment. A potential determinant may be the urinary microbiome, which is closely tied to the host immune system and implicated in genitourinary disease. We sought to investigate commensal microbial associations with BCG responder versus non-responder status in tumors from bladder cancer patients, and identify possible mechanisms for commensal interaction in the BCG response. METHODS: 16S next-generation sequencing (NGS) and shotgun metagenomics were performed on formalin-fixed bladder tumor tissue from patients prior to intravesical BCG therapy for bladder cancer. Sequence reads were assigned to genus-level amplicon sequence variants (ASVs) in DADA2 and analyzed in Phyloseq. To determine microbial influences on BCG internalization, GFP-tagged BCG was co-cultured with a urothelial carcinoma (UCC) cell line and a series of candidate microbial species. BCG response was defined as no disease two years from induction BCG. Differences between BCG responders and non-responders were assessed using t-tests, Permanova, and principal components analyses. RESULTS: 47 patients (23 responders, 24 non-responders) were included in analysis. Overall microbiome composition differed significantly as determined independently by NGS (p=0.042) and shotgun metagenomics (p = 0.047, Figure). Lactobacillus spp were enriched in BCG responders, and Corynebacterium spp were enriched in BCG non-responders. Species richness was not significantly different between BCG responders and non-responders (p=0.053). BCG-GFP internalization by UCCs was significantly greater when co-cultured with Lactobacillus crispatus (197/1156, 17%) compared to controls (160/1490, 10.7%) (p≤0.0001). CONCLUSIONS: There is a robust and consistent compositional difference in the urinary microbiome between BCG responders and non-responders. Lactobacillus crispatus was associated with significantly increased BCG internalization. These findings suggest the urinary tumor microbiome is associated with response status and may directly augment BCG response, opening new avenues for investigations to optimize bladder-sparing therapy in bladder cancer. Source of Funding: CWRU CCCC © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e195 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jacob Knorr More articles by this author Glenn Werneburg More articles by this author Ava Adler More articles by this author Jose Agudelo More articles by this author Prithvi Murthy More articles by this author Rebecca Campbell More articles by this author Petar Bajic More articles by this author Nima Almassi More articles by this author Christopher Weight More articles by this author Georges-Pascal Haber More articles by this author Aaron Miller More articles by this author Byron Lee More articles by this author Expand All Advertisement PDF DownloadLoading ...

Real-world study of chemotherapy plus immunotherapy versus chemotherapy alone as neoadjuvant treatment guided bladder-sparing therapy for localized muscle-invasive bladder cancer.

499 Background: Bladder-preserving combined-modality therapy has been a popular research field as an alternative to radical cystectomy for selected patients with localized muscle-invasive bladder cancer (MIBC). This real-world study aimed to compare the efficacy of neoadjuvant chemotherapy plus immunotherapy versus chemotherapy alone as one of bladder-sparing therapies for localized MIBC. Methods: Patients with cT2-4bN0-3M0-1a pathological and imaging diagnosed MIBC were included in the study. Either chemotherapy (gemcitabine and cisplatin/carboplatin) plus immunotherapy (PD-1 checkpoint inhibitor, including pembrolizumab，tislelizumab and toripalimab) or chemotherapy alone were given as patients’ wish. The primary endpoint was complete response rate (CR, T0/Ta/Tis), and the secondary endpoints were disease control rate (DCR), progression-free survival (PFS), bladder-intact disease-free survival (BI-DFS) and toxicity. Results: In total, 41 patients were included, 25 in combination group and 16 in chemotherapy group respectively. The baseline characteristics were well balanced in two groups. Median follow-up time was 15.3 ±4.4 months(m). No patient died. The efficacy evaluable population was consisted of 34 pts (22 in combination group; 12 in chemotherapy alone group). The CR rate for combination group was 50.0% and 0 for chemotherapy alone group. One patient suffered from disease progression in combination group and three in chemotherapy group. The DCRs for combination group and chemotherapy group were 95.5% and 66.7%, respectively ( p= 0.003). Twelve patients had radiotherapy and six patients had radical cystectomy followed by neoadjuvant treatments in combination group. And two patients had radiotherapy and three patients had radical cystectomy in chemotherapy group. The one-year PFS rates were 95.5% and 62.5% for combination group and chemotherapy group( p= 0.010), and the one-year BI-DFS were 66.1% versus 27.5% respectively( p= 0.159). The bladder-preserving combined-modality therapies used were well-tolerated with acceptable and manageable toxicities. Grade ¾ hematological system adverse events were 15.9% and 6.4% in combination group and chemotherapy group, respectively ( p= 0.021). Conclusions: Neoadjuvant chemotherapy plus immunotherapy showed better efficacy compared with chemotherapy alone as an important bladder-sparing therapy for locally advanced MIBC with acceptable and manageable toxicities.

Intravesical immunotherapy with a GM-CSF armed oncolytic vesicular stomatitis virus improves outcome in bladder cancer

A significant proportion of non-muscle invasive bladder cancer cases will progress to muscle invasive disease. Transurethral resection followed by Bacillus Calmette Guerin immunotherapy can reduce this risk, while cystectomy prior to muscle invasion provides the best option for survival. Currently, there are no effective treatments for Bacillus Calmette Guerin refractory disease. A novel oncolytic vesicular stomatitis virus containing the human GM-CSF transgene (VSVd51-hGM-CSF) was rescued and tested as a potential bladder-sparing therapy for aggressive bladder cancer. The existing variant expressing mouse GM-CSF was also used. Measurement of gene expression and protein level alterations of canonical immunogenic cell death associated events on mouse and human bladder cancer cell lines and spheroids showed enhanced release of danger signals and immunogenic factors following infection with VSVd51-m/hGM-CSF. Intravesical instillation of VSVd51-mGM-CSF into MB49 bladder cancer bearing C57Bl/6 mice demonstrated enhanced activation of peripheral and bladder infiltrating effector immune cells, along with improved survival and reduced tumor volume. Importantly, virus-mediated anti-tumor immunity was recapitulated in bladder cancer patient-derived organoids. These results suggest that VSVd51-hGM-CSF is a promising viro/immunotherapy that could benefit bladder cancer patients.

Comparing Prognosis Associated with Partial Cystectomy and Trimodal Therapy for Muscle-Invasive Bladder Cancer Patients

Objective: This study aimed to compare the survival outcomes between trimodal therapy (TT) and partial cystectomy (PC) in muscle-invasive bladder cancer (MIBC) patients. Methods: The data of 13,096 patients with MIBC diagnosed between 2004 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results database. Among them, 4,041 patients underwent TT and 1,670 patients underwent PC. Propensity score matching was performed to balance the characteristics between the 2 treatment groups. A multivariate Cox regression analysis model and a competing risk model were used to evaluate overall survival (OS) and cancer-specific survival. Cumulative incidence survival curves were obtained using the Kaplan-Meier method. Results: Results of multivariate Cox analysis before propensity score matching showed that the TT group had a 31% reduction in cause-specific survival relative to the PC group (HR: 0.69, 95% CI: 0.61–0.78, p < 0.001) and a 28% reduction in OS (HR: 0.72, 95% CI: 0.66–0.79, p < 0.001). After propensity score matching, the 2 groups yielded 972 patients, with 3-year cause-specific survival rates of 54.1% and 68.5% in the TT group and the PC group, respectively. Conclusions: Patients who underwent PC had a better prognosis than those who received TT. In addition, for MIBC patients who required bladder-sparing therapy, advanced age (≥80 years), pathological type of squamous cell carcinoma, and tumor stage of T3–4, N2–3, and M1 were independent poor prognostic factors.

Survival Analysis of Lymphoepithelioma-Like Carcinoma of the Urinary Bladder and the Effect of Surgical Treatment Modalities on Prognosis.

Purpose: This study aimed to investigate the prognostic factors of patients with lymphoepithelioma-like carcinoma of the urinary bladder (LELCB) and explore the value of surgical treatment.Methods: Data of patients with LELCB were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The multivariate analysis was performed using the stepwise Cox proportional hazards regression model and conditional inference tree method to identify significant prognosticators of overall survival (OS) from the parameters such as age, gender, lymph node involvement, tumor extent, radiation, chemotherapy, and surgery type. Literature review (LR) was performed, and eligible cases were used to validate prognostic classification using the Kaplan–Meier method with log-rank tests.Results: Sixty patients with a median age of 69.5 years were identified from the SEER database and 91 patients through LR. The Cox analysis identified age, gender, lymph node involvement, and surgical approach as independent prognosticators of OS. Based on the nomogram scores, patients were stratified into three prognostic groups: (I) patients younger than 70 years; (II) patients older than 70 years, who received bladder-sparing therapy (BST); and (III) patients older than 70 years undergoing radical cystectomy (RC). Patients in group II had the worst outcomes in terms of OS compared with patients in groups I and III (p < 0.001 and p = 0.03, respectively). A similar survival pattern was found in the LR cohort.Conclusion: The nomogram provided individualized prognostic quantification of OS in patients with LELCB. BST could yield favorable outcomes when treating LELCB, especially for younger patients, whereas older patients might derive more survival benefit from RC.

Treatment Modalities of Muscle Invasive Transitional Cell Carcinoma of Bladder

The treatment of muscle invasive bladder cancer (MIBC) is complex. This review describes the available therapies for invasive urothelial carcinoma. Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) and lymph node dissection has been considered the slandered treatment for MIBC. Many patients those are unfit for surgery or cisplatin ineligible, bladder sparing strategies are considered in highly selected patients. Even though there are no level I data, the treatment outcomes for highly select patients given bladder sparing therapy appear promising, with many patients retaining a functional bladder. So it can be concluded that treatment of MIBC is a multidisciplinary collaborative program of surgery, radiation and medical oncology. Bangladesh Journal of Urology, Vol. 23, No. 2, July 2020 p.205-209

Targeting barriers to wider use of trimodality therapy in localized muscle invasive bladder cancer.

Radical cystectomy with bilateral pelvic lymphadenectomy and trimodality bladder-sparing therapy or TMT, are both curative options for patients with nonmetastatic muscle invasive bladder cancer. Patients should be afforded the opportunity for a multidisciplinary evaluation with equipoise in discussing these options for eligible patients. We discuss the barriers to broader acceptance and utilization of TMT and encourage support of clinical trials of TMT.

Incidence and outcome of salvage cystectomy after bladder sparing therapy for muscle invasive bladder cancer: a systematic review and meta-analysis

ObjectiveWe conducted a systematic review and meta-analysis to assess the available literature regarding the surgical and oncologic outcomes of patients undergoing salvage radical cystectomy (SV-RC) for recurrence or failure of bladder sparing therapy (BST) for muscle-invasive bladder cancer (MIBC).MethodsWe searched MEDLINE (PubMed), EMBASE and Google Scholar databases in May 2020. We included all studies of patients with ≥ cT2N0/xM0 bladder cancer that were eligible for all treatment modalities at the time of treatment decision who underwent BST including radiotherapy (RTX). A meta-analysis was conducted to calculate the pooled rate of several variables associated with an increased need for SV-RC. Study quality and risk of bias were assessed using MINORS criteria.Results73 studies comprising 9110 patients were eligible for the meta-analysis. Weighted mean follow-up time was 61.1 months (range 12–144). The pooled rate of non-response to BST and local recurrence after BST, the two primary reasons for SV-RC, was 15.5% and 28.7%, respectively. The pooled rate of SV-RC was 19.2% for studies with a follow-up longer than 5 years. Only three studies provided a thorough report of complication rates after SV-RC. The overall complication rate ranged between 67 and 72% with a 30-day mortality rate of 0–8.8%. The pooled rates of 5 and 10-year disease-free survival after SV-RC were 54.3% and 45.6%, respectively.ConclusionApproximately one-fifth of patients treated with BST with a curative intent eventually require SV-RC. This procedure carries a proportionally high rate of complications and is usually accompanied by an incontinent urinary diversion.

Abstract IA25: Molecular biomarkers of chemoradiation response in bladder preservation therapy

Abstract The standard definitive treatment options for muscle-invasive bladder cancer are radical cystectomy or bladder-sparing trimodality therapy (TMT), consisting of maximal transurethral resection of bladder tumor followed by chemoradiation therapy. Although multiple series show these two treatment approaches have similar overall long-term outcomes, recent studies suggest that molecular biomarkers may identify subgroups of patients who may preferentially benefit from one type of therapy over the other. Such biomarkers include tumor-intrinsic genes involved in DNA repair and signal transduction, which confer sensitivity or resistance to radiation therapy based on the intrinsic biology of the tumor. Emerging biomarkers also include molecular signatures of the tumor microenvironment, suggesting an important role for tumor-extrinsic factors in governing therapeutic sensitivity or resistance. This presentation will review the evidence and rationale underlying potential prognostic and predictive molecular biomarkers in bladder preservation therapy. A specific focus will be on our recent gene expression profiling of 136 muscle-invasive bladder cancer patients treated with bladder-sparing TMT. Our analysis showed that higher immune infiltration was associated with improved disease-specific survival after TMT, whereas higher stromal infiltration was associated with shorter disease-specific survival in a comparison cohort treated with radical cystectomy after neoadjuvant chemotherapy. These findings require validation studies in additional cohorts, which are currently ongoing. An additional focus of the presentation will be on emerging liquid biopsy biomarkers of minimal residual disease after bladder cancer therapy. The standard follow-up for patients after bladder-sparing TMT includes cystoscopies with biopsies and imaging studies at regular intervals. Liquid biopsy approaches such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) may enable noninvasive monitoring of response and detection of minimal residual disease after therapy, with a substantial lead time over conventional follow-up approaches including imaging. If validated in prospective clinical trials, molecular biomarkers may guide the tailored selection of appropriate treatments for individual patients with muscle-invasive bladder cancer, as well as enable noninvasive monitoring of patients after therapy. Such biomarkers also have potential to guide the use of synergistic combinations of immunotherapy with chemoradiation therapy for bladder cancer. Citation Format: David T. Miyamoto. Molecular biomarkers of chemoradiation response in bladder preservation therapy [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA25.

Phase II trial of durvalumab plus tremelimumab with concurrent radiotherapy as bladder-sparing therapy in patients with localized muscle invasive bladder cancer: A SOGUG study.

TPS5097 Background: Several studies have shown that long-term bladder preservation is feasible in selected patients with muscle-invasive bladder cancer, using a multimodal treatment, including transurethral resection (TUR), radiotherapy and chemotherapy. Durvalumab, a fully human monoclonal antibody against PD-L1, has shown activity in patients with advanced pretreated urothelial cancer. A preclinical study showed that the combination of radiation, anti-CTLA4 and anti-PD-L1 overcome- adaptive immune resistance and has superior activity than either therapy alone (Twyman-Saint Victor et al. Nature 2015). The purpose of the present study is to explore feasibility, toxicity and activity in terms of response and bladder preservation of the integration of TUR, immune double checkpoint inhibition with durvalumab and tremelimumab (a fully human monoclonal antibody against CTLA-4), and radiotherapy in the treatment of localized muscle-invasive. Methods: This is a multicenter prospective phase II study of multimodal therapy in patients with localized urothelial carcinoma of the bladder in clinical stages T2-4a N0 M0, ECOG 0- 1, without contraindications to immunotherapy, who either wish for bladder preservation or are ineligible for cystectomy. The primary endpoint is pathological response (≤T1) at post-treatment biopsy. A 2-stage sequential design (response rate P0=5, P1=0.7, α=0.10, β=0.20) requires at least 6 responses in the first 12 pts to expand to a second cohort of 20 patients. The treatment consists of initial TUR of the tumor, followed by durvalumab 1500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for 3 doses. Normofractionated external-beam radiotherapy is started 2 weeks later, at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder. Patients with pathological response will be candidates to bladder preservation, whereas those with residual muscle invasive tumor will be candidates to salvage cystectomy. At present time, prespecified activity goal for the first stage of accrual was met; second stage accrual began in December 2019. Clinical trial information: NCT03702179 .

Re: Bladder Preservation with Twice-a-Day Radiation plus Fluorouracil/Cisplatin or Once Daily Radiation plus Gemcitabine for Muscle-Invasive Bladder Cancer: NRG/RTOG 0712-A Randomized Phase II Trial.

No AccessJournal of UrologyUrological Survey1 Jul 2020Re: Bladder Preservation with Twice-a-Day Radiation plus Fluorouracil/Cisplatin or Once Daily Radiation plus Gemcitabine for Muscle-Invasive Bladder Cancer: NRG/RTOG 0712-A Randomized Phase II Trial Sam S. ChangMD Sam S. ChangSam S. Chang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001055AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Re: Bladder Preservation with Twice-a-Day Radiation plus Fluorouracil/Cisplatin or Once Daily Radiation plus Gemcitabine for Muscle-Invasive Bladder Cancer: NRG/RTOG 0712-A Randomized Phase II Trial." The Journal of Urology, 204(1), p. 183 Reference 1. : Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J Urol 2017; 198: 552. Link, Google Scholar Suggested Reading : Unconventional bladder preservation: factors predicting failure to receive definitive surgery following chemotherapy for nonmetastatic muscle invasive bladder cancer in the National Cancer Database. J Urol 2018; 200: 535. Link, Google Scholar : Complications and long-term results of salvage cystectomy after failed bladder sparing therapy for muscle invasive bladder cancer. J Urol 2012; 187: 463. Link, Google Scholar : Concurrent radiotherapy and panitumumab after lymph node dissection and induction chemotherapy for invasive bladder cancer. J Urol 2019; 201: 478. Link, Google Scholar : Incidence, clinicopathological risk factors, management and outcomes of nonmuscle invasive recurrence after complete response to trimodality therapy for muscle invasive bladder cancer. J Urol 2018; 199: 407. Link, Google Scholar © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 204Issue 1July 2020Page: 183-183 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sam S. Chang More articles by this author Expand All Advertisement PDF downloadLoading ...

Use of Bladder Sparing Surgery for Muscle Invasive Bladder Cancer by Life Expectancy at Diagnosis.

Patients who are older and sicker are ideal candidates for bladder sparing therapy for muscle invasive bladder cancer given risks of treatment related morbidity with radical cystectomy and cancer mortality with observation. However, little is known about the independent impact of age, comorbidity and life expectancy on utilization of bladder sparing therapy. We sampled 19,228 patients with muscle invasive bladder cancer diagnosed between 2004 and 2013 from the National Cancer Database. We used multivariable multinomial logistic regression to determine relative risk ratios and predicted probabilities of receipt of bladder sparing therapy by estimates of life expectancy, and by age and comorbidity at diagnosis. On multivariable analysis decreasing life expectancy was significantly associated with higher use of bladder sparing compared with cystectomy (relative RR 1.08, 95% CI 1.07-1.08). However, absolute changes were modest with predicted probability of bladder sparing increasing from 8%, 10%, 12%, 14% and 17% among patients with 25-year, 20-year, 15-year, 10-year and 5-year life expectancies, respectively. By comparison, rates of cystectomy decreased from 54%, 47%, 39%, 32% and 26% and rates of observation increased from 22%, 26%, 31%, 36% and 40% across the same life expectancy subgroups, respectively. Age had a stronger effect on relative risk of bladder sparing than comorbidity. Predicted probabilities of bladder sparing therapy increased from 8%, 12%, 16% and 19% among 60-year-old, 70-year-old, 80-year-old and 90-year-old patients, respectively, while the probability was 13%, 13% and 15% among patients with Charlson scores of 0, 1, and 2+, respectively. Bladder sparing therapy is underused in patients who are older and sicker with limited life expectancy who currently primarily receive observation or, less often, radical cystectomy.

Bladder-sparing trimodal therapy versus radical cystectomy for muscleinvasive bladder cancer: A systematic review and meta-analysis of comparative studies

Objective: To compare oncologic outcomes between patients with muscle-invasive bladder cancer who were treated with radical cystectomy (RC) or trimodal therapy (TMT). Materials and Methods: The primary sources were the PubMed, Embase, and Cochrane Library electronic databases. Studies published between June 1990 and July 2017 that evaluated combination bladder-sparing surgery for a bladder tumour with radiotherapy (RT) and chemotherapy compared with RC surgery alone for MIBC were included. Published data were extracted and used to calculate the 5-year overall survival rates. The secondary efficacy endpoints were disease-free survival and local and distant recurrence. Results: Nine studies incorporating 15,160 cases were included in the final analysis. Pooled data from 8 studies that assessed overall survival rates for 15,089 patients showed no significant differences in this metric between the TMT and RC groups (HR: 1.27; 95% CI, 0.98-1.63; P=0.066). No significant differences were found between TMT and RC in the subgroup analyses according to the lymph node stage (Nx), age and physiclal status (PS) stage, but differences were found for patients with node-negative disease (HR: 1.36; 95% CI, 1.02-1.81; P=0.036). Disease-free survival and local and distant recurrence did not differ significantly between the techniques. Conclusion: RC seems to be suitable for node-negative disease patients. TMT yielded survival outcomes similar to those of patients who underwent RC. Given the inherent limitations of the included studies, future well-designed RCTs are needed to confirm and update the findings of this analysis.

Feasibility and outcomes of selective tetramodal bladder-preservation therapy in elderly patients with muscle-invasive bladder cancer.

To assess the feasibility and functional/oncological outcomes of selective tetramodal bladder-preservation therapy in elderly patients with muscle-invasive bladder cancer. This study analyzed 154 patients with non-metastatic muscle-invasive bladder cancer who were enrolled into the protocol. After maximal transurethral resection and induction chemoradiotherapy, patients with clinical complete response were offered consolidative partial cystectomy to achieve bladder preservation; otherwise, radical cystectomy was recommended. Postoperative complications, preserved bladder function, and oncological outcomes were compared between elderly (aged ≥75years) and younger patients (aged <75years). Frailty and sarcopenia were further assessed as potential factors that could affect the feasibility and outcomes of the protocol. A total of 44 patients (29%) were elderly, and 31 (20%) were frail (modified frailty index 2-3). Sarcopenia was observed in 68 (54%) of 126 eligible patients. Clinical complete response to induction chemoradiotherapy was achieved in 125 (81%) patients, and the bladder-preservation protocol was completed in 107 (69%) patientswith consolidative partial cystectomy. Over a median follow-up period of 48months, 5-year cancer-specific and muscle-invasive bladder cancer recurrence-free survival rates after protocol completion were 98% and 95%, respectively. There were no significant differences in complication rates related to partial cystectomy, preserved bladder function, and oncological outcomes between the elderly and younger groups. Neither frailty nor sarcopenia negatively affected these outcomes. Tetramodal bladder-sparing therapy incorporating consolidative partial cystectomy is feasible and yielded favorable functional/oncological outcomes in patients with muscle-invasive bladder cancer, regardless of advanced age, frailty or sarcopenia. This protocol could be a viable treatment option for such high-risk patient populations.

Long-term survival and complications following bladder-preserving brachytherapy in patients with cT1-T2 bladder cancer

Background and purposeRadical cystectomy (RC) is considered standard treatment for muscle-invasive bladder cancer (BC) and high-risk non-muscle invasive BC. In selected cases, bladder-sparing treatment using brachytherapy can be offered. We examined the outcome after brachytherapy in comparison to RC in terms of survival, complications and bladder preservation in patients with cT1G3-T2N0M0 BC. Materials and methodsBetween 1988 and 2016, 301 patients underwent brachytherapy in two centres. Overall survival (OS) and disease specific survival (DSS) after brachytherapy and RC were assessed using Kaplan-Meier curves. Cox proportional hazards modelling was used to determine variables associated with OS and DSS. Local recurrences, bladder preservation and salvage cystectomy (SC) after brachytherapy were reported. Complications after brachytherapy, RC and SC were compared using CTCAE criteria. ResultsMedian follow-up was 9.6 years (95% confidence interval (CI): 8.8–10.4) after brachytherapy and 10.6 years (95% CI: 10.0–11.2) after RC. Five/10-year OS was 66%/49% after brachytherapy and 68%/53% after RC (p = 0.4). Five/10-year DSS was 73%/67% after brachytherapy and 75%/65% after RC (p = 0.8). Intravesical recurrence occurred in 58/259 brachytherapy patients after which salvage cystectomy was performed in 32 patients. In total, 84% of brachytherapy-treated patients preserved their bladder. The brachytherapy cohort experienced less high grade complications than the RC cohort (p = 0.02). ConclusionIn selected patients with solitary, ≤5 cm cT1G3-T2N0M0 bladder tumours brachytherapy is a bladder-sparing therapy with good survival outcome and with a favourable complication rate compared to RC.

Outcomes of trimodality bladder-sparing therapy for muscle-invasive bladder cancer.

Although radical cystectomy is considered the standard of care for muscle-invasive bladder cancer (MIBC), recent data has suggested comparable survival outcomes for bladder-sparing trimodality therapy (TMT). We conducted a retrospective, single-institution analysis of MIBC patients to evaluate the efficacy of TMT as an alternative, curative approach to surgical intervention. We conducted a retrospective analysis of MIBC patients assessed by a multidisciplinary team at the Juravinski Cancer Centre from 2010-2016. Patients underwent transurethral resection of bladder tumor (TURBT) followed by radiotherapy with or without concurrent chemotherapy. Patients could receive neoadjuvant treatment. Clinical data and response rates were summarized, and overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Our analytic cohort included 115 patients, of whom 53 underwent TMT and 62 underwent radiotherapy alone following TURBT. Median age at diagnosis was 79 years and median followup was 21 months. Complete response rates in those receiving TMT and radiation without chemotherapy were 84.4% and 66.7%, respectively. For TMT patients, three-year OS and DFS were 68.5% and 49.6%, respectively. Patients who received TMT had reduction in risk of mortality (hazard ratio [HR] 0.49; p=0.026) and disease recurrence (HR 0.55; p=0.017) compared to those who had radiation without chemotherapy. Overall, four patients had grade 3 or higher late toxicity. In this single-institution analysis, TMT appears to be a safe and effective approach in the short-term management of MIBC in appropriately selected patients. Extended followup and analysis are necessary to validate these results.