Bladder-sparing Approach Research Articles

Perioperative platform for muscle-invasive bladder cancer trials: designs and endpoints.

This review explores the design and endpoints of perioperative platforms in clinical trials for muscle-invasive bladder cancer (MIBC). The choice of clinical trial design in perioperative platforms for MIBC must align with specific research objectives to ensure robust and meaningful outcomes. Novel designs in perioperative platforms for MIBC integrate bladder-sparing approaches. Primary endpoints such as pathological complete response and disease-free survival are highlighted for their role in expediting trial results in perioperative setting. Incorporating patient-reported outcomes is important to inform healthcare decision makers about the outcomes most meaningful to patients. Given the growing body of evidence, potential biomarkers, predictive and prognostic tools should be considered and implemented when designing trials in perioperative platforms for MIBC. Effective perioperative platforms for MIBC trials are critical in enhancing patient outcomes. The careful selection and standardization of study designs and endpoints in the perioperative platform are essential for the successful implementation of new therapies and the advancement of personalized treatment approaches in MIBC.

Bladder sparing options for muscle-invasive bladder cancer.

This review critically evaluates the current state of bladder-sparing options in muscle-invasive bladder cancer (MIBC) and provides an overview of future directions in the field. Bladder-sparing treatments have emerged as viable alternatives to radical cystectomy (RC) for selected patients with MIBC, especially in those who are unfit for RC or elect bladder preservation. Numerous studies have assessed the efficacy of trimodal therapy (TMT), with outcomes comparable to RC in a subgroup of well selected patients. Combining immunotherapy with conventional treatments in bladder-sparing approaches can yield promising outcomes. Current research is making significant progress in optimizing treatment protocols by exploring new combinations of systemic therapy agents, innovative drug delivery methods, and biomarker-based approaches. Furthermore, clinical markers of response are being tested to ensure adequate response assessment. Bladder preservation promise to offer a viable alternative to RC for selected patients with MIBC with the potential to improve patient quality of life. Careful patient selection and ongoing research are essential to optimize patient selection, response assessment, and salvage strategies. As evidence continues to evolve, the role of bladder preservation in MIBC is likely to expand, providing patients with more treatment options tailored to their needs and preferences.

15O]H2O PET/MRI for Assessment of Complete Response to Neoadjuvant or Induction Chemotherapy in Patients with Muscle-Invasive Bladder Cancer: A Pilot Study.

Background: Accurate assessment of therapy response to chemotherapy could possibly offer a bladder-sparing approach in selected patients with localized muscle-invasive bladder cancer (MIBC). The aim of this study was to evaluate whether [15O]H2O PET/MRI can be used for assessment of complete local pathological response to preoperative chemotherapy in patients with MIBC. Methods: This prospective pilot study included 13 patients with MIBC treated with neoadjuvant or induction chemotherapy and subsequent radical cystectomy. Patients underwent a [15O]H2O PET/MRI scan before chemotherapy and another scan after chemotherapy before radical cystectomy. Volumes of interest were delineated on T2-weighted MRI and transferred to parametric images for dynamic analysis. Tumor blood flow (TBF) was estimated by [15O]H2O PET. Changes in TBF were compared with histopathology. The Wilcoxon matched-pairs signed-ranks test was used for comparing pre- and post-chemotherapy measurements. Results: Mean TBF decreased by 49%. Mean TBF in complete responders (ypT0N0/ypTis) was not significantly different from non-complete responders (≥ypT1) (p = 0.52). Conclusions: Despite a measurable decrease in TBF after chemotherapy treatment, we were not able to estimate a TBF threshold for identifying complete responders to chemotherapy for MIBC patients. Further studies are needed to elucidate the potential of [15O]H2O PET/MRI in assessing therapy response in MIBC.

Comparison of the overall survival of different treatment methods in patients with Muscle-invasive bladder cancer: A retrospective study.

Bladder-Sparing Approach was presented in patients who are not willing or not suitable for Radical Cystectomy (RC). There have been inconsistencies in the literature regarding the comparison of survival rates of these two methods. Our objective is to evaluate the survival rate of patients with muscle-invasive bladder cancer (MIBC) undergoing different treatment methods. Retrospective cross-sectional study. A secondary care, multicenter study in Kerman, Iran 2008 to 2016. All 200 patients who were diagnosed with Muscle Invasive Bladder Cancer and were admitted to our hospitals. Patients with inaccessible medical files and patients with pathologies other than TCC were excluded. Radical cystectomy and different methods of bladder preservation were compared based on their survival rate. Radical cystectomy or bladder preservation. Overall survival of the patients was 2 years [95% CI: 1.37-2.63]. The overall 5-year survival rate of patients with MIBC was 32%. Having a 6.4 years overall survival, the RC group showed the highest survival compared with others (p = 0.01); the overall survival of patients undergoing TMT, TURT, chemotherapy, or radiotherapy monotherapy was 3.15 years [95% CI: 2.242-4.061], 4.06 [95% CI: 3.207-4.931], 2.58 [95% CI: 1.767-3.399], and 3.14 [95% CI: 1.614-4.672] years, respectively. Patients younger than 65 undergoing RC had an overall survival of 7 years, compared with 2 years for the TMT group. (p = 0.0001). The Bladder-Preservation method, as a replacement for RC, showed a lower overall survival rate in our study. A prospective randomized clinical trial may declare the best treatment.

Perioperative sacituzumab govitecan (SG) alone or in combination with pembrolizumab (Pembro) for patients with muscle-invasive urothelial bladder cancer (MIBC): SURE-01/02 interim results.

LBA4517 Background: SG is an antibody-drug conjugate composed of an anti-trophoblast cell surface antigen 2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) with US FDA-accelerated approval for locally advanced or metastatic urothelial carcinoma (mUC). A multi-cohort, open-label, phase 2 SURE study is evaluating neoadjuvant SG (SURE-01, NCT05226117) or neoadjuvant SG+pembrolizumab followed by adjuvant pembrolizumab (SURE-02, NCT05535218) in MIBC in a flexible design allowing a bladder-sparing approach. We report interim results from SURE-01. Methods: Pts with cT2-4N0M0 MIBC who were ineligible for or refused cisplatin-based neoadjuvant chemotherapy were planned to receive 4 cycles of neoadjuvant SG 10 mg/kg intravenously (IV) on days 1 and 8, Q3W, followed by radical cystectomy (RC). The trial included pre-post MRI imaging of the pelvis and ctDNA analysis. Pts with clinical complete response (cCR, defined with negative MRI, cystoscopy and ctDNA assays) refusing RC were offered redo transurethral resection of the bladder tumor (reTURBT) followed by observation in case no viable high-grade tumor in the bladder was found. The primary endpoint of the study is to assess the proportion of ypT0N0. The assumptions include a ypT0N0≤20% as H0 and ≥45% as H1 in a single-stage A’Hern’s design. Secondary end points include event-free survival (EFS), cCR rate and OS. Treatment-related adverse events (TRAEs) and safety are assessed using standard criteria (CTCAE v5). Tumor samples underwent comprehensive genomic profiling assay. Results: From 03/22 to 11/23, 21 pts were enrolled. After the initial 8 pts the study was amended with SG at 7.5 mg/Kg dose due to a Grade 5 TRAE. Median age was 71y, 7 pts (33.3%) had a cT3-4N0. Ten pts (47.6%) had a mixed variant histology. All pts received at least 1 cycle of SG: Grade ≥3 TRAE occurred in 9 pts (42.5%), including one Grade 5 event (at 10mg/Kg dose). Toxicity was unrelated to UGT1A1 polymorphism. Ten pts (47.6%) achieved a cCR. Sixteen pts are evaluable for final response at treatment completion: one pt had a disease progression and started palliative therapy, two did not undergo RC due to TRAE. Thirteen pts have undergone surgery (RC: N=10; reTURBT: N=3). ypT0N0-x response was achieved in 6/16 pts (37.5%), 7 (43.7%) an ypT≤1N0-x response. All pts with a residual disease revealed a ctDNA-negative test post-RC. Tumor samples from pts with cCR were enriched in ARID1A and BRCA1/2 mutations vs nonCR: 40 vs 9%, 30 vs 18%; nonCR were enriched in ERBB2 mutations vs cCR: 44 vs 10%. Conclusions: Observed ypT0N0-x responses after neoadjuvant SG showed promising activity in MIBC who have a high unmet need, with a potential to avoid RC. Reduced dose of SG was feasible and the data support the ongoing SURE studies in MIBC. Clinical trial information: NCT05226117 ; NCT05535218 .

Abstract A017: Patient-reported experience related to aspects of quality of life after cystectomy from an exploratory focus group

Abstract Purpose: These exploratory focus groups examined patient experiences after having a cystectomy following bladder cancer. Methods: US individuals aged >50 years with self-reported diagnosis of non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC) who had undergone partial or radical cystectomy were recruited through a Patient Engagement Research Council program and invited to participate in an exploratory focus group (October 2022). Patients completed a prework survey on initial diagnosis, treatments, and how aspects of their life changed over time from pre-diagnosis, around the time of decision to undergo cystectomy, 90 days after cystectomy, and at present day. Patients attended gender-specific focus group sessions to discuss their patient journey, support needs, and how having a cystectomy affected their lives. Discussions were facilitated by a gender-matched moderator using a semi-structured discussion guide. Patients provided written informed consent and were compensated for their time. Key themes were identified by coding of audio transcripts and direct observations via the qualitative research analysis software MAXQDA. Results: Patients were six White adults (female n=3, male n=3, median age 68 years) with NMIBC (n=2) or MIBC (n=4) who underwent radical cystectomy between 2000 and 2020. Patients reported that bladder-sparing approaches were rarely introduced or discussed by their care team during their diagnostic journey, instead identifying disease eradication and pain improvement as primary drivers for choosing cystectomy. In the first 90 days post-surgery, patients reported that cystectomy negatively affected their ability to perform daily activities, mental health, and physical intimacy while adapting to a “new normal,” citing challenges with urinary diversion routes. Female patients cited a general lack of female-centric support (e.g. feminine hygiene and care education) as their support groups were mostly comprised of male patients focusing on male-centric issues (e.g., erectile dysfunction). In the present day, patients reported lower sex drive, satisfaction with body image, and physical intimacy. Patients called for more privacy consideration during medical examinations, better ostomy care support, increased awareness among healthcare professionals about the struggles patients face throughout their cystectomy journey, and improved education about available treatment options (including bladder preservation) and possible ramifications of cystectomy on all aspects of life (including sexual health and female-centric needs). Conclusions: Cystectomy can negatively affect patients’ lives, affecting their ability to participate in daily activities, mental health, and physical intimacy among those with NMIBC and MIBC. Patients expressed the need for holistic, long-term support (including awareness of treatment options, emotional support, and ostomy care) before, during, and after cystectomy. Citation Format: Nida Imran, Wesley Peters, Karen Fixler, Priyanka Madireddi, Lisa M. Shea, Andrea Ireland. Patient-reported experience related to aspects of quality of life after cystectomy from an exploratory focus group [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A017.

Stereotactic Ablative Radiotherapy Boost to Bladder Tumor for Bladder Preservation in Patients with Muscle-Invasive Bladder Cancer

Previous studies showed that selective bladder-sparing approach using TMT is an established therapy of MIBC with outcomes that are comparable to those of radical cystectomy. However, it has been shown that the 5-year local recurrence in the bladder is greater than 40% after TMT. One of the possible reasons was that the RT dose to the bladder tumor or tumor bed was insufficient. Thus, we assessed the effectiveness and safety of Stereotactic Ablative Radiotherapy (SABR) boost to bladder tumor or tumor bed for patients with muscle invasive bladder cancer (MIBC). A total of 59 consecutive patients with cT2-4 bladder cancer underwent transurethral resection of bladder tumor (TURBT). TURBT was visibly complete in 25 cases. Patients received SABR to the tumor or tumor bed in the bladder followed by conventionally fractionated RT (CFRT) to pelvis and total bladder with concomitant weekly radio-sensitizing chemotherapy. During SABR intravesical installation of isovolumetric saline through urinary catheter ensured adequate bladder filling. Response rate was assessed by cystoscopic evaluation and pelvic MRI or CT. Toxicities were reported per the RTOG acute and late Radiation Morbidity Scoring Schema. The median age of all patients was 76 years (35-90 years). All patients completed SBRT boost and 61% patients received concurrent Gemcitabine chemotherapy. After a median follow-up time of 28 months, the rate of local control (LC) at 3 years was 90.0%. The overall survival (OS) and cancer-specific survival (CSS) rates at 3 years were 61.6% and 77.5%, respectively. Of the surviving patients, 84.4% have a disease-free and functioning bladder. Acute grade 3 gastrointestinal (GI) or genitourinary (GU) toxicities occurred in only 1.7% of the patients. Late grade 3 GU toxicity occurred in 5.1% of the patients. No patients experienced grade 4 GI or GU toxicities. SABR boost followed by chemoradiation to the pelvis was found to be a well-tolerated and effective treatment for MIBC patients who are either not candidates for cystectomy or who desire bladder preservation. Randomized study is required to further evaluate this novel tri-modality treatment paradigm.

Induction therapy with ipilimumab and nivolumab followed by consolidative chemoradiation as organ-sparing treatment in urothelial bladder cancer: study protocol of the INDIBLADE trial.

Studies that assessed the efficacy of pre-operative immune checkpoint blockade (ICB) in locally advanced urothelial cancer of the bladder showed encouraging pathological complete response rates, suggesting that a bladder-sparing approach may be a viable option in a subset of patients. Chemoradiation is an alternative for radical cystectomy with similar oncological outcomes, but is still mainly used in selected patients with organ-confined tumors or patients ineligible to undergo radical cystectomy. We propose to sequentially administer ICB and chemoradiation to patients with (locally advanced) muscle-invasive bladder cancer. The INDIBLADE trial is an investigator-initiated, single-arm, multicenter phase 2 trial. Fifty patients with cT2-4aN0-2M0 urothelial bladder cancer will be treated with ipilimumab 3 mg/kg on day 1, ipilimumab 3 mg/kg plus nivolumab 1 mg/kg on day 22, and nivolumab 3 mg/kg on day 43 followed by chemoradiation. The primary endpoint is the bladder-intact event-free survival (BI-EFS). Events include: local or distant recurrence, salvage cystectomy, death and switch to platinum-based chemotherapy. We will also evaluate the potential of multiparametric magnetic resonance imaging of the bladder to identify non-responders, and we will assess the clearance of circulating tumor DNA as a biomarker for ICB treatment response. This is the first trial in which the efficacy of induction combination ICB followed by chemoradiation is being evaluated to provide bladder-preservation in patients with (locally advanced) urothelial bladder cancer. The INDIBLADE trial was registered on clinicaltrials.gov on January 21, 2022 (NCT05200988).

Disitamab vedotin in combination with immune checkpoint inhibitors for locally and locally advanced bladder urothelial carcinoma: a two-center's real-world study.

Objective: Our study aims to assess the effectiveness and safety profile of Disitamab Vedotin (DV, RC48-ADC), an innovative humanized anti-HER2 antibody conjugated with tubulin-disrupting antimitotic drug monomethyl auristatin E (MMAE) via a cleavable peptide linker. This treatment combined immune checkpoint inhibitors as part of the bladder sparing approach for selected patients suffering from locally and locally advanced bladder urothelial carcinoma. Patients and methods: We conducted a two-center, real-world study involving locally advanced urothelial carcinoma (UC) patients. Patients were classified based on HER2 expression (IHC 3+/2+/1+) or lack of HER2 expression (IHC 0). The primary endpoint was the objective response rate (ORR), assessed by the investigator following the criteria of RECIST V1.1. Secondary endpoints encompassed the pathological complete response rate (pCR), pathological partial response rate (pPR), and pathological stable disease (pSD), along with recurrence-free survival (RFS), the pathological downstaging rate, and the safety profile of the treatment. Results: In this study, nine patients were enrolled, with a median follow-up duration of 12.0months. The overall confirmed ORR was 88.9%, Five patients achieved a complete response (CR), and three patients achieved a partial response (PR). The radiological complete response (rCR) aligned perfectly with pCR. The median radiological progression-free survival (rPFS) spanned 12.0months (range from 8.0 to 17.0months). One patient diagnosed with disease progression (PD) underwent a radical cystectomy. The pathological stage evolved from T2N0M0 to T3aN2M0, followed by adjuvant chemotherapy with a gemcitabine-cisplatin (GC) combination radiotherapy. At the 9-month follow-up, neither recurrence nor metastasis was observed. The rate and intensity of complications were manageable among these patients, with no evidence of grade 4 and 5 adverse events. Conclusion: The combination of DV and PD-1 demonstrated considerable activity in the objective response rate (ORR) in patients with HER2 IHC 0/1+/2+/3+ muscle-invasive bladder cancer (MIBC), along with the longest reported median radiological progression-free survival (rPFS) to date. With an extended duration of treatment, the safety profile of DV plus PD-1 was also confirmed to be manageable.

BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Current Treatment Landscape and Novel Emerging Molecular Targets.

Urothelial carcinoma (UC), the sixth most common cancer in Western countries, includes upper tract urothelial carcinoma (UTUC) and bladder carcinoma (BC) as the most common cancers among UCs (90-95%). BC is the most common cancer and can be a highly heterogeneous disease, including both non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) forms with different oncologic outcomes. Approximately 80% of new BC diagnoses are classified as NMIBC after the initial transurethral resection of the bladder tumor (TURBt). In this setting, intravesical instillation of Bacillus Calmette-Guerin (BCG) is the current standard treatment for intermediate- and high-risk patients. Unfortunately, recurrence occurs in 30% to 40% of patients despite adequate BCG treatment. Radical cystectomy (RC) is currently considered the standard treatment for NMIBC that does not respond to BCG. However, RC is a complex surgical procedure with a recognized high perioperative morbidity that is dependent on the patient, disease behaviors, and surgical factors and is associated with a significant impact on quality of life. Therefore, there is an unmet clinical need for alternative bladder-preserving treatments for patients who desire a bladder-sparing approach or are too frail for major surgery. In this review, we aim to present the strategies in BCG-unresponsive NMIBC, focusing on novel molecular therapeutic targets.

Recent advancements in the diagnosis and treatment of non-muscle invasive bladder cancer: Evidence update of surgical concept, risk stratification, and BCG-treated disease.

In the management of non-muscle invasive bladder cancer (NMIBC), disease progression and long-term control are determined by the intensity of delivered treatment and surveillance and the cancer cells' biological nature. This requires risk stratification-based postoperative management, such as intravesical instillation of chemotherapy drugs, Bacillus Calmette-Guérin (BCG), and radical cystectomy. Advancements in mechanical engineering, molecular biology, and surgical skills have evolved the clinical management of NMIBC. In this review, we describe the updated evidence and perspectives regarding the following aspects: (1) advancements in surgical concepts, techniques, and devices for transurethral resection of the bladder tumor; (2) advancements in risk stratification tools for NMIBC; and (3) advancements in treatment strategies for BCG-treated NMIBC. Repeat transurethral resection, en-bloc transurethral resection, and enhanced tumor visualization, including photodynamic diagnosis and narrow-band imaging, help reduce residual cancer cells, provide accurate diagnosis and staging, and sensitive detection, which are the first essential steps for cancer cure. Risk stratification should always be updated and improved because the treatment strategy changes over time. The BCG-treated disease concept has recently diversified to include BCG failure, resistance, refractory, unresponsiveness, exposure, and intolerance. A BCG-unresponsive disease is an extremely aggressive subset unlikely to respond to a rechallenge with BCG. Numerous ongoing clinical trials aim to develop a future bladder-sparing approach for very high-risk BCG-naïve NMIBC and BCG-unresponsive NMIBC. The key to improving the quality of patient care lies in the continuous efforts to overcome the clinical limitations of bedside management.

Bladder-sparing approaches for muscle invasive bladder cancer: a narrative review of current evidence and future perspectives.

In recent years, the application of less-invasive "bladder-sparing" trimodal therapy (TMT) in selected muscle-invasive bladder cancer (MIBC) patients unfit for or who declined radical cystectomy (RC) has been increasing. This review aims to summarize the current evidence and future perspectives of bladder-sparing therapy for MIBC. A non-systematic Medline/PubMed literature search was conducted on July 2022 with the following keywords 'MIBC', 'bladder-sparing', 'chemotherapy', 'radiotherapy', 'trimodal', 'multimodal', and 'immunotherapy'. All monotherapies are inferior to RC or combination therapy and should not be routinely used for curative intent. Radiotherapy (RT) alone has been shown to have poorer outcomes when compared to chemoradiotherapy. The ideal selection criteria for TMT include good bladder function and capacity, clinical stage within cT2, complete transurethral resection of bladder tumor (TURBT), no prior history of pelvic RT, no extensive carcinoma in situ (CIS), and absence of hydronephrosis. The emergence of immunotherapy may further increase the effect of bladder-sparing therapy. Novel predictive biomarkers are awaited for more precise patient selection and better oncological outcomes. TMT is a well-tolerated and offers a curative alternative approach to RC for selected patients with localized MIBC. Appropriate patient selection and a multi-disciplinary approach is crucial in achieving good oncologic control with bladder-sparing therapy.

Transurethral resection of bladder tumor-based bladder preservation therapy for refractory high risk non-muscle invasive bladder cancer: Current landscape and future directions.

Bladder cancer is the most common malignant tumor of urinary system worldwide. Approximately 75% of patients with bladder cancer present with non-muscle-invasive bladder cancer (NMIBC), which is effectively managed with transurethral resection of bladder tumor (TURBT). For refractory high risk NMIBC, patients are typically treated by radical cystectomy (RC). TURBT deserves further evaluation. Growing evidence suggests that repeated TURBT-based bladder-sparing approaches may improve oncological outcomes and quality of life in highly selected patients. Novel imaging techniques and biomarkers may aid in patients selection and postoperative surveillance. With growing interest in adding immunotherapy to refractory bladder cancer, TURBT based approaches enable the bladder preservation therapy for high risk NMIBC. Here we summarize the current landscape, biomarkers for surveillance, and future directions for applying TURBT-based bladder preservation therapy.

Implications for diagnosis and treatment strategies in non-muscle invasive bladder cancer with variant histology: a systematic review.

The identification of variant histology (VH) has been recognized as a critical element in the diagnostic pathway of bladder cancer (BCa), both for prognostic and therapeutic implications. However, the current evidence on the oncological outcomes of patients harboring VH BCa mostly derives from studies including muscle-invasive disease. Consequently, the correct management of patients with non-muscle invasive bladder cancer (NMIBC) and VH is limited and conflicting, and the optimal therapeutic approach remains therefore controversial. In this review, we aimed at reporting the current evidence on NMIBC with VH. Despite a constant increase in VH reporting at transurethral resection of bladder tumor (TURBT) specimens as compared to previous decades, we found that the incidence of VH is still sparse among studies. Furthermore, the agreement between TURBT and radical cystectomy (RC) specimens in VH identification is another matter of debate. Currently, most of the included studies report a poor overall concordance, especially for the micropapillary variant. Finally, while squamous and micropapillary variants are those associated with the worst survival outcomes, immediate RC is mostly considered for micropapillary tumors. Conversely, the survival benefit of immediate RC as compared to bladder-sparing approaches (i.e., BCG immunotherapy) for the other types of VH BCa is still an open question owing to the paucity of data available. Thus, in these patients, BCG treatment could be proposed considering the need for more intensive oncological surveillance.

Quality of life after radical treatment for muscle invasive bladder cancer: A systematic review and meta-analysis.

489 Background: Radical cystectomy (RC) with or without perioperative chemotherapy is considered the standard treatment option for Muscle invasive bladder cancer (MIBC), despite poor oncological outcomes. However, RC is often burdened by significant impact on quality of life (QoL); Continence preserving methods (e.g continent cutaneous urinary diversion and orthotopic neobladder-ONB), have been proposed as alternatives to improve the postoperative QoL, but real benefit of these approaches is questioned. Bladder sparing approach, such as trimodal therapy (TMT) emerged as an alternative to surgery. Aiming to assess the impact of these treatment options from the patients’ perspective, we undertook a systematic review and meta-analysis of literature, focusing on studies specifically reporting QoL data about each of the above mentioned approaches. Main purpose of this review is to compare available treatment options from the QoL point of view and highlight the potential advantage of a bladder sparing approach if compared to different postoperative urinary diversion methods. Methods: A systematic review was carried out including all prospective and retrospective studies enrolling patients treated with radical intent for non-metastatic MIBC from 1999 to 2021 (either RC or TMT). All studies included specifically reported QoL for one of the main treatment approaches explored (RC followed by ileal conduit urinary diversion-ICUD, ONB or TMT). Review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement Results: Fifty studies were included in the final analysis, assessing QoL after RC followed by ICUD or ONB in 6 and 15 cases, respectively. Six studies addressed QoL after TMT. ICUD vs ONB and TMT vs ICUD/ONB comparisons were carried out in 21 and 1 studies, respectively. Pooled analysis for EORTC QLQ- C30 and BLM-30 questionnaires showed that ONB yielded a significant advantage if compared to ICUD only for Physical Functioning (pooled mean standardized difference -0.73 SD, p-value 0.019, I 2 =93%) and for Emotional Functioning (pooled mean standardized difference -0.16 SD, p-value 0.029, I 2 =0%). A trend in favour of higher mean reported values after TMT for Global Health Score, Physical Functioning and Role Functioning was found, if compared to both RC approaches. Conclusions: Significant benefit for ONB if compared to ICUD was detected only for specific subdomains of QoL questionnaires. No direct comparison with TMT is available, but data suggest advantage of this approach if compared to both reconstructive scenarios. These data should be used in clinical practice to help well informed patients decision about local treatment choice.

Incarcerated Inguinal Bladder Hernia: Case Report

The incidence of urinary bladder hernia accompanying inguinal hernias is 1-4%. Herniation of the urinary bladder into the inguinal canal and scrotum can cause urinary retention and hydronephrosis, bladder necrosis, and renal dysfunction. This study presents a case that underwent emergency surgery for an incarcerated inguinal hernia. The hernia sac included the urinary bladder in addition to bowel segments. An attempt to save the ischemic bladder wall during partial bowel resection failed, and the patient developed a vesicocutaneous fistula. The fistula was repaired, and the ischemic bladder wall was resected. During the repair of an inguinal hernia, general surgeons and urologists must be aware of this rare condition and work together in terms of patient management. Although the bladder-sparing approach can be performed in cases without signs of severe bladder ischemia, patients should be followed closely for complications related to ischemia.

Intra-Diverticular Bladder Tumours: How to Manage Rationally

Objective To report changing practice in the management of intra-diverticular bladder tumours. Methods We undertook a review of all intra-diverticular bladder tumours in our prospectively maintained institutional database. Results A total of 28 patients (male = 27, female = 1) with a median age of 71 years (IQR 61 to 76) were diagnosed with intra-diverticular bladder tumours (IDBT) between March 2013 and February 2021. Fourteen had visible and 3 had non-visible haematuria, while 11 patients had lower urinary tract symptoms. Median axial diameter of the diverticula was 46 mm (IQR 35 to 69), and median neck diameter was 9 mm (IQR 7 to 11). All patients had CT-urography and 5 patients also had an MRI. Surgical treatment consisted of diverticulectomy (n = 11), diverticulectomy and ipsilateral ureteric reimplantation (n = 11), radical cystectomy and ileal conduit (n = 4), or radical cystectomy and orthotopic bladder (n = 2). Eleven patients had open procedures, and 17 had robotic assisted surgery. Final pathological stages were T0 (n = 2), Ta (n = 5), T1 (n = 7), T3a (n = 8) and T3b (n = 6). Twenty-four patients had urothelial carcinoma (including one nested variant and 4 with squamous differentiation) and 2 had small cell carcinoma. Three patients had neoadjuvant systemic chemotherapy, 2 had intravesical bacillus Calmette-Guerin (BCG) with mitomycin, and one had BCG monotherapy preoperatively. Five patients had adjuvant systemic chemotherapy while 7 had adjuvant intravesical therapies. Mean follow-up period was 37.8 months (±25.3). Mean recurrence-free survival was 61.5% (CI 45.7 to 77.4) and mean overall survival 71.6 % (CI 57.4 to 85.8). Ten patients (37%) died of cancer. Conclusion Management of intra-diverticular bladder tumours is evolving. Bladder-sparing approaches are gaining popularity. Robot-assisted diverticulectomy is preferable as it reduces the morbidity resulting from treatment.

A phase II study of gemcitabine plus cisplatin chemotherapy in patients with muscle-invasive bladder cancer with bladder preservation for those patients whose tumors harbor deleterious DNA damage response (DDR) gene alterations (Alliance A031701).

TPS4615 Background: While a standard approach to muscle-invasive bladder cancer (MIBC) management involves neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC), up to 50% of pts recur with metastatic disease. Moreover, removal of the bladder has a significant impact on pts’ quality of life. Pathologic downstaging to non-muscle-invasive disease (<pT2) or complete response (pT0) at RC is associated with long-term survival benefit. Somatic DDR gene alterations were shown to be enriched in pts who were pT0 at RC following NAC in multiple retrospective analyses. We hypothesize that MIBC pts with somatic loss-of-function alterations within specific DDR genes and clinical responses to NAC can be uniquely managed with a bladder-sparing approach consisting of close cystoscopic and radiographic surveillance, avoiding the toxicities of definitive local therapy. Methods: A031701 is a multicenter phase II trial that will enroll 271 pts with T2-T4aN0/xM0 MIBC diagnosed within 60 days prior to enrollment. Multifocal MIBC, tumors >5 cm by cystoscopic assessment, and Bacillus Calmette-Guérin (BCG)-refractory disease (beyond standard induction and maintenance) are not allowed. Intravesical chemotherapy is allowed. Pts must be eligible for cisplatin chemotherapy. Eligible pts will receive either standard dose or dose dense gemcitabine and cisplatin chemotherapy (investigator’s choice) with simultaneous genetic sequencing of pre-treatment transurethral resection specimens. Pts whose tumors contain deleterious alterations in any 1 of 9 pre-selected DDR genes ( ERCC2, ERCC5, BRCA1, BRCA2, RECQL4, RAD51C, ATM, ATR, and FANCC) and who exhibit <T1 response on clinical restaging are eligible for organ-sparing management. Pts without deleterious DDR gene alterations or with >T1 disease after NAC will undergo RC or chemoradiation therapy (investigator/patient choice). The primary endpoint is 3-year event-free survival in DDR-altered pts who undergo bladder sparing, defined as the proportion of pts without BCG-unresponsive non-muscle invasive recurrences, any >T2 recurrences, or any metastatic recurrences. Secondary endpoints include clinical response rate (<cT1) in patients with deleterious DDR gene alterations following NAC, bladder-intact survival, overall survival, pT0 rate in DDR-altered pts who elect to undergo RC, pT0 rate in pts without DDR gene alterations, 3-year RC rate in pts with DDR gene alterations, and proportion of pts undergoing intravesical management for in-bladder recurrences. The study opened for enrollment in September 2018. Support: U10CA180821, U10CA180882. Clinical trial information: NCT03609216.

Integrative analysis of urine cell-free DNA for the detection of residual disease in localized bladder cancer patients.

559 Background: We previously developed a liquid biopsy assay to measure urine tumor DNA (utDNA) levels based on detection of single nucleotide variants (SNVs) in urine cell-free DNA (cfDNA). Nonsilent SNV detection in urine from muscle-invasive bladder cancer (MIBC) patients prior to radical cystectomy (RC) was associated with pathologic residual disease and worse progression-free survival (Chauhan et al., PLOS Medicine, 2021). Given the multiple types of genomic alterations present in bladder cancer (BC), here we developed a multi-omics approach for estimating utDNA levels without restricting our approach to SNVs. We performed ultra-low pass whole genome sequencing (ULP-WGS) based copy number analysis and urine Cancer Personalized Profiling by deep Sequencing (uCAPP-Seq) of urine cell-free DNA to predict pathologic complete response (pCR) in localized BC patients. Methods: We acquired urine preoperatively from 65 BC patients (69% muscle-invasive) on the day of standard-of-care RC, and after neoadjuvant chemotherapy in 48% of patients. We performed ULP-WGS of urine cfDNA from all 65 BC patients and 11 healthy adults. utDNA levels based on genome-wide copy number alterations (CNAs) in urine cfDNA was estimated using ichorCNA. In order to derive a SNV-based utDNA level as well, uCAPP-Seq was applied to urine cfDNA samples derived from 42 patients using a 145 kb panel of 49 consensus driver genes commonly mutated in MIBC. Results: In our cohort of 65 BC patients, 55% of patients achieved pCR ( n = 36) while 45% had residual disease detected in their surgical sample (no pCR; n = 29). Comparing ULP-WGS-derived utDNA levels between the groups, patients with no pCR had significantly higher CNA-derived tumor fractions in urine compared to patients with pCR (median 8.9% vs 1.8%, p = 0.01) and healthy adults ( n = 11) (median 8.9% vs 0%, p = 0.006). Further analysis with uCAPP-Seq in 42 patients revealed that nonsilent SNV-based utDNA detection correlated significantly with the absence of pCR ( p < 0.001) with a sensitivity of 81% and specificity of 81%. Moreover, utDNA-positive patients exhibited significantly worse progression-free survival compared to utDNA-negative patients (HR = 7.4; 95% CI: 1.4–38.9; p = 0.02). Conclusions: Bladder cancer patients who did not attain a pCR at the time of RC had greater genome-wide copy number alterations and nonsilent single nucleotide variants in their urine cfDNA compared to patients with pCR. These results suggest that integrative multi-omics of urine derived from MIBC patients has potential real-world clinical impact for bladder-sparing approaches in select patients.

High Androgen Receptor mRNA Expression Is Associated with Improved Outcome in Patients with High-Risk Non-Muscle-Invasive Bladder Cancer

The role of the androgen receptor (AR) in non-muscle-invasive bladder cancer (NMIBC) remains controversial. We retrospectively analyzed the mRNA expression of AR using RT-qPCR in 95 patients with high-risk NMIBC treated with a bladder-sparing approach and correlated AR with clinical data and recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). The mRNA expression of AR and KRT5, i.e., the basal-like subtype, was strongly correlated (rs = 0.456; p < 0.001). AR (p = 0.053) and KRT5 (p = 0.029) mRNA expression was negatively correlated with tumor grade. Kaplan–Meier analyses indicated significantly prolonged CSS (p = 0.020) and OS (p = 0.015) and a trend towards longer RFS (p = 0.051) in patients with high AR expression. High KRT5 expression was associated with significantly longer RFS (p = 0.033), CSS (p = 0.029) and OS (p = 0.030), while high KRT20 expression was associated with reduced RFS (p = 0.042). In multivariable analysis, none of the molecular markers was an independent prognostic factor. When performing a substratification with regard to molecular markers and clinicopathological parameters, high AR expression showed improved OS in patients with high KRT20 mRNA expression (p = 0.041). Women showed significantly longer OS in cases with high AR expression (p = 0.011). High AR was associated with significantly improved CSS in males (p = 0.044) and patients with instillation therapy (p = 0.040), while OS was improved regardless of instillation therapy. Younger patients with high AR expression had significantly improved RFS (p = 0.021), CSS (p = 0.014) and OS (p = 0.007). RFS was also improved in patients with high AR and low expression of either KRT5 (p = 0.003) or KRT20 (p = 0.014), but not in patients with high expression of KRT5 or KRT20. In conclusion, high AR mRNA expression is correlated with KRT5 mRNA expression and is associated with an improved outcome in high-risk NMIBC.