Treatment Of Muscle-invasive Bladder Cancer Research Articles

Neoadjuvant Chemoradiotherapy Followed by Radical Cystectomy for Muscle-Invasive Bladder Cancer: Analysis of Efficacy and Safety in 119 Patients

IntroductionCisplatin-based systemic chemotherapy is recommended as neoadjuvant treatment for muscle-invasive bladder cancer (MIBC) before radical cystectomy (RC). However, clinical challenges include the possibility of primary chemoresistance and limited feasibility in patients with renal impairment. This study investigated the efficacy and safety profiles of neoadjuvant chemoradiotherapy (NCRT) followed by RC. Materials and MethodsWe retrospectively analyzed 119 patients with nonmetastatic MIBC, who were pathologically diagnosed with urothelial carcinoma and underwent NCRT before RC. The pathological response to NCRT was evaluated using RC specimens. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were compared according to pathological responses to NCRT. ResultsOf the 119 patients, 111 (93%) underwent RC; ypT0 and downstaging to ≤ypT1 were observed in 42 (38%) and 76 (68%) patients, respectively. In the multivariable analysis, smaller tumor size was independently associated with ypT0. During a median follow-up of 5.2 years, 28 (25%) patients developed recurrence and 22 (20%) died of bladder cancer after RC. The 5-year RFS and CSS rates were 75% and 80%, respectively. The 5-year RFS rates in patients with ypT0, ypTa/is/1, and ≥ypT2 were 87%, 87%, and 46%, respectively. Similarly, patients with ypT0 and ypTa/is/1 had more favorable CSS (90% and 87% at 5 years, respectively) than those with ≥ypT2 (60%, P = .001). None of the patients experienced ≥grade 4 adverse events related to NCRT or ≥grade 4 complications of RC. ConclusionsThis study demonstrated sufficient efficacy and safety profile of NCRT followed by RC. Chemoradiotherapy may be a helpful alternative for neoadjuvant treatment before RC.

Role of Maximal Transurethral Resection Preceding Partial Cystectomy for Muscle-Invasive Bladder Cancer.

We aimed to evaluate whether maximal transurethral resection (TUR) affects the oncological outcome of partial cystectomy (PC) performed in patients with muscle-invasive bladder cancer (MIBC), although radical cystectomy (RC) and trimodal therapy (TMT) are regarded as standard treatments for MIBC. In this retrospective study, we evaluated the data of 98 patients who underwent PC due to MIBC between January 2006 and December 2018. Of the 98 patients, 71 underwent maximal TUR. We evaluated the recurrence-free survival (PFS), pelvic recurrence-free survival (pPFS), cancer-specific survival (CSS), and overall survival (OS) using the Kaplan-Meier method according to the maximal TUR status. Variables associated with survival were analyzed using Cox regression analyses. The 5-year PFS (42.5% vs. 20.3%, p = 0.008), pPFS (50.7% vs. 24.1%, p = 0.003), and CSS (74.0% vs. 51.0%, p = 0.016) were also higher in patients who underwent maximal TUR. The multivariable Cox regression analysis showed that maximal TUR was associated with PFS (hazard ratio [HR] = 0.500, p = 0.029), pPFS (HR = 0.353, p = 0.004), and CSS (HR = 0.416, p = 0.027). However, maximal TUR did not affect the OS (HR = 0.618, p = 0.132). PC resulted in acceptable oncological outcomes in patients with MIBC, while maximal TUR played an important role in improving the oncological outcomes. PC after maximal TUR can be suggested as a treatment option for MIBC patients who are unable to undergo RC and TMT.

Effectiveness of perioperative chemotherapy and radical cystectomy in treating bladder cancer

BackgroundDespite abundant evidence supporting the use of perioperative chemotherapy from clinical trials, no study to date has comprehensively evaluated its use in the treatment of muscle-invasive bladder cancer (MIBC) in the real-world setting. Little is known regarding the impact of pretreatment disease stage and real-world factors such as patient comorbidities preventing timely completion of therapy on its effectiveness. This study aims to assess the usage of perioperative chemotherapy and examines its impact on pathologic downstaging rates and recurrence free survival in patients undergoing radical cystectomy. MethodsA retrospective review was conducted in 805 patients with muscle invasive bladder cancer undergoing radical cystectomy with no perioperative chemotherapy, 761 with presurgical chemotherapy followed by radical cystectomy, and 134 radical cystectomy followed by adjuvant chemotherapy. Relevant clinicopathologic features were reviewed. Recurrence-free survival and Overall Survival probability estimates were calculated using the Kaplan–Meier method and compared using the Log-rank or Gehan-Breslow tests. The prognostic effects of presurgical chemotherapy and adjuvant chemotherapy regimens were evaluated by estimating hazard ratio and 95% confidence interval from an adjusted Cox proportional hazards model. Statistical tests were 2-sided, and significance was defined as P-value < 0.05. ResultsIn this contemporary, real-world cohort, 5-yr RFS was found to be 65.6% in pT0, 59.1%in <pT2, 35.4% in pT2, 15.3% in >pT2, and 10.8% in pN+ patients. Presurgical chemotherapy increased pathologic downstaging rates from 27.5% to 41.1% in patients with ≥cT2 BCa. Stratified by clinical T-stage, only cT2 patients derived recurrence-free survival (Median 45.3 months vs. 29.0 months, P < 0.01) and overall survival (Median 62.3 months vs. 41.9 months, P < 0.001) benefits. In patients with adverse pathologic features (≥pT3 or pN+), adjuvant chemotherapy improved recurrence-free survival (Median 22.8 months vs. 10.0 months, P < 0.0001) and overall survival (Median OS 32.4 months vs. 16.3 months, P < 0.0001). ConclusionsWe report real-world outcomes from a large cohort of muscle-invasive bladder cancer patients undergoing surgical treatment with/out perioperative chemotherapy. Pathologic response rates to pre-surgical chemotherapy were modest and led to clinical benefit only in cT2 patients. Adjuvant chemotherapy provided survival benefit for pathologically advanced MIBC patients irrespective of pT/N staging.

Oncological and functional outcome of robotic-assisted radical cystectomy with total intracorporeal stentless J-pouch neobladder reconstruction.

Robotic-assisted radical cystectomy (RARC) with neobladder reconstruction has gained popularity in recent years. We conducted a retrospective study of 17 consecutive patients who underwent RARC with totally intracorporeal J-pouch neobladder reconstruction without ureteral stent by a single experienced surgeon to evaluate perioperative, oncological and functional outcomes. The median follow-up duration was 32.8months (range: 17.4-59.0months), and the 2-year disease-free survival rate was 88.2%. Five out of 12 patients were totally continent, and none required more than one pad per day. The overall complication rate was 41.2%, and hydronephrosis was the most common adverse event. The renal function remained stable, and no long-term renal function impairment was detected. Our study suggests that RARC with totally intracorporeal J-pouch neobladder reconstruction without ureteral stent is a safe and feasible option for the treatment of muscle-invasive bladder cancer, with good oncological and functional outcomes.

Pembrolizumab with Chemoradiation as Treatment for Muscle-invasive Bladder Cancer: Analysis of Safety and Efficacy of the PCR-MIB Phase 2 Clinical Trial (ANZUP 1502)

BackgroundRadiation may improve the efficacy of immune checkpoint inhibition. This study investigates the combination of pembrolizumab and chemoradiation (CRT) for muscle-invasive bladder cancer (MIBC). ObjectiveTo assess the feasibility and safety of pembrolizumab combined with CRT for MIBC. Design, setting, and participantsA single-arm phase 2 trial was performed with 28 participants having cT2-T4aN0M0 MIBC (Eastern Cooperative Oncology Group performance status 0–1; estimated glomerular filtration rate ≥40 ml/min; no contraindications to pembrolizumab) suitable for CRT. InterventionWhole bladder radiation therapy (RT; 64 Gy in 32 daily fractions, over 6.5 wk, combined with cisplatin (35 mg/m2 intravenously [IV] weekly, six doses) and pembrolizumab (200 mg IV q3 weeks, seven doses), both starting with RT. Surveillance cystoscopy/biopsy and computerised tomography scans performed 12 and 24 wk after CRT. Outcome measurements and statistical analysisThe primary endpoint was feasibility, determined by a prespecified satisfactory low rate of grade 3 or worse nonurinary toxicity or completion of planned CRT according to defined parameters. Secondary endpoints were complete cystoscopic response, locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), and overall survival (OS). Results and limitationsTwenty-eight patients were enrolled with a 31-mo median follow-up. Six had Grade >3 nonurinary adverse events during/within 12 wk after treatment; three had more than one cisplatin dose reduction. The 24-wk post-CRT complete response (CR) rate was 88%. Eight patients developed metastatic disease, and three had nonmetastatic progression. The DMFS at 2 yr is 78% (95% confidence interval [CI] 54–90%), with LRPFS at 2 yr of 87% (95% CI 64–96%) and median OS of 39 mo (95% CI 17.1–not evaluable). Limitations are the single-arm design and sample size. ConclusionsCombining pembrolizumab with CRT for MIBC was feasible, with manageable toxicity and promising CR rates. Patient summaryImmunotherapy treats nonmetastatic/metastatic bladder cancer effectively. We combined pembrolizumab with chemotherapy and radiation to assess its safety and impact on treatment delivery. The combination was feasible with encouraging early activity. Further larger trials are warranted.

Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial

Cystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC), but it is life-altering. We initiated a phase 2 study in which patients with MIBC received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Patients achieving a clinical complete response (cCR) could proceed without cystectomy. The co-primary objectives were to assess the cCR rate and the positive predictive value of cCR for a composite outcome: 2-year metastasis-free survival in patients forgoing immediate cystectomy or <ypT1N0 in patients electing immediate cystectomy. Seventy-six patients were enrolled; of these, 33 achieved a cCR (43%, 95% confidence interval (CI): 32%, 55%), and 32 of 33 who achieved a cCR opted to forgo immediate cystectomy. The positive predictive value of cCR was 0.97 (95% CI: 0.91, 1), meeting the co-primary objective. The most common adverse events were fatigue, anemia, neutropenia and nausea. Somatic alterations in pre-specified genes (ATM, RB1, FANCC and ERCC2) or increased tumor mutational burden did not improve the positive predictive value of cCR. Exploratory analyses of peripheral blood mass cytometry and soluble protein analytes demonstrated an association between the baseline and on-treatment immune contexture with clinical outcomes. Stringently defined cCR after gemcitabine, cisplatin, plus nivolumab facilitated bladder sparing and warrants further study. ClinicalTrials.gov identifier: NCT03451331.

Real World Multi-Institutional Outcomes of Bladder Carbogen and Nicotinamide (BCON) in Muscle-Invasive Bladder Cancer (MIBC).

Bladder carbogen and nicotinamide (BCON), combined with radiotherapy, is a standard of care in the bladder-preserving treatment of muscle-invasive bladder cancer (MIBC). UK national guidelines recommend neoadjuvant chemotherapy (NAC) before bladder preservation. However, patients did not receive NAC in the definitive phase III BCON trial. This study assessed tolerability and real-world outcomes of BCON alone or with NAC (NAC-BCON). With institutional approval, demographics and clinical information were obtained for a retrospective cohort study of BCON patients (2017-2021) across 3 UK centers. Clinician-reported toxicity was assessed using RTOG grading during radiotherapy, 6 weeks and 12 months after. Cross-sectional imaging and cystoscopy determined local control, metastasis-free survival (MFS), and cancer-specific survival (CSS). Subgroup differences were compared using T and χ2 tests. Survival was analyzed by Kaplan-Meier, log-rank, and multivariate Cox proportional hazard regression. Statistical analysis was conducted using R version 4.2.1 (R Core Team (2022)). A total of 317 patients were treated with BCON; 75 (24%) received NAC-BCON. Median follow-up was 29 months (4-63m). Patient characteristics are shown in Table 1. NAC-BCON patients were younger (median 72 vs 78 years, p<0.05), with better PS (p<0.05) and ACE-27 (p<0.05), with no statistical difference in T-staging and histopathology. 298 (94%) completed BCON, whilst 59/75 (79%) completed ≥3 cycles of NAC. There was no significant increased grade 3 acute or late bowel or bladder toxicity with NAC. 3-month cystoscopy post radiotherapy demonstrated complete response in 282/317 (89%). 121 (38%) developed metastases, and 112 (35%) died of MIBC. 5-year BCON MFS was 62% and 49% for NAC-BCON (HR 0.69, 95% CI 0.98- 2.51, p = 0.064); 5-year BCON CSS was 55% and 52% for NAC-BCON (HR 0.83, 95% CI 0.79-1.83, p = 0.39). This remained after adjusting for clinical factors in a multivariate Cox model for both MFS (p = 0.22) and CSS (p = 0.37). Our real-world data compares favorably to published BCON 5-year relapse-free survival (41%) and OS (49%). NAC-BCON has no increased toxicity with comparable treatment completion rates to BCON alone. No significant improvement in survival outcomes was seen with NAC, possibly due to small numbers and patient selection in a non-randomized cohort. Further analysis is planned with additional center input.

Early Experience with CBCT-Guided Online Adaptive Radiotherapy for Muscle Invasive Bladder Cancer.

Radiation therapy for muscle-invasive bladder cancer (MIBC) requires substantial planning target volume (PTV) margins to account for variability in bladder filling as well as other anatomic changes. We hypothesized that CBCT-guided online adaptive RT (oART) may both improve target coverage and reduce normal tissue exposure as compared to non-adaptive RT. The purpose of this study is to report the dosimetric results of our initial experience utilizing oART for treatment of MIBC. Seven patients with MIBC were treated with oART over a 1-year period. Patients were simulated with an empty bladder and were asked to void prior to each treatment. Five patients received 55 Gy in 20 fractions to a clinical target volume (CTV) expanded from the TURBT bed and 46 Gy simultaneously to the remaining bladder and for 2 patients the high dose CTV was the entire bladder. PTVs consisted of a 7mm isometric expansion of the CTV. The oART delivery process initially coregisters the daily CBCT to the treatment planning CBCT using skeletal alignment. Target volumes and organs-at-risk (OARs) were modified at each treatment session and the plan re-optimized to meet prespecified clinical goals. Target coverage and OAR dosimetric parameters for the adaptive were compared non-adaptive (scheduled) plan for each fraction using the Wilcoxon paired test of means. The adapted plan was selected for delivery for all fractions across all patients. Daily bladder volumes differed from the bladder volume at simulation by a mean of 60cc ± 66cc. At least 95% of the high dose CTV was covered by the prescription dose for 139 (99.3%) fractions with the oART plan as compared to 70 (50%) fractions with scheduled. A portion of the high dose CTV was outside of the 80% isodose line for 13 (9.3%) of scheduled fractions and was outside of the 50% isodose line for 2 (0.01%) of scheduled fractions. There were no cases of oART plans where any portion of the high dose CTV was outside of the 90% isodose line. A comparison of selected target and OAR dosimetric parameters is shown in the Table. oART treatment plans were associated with greater target coverage and less OAR exposure for all metrics. In this initial experience, oART resulted in acceptable delivered dosimetry to target volumes with a reduced PTV margin of 7mm despite considerable daily variation in bladder volume. As expected, oART plans were associated with improved target coverage and OAR dosimetry. Future patient-centered studies should explore the clinical impact of reduced margin oART for patients with MIBC.

Radiotherapy vs. Cystectomy for Treatment of Muscle Invasive Bladder Cancer in Very Elderly Patients

Radical cystectomy (RC) has long remained the principal treatment of muscle invasive bladder cancer (MIBC). It is, however, associated with significant morbidity, long recovery, and reported worse overall and cancer specific survival, particularly for the very elderly (age > = 80). Bladder preservation with transurethral resection of bladder tumor (TURBT) followed by radiotherapy (RT) +/- concurrent chemotherapy (ChT) is regarded as a curative-intent alternative to RC in well-selected patients. The optimal treatment strategy remains unclear in very elderly patients. We hypothesize that outcomes following RT vs RC are clinically equivalent for treatment of MIBC in very elderly patients. Patients > = 80 years old with T2-T4 N0-N1 bladder cancer treated definitively with RT versus RC were included. Exclusion criteria included history of pelvic RT, prior cystectomy, or palliative treatment intent. Clinicopathologic and treatment-related details, as well as clinical outcomes and toxicities were retrospectively abstracted. Kaplan-Meier analyses were performed. At a median follow-up of 17 months (range 0.25-190), 47 patients received RT vs 83 patients who underwent RC with median age of 86 years (80-97) vs 83 years (range 80-91) (p<0.01), respectively. Median Charlson Comorbidity Index was similar between groups (p = 0.35) with median 7 for both cohorts, predicting 0% estimated 10y survival. Most patients had cT2 tumors (91% vs 99%, p = 0.06), cN0 nodal status (96% vs 100%, p = 0.06), and urothelial carcinoma histology (79% vs 90%, p = 0.22). Most RT patients received concurrent ChT (90%) and a minority of RC patients received neoadjuvant ChT (16%). 70% of RT pts had complete TURBTs prior to RT. Common RT regimens were 50-55 Gy in 20-25 fractions or 60-64.8 Gy in 30-36 fractions, using IMRT (89%) or 3D conformal (11%) technique. Overall survival for RT vs RC at 1- and 2- years was 79% vs 85% and 57% and 69%, respectively (p = 0.20). Locoregional control at 1- and 2-years was 73% vs 70% and 63% vs 66% (p = 0.59), respectively. Progression free survival at 1- and 2-years was 69% vs 66% and 52% vs 54% (p = 0.75), respectively. No RT patients went on to receive salvage cystectomy. Treatment complications are listed in Table 1; the Clavien Dindo classification system was used to describe acute surgical complications of RC and the Common Terminology Criteria for Adverse Events (CTCAE) Dictionary v5.0 was used for acute and late toxicity of RT. In the very elderly, RT (with or without concurrent ChT) offers survival and locoregional control rates comparable to RC, with a favorable side effect profile. RT should be offered for definitive management of non-metastatic MIBC as an alternative to RC in selected, well- informed, and compliant very elderly patients.

Advantages of enhanced recovery after surgery program in robot-assisted radical cystectomy

Radical cystectomy is a gold-standard treatment for muscle-invasive bladder cancer. We recently introduced robot-assisted radical cystectomy (RARC) with perioperative enhanced recovery after surgery (ERAS). The medical records of patients with bladder cancer who underwent open radical cystectomy (ORC) or RARC/ERAS at NTT Medical Center Tokyo were retrospectively reviewed to compare the surgical outcomes, hospital stay, and medical costs between groups. Multidisciplinary full ERAS items were provided for the RARC/ERAS group. The median estimated blood losses in the ORC and RARC/ERAS groups were 650 and 100 mL, and the median operative times were 312 and 445 min, respectively. In addition, the median times to liquid food intake in these groups were 6 and 0 days, the median times to first flatus and first defecation were 2 and 1 day, and 3 and 1.5 days, respectively. The rates of postoperative ileus in the ORC and RARC/ERAS groups were 27.5% and 4.5%, and the median postoperative hospital stays was 26.5 and 12 days, respectively. Medical costs excluding surgery were significantly lower in the RARC/ERAS group. In conclusion, RARC/ERAS represents a safe treatment option for muscle-invasive bladder cancer with decreased perioperative complications and lower medical costs.

The bladder cancer immune micro-environment in the context of response to immune checkpoint inhibition.

Treatment with neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the default treatment for muscle-invasive bladder cancer (BC). However, with the encouraging results of immune checkpoint inhibitiors (ICI) directed against PD-1/PD-L1 and CTLA-4 in recent years, the treatment landscape of BC is rapidly changing. In addition, it is becoming clear that the effect of ICI is highly dependent on the interaction between tumor cells and the tumor immune micro-environment (TIME). Different immune cells are involved in an anti-tumor response in BC. Cytotoxic CD8+ T-cells are the main effector cells, aided by other immune cells including other T-cells, B-cells and pro-inflammatory macrophages. As part of the ongoing anti-tumor immune response, lymphocytes aggregate in clusters called tertiary lymphoid structures (TLS). Tumor mutational burden (TMB) and infiltration of immune cells into the tumor are both important factors for establishing an anti-tumor immune response. In contrast, transforming growth factor beta (TGF-β) signaling in cancer-associated fibroblasts (CAFs) prevents infiltration of lymphocytes and potentially has an immunosuppressive effect. In conclusion, the effect of ICI seems to be reliant on a combination of tumor-intrinsic and TIME-related parameters. More research is needed to fully understand the underlying biological mechanisms to further improve patient care.

Adequate Pelvic Lymph Node Dissection in Radical Cystectomy in the Era of Neoadjuvant Chemotherapy: A Meta-Analysis and Systematic Review.

Radical cystectomy (RC) with pelvic lymphadenectomy (PLND) serves as the gold-standard treatment for muscle-invasive bladder cancer (MIBC). Numerous studies have shown that the number of lymph nodes (LN) removed during RC could affect patient prognosis. However, these studies confirmed the association between PLND and survival outcomes prior to the widespread adoption of neoadjuvant chemotherapy (NAC). Consequently, this study aimed to investigate the prognostic role of PLND in patients previously pretreated with NAC. A systematic review and meta-analysis were performed using PubMed, Web of Knowledge, and Scopus databases. The selected studies contained a total of 17,421 participants. The meta-analysis indicated a significant correlation between adequate PLND and overall survival in the non-NAC group. However, a survival benefit was not observed in patients undergoing RC with preoperative systemic therapy, regardless of the LN cut-off thresholds. The pooled HR for ≥10 and ≥15 LN were 0.87 (95% CI 0.75-1.01) and 0.87 (95% CI 0.76-1.00), respectively. The study results suggest that NAC mitigates the therapeutic significance of PLND, as patients pre-treated with NAC no longer gain oncological benefits from more extensive lymphadenectomy. This highlights the analogous roles of NAC and PLND in eradication of micrometastases and in prevention of distal recurrence post-RC.

Perioperative Immunotherapy in Muscle-Invasive Bladder Cancer.

There is an acute unmet need to develop novel treatment regimens in the perioperative setting since many patients with muscle-invasive bladder cancer (MIBC) are not eligible for the current standard of care (SOC) neoadjuvant treatment with cisplatin-based chemotherapy. The introduction of immune checkpoint inhibitors (ICIs), both as monotherapy and in combination regimens with other ICIs, chemotherapy, or targeted drugs, may provide safe and clinically effective treatment options that could revolutionize current standard of care. In the neoadjuvant setting, compelling data from phase II clinical trials suggests that single-agent immunotherapy, as well as dual-checkpoint blockade, may emerge as reasonable alternatives to traditional cisplatin-based chemotherapy. Prospective studies combining ICIs with chemotherapy or with antibody-drug conjugates have also demonstrated robust outcomes. However, these studies are not yet practice changing and data from larger randomized studies are needed to confirm this benefit. In the adjuvant setting, nivolumab is the FDA-approved treatment based on a disease-free survival benefit relative to placebo in a randomized trial. However, it will be important to confirm an overall survival benefit of this treatment and to better identify patients who need additional adjuvant treatment based on novel biomarker data. The treatment of muscle-invasive bladder cancer is moving toward the individualization of treatment options based on specific tumor and patient characteristics and away from the one-size-fits-all approach that has dominated this space for the last couple of decades. Emerging biomarker data, such as with ctDNA, suggests that immunotherapy may confer greater benefit to selected patients. Identifying who those patients are will be of paramount importance since additional treatments always come with additional toxicities. On the other hand, the more favorable toxicity profiles of certain immunotherapy-based regimens may make them superior options for some patients who would otherwise be unable to tolerate other systemic regimens. In the near future, it is likely that subsets of patients with MIBC will be receiving treatments with predominantly immunotherapy-based regimens while many patients may still be treated with regimens containing a cisplatin-based chemotherapy backbone. Currently ongoing clinical trials will help to better define patient populations optimized for each treatment.

Bladder only versus bladder plus pelvic lymph node chemoradiation for muscle-invasive bladder cancer.

Bladder-sparing chemoradiation therapy (CRT) is a definitive first-line treatment for muscle-invasive bladder cancer. The optimal radiotherapy target volume, either bladder-only (BO) or bladder plus pelvic lymph nodes (BPN), remains unclear. We identified 2,104 patients in the National Cancer Database with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with CRT following maximal transurethral resection of bladder tumor from 2004 to 2016. The exposure of interest was BO vs. BPN treatment volume. The primary outcome was overall survival (OS), compared between groups using Kaplan-Meier and multivariable Cox proportional hazards. Sensitivity analysis tested an interaction term for clinical T stage (T2 vs. T3-4) and radiation modality (3-dimensional conformal radiotherapy vs. intensity modulated radiotherapy or proton therapy). Annual use of BO vs. BPN from 2004 to 2016 was compared using Cochran-Armitage test. A total of 578 patients were treated with BO and 1,526 patients treated with BPN CRT. There was a significant increase in BPN use from 2004 to 2016 (66.9%-76.8%, P < 0.0001). With a median follow-up of 6.2 years, there was no survival difference between groups: 5- and 10-year OS 27.4% (95% CI 23.4%-31.4%) in the BO group vs. 31.9% (95% CI 29.3%-34.6%) in the BPN group, and 13.1% (95% CI 9.7%-17.1%) in the BO group vs. 13.2% (95% CI 10.6%-16.0%) in the BPN group, respectively (log-rank P = 0.10). On multivariable analysis, there was no significant association between BPN and OS (adjusted HR 0.90, 95% CI 0.81-1.02, P = 0.09). On sensitivity analysis, we found no differential effect by T stage or radiation modality. Use of pelvic lymph node radiation has risen in the US but may not impact long-term survival outcomes for patients with node-negative muscle-invasive bladder cancer (MIBC). Optimizing radiation treatment volumes for CRT for MIBC will be important to study under prospective trials, such as the SWOG/NRG 1806.

Intraoperative ICG-Fluorescence as a Method to Prevent Postoperative Strictures of Uretero-Ileal Anastomoses in Robot-Assisted Radical Cystectomy

Introduction. Radical cystectomy with urine diversion is recognized as the standard for the treatment of muscle-invasive bladder cancer. One of the dangerous complications in the postoperative period is the stricture of uretero-ileal anastomosis leading to hydroureteronephrosis, renal failure, and urosepsis. One of the factors in the development of the anastomotic stricture is ischemia. In order to reduce possible ischemic injury, the following manipulations are performed: careful treatment of tissues in the area of future anastomosis, preservation of periureteral adventitia, minimal mobilization of ureters before implantation into conduit. Intraoperative assessment of ureteral and intestinal tissue perfusion using ICG-fluorescence is a promising area. Materials and methods. The study enrolled 56 patients who underwent a robotic-assisted radical cystectomy with intracorporeal urine diversion from January 2021 to March 2022 at the Bashkir State Medical University Clinic. Patients were divided into two groups: group 1 (22 patients) underwent intraoperative ICG-imaging, and group 2 (34 patients) — imaging without fluorescence. The median follow-up period was 14 months for group 1 and 12 months for group 2. The comparison criteria between the groups were demographic indicators, perioperative outcomes (including 30- and 90-day complications), and the incidence of strictures of uretero-ileal anastomoses. The groups were compared using a test for equality of means and a test for sampling distributions. Results and discussion. No statistically significant differences between patients were reported during the time of surgery, estimated blood loss, and duration of hospital stay. No significant differences were also detected in the incidence of 30- and 90-day complications and the number of readmissions among patients in group 1 and group 2 (p = 0.477 and p = 0.089, respectively). The incidence of strictures of uretero-ileal anastomosis in group 1 demonstrated a statistically significant decrease, as compared with group 2 (0/34 [0 %] and 7/68 [10.3 %], p = 0.020). Conclusion. The ICG-fluorescence imaging to assess vascularization of the distal ureter during robotic-assisted radical cystectomy with intracorporeal urine diversion may reduce the risk of postoperative uretero-ileal anastomotic ischemic strictures.

#5001 AKI AND AKD AFTER RADICAL CYSTECTOMY FOR MUSCLE INVASIVE BLADDER CANCER: AN UNEXPECTED NEPHROLOGICAL AFFAIR

Abstract Background and Aims Radical cystectomy (RC) represents the first line surgical treatment for muscle-invasive bladder cancer (MIBC). RC is a complex surgical procedure characterized by significant morbidity and mortality. The incidence of significant complications following RC is a well-recognized issue however still paucity of data exists regarding postoperative renal function. Aim of the study was to evaluate the incidence of acute kidney injury (AKI) and Acute kidney disease (AKD) after RC, evaluating the impact of surgery (open or robotic one), comorbidities (hypertension, diabetes, CAD) and previous oncological treatments (chemotherapy, immunotherapy and radiotherapy). Method We collected a consecutive cohort of 839 patients who underwent RC for MIBC in a single tertiary institution between 2010 and 2022. All clinical variables and comorbidities were reported pre and after surgery. Serum creatinine with subsequently eGFR using CKD-EPI formula were collected at baseline pre-operative and in the acute setting at 24h, 48, 72h, 6 days for the AKI onset, and after 9,12,15,18,21,24,27,30,45, 60, 75, 90 days for the AKD establishment. We compared the incidence of AKI and AKD upon the two different surgical approaches for RC :the open and robotic one. Fisher's exact test; Wilcoxon rank sum test; Pearson's Chi-squared test were used for the statistical analysys. Results General characteristics of patients included in the study are summarized in Table 1. Surprisingly, a very high rate of both AKI (30%) and AKD (50%) was reported in the total cohort of patients, with an augmented incidence in the robotic surgery (p &amp;lt; 0.001). Moreover, stage II and III of both AKI and AKD affected a non-negligible percentage of patients, requiring advanced nephrological medical treatments and prolonged hospitalization (Table 1). The multivariate analysis showed that age, blood hypertension and BMI represent the major risk factors to develop both AKI and AKD (Table 3 and Figure 1). Conclusion AKI and AKD are very frequent and insidious side effects in the RC for MIBC. Therefore, a personalized nephrological counseling both in the pre and post -surgery asset is mandatory to reduce morbidity and mortality.

Medicaid Expansion and Racial Disparity in Timely Multidisciplinary Treatment in Muscle Invasive Bladder Cancer.

Multidisciplinary cancer care (neoadjuvant chemotherapy+radical cystectomy (NAC+RC) or trimodality treatment (TMT)) is crucial for outcome of muscle invasive bladder cancer (MIBC), a potentially curable illness. Medicaid expansion through Affordable Care Act (ACA) increased insurance coverage especially among patients of racial minorities. This study aims to investigate the association between Medicaid expansion and racial disparity in timely treatment in MIBC. This quasi-experimental study analyzed 18-64-year-old Black and White people with stage II&III bladder cancer treated with NAC+RC or TMT from National Cancer Database 2008-2018. Primary outcome was timely treatment started within 45 days following cancer diagnosis. Racial disparity is the percentage-point difference between Black and White patients. Patients in expansion and nonexpansion states were compared using difference-in-differences (DID) and difference-in-difference-in-differences (DDD) analyses, controlling for age, sex, area level income, clinical stage, comorbidity, metropolitan status, treatment type, and year of diagnosis. The study included 4991 patients (92.3% White, N = 4605; 7.7% Black, N = 386). Percent of Black patients received timely care increased following the ACA in Medicaid expansion states (54.5% pre-ACA vs 57.4% post-ACA) whereas decreased in non-expansion states (69.9% pre-ACA vs 53.7% post-ACA). After adjusting covariates, Medicaid expansion was associated with a net 13.7 percentage-point reduction of Black-White disparity in timely receipt of MIBC treatment (95%CI: 0.5%-26.8%; p < .01). Medicaid expansion was associated with statically significant reduction in racial disparity between Black and White patients in timely multidisciplinary treatment for MIBC.

A proof-of-concept study on endoscopic ultrasound-guided biopsy of detrusor muscle in porcine bladders.

Conventionally, we rely on transurethral resection of bladder tumour (TURBT) for local staging of muscle-invasive bladder cancer (MIBC). However, the procedure is limited by its staging inaccuracy which may delay the definitive treatment of MIBC. We conducted a proof-of concept study on endoscopic ultrasound (EUS)-guided biopsy of detrusor muscle in porcine bladders. Five porcine bladders were used in this experiment. Upon EUS, four layers of tissue including the mucosa (hypoechoic), submucosa (hyperechoic), detrusor muscle (hypoechoic) and serosa (hyperechoic) could be identified. A total of 37 EUS-guided biopsies were taken from 15 sites (three sites per bladder), and the mean number of biopsies taken from each site was 2.47±0.64. Among the 37 biopsies, 30 of them (81.1%) obtained detrusor muscle in the biopsy specimen. For the per biopsy site analysis, detrusor muscle was obtained in 73.3% if only one biopsy was taken, and 100% if two or more biopsies were taken from the same biopsy site. Overall, detrusor muscle was successfully obtained from all 15 biopsy sites (100%). No bladder perforation was observed throughout all biopsy processes. EUS-guided biopsy of the detrusor muscle could be performed during the initial cystoscopy session, thus expediting the histological diagnosis and subsequent treatment of MIBC.

Urine DNA model to predict response to neoadjuvant immune checkpoint inhibitors combined with chemotherapy in muscle-invasive bladder cancer.

e16594 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) combined with chemotherapy show promise in the treatment of muscle-invasive bladder cancer (MIBC). However, not all patients benefit from the treatment. Urine can overcome shortcomings of tissue-based biomarkers to guide treatment decisions. Methods: Thirty-Three patients were recruited in this study and they received three cycles of tislelizumab 200 mg intravenously on day 1 plus nab-paclitaxel 200 mg intravenously on day 2 every three weeks, followed by surgical treatment. Acornmed 808 panel and shallow whole-genome sequencing were performed to predict the efficacy based on the urine DNA. Results: The urine ctDNA levels (highest variant allele fraction) were significantly lower in responder (CR and PR ) patients than this in non-responder (SD and PD) patients (p &lt; 0.001). In addition, a decrease in chromosomal instability number (CIN) occurred in responding tumors (p = 0.028). Furthermore, ROC curves were used to compare the sensitivity and specificity of efficacy prediction, including the urine ctDNA level and CIN. In the ROC analysis, urine ctDNA level setting with an area under the ROC curve (AUROC) of 0.781 (95% CI 0.603 - 0.905, p = 0.005), achieving 100% sensitivity and 54.6% specificity in efficacy prediction. The ROC curve for CIN achieved a sensitivity of 68.2% and specificity of 72.7% (AUC = 0.731; 95% CI: 0.549-0.870, p = 0.013). Combination urine ctDNA level and CIN achieved a sensitivity of 100%, specificity of 63.6% (AUC = 0.806; 95% CI: 0.631-0.922, p = 0.002), positive predictive value (PPV) of 0.846, and negative predictive value (NPV) of 1.000. Conclusions: The classifier provides a framework for novel biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

Identification of biomarkers for early progression in muscle invasive bladder cancer (MIBC) using real-world data.

e16568 Background: MIBC accounts for ~25% of all newly diagnosed bladder cancers and is associated with a high rate of recurrence despite radical treatment. The time to progression (TTP) can vary significantly between patients and can affect their prognosis. We leveraged a real world clinico-genomics database to classify patients as early vs late progressors, understand its impact on their outcomes and identify genetic drivers of early progression. Methods: This retrospective study was executed using the deeply curated ConcertAI Genome360 bladder cancer dataset. Only patients with confirmed MIBC status with reported tumor progression after initial treatment were considered. Based on the distribution of TTP from MIBC diagnosis of this patient cohort, we subdivided the patients into early vs late progressors. Overall survival (OS) and progression free survival (PFS) analyses were performed between these 2 cohorts. The underlying deleterious genomic mutations were identified in each cohort and differential genomic enrichment analysis was performed to identify statistically significant biomarkers correlated with early progression (p-value &lt; = 0.05). Additionally, identified biomarkers were analyzed in the context of administered therapies. Results: The TTP exhibited a bimodal distribution with a break at around 500 days, so we chose this as the cut-off to define early (N = 203) vs late progressors (N = 51). As expected, there was a significant difference in the median PFS of early vs late progressors (0.62 vs 2.41 years (p &lt; 1e-6)). The OS was also significantly different (1.98 vs 4.36 years (p = 6e-6)). We further identified mutations in 6 biomarkers which were enriched in early vs late progressors. These were CDK12 (p = 0.05), EGFR (p = 0.034), LRP1B (p = 0.05), MET (p = 0.045), PTEN (p = 0.026) and SMAD4 (p = 0.047). These patients were primarily treated with platinum-based therapies +/- gemcitabine/PD-L1 therapies in-line with MIBC treatment guidelines. The identified driver genes activate PI3K-AKT-MTOR, JAK-STAT3, b-catenin and ERK pathways which are known to interfere with the mechanism of action of platinum-based therapies, thus potentially forming the basis of early progression. Conclusions: Using our Genome360 bladder dataset, we have identified prognostic biomarkers for early progression in MIBC. This may provide clinicians with a tool to identify and modify treatment for a subset of MIBC patients who are at risk of early progression on standard of care therapies.