Treatment Of Muscle-invasive Bladder Cancer Research Articles

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.

Gender and postoperative surgical margin status in MIBC: An analysis of the National Cancer Database.

4599 Background: Women with muscle-invasive bladder cancer (MIBC) continue to experience persistent disparities in health outcomes despite accounting for less than 1/3 of newly diagnosed bladder cancer cases. Multiple studies have acknowledged the aggressive profile of female bladder cancer. This study aims to identify tangible areas to intervene and improve the delivery of oncologic care. Methods: The National Cancer Database (NCDB) was queried from 2004-2017 to conduct a retrospective cohort analysis of men and women with MIBC (cT2a-T4). N=41,037 patients with MIBC were reviewed, (30,313 male; 10,724 female). The primary endpoints were OS and surgical margin status. Logistic regression was performed to determine whether female sex conferred differential impact on surgical margin status when controlling for baseline clinical stage, age, receipt of neoadjuvant chemotherapy (NAC), Charleson-Deyo Comorbidity Classification (CDCC), and facility type. Cox proportional hazards assessed the impact of age, gender, margin status, CDCC and NAC on OS. Results: Logistic regression showed that sex, age, baseline clinical stage, CDCC, facility type and NAC were significant predictors of surgical margin status (p&lt;.001). Female sex was found to have a 14.4% higher probability of having positive residual margins (HR 1.144 (95% CI: 1.07-1.23), p&lt;.001). When adjusting for age, margin status, CDCC and NAC, Female gender (OS HR 1.063 (95% CI: 1.03-1.09), p&lt;.001), positive microscopic margins (OS HR 2.0 (95% CI: 1.90-2.10), p&lt;.001) and positive macroscopic margins (OS HR 2.62 (95% CI: 2.40-2.90), p&lt;.001) independently portended poorer OS and necessitated increased adjuvant XRT (p&lt;.001). Unexpected demographic findings included a significantly greater number of females than expected with a median household income &lt;$38,000 (p= 0.047) and a greater number of females in the upper quartile of patients without a HS diploma (p&lt;.001). The median days from diagnosis to definitive surgical treatment was significantly lower compared to males (58 vs 67 days; p&lt;.001). Conclusions: Women with MIBC faced obstacles to getting treatment (less education and lower median income). Despite these hurdles they may be more proactive with their health as seen by a shorter time from diagnosis to the surgical table. However, this proactivity has yet to pay off as women undergoing surgical treatment for MIBC were significantly less likely to have clear margins post-operatively. The urologic community must mirror female patient’s proactivity and further investigate the gender disparity in surgical treatment of MIBC. [Table: see text]

Clinical application and efficacy analysis of partial cystectomy combined with intravesical chemotherapy in muscle-invasive bladder cancer

ObjectivesComparing the long-term tumor control results of partial cystectomy(PC)and radical cystectomy(RC)in the treatment of muscle-invasive bladder cancer, and to explore the feasible method of bladder preservation therapy (BPT)in patients with MIBC.MethodsWe retrospectively analyzed the clinical data of 102 patients with muscle-invasive bladder cancer in our hospital between January 2012 and December 2018, of whom 32 cases in the partial cystectomy group and 70 cases in the radical cystectomy group. We performed a comparative analysis of patient general information, perioperative-related indicators and postoperative follow-up data, comparing OS, PFS, and DSS at 1, 2, 3, 4, and 5 years in both groups, and comparing tumour recurrence and metastasis in postoperative patients.ResultsAll the 102 cases in this study were successfully completed. Partial cystectomy group and Radical cystectomy group median operating time (169.50(130.00 ~ 225.25) min and 420.00(343.75 ~ 483.75) min, p < 0.001), median intraoperative blood loss was (100(50 ~ 100)ml and 400(200 ~ 1000)ml, p < 0.001), median perioperative blood transfusion volume (0(0 ~ 0)ml and 600(150.00 ~ 906.25)ml, p < 0.001), median total hospital stay (18(14.25 ~ 20.00) and 24.5(20.00 ~ 34.25) days, p < 0.001), median preoperative preparation time (7(4.25 ~ 8.00) and 10(8.00 ~ 13.00) days, p < 0.001), median postoperative hospital stay (9(8.00 ~ 13.50) and 14(11.00 ~ 21.25) days, p < 0.001), the incidence of perioperative blood transfusion was (15.6% and 75.7%, p < 0.001), the incidence of surgical complications was(28.1%(9/32) and 50.0%(35/70), p = 0.033), average hospitalization cost ((26435.76 ± 9877.82) yuan and (58464.36 ± 19753.13) yuan, p < 0.001), the differences were statistically significant (p < 0.05). Perioperative mortality (0 vs. 2.9%(2/70), p = 1), and OS at 1, 2, 3, 4, and 5 years after surgery were (80.0%, 59.8%, 56.1%, 51.0%, 44.6% vs. 76.5%, 67.4%, 64.9%, 57.9%, 52.6%, p = 0.524), PFS (68.2%, 64.6%, 60.3%, 54.8%, 54.8% vs. 82.7%, 78.3%, 75.4%, 67.3%, 62.1%, p = 0.259). DSS (89.9%, 72.4%, 68.6%, 68.6%, 62.4% vs. 87.3%, 83.4%, 80.9%, 73.6%, 68.0%, p = 0.424), and the incidence of tumor recurrence or metastasis was (40.0%(12/30) vs. 25.4%(16/63), p = 0.151), the differences were not statistically significant (p > 0.05).ConclusionIn patients with limited solitary T2N0M0 and T3N0M0 muscle-invasive bladder cancer, partial cystectomy plus bladder instillations treatment can achieve comparable tumour control to radical cystectomy. However, patients in the PC group have significant advantages in terms of operative time, intraoperative bleeding, intraoperative and postoperative blood transfusion, preoperative preparation time, total hospital stay, postoperative recovery time, operative costs and operative complications. This option may be considered for such patients with a need for bladder preservation.

Impact of Minimally Invasive Approach to Radical Cystectomy in Bladder Cancer Patients with Malnutrition

Malnutrition is associated with higher rates of complications following radical cystectomy (RC) for the treatment of muscle-invasive bladder cancer. The newer robotic approach to RC has yet to be analyzed against the open approach in malnourished patients with respect to perioperative complications. A retrospective cohort analysis of RC patients with a postoperative diagnosis of bladder cancer and non-disseminated disease was performed. Malnourishment was defined as either low serum albumin (<3.5 g/dL), >10% 6-month preoperative weight loss, or BMI <18.5 kg/m2). Multivariable and generalized logistic regression were used for categorical and continuous outcomes respectively. Malnourishment was associated with greater systemic sepsis, bleeding transfusions, 30-day mortality, postoperative C. difficile infection, and days from operation to discharge (DOD) (all P < 0.05). In malnourished patients, robotic approach was associated with lower adjusted odds of bleeding transfusions (aOR = 0.51, P < 0.05) and fewer adjusted days from operation to discharge (β[SE]= −5.2[1.1], P < 0.05) compared to open. Typical benefits seen with minimally-invasive robotic surgery translate to malnourished patients, although they were still prone to longer hospital stay than their adequately nourished counterparts. Robotic approach to RC may help mitigate the increased need for transfusions and longer DOD seen in malnourishment and may be preferable for patients with preoperative nutritional deficits.

Abstract 2852: Targeting NPEPPS overcomes cisplatin resistance in patient-derived bladder cancer tumoroids

Abstract Introduction and Objectives: Cisplatin-based neoadjuvant chemotherapy (NAC) is the recommended treatment for muscle-invasive bladder cancer (MIBC) patients. Patients with a pathological complete response after NAC (pCR), have a good 5-yr OS of 80%. However, due to NAC resistance, only 25% of patients achieve a pCR. Our aim is to increase the number of patients reaching a pCR by overcoming cisplatin resistance. Previously we identified NPEPPS as a key player in cisplatin resistance that prevents cisplatin uptake via volume-regulated anion channels (VRAC) in cisplatin-resistant cell lines. Studies have demonstrated that patient-derived bladder cancer tumoroids recapitulate the originating tumor at the molecular level, presenting a model system to study chemotherapy resistance ex vivo. Here, we used MIBC tumoroids to functionally interrogate NPEPPS’ role in cisplatin resistance. Material and Methods: Ex vivo interrogation of NPEPPS function in cisplatin resistance was performed in tumoroid cultures generated from MIBC patients (N=10). Tumor tissue was obtained either at transurethral resection of bladder tumor (TURBT, N=5) or RC (N=5), and clinical resistance to NAC was defined as ypT≥2, nodal positive disease at RC or progression during NAC. Molecular characterization of tumor specimens and corresponding tumoroids was performed by bladder cancer-specific SNaPshot mutation analysis, copy-number aberrations analysis, immunohistochemistry (IHC), and hematoxylin &amp; eosinophilic staining (HE). The effect of NPEPPS on cisplatin uptake was investigated using cisplatin treatment combined with the pharmacological NPEPPS-inhibitor tosedostat, shRNA-mediated NPEPPS knock-down or lentiviral NPEPPS over-e xpression followed by cytometry by time of flight (CyTOF) analysis. CellTiter-Glo cell viability assays and caspase 3/7 apoptosis assays were used to investigate whether NPEPPS inhibition overcomes cisplatin resistance ex vivo. Results: Five out of ten patients received NAC, all whom had tumors that were clinically resistant to NAC. Tumoroid cultures from MIBC patients unresponsive to NAC showed resistance to serum concentrations of cisplatin as well as increased NPEPPS mRNA expression. Meanwhile, molecular characterization of tumor and tumoroid pairs confirmed that patient-specific tumor traits were maintained in tumoroids. Pharmacological NPEPPS inhibition or NPEPPS depletion by shRNA-mediated knock-down increased cisplatin influx into the cell and resensitized NAC resistant tumoroids to serum concentrations of cisplatin. Furthermore, NPEPPS overexpression increased cisplatin resistance in cisplatin-sensitive tumoroids. Conclusion: We confirm that NPEPPS is associated with cisplatin-resistance in an ex vivo MIBC tumoroid model. These findings have potential for rapid translation into the clinic and invite trials investigating tosedostat to overcome chemoresistance. Citation Format: Mathijs P. Scholtes, Maryam Akbarzadeh, Shahla Romal, Miranda van Dijk, Tsung Wai Kan, Tokameh Mahmoudi, Tahlita C. Zuiverloon. Targeting NPEPPS overcomes cisplatin resistance in patient-derived bladder cancer tumoroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2852.

PD36-02 A COMPOSITE BIOMARKER APPROACH TO SPARE NEOADJUVANT CHEMOTHERAPY IN SELECT MUSCLE-INVASIVE BLADDER CANCER PATIENTS

You have accessJournal of UrologyCME1 Apr 2023PD36-02 A COMPOSITE BIOMARKER APPROACH TO SPARE NEOADJUVANT CHEMOTHERAPY IN SELECT MUSCLE-INVASIVE BLADDER CANCER PATIENTS Joep De Jong, A. Gordon Robertson, Nick Beije, John Martens, Ellen Zwarthoff, Arno Van Leenders, Ewan Gibb, and Joost Boormans Joep De JongJoep De Jong More articles by this author , A. Gordon RobertsonA. Gordon Robertson More articles by this author , Nick BeijeNick Beije More articles by this author , John MartensJohn Martens More articles by this author , Ellen ZwarthoffEllen Zwarthoff More articles by this author , Arno Van LeendersArno Van Leenders More articles by this author , Ewan GibbEwan Gibb More articles by this author , and Joost BoormansJoost Boormans More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003334.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Clinical guidelines recommend neoadjuvant chemotherapy (NAC) for the treatment of muscle-invasive bladder cancer (MIBC). However, NAC prior to radical cystectomy (RC) is associated with treatment-related toxicity and confers a modest survival benefit. Here, we aimed to identify MIBC patients who may avoid NAC by combining circulating tumor cell status and molecular subtypes in a composite biomarker approach. METHODS: TURBT tissue specimen were collected from clinical stage T2-T4aN0-N1M0 MIBC cases that were included within the CirGuidance study (NL3954), a prospective trial that analyzed circulating tumor cell (CTC) status in a patient’s blood sample using the CELLSEARCH system. For the present study, transcriptome-wide expression profiling was performed on 234 TURBT samples using an array-based approach. Molecular subtypes, long non-coding RNA (lncRNA) based FGFR3+ status and gene signatures were determined as described previously (de Jong et al., Genome Med. 2019). The primary endpoint of this study was cancer-specific mortality (CSM), calculated as the date of study inclusion till date of bladder cancer related death. Median follow-up was 28.8 (IQR: 16.6-40.2) months. RESULTS: Of 234 patients, 21 (9%) were treated with NAC and RC, while 213 (91%) received RC alone. A CTC-negative status was observed in 172 (81%) of RC-only cases. Molecular subtyping identified 28 luminal FGFR3+ cases with high FGFR3, SHH and p53 pathway activity, and lower EMT hallmark scores. Adjusting for clinical risk factors, both CTC and FGFR3+ status were significant predictors for cancer specific mortality on MVA (p<0.05). Of interest, the subgroup of FGFR3+ cases that were CTC-negative (N=26) showed most favorable outcomes with only one CSM event after a median of 33.4 (IQR: 24.8-44.5) months of follow-up. CONCLUSIONS: Using a composite biomarker approach of blood-based CTC status and molecular subtyping, we identified a biologically distinct subgroup of MIBC with favorable prognosis after RC-only, validating the performance of a previously developed lncRNA based FGFR3+ classifier. Clinical trials which withhold NAC from CTC-negative, FGFR3+ MIBC patients are warranted. Source of Funding: Gene expression profiles were generated using the Decipher Bladder assay © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e980 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joep De Jong More articles by this author A. Gordon Robertson More articles by this author Nick Beije More articles by this author John Martens More articles by this author Ellen Zwarthoff More articles by this author Arno Van Leenders More articles by this author Ewan Gibb More articles by this author Joost Boormans More articles by this author Expand All Advertisement PDF downloadLoading ...

PD44-06 CHEMOTHERAPY VS IMMUNOTHERAPY AS NEOADJUVANT THERAPIES IN CISPLATIN-ELIGIBLE PATIENTS UNDERGOING RADICAL CYSTECTOMY FOR MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023PD44-06 CHEMOTHERAPY VS IMMUNOTHERAPY AS NEOADJUVANT THERAPIES IN CISPLATIN-ELIGIBLE PATIENTS UNDERGOING RADICAL CYSTECTOMY FOR MUSCLE INVASIVE BLADDER CANCER Luigi Nocera, Marco Bandini, Giuseppe Basile, Marco Moschini, Shreyas Naidu, Kyle Rose, Roger Li, Philippe Spiess, and Andrea Necchi Luigi NoceraLuigi Nocera More articles by this author , Marco BandiniMarco Bandini More articles by this author , Giuseppe BasileGiuseppe Basile More articles by this author , Marco MoschiniMarco Moschini More articles by this author , Shreyas NaiduShreyas Naidu More articles by this author , Kyle RoseKyle Rose More articles by this author , Roger LiRoger Li More articles by this author , Philippe SpiessPhilippe Spiess More articles by this author , and Andrea NecchiAndrea Necchi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003354.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Chemotherapy has represented one of the cornerstone of the treatment landscape of muscle invasive bladder cancer (MIBC), due to its improvement in survival outcomes. Recently, also immunotherapy also showed to improve both pathological response, as well as survival outcomes. However, no comparison has ever been performed between the two neoadjuvant treatments. We aimed to compare cisplatinum-based chemotherapy and pembrolizumab in MIBC patients undergoing radical cystectomy (RC). METHODS: We retrospectively identified patients with MIBC and treated with RC after neoadjuvant treatment with either cisplatin or pembrolizumab in two tertiary referral centers. Cisplatinum-eligibility represented an inclusion criterion. Conversely, clinical node positive disease and adjuvant chemotherapy administration were exclusion criteria. The endpoint of the analyses was recurrence-free survival (RFS). Statistical analyses consisted of Kaplan-Meier (KM) curves before and after inverse-probability treatment weighting (IPTW), adjusting for age, gender, pathological stage, concomitant CIS and variant histology (VH). RESULTS: Of all 346 patients, median age was 67 years (IQR 60-73) and the majority of patients were male (80.3%). The majority of patients harbored a pT0N0 disease (30.3%) at RC pathology followed by pT2-4N0 (29.5%), pTanyN1-3 (20.5%) and pT1-a-isN0 (19.6%). Moreover, 113 patients (32.6%) exhibited concomitants CIS, while 255 patients (73.7%), 27 patients (7.8%) and 64 patients (18.5%) showed respectively presence of pure/mixed urothelial carcinoma, pure VH and other histology. Overall, 70 patients (20.2%) experienced recurrence (33.9% pelvic vs 66.1% distant) after a median follow-up of 24 months (12-39). KM showed a 24-months RFS of 76.9 vs 86.6% for cisplatinum-based chemotherapy versus pembrolizumab (p<0.01). After IPTW for age, gender, pathological stage, concomitant CIS and VH, KM showed 76.8 vs 93.2% for cisplatinum-based chemotherapy versus pembrolizumab (p=0.01). CONCLUSIONS: We compared RFS after cisplatinum chemotherapy vs pembrolizumab as neoadjuvant treatment in MIBC undergoing RC. Our findings suggest a potentially higher benefit of pembrolizumab, that was confirmed after adjustment for confounders. Source of Funding: NONE © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1126 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Luigi Nocera More articles by this author Marco Bandini More articles by this author Giuseppe Basile More articles by this author Marco Moschini More articles by this author Shreyas Naidu More articles by this author Kyle Rose More articles by this author Roger Li More articles by this author Philippe Spiess More articles by this author Andrea Necchi More articles by this author Expand All Advertisement PDF downloadLoading ...

PD44-05 AGE RELATED TRENDS IN THE UTILIZATION OF NEOADJUVANT CHEMOTHERAPY FOR MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023PD44-05 AGE RELATED TRENDS IN THE UTILIZATION OF NEOADJUVANT CHEMOTHERAPY FOR MUSCLE INVASIVE BLADDER CANCER Jeffrey Orf, Dominic Barressi, Facundo Davaro, Mohammad Mahmoud, and Zachary Hamilton Jeffrey OrfJeffrey Orf More articles by this author , Dominic BarressiDominic Barressi More articles by this author , Facundo DavaroFacundo Davaro More articles by this author , Mohammad MahmoudMohammad Mahmoud More articles by this author , and Zachary HamiltonZachary Hamilton More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003354.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The current standard of care for muscle invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). Previous research has shown under-utilization of NAC for treatment of MIBC, especially among the elderly. Our aim was to stratify NAC use by decade of life and analyze trends in use over time along with recording pathologic downstaging and perioperative outcomes. METHODS: The National Cancer Database (NCDB) was quarried for patients with cT2-4NanyM0 MIBC treated with RC from 2010-2016 with urothelial carcinoma. 19,957 patients met criteria for analysis. We retrospectively analyzed trends in use of NAC, readmission rate, mortality rate, and pathologic downstaging with NAC all stratified by decade of life. RESULTS: Of the 19,957 patients treated with RC for MIBC, only 30.9% underwent NAC. There was a statistically significant increase in NAC use across all age groups from 2010-2016 (Figure 1). Receipt of NAC was associated with decreased age on univariate analysis (p<.001) and on logistic regression (odds ratio (OR): 0.62 age 70-79, OR: 0.22 age≥80 vs.<60; p<.001). At time of RC for those who underwent NAC, the rate of pathologic downstaging decreased with increasing age (p<.001). Logistical regression also revealed a positive association between pathologic downstaging and younger age after receipt of NAC (OR: 0.73 age 70-79, OR: 0.61≥80 vs.<60; p<.001). Among patients receiving NAC, the risk of 30 and 90-day mortality was associated with increasing age (p<.002 and p<.001 respectively); however, age was not associated with 30-day readmission for those receiving NAC. CONCLUSIONS: Rates of NAC use prior to RC have increased among all age groups with the lowest utilization rate among the elderly. Younger patients were more likely to see pathologic downstaging at time of RC after NAC. These data show a promising trend in the uptake of the gold standard for treatment of MIBC; however, the underlying etiology of differing rates of pathologic downstaging remains unknown. Source of Funding: n/a © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1126 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jeffrey Orf More articles by this author Dominic Barressi More articles by this author Facundo Davaro More articles by this author Mohammad Mahmoud More articles by this author Zachary Hamilton More articles by this author Expand All Advertisement PDF downloadLoading ...

Radical radiotherapy for muscle-invasive bladder cancer: A single centre experience.

519 Background: Muscle-invasive bladder cancer (MIBC) is managed with radical cystectomy or (chemo)radiotherapy ((C)RT), CRT offers the chance of cure alongside organ preservation. Patients presenting with MIBC are often elderly and frail, with comorbidities precluding cystectomy and systemic treatment. We report outcome data for our institution of patients treated with radical (C)RT. Methods: Patients with T2-4N0 MIBC diagnosed between December 2014 and December 2021 were retrospectively identified from the radiotherapy planning system. Baseline demographic, clinical and follow up data were collated from electronic patient records. Results: 54 patients were identified. Mean patient age was 78.5 (range 47 – 94); 51 patients had urothelial cancer and 3 squamous cell carcinoma. 20 patients had evidence of carcinoma in situ (CIS) at diagnosis. 19 patients had neoadjuvant chemotherapy (NACT) (13 patients had cisplatin-gemcitabine, 6 patients had carboplatin-gemcitabine). 12/19 patients completed 3 cycles of NACT, 7 patients received 1-2 cycles. 24/54 patients had concurrent chemotherapy (6 patients receiving mitomycin-5-FU, 17 weekly gemcitabine and 1 weekly cisplatin). 14/24 patients completed concurrent chemotherapy as planned. Of the 24 patients treated with CRT, 18 had NACT. 12 patients received 64 Gy 32 fractions, 2 received 60 Gy 30 fractions, and 40 received 55 Gy 20 fractions. All except 1 patient completed the prescribed course. With a median follow up of 9.4 months (range 0.7-79 months), 3-year overall survival was 43% for all patients; 63% with CRT and 21% with RT alone (log-rank test p=0.0052 HR 3.15 (95% CI 1.48-6.7)). At 3 years 49% were free of recurrence (distant or local); 72% with CRT and 25% with RT alone (log-rank test 0.0079 HR 3.12 (95% CI 1.38-7.01)). 3yr OS and % free of recurrence were not impacted by the presence of CIS. OS was 46% with CIS and 41% without (log-rank test p=0.6649); 3yr % free of recurrence was 43% with CIS and 49% without (log-rank test p=0.4055). Median time to recurrence with CIS was shorter at 13.3 months vs 26.1 months. Conclusions: Radical radiotherapy to the bladder is an effective option for the treatment of MIBC and should be routinely discussed with patients. Patients should be treated with CRT as opposed to RT alone as both OS and RFS are significantly improved. Ensuring patients are fit to receive systemic treatment alongside RT may require prehabilitation in this elderly and more co-morbid group.

Neutralizing GDF-15 in muscle-invasive bladder cancer (MIBC): A neoadjuvant immunotherapy trial of visugromab (CTL-002) in combination with the anti-PD1 antibody nivolumab (NEO-GDFATHER).

TPS595 Background: Neoadjuvant chemotherapy (NACT) is a well-established treatment modality in MIBC but suffers from limited activity and significant toxicity. Recently, neoadjuvant immunotherapy (I/O) has demonstrated clinical safety and efficacy in various solid tumor indications including MIBC, with potentially less toxicity. Results from previous studies of single-agent I/O indicated a proportion of pathologic complete responses (ypT0N0) similar to that reported with NACT. Therefore, improving ypT0N0 responses remains a major task for successful treatment of MIBC in the future. Increasing evidence has emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical local immunosuppressive. Apart from blocking immune-cell entry into tissues GDF-15 also has major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block I/O therapy success. Various translational research efforts have indicated that GDF-15 may play a significant role for immunosuppression and T-cell exclusion in urothelial carcinoma (UC). Visugromab (CTL-002) is a GDF-15 neutralizing IgG4 monoclonal antibody that has demonstrated in Phase 1 a favorable safety profile and promising clinical activity with durable and deep responses in PD-1/PD-L1 relapsed/refractory metastatic solid tumors in combination with the anti-PD1 antibody Nivolumab (Nivo)*. This clinical trial is intended to investigate the combination of Visugromab with Nivo vs. Nivo monotherapy as neoadjuvant therapy for MIBC in patients (pts) who are ineligible for or elect not to undergo NACT. Primary endpoints are the complete pathologic response rate and radiologic response. Methods: This is a multi-center, parallel-cohorts and single-blinded Phase 2 study of neoadjuvant therapy in pts planned for radical cystectomy (RC). A total number of 30 subjects with stage T2-T4N0M0 MIBC will be enrolled and assigned 1:1 to receive either Nivo + Visugromab or Nivo + Placebo after stratification for CPS PD-L1 expression and cT-stage. No statistical assumptions have been undertaken at this stage. Treatment consists of three 4-week cycles [i.v., Q4Wk], and RC is planned 4-8 weeks after last dose of study drug. After RC, pts will follow standard recommendations according to EAU guidelines. Primary endpoints are the proportion of ypT0N0 response and radiologic response rate. Secondary endpoints comprise additional efficacy parameter, surgical and medical safety, PK and PD assessments. Translational research includes evaluation of immunologic parameters in the tumor, other immune-correlates and molecular profiles, as well as evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood. * Melero et al., Annals of Oncology (2022) 33 (suppl_7): S331-S355.