High-risk NMIBC Research Articles

Predicting Response to Intravesical BCG in High-Risk NMIBC Using an Artificial Intelligence-Powered Pathology Assay: Development and Validation in an International 12-Center Cohort.

There are few markers to identify those likely to recur or progress after treatment with intravesical bacillus Calmette-Guérin (BCG). We developed and validated artificial intelligence-based histologic assays that extract interpretable features from transurethral resection of bladder tumor digitized pathology images to predict risk of recurrence, progression, development of BCG-unresponsive disease, and cystectomy. Pre-BCG resection-derived whole-slide images and clinical data were obtained for high-risk NMIBC cases treated with BCG from 12 centers and were analyzed through a segmentation and feature extraction pipeline. Features associated with clinical outcomes were defined and tested on independent development and validation cohorts. Cases were classified into high or low risk for recurrence, progression, BCG-unresponsive disease, and cystectomy. Nine hundred forty-four cases (development: 303, validation: 641, median follow-up: 36 months) representative of the intended use population were included (high-grade Ta: 34.1%, high-grade T1: 54.8%; carcinoma in situ only: 11.1%, any carcinoma in situ: 31.4%). In the validation cohort, "high recurrence risk" cases had inferior high-grade recurrence-free survival vs "low recurrence risk" cases (HR, 2.08, P < .0001). "High progression risk" patients had poorer progression-free survival (HR, 3.87, P < .001) and higher risk of cystectomy (HR, 3.35, P < .001) than "low progression risk" patients. Cases harboring the BCG-unresponsive disease signature had a shorter time to development of BCG-unresponsive disease than cases without the signature (HR, 2.31, P < .0001). AI assays provided predictive information beyond clinicopathologic factors. We developed and validated AI-based histologic assays that identify high-risk NMIBC cases at higher risk of recurrence, progression, BCG-unresponsive disease, and cystectomy, potentially aiding clinical decision making.

Novel intravesical therapies and delivery systems for the management of bladder cancer.

Bladder cancer is a substantial burden for public health worldwide. A risk-adapted treatment strategy is required for non muscle-invasive (NMIBC) and muscle-invasive bladder cancer (MIBC). To date, treatment includes surgery with or without peri-operative local or systemic treatment. The aim of this review was to explore novel intravesical therapies and delivery systems emerging in NMIBC and MIBC. Several novel intravesical therapies and delivery systems for NMIBC and MIBC treatment recently emerged. Hyperthermic intravesical chemotherapy (HIVEC) allows a reasonable cancer control in selected high-risk NMIBC. Novel intravesical drugs such as nadofaragene firadenovec, Oncofid-P-B or Nogapendekin alfa-inbakicept seem to be safe and well tolerated. However, their efficacy in high-risk NMIBC should be further investigated. Hydrogels appear to be safe, well tolerated and potentially efficient in primary chemoablation in selected cases of low-grade intermediate-risk NMIBC tumors. Drug-releasing intravesical systems (drug-RIS) such as TAR-200 are safe and well tolerated, providing high partial and complete response rate in both NMIBC and MIBC patients. The armamentarium for the treatment of bladder cancer patients is expanding, notably with HIVEC, hydrogels, drug-RIS and novel therapies. However, accurate patients' selection is key to prevent disease progression in any bladder-sparing strategy, and radical cystectomy remains the gold-standard to date.

Selecting the right treatment: Health outcome priorities in older patients with bladder cancer

IntroductionSelecting the appropriate treatment for older patients with non-muscle invasive (NMIBC) or muscle-invasive bladder cancer (MIBC) is challenging due to smoking-related comorbidities, treatment toxicity, and an increased risk of adverse health outcomes. Considering patient preferences prior to treatment is therefore crucial. Here, we aimed to identify the health outcome priorities of older patients with high-risk NMIBC (HR-NMIBC) or MIBC. Materials and MethodsPatients aged 70 years or older or at risk for frailty, diagnosed with HR-NMIBC or MIBC without distant metastases, were referred for a comprehensive geriatric assessment (CGA). The CGA consisted of an interview, physical examination, and several tests to examine physical, cognitive, functional, and social status. Quality of life was assessed using EQ5D and EORTC QLQ-C30 questionnaires. Health outcome priorities were discussed using the Outcome Prioritization Tool (OPT) and associations between health outcome priorities and CGA-determinants and quality of life were studied. ResultsOf 146 patients (14 HR-NMIBC, 132 MIBC), OPT data was available for 139. Life extension was most often prioritized (44%), closely followed by preserving independence (40%). Reducing pain (7%) and other symptoms (9%) were less often prioritized. Patients prioritizing life extension had fewer musculoskeletal problems than patients prioritizing reducing pain or other symptoms (p = 0.02). Patients at risk of or suffering from malnutrition more frequently selected reducing pain or other symptoms as their health outcome priority (p = 0.004). For all other CGA-determinants and quality of life, there were no significant differences between groups based on health outcome priorities. DiscussionIn older patients with HR-NMIBC and MIBC, life extension and preserving independence are the most common health outcomes priorities. CGA-determinants and quality of life are generally not associated with the prioritization of health outcomes. As health outcome priorities cannot be predicted by CGA-determinants or quality of life, it is crucial to discuss health outcome priorities with patients to promote shared decision-making.

BCG and bladder cancer. Forty-eight years after Morales report.

Although BCG use as an anticancer drug was nearly abandoned due to the poor results in most tumors, in 1976 Morales reported a relevant reduction in recurrence with intravesical BCG in few patients affected by NMIBC. Since then BCG was globally accepted as an empirical and effective therapy in treating Tis and preventing recurrence of intermediate and high risk NMIBC. Forty-eight years after Morales' report, although some open questions remain object of debate, we have been able to find answers to many doubts improving BCG activity and toxicity. We better select patients undergoing BCG and many trials have indicated the best dosage and schedule. Moreover, we are able to better identify the patient unresponsive to BCG who might benefit of a timely radical cystectomy. We are also aware of the difficulties and toxicities that can be encountered with BCG use in every-day clinical practice. Research is ongoing to obtain genetically modified BCG to increase its efficacy and reduce toxicity. Moreover, the combination of BCG with other immunotherapeutic drugs given intravesically or systemically, first immune checkpoint inhibitors, is under study to obtain a response in patients unresponsive or intolerant to BCG. Almost 50 years after Morales publication, intravesical BCG remains an inalienable tool against NMIBC.

Ninety Days complications rate in patients undergoing radical cystectomy with enhanced recovery protocol

Bladder cancer is a carcinoma of the urothelial, or “umbrella,” cells that line the lumen of the urinary bladder. Technically, urothelial carcinoma includes tumors of the bladder, upper urinary tract (renal pelvis and ureters), and proximal urethra. Bladder cancer accounts for approximately 90% to 95% of urothelial carcinoma; bladder cancer comprises 75% pure urothelial carcinoma and 25% “variant” histology, adding complexity to the management of this disease. Bladder cancer can be categorized in several way, almost all bladder cancers originate in the urothelium, which is a 3- to 7-cell mucosal layer within the muscular bladder. Squamous cell carcinoma of the bladder can involve multiple sites; however, the lateral wall and trigone are more commonly involved by this tumor. All small cell carcinomas of the urinary system identified so far have been located in the urinary bladder, most commonly in the dome and vesical lateral wall. Radical cystectomy is a crucial surgical technique in managing MIBC, high-risk NMIBC, and treatment-refractory NMIBC. Despite a high perioperative mortality rate (5-10%), it now carries a 1-2% mortality rate due to improvements in surgical technique, intensive care medicine evolution, and antibiotic availability.

A Phase 2 Trial of Intravesical Gemcitabine and Docetaxel in the Treatment of Bacillus Calmette-Guérin‒Naïve Nonmuscle-Invasive Urothelial Carcinoma of the Bladder.

Combination intravesical gemcitabine and docetaxel (GemDoce) has demonstrated efficacy as second-line therapy for patients with bacillus Calmette-Guérin (BCG)‒unresponsive nonmuscle-invasive urothelial carcinoma of the bladder (NMIBC). In the context of widespread BCG shortages, we performed a phase 2 prospective trial to assess GemDoce for BCG-naïve NMIBC. This study is a prospective, single-arm, open-label phase 2 trial for patients with BCG-naïve high-risk NMIBC. Intravesical GemDoce was given weekly for 6 weeks as induction followed by monthly maintenance therapy for 2 years among responders. The primary end point was 3-month complete response, and key secondary end points included adverse events (AEs) and 12-month recurrence-free survival. Twenty-five patients were enrolled between August 2020 and August 2022 with median follow-up of 19.6 months. The pretreatment pathologic stages were high-grade (HG) T1 with carcinoma in situ (CIS; n = 7), HGT1 without CIS (n = 6), HGTa (n = 9), and CIS alone (n = 3). The 3-month complete response rate was 100% and recurrence-free survival at 12 months was 92%. Two patients with pretreatment HGT1 had HGT1 recurrences at 9 and 12 months. No patients progressed to T2 disease, underwent radical cystectomy, or had any radiographic evidence of progressive disease. Grade 1 AEs were common (23/25 patients) including hematuria, urinary frequency, urgency, and fatigue. Five patients (20%) experienced a grade 3 AE including hematuria and UTI. In this single-arm phase 2 trial, GemDoce was well tolerated with promising efficacy for patients with BCG-naïve high-risk NMIBC.

Treatment patterns and prognosis in patients with Bacillus Calmette-Guérin-exposed high-risk non-muscle invasive bladder cancer: a real-world data analysis.

The International Bladder Cancer Group designated the subgroup that is resistant to Bacillus Calmette-Guérin (BCG) but does not meet the criteria for BCG-unresponsive NMIBC as "BCG-exposed high-risk NMIBC" to guide optimal trial design. We aimed to investigate the treatment patterns and prognoses of patients with BCG-exposed NMIBC. We conducted a retrospective chart review of 3283 patients who received intravesical BCG therapy for NMIBC at 14 participating institutions between January 2000 and December 2019. Patients meeting the criteria for BCG-exposed and BCG-unresponsive NMIBC, as defined by the Food and Drug Administration and International Bladder Cancer Group, were selected. To compare treatment patterns and outcomes, high-risk recurrence occurring more than 24months after the last dose of BCG was defined as "BCG-treated NMIBC." In addition, we compared prognoses between BCG rechallenge and early cystectomy in patients with BCG-exposed NMIBC. Of 3283 patients, 108 (3.3%), 150 (4.6%), and 391 (11.9%) were classified as having BCG-exposed, unresponsive, and treated NMIBC, respectively. BCG-exposed NMIBC demonstrated intermediate survival curves for intravesical recurrence-free and progression-free survival, falling between those of BCG-unresponsive and treated NMIBC. Among patients with BCG-exposed NMIBC, 48 (44.4%) received BCG rechallenge, which was the most commonly performed treatment, and 19 (17.6%) underwent early cystectomy. No significant differences were observed between BCG rechallenge and early cystectomy in patients with BCG-exposed NMIBC. The newly proposed definition of BCG-exposed NMIBC may serve as a valuable disease subgroup for distinguishing significant gray areas, except in cases of BCG-unresponsive NMIBC.

Cost-utility of Initial Management of High-grade T1 Bladder Cancer With Intravesical BCG vs Immediate Radical Cystectomy

ObjectivesTo compare the cost-utility of initial management of high-grade T1 non-muscle invasive bladder cancer (HGT1 NMIBC) with intravesical BCG versus immediate radical cystectomy. High risk NMIBC patients may climb a costly ladder of treatments, culminating in radical cystectomy for oncologic or symptomatic benefit in up to one-third. This high healthcare resource utilization presents a challenging dilemma in balancing sufficiently aggressive management with cost, toxicity, and quality-of-life. MethodsCost-utility of initially managing HGT1 with intravesical BCG and early radical cystectomy with ileal conduit urinary diversion was compared using decision-analytic Markov models. Five-year oncologic outcomes, adverse event rates, and published utility values were extracted from literature. Costs were calculated from a US Medicare perspective in 2021 US dollars. Sensitivity analysis identified drivers of cost and break-even points for recurrence and progression. ResultsMean costs were $26,093 for intravesical BCG and $39,720 for immediate radical cystectomy, though cystectomy generated a gain of 2.2 QALYs compared to intravesical BCG. Immediate cystectomy was a more cost-effective management strategy for HGT1 NMIBC with an ICER of $7120/QALY.The costs associated with cystectomy, TURBT, and BCG toxicity had the greatest impact on ICER. One-way sensitivity analysis demonstrated that intravesical BCG became a cost-effective management strategy if the five-year recurrence rate of HG T1 was less than 56% or the five-year progression rate to MIBC was less than 4%. ConclusionsAt current prices, treatment of high-grade T1 NMIBC with early radical cystectomy is more cost-effective management strategy than initial treatment with intravesical BCG.

Efficacy and safety of short-term intravesical gemcitabine vs. long-term intravesical epirubicin in the treatment of moderate to high-risk non-muscle-invasive bladder cancer: a pilot study

PurposeLong-term bladder instillation therapy will bring more infusion side effects and economic consumption to patients. This study aims to compare short-term gemcitabine vs. long-term epirubicin for intravesical chemotherapy in patients diagnosed with moderate- to high-risk NMIBC treated using transurethral resection of bladder tumor (TURBT).Materials and methodsThis randomized controlled trial enrolled patients diagnosed with pT1 bladder cancer who underwent TURBT at Tianjin Medical University Cancer Institute from (01/2015- 07/2018), randomized 1:1 to gemcitabine vs. epirubicin. Recurrence-free survival (RFS) and progression-free survival (PFS) were monitored by cystoscopy. Side-effects after intravesical instillation and QLQ-C30 questionnaire were collected.ResultsFinally, 208 patients were enrolled. The median follow-up was 50.6 (6–69) months. The median RFS of the gemcitabine vs. epirubicin groups were 46.7 (6–69) vs. 47.2 (8–69) months, respectively (P > 0.05); the median PFS was 51.3 (9–69) vs. 50.9 (27–69) months, respectively (P > 0.05). The incidence rates of lower urinary tract symptoms, dysuria, hypo gastralgia, and gastrointestinal symptoms in the epirubicin group were 33.3%, 6.7%, 17.7%, and 18.3%, compared with 8.5%, 3.4%, 8.5% and, 1.2%, respectively, for gemcitabine. The gemcitabine group had a better quality of life than epirubicin in global health status (82.8 ± 8.5 vs. 79.6 ± 4.2, P = 0.01) and pain symptom domain (1.1 ± 2.8 vs. 2.4 ± 3.8, P = 0.04).ConclusionsThere are no significant differences in efficacy between gemcitabine and epirubicin for intravesical chemotherapy in patients with moderate to high-risk NMIBC to prevent tumor recurrence or progression for patients intolerant to BCG or those for whom BCG is not accessible. Patients with gemcitabine suffer fewer adverse events and have a better health status than with epirubicin.

Prognostic Role of Preoperative Neutrophil-To-Lymphocyte Ratio (NLR) and Recurrence at First Evaluation after Bacillus Calmette-Guérin (BCG) Induction in Non-Muscle-Invasive Bladder Cancer.

We investigated the prognosis of BCG induction-only treatment and non-complete response (CR) at the first 3-month evaluation and examined factors associated with CR. In total, 209 patients with moderate- and high-risk NMIBC who received BCG induction-only treatment between 2008 and 2020 were retrospectively analyzed. Recurrence-free survival (RFS) and progression-free survival (PFS) were assessed based on the initial NMIBC stage. PFS and associated factors of non-CR compared to CR were also assessed. Initial T1 high-grade (HG) (n = 93) had poorer RFS and PFS after BCG induction-only treatment than Ta low-grade (LG) (p = 0.029, p = 0.002). Non-CR (n = 37) had a different neutrophil-to-lymphocyte ratio (NLR) (2.81 ± 1.02 vs. 1.97 ± 0.92) and T staging from CR (p < 0.001, p = 0.008). T1HG recurrence was associated with a worse PFS compared to non-T1HG (13.7 months vs. 101.7 months, p < 0.001). There was no difference in PFS between T1HG and T1LG. T1 and NLR were predictors of response at 3 months in multivariable analysis (p = 0.004, p = 0.029). NLR was also found to be an associated factor with RFS and PFS of bladder cancer (p < 0.001, p < 0.001). BCG induction-only treatment was effective for high-risk TaLG but not for T1HG. T1HG recurrence at 3 months after BCG induction has a poor prognosis for bladder cancer. Preoperative NLR and T1 were predictors of non-CR, and NLR was also associated with the long-term prognosis of bladder cancer.

Xpert Bladder Cancer Monitor for the Early Detection of Non-Muscle Invasive Bladder Cancer Recurrences: Could Cystoscopy Be Substituted?

XBM was prospectively assessed in spontaneous urine collected just before flexible cystoscopy and washing cytology carried out within the first 2 years follow-up of 337 patients with NMIBC. Recurrences were pathologically confirmed in 49 patients (14.5%), 22 of them being high-risk (6.5%). The XBM sensitivity for detecting any type of recurrence was 69.4% and 63.6% in the cases of high-risk NMIBC. Negative predictive value (NPV) for XBM was 93% for all recurrences and 96.2% for high-risk recurrences. XBM could have avoided 213 invasive controls but missed the detection of 15 recurrences (30.6%)-8 of them of high-risk (36.4%). XBM false positive elevations were detected in 90 patients (26.7%), whereas 10 patients with the invasive method had a false positive result (3%), p <0.001. However, early detection of recurrences during the first year's follow-up after an XBM false positive result was observed in 18 patients (20%). On the other hand, 19 recurrences were detected during this period among the rest of the patients (7.7%)-p = 0.003, and odds ratio (OR) 3.0 (95% CI 1.5-6.0). Regarding one-year follow-up recurrences, 10% were high-risk recurrences in the XBM false positive group and 3.2% in the rest of the patients-p = 0.021, and OR 3.3 (95% CI 1.2-8.9). Additionally, 11.3% of the patients without false positive results developed a recurrence, p = 0.897, for any recurrence, being 10% and 5.2%, respectively, and high-risk and low-risk recurrences, p = 0.506. After searching for the best XBM cutoff for detecting the 38 high-risk initial recurrences and the early high-risk recurrences after a one-year follow-up, a linear discriminant analysis (LDA) of 0.13 could have avoided 11.3% of cystoscopies and bladder wash cytologies, as this cutoff missed only 1 high-risk recurrence (2.6%). More extensive and well-designed studies will confirm if XBM can improve the surveillance of NMIBC.

Sequential intravesical gemcitabine and docetaxel for treatment-naïve and previously treated intermediate-risk nonmuscle invasive bladder cancer

IntroductionAdjuvant intravesical therapy is recommended for patients with intermediate-risk NMIBC. While intravesical gemcitabine-docetaxel (Gem/Doce) has demonstrated favorable outcomes for high-risk NMIBC, its utility in the intermediate-risk setting is not well described. We report outcomes of Gem/Doce as an adjuvant treatment for intermediate-risk NMIBC. MethodsWe retrospectively identified patients with intermediate-risk NMIBC by AUA criteria treated with Gem/Doce following TURBT between 2012 and 2022. Patients received weekly sequential intravesical instillations of 1 g gemcitabine and 37.5 mg docetaxel for 6 weeks. Monthly maintenance of 2 years was initiated if disease-free at first surveillance. The primary outcome was recurrence-free survival (RFS), assessed using the Kaplan-Meier method. ResultsThe cohort included 77 patients with median follow-up of 26 (IQR 14–50) months. Prior to induction, 67 (87%) patients presented with Ta low-grade (LG) lesions, 3 (3.9%) with Ta high-grade (HG), 5 (6.5%) with TaLG plus focal TaHG, and 2 (2.6%) with T1LG. Thirty-three (43%) patients received previous intravesical therapy including BCG (23), mitomycin (13), and docetaxel monotherapy (12). The 2-year RFS was 71% among all patients. Treatment-naïve patients had superior RFS compared to previously treated patients (P = 0.04); 2-year estimates were 79% and 64%, respectively. Twenty-nine (38%) patients experienced adverse events; all were Grade 1 to 2 except 1 (1.3%) Grade 3 (acute oxygen desaturation). Three (3.9%) patients did not tolerate a full induction course. ConclusionsIn this retrospective review of a heterogenous population of patients with intermediate-risk NMIBC, Gem/Doce was an effective and well-tolerated adjuvant therapy. Further prospective evaluation in this setting is needed.

Elevated levels of MMP12 sourced from macrophages are associated with poor prognosis in urothelial bladder cancer

BackgroundUrothelial bladder cancer is most frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact the quality of life. Biomarkers for patient stratification could help to avoid unnecessary interventions whilst indicating aggressive measures when required.MethodsIn this study, immuno-oncology focused, multiplexed proximity extension assays were utilised to analyse plasma (n = 90) and urine (n = 40) samples from 90 newly-diagnosed and treatment-naïve bladder cancer patients. Public single-cell RNA-sequencing and microarray data from patient tumour tissues and murine OH-BBN-induced urothelial carcinomas were also explored to further corroborate the proteomic findings.ResultsPlasma from muscle-invasive, urothelial bladder cancer patients displayed higher levels of MMP7 (p = 0.028) and CCL23 (p = 0.03) compared to NMIBC patients, whereas urine displayed higher levels of CD27 (p = 0.044) and CD40 (p = 0.04) in the NMIBC group by two-sided Wilcoxon rank-sum tests. Random forest survival and multivariable regression analyses identified increased MMP12 plasma levels as an independent marker (p < 0.001) associated with shorter overall survival (HR = 1.8, p < 0.001, 95% CI:1.3–2.5); this finding was validated in an independent patient OLINK cohort, but could not be established using a transcriptomic microarray dataset. Single-cell transcriptomics analyses indicated tumour-infiltrating macrophages as a putative source of MMP12.ConclusionsThe measurable levels of tumour-localised, immune-cell-derived MMP12 in blood suggest MMP12 as an important biomarker that could complement histopathology-based risk stratification.As MMP12 stems from infiltrating immune cells rather than the tumor cells themselves, analyses performed on tissue biopsy material risk a biased selection of biomarkers produced by the tumour, while ignoring the surrounding microenvironment.

Abstract LB246: Enfortumab vedotin, a nectin-4-directed antibody-drug conjugate, demonstrates compelling antitumor activity in non-muscle invasive bladder cancer models which predicts minimal systemic exposure when administered by intravesical instillation in patients

Abstract Enfortumab vedotin (EV) is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder cancers. Preclinically, EV has demonstrated tumor cell killing by direct cytotoxicity and bystander effect and can induce the hallmarks of immunogenic cell death. EV improves survival in adults with previously treated locally advanced or metastatic urothelial carcinoma (la/mUC) and is approved in the US, Europe, Japan, and others. Most newly diagnosed bladder cancer cases are non-muscle invasive (NMIBC). Standard treatment of high-risk NMIBC involves transurethral resection followed by intravesical Bacillus Calmette-Guerin (BCG) or chemotherapy. Although response to BCG is high, recurrence is common, and treatment options for patients with BCG-unresponsive tumors are limited, underscoring the significant unmet need. Previously, we demonstrated compelling preclinical antitumor activity of EV in NMIBC models with a favorable safety profile and minimal systemic exposure. EV-mediated antitumor activity was confirmed in a mouse model of NMIBC by both bioluminescence imaging and IHC for hNectin-4-expressing cancer cells. Following intravesical administration of EV, tumor growth inhibition ranged 46-96% across the dose range tested. Colocalization of EV to Nectin-4-positive tumor tissues was confirmed by IHC in the engrafted tumor cells. Systemic EV exposure in tumor-bearing mice was low, consistent with previous nonclinical studies, supporting that the antitumor activity is driven by local exposure within the bladder. In a repeat-dose GLP toxicology study in rats, no systemic toxicities were observed at intravesical doses up to 6-fold higher than the maximum tolerated IV dose. This lack of systemic toxicities that can occur with IV administration in rats was likely due to minimal systemic exposure of both EV and unconjugated MMAE. Currently, the safety, tolerability, and antitumor activity of intravesical EV are being evaluated in a Phase 1 study in adults with high-risk, BCG-unresponsive NMIBC (EV-104, NCT05014139). The initial dose level for EV-104 was selected to be active and predicted to have minimal systemic absorption based on preclinical and known clinical IV data. Here, we present confirmatory clinical data demonstrating that EV and unconjugated MMAE are undetectable in the bloodstream at the starting dose. These findings confirm the translatability of our nonclinical models and provide evidence that intravesical administration of EV in NMIBC is a promising approach that limits systemic exposure. These data support the potential for a favorable safety and activity profile and warrant continued investigation of intravesical EV in patients with NMIBC. Citation Format: Devra Olson, Yen Lin Chia, Enaharo Iboi, Lauren Farr, Maddy Burcher, Anthony Lee, Kelly Hensley, Sean Allred, Abbie Wong, Masashi Shimazaki, Masamichi Mori, Sharsti Sandall, Christopher Carosino. Enfortumab vedotin, a nectin-4-directed antibody-drug conjugate, demonstrates compelling antitumor activity in non-muscle invasive bladder cancer models which predicts minimal systemic exposure when administered by intravesical instillation in patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB246.

Évaluation de l’efficacité et de la tolérance de la thermo-chimiothérapie intravésicale HIVEC pour les tumeurs de vessie non infiltrant la musculeuse de risque intermédiaire et de haut risque

Non-muscle-infiltrating cancers (NMIBC) represent 75% of bladder tumors. The objective of our study is to report a single-center experience of the efficacy and tolerability of HIVEC on intermediate- and high-risk NMIBC in adjuvant therapy. Between December 2016 and October 2020, patients with intermediate-risk or high-risk NMIBC were included. They were all treated with HIVEC as an adjuvant therapy to bladder resection. Efficacy was assessed by endoscopic follow-up and tolerance by a standardized questionnaire. A total of 50 patients were included. The median age was 70years (34-88). The median follow-up time was 31 months (4-48). Forty-nine patients had cystoscopy as part of the follow-up. Nine recurred. One patient progressed to Cis. The 24-month recurrence-free survival was 86.6%. There were no severe adverse events (grade 3 or 4). The ratio of delivered instillations to planned instillations was 93%. HIVEC with the COMBAT system is well tolerated in adjuvant treatment. However, it is not better than standard treatments, especially for intermediate-risk NMIBC. While waiting for recommendations, it cannot be proposed as an alternative to standard treatment.

MP08-02 RISK SCORE-BASED SUBSTRATIFICATION IMPROVES SURVEILLANCE COSTS AFTER TRANSURETHRAL RESECTION OF BLADDER TUMOR IN PATIENTS WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP08-02 RISK SCORE-BASED SUBSTRATIFICATION IMPROVES SURVEILLANCE COSTS AFTER TRANSURETHRAL RESECTION OF BLADDER TUMOR IN PATIENTS WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER Naoki Fujita, Shingo Hatakeyama, Masaki Momota, Teppei Okamoto, Hayato Yamamoto, Hiroyuki Ito, Takahiro Yoneyama, Yasuhiro Hashimoto, Kazuaki Yoshikawa, and Chikara Ohyama Naoki FujitaNaoki Fujita More articles by this author , Shingo HatakeyamaShingo Hatakeyama More articles by this author , Masaki MomotaMasaki Momota More articles by this author , Teppei OkamotoTeppei Okamoto More articles by this author , Hayato YamamotoHayato Yamamoto More articles by this author , Hiroyuki ItoHiroyuki Ito More articles by this author , Takahiro YoneyamaTakahiro Yoneyama More articles by this author , Yasuhiro HashimotoYasuhiro Hashimoto More articles by this author , Kazuaki YoshikawaKazuaki Yoshikawa More articles by this author , and Chikara OhyamaChikara Ohyama More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The aim of the present study was to develop optimized surveillance protocols based on the risk score-based substratifications to improve surveillance costs. METHODS: We retrospectively evaluated 428 patients with high-risk NMIBC who underwent TURBT from November 1993 to April 2019. Independent risk factors for intravesical and upper urinary tract (UUT) recurrences were assessed by multivariable analyses. Patients were substratified into intra-lower, intra-intermediate, and intra-higher groups or UUT-lower, UUT-intermediate, and UUT-higher groups by summing each of the independent risk factors of intravesical and UUT recurrences, respectively. Optimized surveillance protocols to enhance cost-effectiveness were developed using real incidences of recurrence after TURBT. The 10-year total surveillance costs were compared between the European Association of Urology (EAU) guidelines-based and optimized surveillance protocols. RESULTS: Median age and follow-up periods were 72 years and 54 months, respectively. Multivariable analyses showed that chronic kidney disease, tumor size ≥30 mm, and grade 3 were independently associated with intravesical and/or UUT recurrences. Patients were substratified into intra-lower (0 score), intra-intermediate (1 score), and intra-higher (2 or 3 scores) groups for the intravesical recurrence risk estimation or into UUT-lower (0 score), UUT-intermediate (1 score), and UUT-higher (2 scores) groups for the UUT recurrence risk estimation (Figure A). The Kaplan–Meier curves of intravesical and UUT RFS could be clearly separated among the three groups (Figure B and C). Optimized surveillance protocols (Table) promoted a 43% reduction in the 10-year total surveillance cost compared with the EAU guidelines-based surveillance protocol (Figure D). CONCLUSIONS: Optimized surveillance protocols based on risk score-based substratifications could potentially improve surveillance costs after TURBT in patients with high-risk NMIBC. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e93 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Naoki Fujita More articles by this author Shingo Hatakeyama More articles by this author Masaki Momota More articles by this author Teppei Okamoto More articles by this author Hayato Yamamoto More articles by this author Hiroyuki Ito More articles by this author Takahiro Yoneyama More articles by this author Yasuhiro Hashimoto More articles by this author Kazuaki Yoshikawa More articles by this author Chikara Ohyama More articles by this author Expand All Advertisement PDF downloadLoading ...

MP63-12 THE EFFECTS OF SEQUENTIAL MITOMYCIN AND BACILLUS CALMETTE-GUÉRIN TREATMENT VERSUS BACILLUS CALMETTE-GUÉRIN MONOTHERAPY IN PATIENTS WITH HIGH-RISK NON-MUSCLE INVASIVE BLADDER CANCER: MITO-BCG (EUDRACT-2017-004540-37)

You have accessJournal of UrologyCME1 Apr 2023MP63-12 THE EFFECTS OF SEQUENTIAL MITOMYCIN AND BACILLUS CALMETTE-GUÉRIN TREATMENT VERSUS BACILLUS CALMETTE-GUÉRIN MONOTHERAPY IN PATIENTS WITH HIGH-RISK NON-MUSCLE INVASIVE BLADDER CANCER: MITO-BCG (EUDRACT-2017-004540-37) Cosimo DE Nunzio, Costantino Leonardo, Antonio Carbone, Antonio Luigi Pastore, Riccardo Lombardo, Antonio Nacchia, Antonio Cicione, Beatrice Turchi, Giorgia Tema, and Andrea Tubaro Cosimo DE NunzioCosimo DE Nunzio More articles by this author , Costantino LeonardoCostantino Leonardo More articles by this author , Antonio CarboneAntonio Carbone More articles by this author , Antonio Luigi PastoreAntonio Luigi Pastore More articles by this author , Riccardo LombardoRiccardo Lombardo More articles by this author , Antonio NacchiaAntonio Nacchia More articles by this author , Antonio CicioneAntonio Cicione More articles by this author , Beatrice TurchiBeatrice Turchi More articles by this author , Giorgia TemaGiorgia Tema More articles by this author , and Andrea TubaroAndrea Tubaro More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003321.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Aim of our study was to evaluate recurrence free survival of sequential Mitomycin and Bacillus Calmette-Guérin (BCG) treatment versus BCG monotherapy in patients with High risk Non-Muscle Invasive Bladder Cancer. METHODS: MITO-BCG is an open-label phase 4 study designed to evaluate the efficacy and safety of the sequential MMC and BCG combination treatment in patients with high-risk NMIBC. Eligibility criteria: males with a diagnosis of High risk NMIBC (T1 tumor, G3, CIS, or multiple and recurrent and large (>3 cm) Ta, G1G2 tumors or patients in the last EAU recurrence category EAU/EORTC recurrence score ≥10), age >40 years and <75 years, ability of consent. Patients are randomized in two groups: first with BCG induction treatment according to the standard protocol (an instillation once a week for six weeks) with 81 mg Connaught strain BCG and second receiving BCG treatment with the same protocol with a 40 mg mitomycin instillation the day before. Response will be assessed using cystoscopy and urine citology every 12 weeks for 2 years. Primary end points are recurrence rate; secondary end points are overall toxicity. RESULTS: The protocol study started on March 2019. Nowadays we enrolled 72 patients with a median age of 67 (IQR 59/73). Overall, 41 (57%) patients were randomized in the group of sequential combination therapy and 31 (43%) in the group of monotherapy with BCG. Mean Follow-up was 71±50 months. In BCG group 6/31 (19%) presented a recurrence while 10/41 (24 %) presented a recurrence in the combination group (p=0,611). On Cox regression analysis no differences were recorded in terms of recurrence when comparing both groups (HR: 1,23 95% CI: 0,46-3,50; p=0,640) (Figure). During follow-up only one patient experienced progression. Only 9 patients experienced adverse events with 8/9 grade I and one grade 4 (orchiectomy). No statistically significant differences were recorded in terms of complications between groups. CONCLUSIONS: The interim analysis of the Mito-BCG study suggests no differences in terms of recurrence free survival when comparing BCG alone vs sequential Mitomicin and BCG treatment. Both treatments present good and comparable tollerability. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e876 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Cosimo DE Nunzio More articles by this author Costantino Leonardo More articles by this author Antonio Carbone More articles by this author Antonio Luigi Pastore More articles by this author Riccardo Lombardo More articles by this author Antonio Nacchia More articles by this author Antonio Cicione More articles by this author Beatrice Turchi More articles by this author Giorgia Tema More articles by this author Andrea Tubaro More articles by this author Expand All Advertisement PDF downloadLoading ...

PD13-08 CORE1: PHASE 2 SINGLE ARM STUDY OF CG0070 COMBINED WITH PEMBROLIZUMAB IN PATIENTS WITH NON MUSCLE INVASIVE BLADDER CANCER UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN (BCG)

You have accessJournal of UrologyCME1 Apr 2023PD13-08 CORE1: PHASE 2 SINGLE ARM STUDY OF CG0070 COMBINED WITH PEMBROLIZUMAB IN PATIENTS WITH NON MUSCLE INVASIVE BLADDER CANCER UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN (BCG) Roger Li, Gary Steinberg, Edward M. Uchio, Donald Lamm, Paras Shah, Ashish M. Kamat, Trinity J Bivalacqua, Vignesh Packiam, Michael J. Chisamore, John Mcadory, Paola Grandi, Nataliya Hnat, and James Burke Roger LiRoger Li More articles by this author , Gary SteinbergGary Steinberg More articles by this author , Edward M. UchioEdward M. Uchio More articles by this author , Donald LammDonald Lamm More articles by this author , Paras ShahParas Shah More articles by this author , Ashish M. KamatAshish M. Kamat More articles by this author , Trinity J BivalacquaTrinity J Bivalacqua More articles by this author , Vignesh PackiamVignesh Packiam More articles by this author , Michael J. ChisamoreMichael J. Chisamore More articles by this author , John McadoryJohn Mcadory More articles by this author , Paola GrandiPaola Grandi More articles by this author , Nataliya HnatNataliya Hnat More articles by this author , and James BurkeJames Burke More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003260.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. IV pembrolizumab, was recently approved by the FDA for patients with BCG- unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ∼20%. This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. METHODS: 35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravescical CG0070 (1x1012 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Patients with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24m. Assessment of response will include q3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence. The primary endpoint of the study is CR at 12m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety. Correlate assessments includes changes in the TME, systemic immune induction, viral replication. RESULTS: Enrollment has been completed. Based on follow up thus far, CR rate of 92% (22/24) at 3 m has been observed. All patients in CR at 3 m remain in CR at downstream timepoints including: 14/16 at 6m, 9/11 at 9m, and 6/8 at 12 m. Treatment related AE are consistent with those observed in studies of each agent alone. CONCLUSIONS: This initial data on the efficacy and safety of CG0070 plus pembrolizumab for the treatment of BCG unresponsive NMIBC is encouraging. Data on efficacy and safety for all enrolled patients, N=35, as well as biomarker (CAR, E2F, and PDL1) assessment will be presented at the time of the conference. Source of Funding: CG Oncology © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e408 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Roger Li More articles by this author Gary Steinberg More articles by this author Edward M. Uchio More articles by this author Donald Lamm More articles by this author Paras Shah More articles by this author Ashish M. Kamat More articles by this author Trinity J Bivalacqua More articles by this author Vignesh Packiam More articles by this author Michael J. Chisamore More articles by this author John Mcadory More articles by this author Paola Grandi More articles by this author Nataliya Hnat More articles by this author James Burke More articles by this author Expand All Advertisement PDF downloadLoading ...

MP08-12 SEQUENTIAL INTRAVESICAL GEMCITABINE AND DOCETAXEL FOR TREATMENT-NAIVE AND PREVIOUSLY TREATED INTERMEDIATE-RISK NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP08-12 SEQUENTIAL INTRAVESICAL GEMCITABINE AND DOCETAXEL FOR TREATMENT-NAIVE AND PREVIOUSLY TREATED INTERMEDIATE-RISK NON-MUSCLE INVASIVE BLADDER CANCER Ian M. McElree, Joanna Orzel, Ryan L. Steinberg, Sarah L. Mott, Michael A. O'Donnell, and Vignesh T. Packiam Ian M. McElreeIan M. McElree More articles by this author , Joanna OrzelJoanna Orzel More articles by this author , Ryan L. SteinbergRyan L. Steinberg More articles by this author , Sarah L. MottSarah L. Mott More articles by this author , Michael A. O'DonnellMichael A. O'Donnell More articles by this author , and Vignesh T. PackiamVignesh T. Packiam More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Adjuvant intravesical therapy is recommended for patients with intermediate-risk NMIBC. While intravesical gemcitabine-docetaxel (Gem/Doce) has demonstrated favorable outcomes for high-risk NMIBC, its utility in the intermediate-risk setting is not well-described. We report efficacy and tolerance outcomes of Gem/Doce as an adjuvant treatment for intermediate-risk NMIBC. METHODS: We retrospectively identified all patients with intermediate-risk NMIBC by AUA criteria who were treated with Gem/Doce between March 2012 and July 2022. Patients were treated with weekly sequential intravesical instillations of 1 g gemcitabine and 37.5 mg docetaxel for 6 weeks. Monthly maintenance of 2 years was initiated if disease free at first follow up. The primary outcome was recurrence-free survival (RFS). Survival was assessed using the Kaplan-Meier method, indexed from start of Gem/Doce induction. Surveillance was performed according to AUA guidelines. RESULTS: The cohort included 77 patients with median follow-up of 26 (IQR: 14-50) months. Prior to Gem/Doce induction, 67 (87%) patients presented with TaLG, 3 (3.9%) with isolated <3 cm TaHG, 5 (6.5%) with TaLG plus focal TaHG, and 2 (2.6%) with T1LG. A total of 33 (43%) patients received previous intravesical therapy with a median of 1 (IQR: 1-2) prior induction courses. There were 23, 13, and 13 patients with at least 1 previous induction course of BCG, single-agent docetaxel, and mitomycin, respectively. The 2-year RFS was 71% among all patients. Patients who were treatment naïve had superior RFS compared to those previously treated (p=0.04, Figure 1); 2-year estimates were 79% and 64%, respectively. There were 3 patients with a HG recurrence during the study period. There were 29 (38%) patients with adverse events; all were Grade 1-2 except one (1.3%) Grade 3 (acute oxygen desaturation). The most frequent adverse events were urinary urgency/frequency (10.4%), bladder spasms (9.1%), and UTI (5.2%). Three (3.9%) patients did not tolerate a full induction course. CONCLUSIONS: In a heterogenous population of patients with intermediate-risk NMIBC, Gem/Doce was an effective and well-tolerated adjuvant therapy. Further prospective evaluation is needed. Source of Funding: Supported by the John & Carol Walter Family Foundation and the Cancer Center Support Grant. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e98 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ian M. McElree More articles by this author Joanna Orzel More articles by this author Ryan L. Steinberg More articles by this author Sarah L. Mott More articles by this author Michael A. O'Donnell More articles by this author Vignesh T. Packiam More articles by this author Expand All Advertisement PDF downloadLoading ...

Relationship between Preoperative Pyuria and Bacille Calmette-Guerin Treatment in Intravesical Recurrence after Transurethral Resection of High-Risk, Non-Muscle Invasive, Bladder Carcinoma: A Retrospective Study of Human Data

Some researchers have found that preoperative pyuria is a risk factor for recurrence after transurethral resection of high-risk non-muscle invasive bladder cancer. However, to our knowledge, none have clarified the risks associated with pyuria according to bacille Calmette-Guerin (BCG) treatment status. We retrospectively selected patients with high-risk non-muscle invasive bladder cancer according to Japanese Urological Association guidelines. Pyuria was defined as ≥10 white blood cells per high-powered field. We analyzed recurrence-free rates (RFS) in 424 patients who had and had not undergone BCG treatment. The median duration of follow-up was 45.2 months. According to multivariate analysis, postoperative intravesical BCG induction and preoperative pyuria were independent risk factors for intravesical recurrence in the whole study cohort. We found no significant risk factors for recurrence in the BCG-treated group (n = 179). In the non-BCG-treated group (n = 245), patients with pyuria were much more frequently female and more often had T1 disease than patients without pyuria. According to univariate and multivariate analysis, preoperative pyuria is an independent risk factor for intravesical recurrence. There was no significant difference in the severity of pyuria between the BCG and non-BCG-treated groups. Aggressive BCG treatment may need to be considered in patients with high-risk NMIBC and pyuria.