Deintensification of Treatment for Low-grade Bladder Tumors: A Collaborative Review by the International Bladder Cancer Group (IBCG).

BACKGROUND AND OBJECTIVE: Management of low-grade (LG) urothelium-confined (Ta stage) non-muscle-invasive bladder cancer (NMIBC) poses a distinct therapeutic challenge. Transurethral resection of bladder tumor (TURBT), the standard treatment, frequently has to be repeated because of high tumor recurrence rates. This places a considerable strain on both patients and health care infrastructure, underscoring the need for alternative management approaches. Herein, the IBCG (International Bladder Cancer Group), conducted a review to explore the efficacy and safety of deintensified treatment strategies for recurrent LG Ta NMIBC. METHODS: We conducted a collaborative review of relevant literature in the PubMed/MEDLINE and Cochrane CENTRAL databases. Our focus was on high-quality evidence, including randomized controlled trials, systematic reviews, and meta-analyses. We also reviewed guidelines published by prominent urological associations. KEY FINDINGS AND LIMITATIONS: Active surveillance, chemoablation, and office fulguration are valid treatment options for recurrent LG Ta NMIBC. These deintensified approaches offer several advantages over TURBT: lower complication rates, less morbidity, lower health care costs, and better quality of life for patients. Importantly, these benefits are achieved without compromising oncological safety. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our review demonstrates that less intensive treatment strategies for recurrent LG Ta NMIBC are both feasible and valuable. The IBCG recommends use of these approaches for carefully selected patients to help lower health care costs and enhance patients' quality of life. PATIENT SUMMARY: We reviewed studies on less invasive management options for low-grade noninvasive bladder cancer, including active surveillance, chemical ablation, and heat treatment. Recent results confirm that these less intense treatment options can reduce the treatment burden and costs for patients and preserve their quality of life without negatively affecting cancer control outcomes.

Bladder-sparing Therapy for Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Bladder Cancer: International Bladder Cancer Group Recommendations for Optimal Sequencing and Patient Selection.

BACKGROUND AND OBJECTIVE: There has been a recent surge in the development of agents for bacillus Calmette-Guérin-unresponsive (BCG-U) non-muscle-invasive bladder cancer (NMIBC). Critical assessment of these agents and practical recommendations for optimal selection of patients and therapies are urgently needed, especially in the absence of randomized trials on bladder-sparing treatment (BST) options. METHODS: A global committee of bladder cancer experts was assembled to develop recommendations on BST for BCG-U NMIBC. Working groups reviewed the literature and developed draft recommendations, which were then voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined on the basis of meeting discussions. Final recommendations achieved >75% agreement during the meeting, and some were further refined via web conferences and e-mail discussions. KEY FINDINGS AND LIMITATIONS: There is currently no single optimal agent for patients with BCG-U disease who seek to avoid radical cystectomy (RC). BST selection should be personalized, taking into account individual patient characteristics and preferences, tumor attributes, and efficacy/toxicity data for the agents available. For patients with BCG-U carcinoma in situ (CIS), gemcitabine/docetaxel (GEM/DOCE), nadofaragene firadenovec (NFF), and nogapendekin alfa inbakicept-pmln (NAI) + BCG are recommended; because of its systemic toxicity, pembrolizumab should only be offered after other options are exhausted. For patients with BCG-U papillary-only tumors, GEM/DOCE, NFF, NAI + BCG, single-agent chemotherapy, hyperthermic mitomycin C, and pembrolizumab are recommended. Given the modest efficacy of available options, clinical trial participation is encouraged. For unapproved agents with reported data, IBCG recommendations await the final results of pivotal trials. CONCLUSIONS AND CLINICAL IMPLICATIONS: The IBCG consensus recommendations provide practical guidance on BST for BCG-U NMIBC.

Long-term outcomes and cost savings of office fulguration of papillary Ta low-grade bladder cancer.

OBJECTIVES: To assess whether office-based fulguration (OF) under local anaesthesia for small, recurrent, pathological Ta low-grade (LG) non-muscle-invasive bladder cancer (NMIBC) is an effective alternative to transurethral resection of bladder tumour (TURBT), avoiding the costs and risks of procedure, and anesthesia. PATIENTS AND METHODS: Of 521 patients with primary TaLG NMIBC, this retrospective study included 270 patients who underwent OF during follow-up for recurrent, small, papillary LG-appearing tumours at a university centre (University Health Network, University of Toronto, Canada). We assessed the cumulative incidence of cancer-specific mortality (CSM) and disease progression (to MIBC or metastases), as well as possible direct cost savings. RESULTS: In the 270 patients with recurrent TaLG NMIBC treated with OF, the mean (sd) age was 64.9 (13.3) years, 70.8% were men, and 60.3% had single tumours. The mean (sd, range) number of OF procedures per patient was 3.1 (3.2, 1-22). The median (interquartile range) follow-up was 10.1 (5.8-16.2) years. Patients also underwent a mean (sd) of 3.6 (3.0) TURBTs during follow-up in case of numerous or bulkier recurrence. In all, 44.4% of patients never received intravesical therapy. The 10-year incidence of CSM and progression were 0% and 3.1% (95% confidence interval 0.8-5.4%), respectively. Direct cost savings in Ontario were estimated at $6994.14 (Canadian dollars) per patient over the study follow-up. CONCLUSIONS: This study supports that properly selected patients with recurrent, apparent TaLG NMIBC can be safely managed with OF under local anaesthesia with occasional TURBT for larger or numerous recurrent tumours, without compromising long-term oncological outcomes. This approach could generate substantial cost-saving to healthcare systems, is patient-friendly, and could be adopted more widely.

International Bladder Cancer Group Intermediate-risk Nonmuscle-invasive Bladder Cancer Scoring System Predicts Outcomes of Patients on Active Surveillance.

PURPOSE: We sought to determine if the International Bladder Cancer Group IR-NMIBC (Intermediate-risk Nonmuscle-invasive Bladder Cancer) scoring system can predict the requirement of delayed transurethral resection of bladder tumor in low-grade nonmuscle-invasive bladder cancer managed by active surveillance. MATERIALS AND METHODS: We prospectively studied recurrent low-grade Ta/T1 nonmuscle-invasive bladder cancer patients managed with active surveillance with the following characteristics: low-grade papillary nonmuscle-invasive bladder cancer, ≤5 apparent low-grade nonmuscle-invasive bladder tumors, tumor diameter ≤1 cm, absence of gross hematuria, and negative urinary cytology. Subsequent transurethral resection of bladder tumor was offered to patients who no longer met the inclusion criteria or patient choice. The ability of the International Bladder Cancer Group IR-NMIBC scoring system to predict receipt of subsequent transurethral resection of bladder tumor was determined. Multivariable Cox proportional hazards analysis was used to determine factors associated with subsequent transurethral resection of bladder tumor. RESULTS: A total of 163 patients with low-grade Ta/T1 nonmuscle-invasive bladder cancer were included for analysis. After a median follow-up of 33 months (IQR: 21-46), transurethral resection of bladder tumor was performed on 109 patients. At landmark time point of 24 months, patients with 0 risk factors were over 2-fold more likely to continue active surveillance compared to patients with ≥3 risk factors (59% vs 24%). Multivariable Cox regression suggested that the International Bladder Cancer Group IR-NMIBC scoring system was associated with subsequent transurethral resection of bladder tumor (1-2 risk factors [HR: 1.66, 95% CI: 0.96-2.90, P = .072], ≥3 risk factors [HR: 3.21, 95% CI: 1.70-6.09, P < .001]) after adjusting for age, T stage, and sex. CONCLUSIONS: The International Bladder Cancer Group IR-NMIBC scoring system can predict the risk of subsequent transurethral resection of bladder tumor in patients with low-grade nonmuscle-invasive bladder cancer on active surveillance.

Targeting hyaluronic acid synthase-3 (HAS3) for the treatment of advanced renal cell carcinoma.

BACKGROUND: Hyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment. METHODS: We analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts. RESULTS: RCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant. CONCLUSION: HAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6-1.1-g/day), SF targets HAS3 and effectively abrogates mRCC.

International Bladder Cancer Group Consensus Statement on Clinical Trial Design for Patients with Bacillus Calmette-Guérin-exposed High-risk Non-muscle-invasive Bladder Cancer.

CONTEXT: A large proportion of patients with non-muscle-invasive bladder cancer (NMIBC) fall in the gap between bacillus Calmette-Guérin (BCG)-naïve and BCG-unresponsive disease. As multiple therapeutic agents move into this gray area, there is a critical need to define the disease state and establish recommendations for optimal trial design. OBJECTIVE: To develop a consensus on optimal trial design for patients with BCG-exposed NMIBC, defined as high-grade recurrence after BCG treatment that does not meet the criteria for BCG-unresponsive disease. EVIDENCE ACQUISITION: We conducted a literature review using the Cochrane Library, Medline, and Embase and a review of clinical trials in ClinicalTrials.gov as a basis to generate consensus recommendations for clinical trial design in BCG-exposed NMIBC. EVIDENCE SYNTHESIS: BCG-exposed NMIBC encompasses BCG resistance (presence of high-grade Ta or carcinoma in situ [CIS] at 3-mo evaluation after induction BCG) and delayed relapse. Randomized controlled trials are required to compare experimental therapies to a control arm receiving additional BCG, although ongoing BCG shortages may impact our ability to follow an optimal trial design. A placebo should be used in combination with BCG if the treatment arm includes BCG plus a study drug. Trials will either need to separate patients with and without CIS into two cohorts, or stratify by the presence of CIS at the time of randomization. If two cohorts are used, the primary endpoint for CIS patients should be complete response within a predetermined time. The primary endpoint in a cohort with Ta/T1 only, or if a single combined cohort is used, should be the duration of event-free survival. Suggested efficacy thresholds and corresponding sample sizes are provided. CONCLUSIONS: The International Bladder Cancer Group has developed recommendations regarding definitions, endpoints, and clinical trial design for BCG-exposed NMIBC to encourage uniformity among studies in this disease state. PATIENT SUMMARY: Our consensus provides a precise definition of the disease state for bladder cancer not invading the bladder muscle and exposed to bacillus Calmette-Guérin (BCG) treatment. Clear guidance for conducting optimal clinical trials in this disease setting was established and we believe that this will promote further progress in this field.