BCG-unresponsive high-grade non-muscle invasive bladder cancer: what does the practicing urologist need to know?
Ontology highlight
ABSTRACT: Purpose
Bacille Calmette-Guérin (BCG) is a well-established treatment for preventing or delaying tumour recurrence following high-grade nonmuscle invasive bladder cancer (NMIBC) resection. However, many patients will experience recurrence or progression during or following BCG. This scenario has been one of the most challenging in urologic oncology for several decades since BCG implementation. Finally, significant progress has occurred lately. The aim of this review was to summarize for the practising urologist the current treatment options available in 2020 or expected to be ready for routine use in the near future for patients with high-risk NMIBC who experience BCG failure.Methods
Narrative review using data through the end of 2020.Results
First, the definition of BCG unresponsive disease which is critical in counseling and managing patients has finally reached a consensus. Second, some promising options other than radical cystectomy are finally available and many other should be in a near future. The options can be categorized as chemotherapy, device-assisted therapy, check-point inhibitors, new intravesical and systemic agents and sequential combinations of these newer modalities with conventional therapy.Conclusions
Considering the options that are currently under scrutiny, many of which in phase III trials, clinicians should have at their disposal several new treatment options in the next five years.
SUBMITTER: Lebacle C
PROVIDER: S-EPMC7997797 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundHigh-risk non-muscle-invasive bladder cancer (HR-NMIBC) presents a challenge to many physicians due to its ability to resist Bacillus Calmette-Guérin (BCG) intravesical therapy and the substantial rate of progression into muscle-invasive bladder cancer (MIBC). Patients who are BCG-unresponsive have worse prognosis and thus require further management including radical cystectomy (RC), which significantly impacts quality of life. Moreover, the ongoing worldwide shortage of BCG warrants the need for policies that prioritize drug use and utilize alternative treatment strategies. Hence, there is a significant unmet need for bladder preserving therapy in this subset of patients.MethodsTo address this issue, we searched the relevant literature in PUBMED for articles published from 2019 through May of 2023 using appropriate keywords. All clinical trials of patients with HR-NMIBC treated with immune-related agents were retrieved from clinicaltrials.gov.Findings and future perspectivesExploratory treatments for BCG-Unresponsive HR-NMIBC included immune checkpoint inhibitors (ICI), oncolytic viral therapy, cytokine agonists, and other immunomodulators targeting TLR, EpCaM, FGFR, MetAP2, and IDO1. Some combination therapies have been found to work synergistically and are preferred therapeutically over monotherapy. Three drugs-pembrolizumab, valrubicin, and most recently, nadofaragene firadenovec-vncg-have been FDA approved for the treatment of BCG-unresponsive NMIBC in patients who are ineligible for or decline RC. However, all explored treatment options tend to postpone RC rather than provide long-term disease control. Additional combination strategies need to be studied to enhance the effects of immunotherapy. Despite the challenges faced in finding effective therapies, many potential treatments are currently under investigation. Addressing the landscape of biomarkers, mechanisms of progression, BCG resistance, and trial design challenges in HR-NMIBC is essential for the discovery of new targets and the development of effective treatments.
| S-EPMC10757155 | biostudies-literature
Project description:Urothelial carcinoma (UC), the sixth most common cancer in Western countries, includes upper tract urothelial carcinoma (UTUC) and bladder carcinoma (BC) as the most common cancers among UCs (90-95%). BC is the most common cancer and can be a highly heterogeneous disease, including both non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) forms with different oncologic outcomes. Approximately 80% of new BC diagnoses are classified as NMIBC after the initial transurethral resection of the bladder tumor (TURBt). In this setting, intravesical instillation of Bacillus Calmette-Guerin (BCG) is the current standard treatment for intermediate- and high-risk patients. Unfortunately, recurrence occurs in 30% to 40% of patients despite adequate BCG treatment. Radical cystectomy (RC) is currently considered the standard treatment for NMIBC that does not respond to BCG. However, RC is a complex surgical procedure with a recognized high perioperative morbidity that is dependent on the patient, disease behaviors, and surgical factors and is associated with a significant impact on quality of life. Therefore, there is an unmet clinical need for alternative bladder-preserving treatments for patients who desire a bladder-sparing approach or are too frail for major surgery. In this review, we aim to present the strategies in BCG-unresponsive NMIBC, focusing on novel molecular therapeutic targets.
| S-EPMC10454200 | biostudies-literature
Project description:ObjectivesThe treatments for high-grade non-muscle invasive bladder cancer (NMIBC) vary between bladder preserving intravesical approaches and radical cystectomy. The impact of these treatments on health-related quality of life may vary widely. The purpose of this study was to elicit the general public's perspective on quality of life, measured as utility scores associated with treatment for Bacillus Calmette-Guerin (BCG)-unresponsive NMIBC and disease progression, for supporting economic evaluation of newly developed treatments for NMIBC.Materials and methodsPart I involved the development and testing of health states describing NMIBC, which was informed by a rapid review, expert input and a patient advisor. Part II involved elicitation of societal utility values for the different health states. Time trade-off (TTO) interviews were conducted with members of the UK general public. Five health states described different NMIBC scenarios including disease recurrence and progression. Participants ranked each health state, followed by the TTO valuation exercise. Descriptors included NMIBC symptom severity, impact and treatment characteristics.ResultsIn total, 202 members of the general public participated. The mean age was 46 (standard deviation [SD] 14.6) years. Sample mean (SD) EQ-5D-5L visual analogue scale (VAS) and index scores were 83.2 (12.3) and 0.89 (0.18), respectively. Mean utilities were 0.781 for No High-Grade Recurrence, 0.586 for High-Grade Recurrence, 0.572 for > 1-Year Post-cystectomy and 0.283 for metastatic disease. The First Year Post-cystectomy path health state had a mean utility of 0.288. Pairwise comparisons found statistically significant differences between utilities (p < 0.001), except between High-Grade Recurrence and > 1-Year Post-cystectomy (p = 0.524). There were significant differences in utility scores by age and employment status.ConclusionThis study provides utility scores for health states describing living with NMIBC, which is associated with a significant health-related quality-of-life burden. These values address an existing gap in available data and have the potential to be used in models evaluating the cost-effectiveness of both current and newly developed treatments for bladder cancer.
| S-EPMC9897878 | biostudies-literature
Project description:Management of patients with bacillus Calmette-Guérin (BCG)-unresponsive, high-risk, non-muscle-invasive bladder cancer (NMIBC) presents a formidable clinical challenge that requires urologists to weigh the competing risks of progression during further intravesical therapy vs. the morbidity of radical cystectomy. The prognosis of high-risk NMIBC recurring after BCG depends on the adequacy of prior BCG, timing of recurrence, and tumor histology. The standard of care is currently radical cystectomy, as effective salvage intravesical therapy has not been established. The development of bladder-sparing treatments has been hampered to date by inconsistent definitions of BCG failure and difficulties in identifying appropriate control treatments in clinical trials. Despite these limitations, the spectrum of salvage therapy is expanding to include enhanced intravesical chemo-, gene, and immuno-therapies. In this review, we provide an overview of these emerging agents in the context of our current understanding of BCG failure and the unique considerations for clinical trial design in this disease state.
| S-EPMC7654668 | biostudies-literature
Project description:BackgroundSingle-arm trials are currently an accepted study design to investigate the efficacy of novel therapies (NT) in non-muscle invasive bladder cancer (NMIBC) unresponsive to intravesical Bacillus Calmette-Guérin (BCG) immunotherapy as randomized controlled trials are either unfeasible (comparator: early radical cystectomy; ERC), or unethical (comparator: placebo). To guide the design of such single-arm trials, expert groups published recommendations for clinically meaningful outcomes. The aim of this study was to quantitatively verify the appropriateness of these recommendations.MethodsWe used a discrete event simulation framework in combination with a supercomputer to find the required efficacy at which a NT can compete with ERC when it comes to quality-adjusted life expectancy (QALE). In total, 24 different efficacy thresholds (including the recommendations) were investigated.ResultsAfter ascertaining face validity with content experts, repeated verification, external validation, and calibration we considered our model valid. Both recommendations rarely showed an incremental benefit of the NT over ERC. In the most optimistic scenario, an increase in the IBCG recommendation by 10% and an increase in the FDA/AUA recommendation by 5% would yield results at which a NT could compete with ERC from a QALE perspective.ConclusionsThis simulation study demonstrated that the current recommendations regarding clinically meaningful outcomes for single-arm trials evaluating the efficacy of NT in BCG-unresponsive NMIBC may be too low. Based on our quantitative approach, we propose increasing these thresholds to at least 45%-55% at 6 months and 35% at 18-24 months (complete response rates/recurrence-free survival) to promote the development of clinically truly meaningful NT.
| S-EPMC7221312 | biostudies-literature
Project description:Background Intravesical bacillus Calmette-Guérin (BCG) fails in a considerable proportion of non-muscle invasive bladder cancer (NMIBC) patients despite treatment per recommended protocol. This real-world study aimed to understand the current patterns of treatment and disease management for the broad BCG-unresponsive NMIBC patient population, alongside collecting sufficient data on patients who do not undergo cystectomy. Methods This was a multicenter, retrospective survey of physicians treating BCG-unresponsive NMIBC patients. Data were collected in eight countries – France, Germany, Spain, Italy, United Kingdom, United States, China, and Japan – between January and May 2019. The study consisted of a short online physician survey and a retrospective chart review of eligible BCG-unresponsive NMIBC patients. Physicians abstracted chart data for the last 10 (five patients in Japan) eligible BCG-unresponsive NMIBC patients meeting the inclusion criteria, and the data were analysed for all countries combined using descriptive statistics. Country-specific analyses were also carried out, as appropriate. Results Overall, 508 physicians participated in the study. Almost one-quarter (22.9%) of physicians’ current NMIBC patient caseload was BCG-unresponsive, whereby BCG therapy was no longer considered an option. Half of physicians (49.4%) did not regularly use biomarker tests in their practice, with particularly few physicians undertaking biomarker testing in Spain and Japan. Biomarker testing varied considerably, with the proportions of physicians selecting ‘none’ ranging from 11.4% in China to 70.3% in Japan. Physicians reported transurethral resection of the bladder tumor (TURBT) and BCG as the most common current treatments received by their patients. Chemotherapy and anti-PD-L1 treatment options were considered impactful new therapies by 94.7% and 90.0% of physicians surveyed in this study, respectively. Conclusions The most common treatments received by patients in this study were TURBT and BCG. Emerging new treatments are driven by exploring biomarkers, but in real-world clinical practice only half of physicians or fewer regularly tested their NMIBC patients for biomarkers; PD-1/PD-L1 was the most common biomarker test used. Most physicians reported that, in addition to chemotherapy, anti-PD-L1 was an impactful new therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12894-022-00959-z.
| S-EPMC8882282 | biostudies-literature
Project description:BackgroundBCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer.MethodsIn this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849.FindingsBetween Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths.InterpretationIntravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state.FundingFKD Therapies Oy.
| S-EPMC7988888 | biostudies-literature
Project description:Bladder cancer is a heterogeneous disease. Treatment decisions are mostly decided based on disease stage (non-muscle invasive or muscle invasive). Patients with muscle-invasive disease will be offered a radical treatment combined with systemic therapy, while in those with non-muscle-invasive disease, an attempt to resect the tumor endoscopically will usually be followed by different intravesical instillations. The goal of intravesical therapy is to decrease the recurrence and/or progression of the tumor. In the current landscape of bladder cancer treatment, BCG is given intravesically to induce an inflammatory response and recruit immune cells to attack the malignant cells and induce immune memory. While the response to BCG treatment has changed the course of bladder cancer management and spared many "bladders", some patients may develop BCG-unresponsive disease, leaving radical surgery as the best choice of curative treatment. As a result, a lot of effort has been put into identifying novel therapies like systemic pembrolizumab and Nadofaragene-Firadenovac to continue sparing bladders if BCG is ineffective. Moreover, recent logistic issues with BCG production caused a worldwide BCG shortage, re-sparking interest in alternative BCG treatments including mitomycin C, sequential gemcitabine with docetaxel, and others. This review encompasses both the historic and current role of BCG in the treatment of non-muscle-invasive bladder cancer, revisiting BCG alternative therapies and reviewing the novel therapeutics that were approved for the BCG-unresponsive stage or are under active investigation.
| S-EPMC10888316 | biostudies-literature
Project description:Intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG immunotherapy prevents disease recurrence and progression to muscle-invasive disease following TURBT. Although most patients initially respond well to intravesical BCG, considerable concern has been raised for patients with BCG failure who are refractory or recur in 6 months after their last BCG, which implies 'BCG-unresponsiveness'. Based on current clinical guidelines, early radical cystectomy (RC) is recommended to treat BCG-unresponsive NMIBC. However, due to the high risk of morbidity and mortality of RC and patients' desire to preserve their own bladder, there is a critical unmet need for alternative conservative treatments as bladder-sparing strategies in BCG-unresponsive patients. Trials for effective bladder-sparing treatments are ongoing, and several novel agents have been recently tested in the NMIBC setting. The goal of this review is to introduce and summarize recently reported novel and emerging drugs and ongoing clinical trials for BCG-unresponsive NMIBC.
| S-EPMC8246016 | biostudies-literature
Project description:Intravesical instillation of live attenuated bacillus Calmette-Guérin (BCG) is the gold standard for patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC). BCG-failures include a heterogenous population of patients who share a designation of disease recurrence or progression following BCG and include patients with complete unresponsiveness to BCG, patients who respond initially but develop relapse and, in some cases, patients who are intolerant to BCG due to side effects. Given the efficacy and relatively rapid approval of several monoclonal antibodies against PD-L1 or PD-1 for advanced and metastatic bladder cancer, the role of these checkpoint inhibitors in BCG-relapsing disease at various disease stages is under consideration. Data supporting a role for immune checkpoint inhibitors is largely theoretical with limited supportive data from animal models and from clinical evidence of increased PD-L1 expression in BCG-unresponsive tumors. Current trials in BCG-unresponsive disease are underway and expected to provide insight regarding these concepts.
| S-EPMC6428193 | biostudies-literature