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Emerging treatments for bacillus Calmette-Guerin-unresponsive non-muscle-invasive bladder cancer.

ABSTRACT: 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.

SUBMITTER: Kim HS

PROVIDER: S-EPMC8246016 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

Project description:BackgroundA phase 1b study of photosensitizer TLD-1433-mediated photodynamic therapy (PDT) was performed in bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients.ObjectiveThe primary objectives were safety and tolerability of PDT, with secondary objectives of (1) pharmacokinetic (PK) properties of TLD-1433 and (2) efficacy, as evaluated by recurrence-free survival and complete response (CR) at 90 and 180 d for patients treated at the maximum recommended starting dose (0.35 mg/cm2 bladder surface area) and the therapeutic dose (0.70 mg/cm2).Design setting and participantsSix BCG-unresponsive patients were enrolled in an open-label, single-arm, dose-escalating study of PDT. TLD-1433 was instilled intravesically for 60 min preoperatively. PDT was performed under general anesthesia using intravesically delivered irradiation of the bladder wall with green light (520 nm) to a dose of 90 J/cm2.Outcome measurements and statistical analysisPatients were followed by standard cystoscopy and cytology for up to 18 mo to assess time to recurrence.Results and limitationsPDT was well tolerated by all patients. All patients experienced at least one grade ≤2 adverse event (AE). There were no patient deaths or light sensitivity reactions. The most common AE was moderate bladder irritability, which resolved within the first weeks after treatment. AEs were independent of the TLD-1433 dose. TLD-1433 was cleared in the urine and from the plasma within 24 and 72 h, respectively. Of three patients treated at the therapeutic dose, two achieved a CR at 180 d, which was durable at 18 mo. The other patient was diagnosed with metastatic disease at 138 d.ConclusionsPDT with TLD-1433 appears safe for the treatment of BCG-unresponsive NMIBC. Early efficacy signals from full-dose photosensitizer are encouraging and warrant phase 2 trial investigation. The safety and PK results obtained support the potential for administration of consecutive PDT treatments as required.Patient summaryPhotodynamic therapy with TLD-1433 appears to be safe and effective for the treatment of bacillus Calmette-Guérin (BCG)-unresponsive bladder cancer.

Project description:ContextThere is a critical need for effective bladder-sparing therapies for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). Owing to the current lack of effective agents that can be used as a control, the US Food and Drug Administration began to accept single-arm trials for patients with carcinoma in situ (CIS), using complete response rate (CRR) and duration of response as the primary endpoints to support marketing applications. Despite the ensuing growth of clinical trials in this space, no consensus exists on a clinically relevant benchmark for CRR.ObjectiveTo elucidate the CRR and recurrence-free rate (RFR) using bladder-sparing agents after BCG failure in order to provide a frame of reference for future clinical trial results.Evidence acquisitionWe performed a systematic review of clinical trials utilizing bladder-sparing therapeutics for NMIBC recurring after intravesical BCG (PROSPERO CRD42019130553). The search was performed in MEDLINE, EMBASE, and Cochrane Library. Relevant studies identified from bibliography search and conference abstracts were searched to complement the systematic review. A total of 42 studies utilizing 24 treatment options and consisting of 2254 patients were included for final analysis.Evidence synthesisMedian CRRs in the treatment of CIS-containing tumors were 26% at 6 mo, 17% at 12 mo, and 8% at 24 mo after treatment. In comparison, median RFRs in the papillary-only studies were 67% at 6 mo, 44% at 12 mo, and 10% at 24 mo. Specifically in the BCG-unresponsive population, 6- and 12-mo CRRs in CIS-containing patients treated with Mycobacterium phlei cell wall-nucleic acid complex were 45% and 27%, respectively, and the median 6-, 12-, and 24-mo disease-free rates in the other studies were 43%, 35%, and 18%, respectively. The median progression-free rate was 91%: 95% in the CIS-containing studies and 89% in studies restricted to papillary-only recurrences. Toxicities of intravesical agents were generally mild, with very few dose limiting toxicities.ConclusionsWe demonstrate that, to date, bladder-sparing therapies achieved modest efficacy in patients with NMIBC after BCG. Results from the current study will serve as a frame of reference for emerging trial results in the BCG-unresponsive space.Patient summaryIn this study, we found that bladder-sparing therapies achieved modest efficacy in patients with non-muscle-invasive bladder cancer after bacillus Calmette-Guérin (BCG). These results will serve to inform future clinical trial results for salvage agents used to treat BCG-unresponsive bladder cancer.

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Emerging treatments for bacillus Calmette-Guerin-unresponsive non-muscle-invasive bladder cancer.

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