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Role of immunotherapy in bacillus Calmette-Guerin-unresponsive non-muscle invasive bladder cancer.

ABSTRACT: 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.

SUBMITTER: Mukherjee N

PROVIDER: S-EPMC6428193 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Role of immunotherapy in bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer.

Mukherjee Neelam N Svatek Robert S RS Mansour Ahmed M AM

Urologic oncology 20180209 3

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 e ...[more]

PMID: 29429897

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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.

Dataset Information

Role of immunotherapy in bacillus Calmette-Guerin-unresponsive non-muscle invasive bladder cancer.

Publications

Role of immunotherapy in bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer.

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