ABSTRACT
Introduction & Objectives: Patients with high risk non muscle invasive bladder cancer (NMIBC) who experience BCG failure have limited bladder preserving treatment options as radical cystectomy currently represents the standard therapeutical approach. Systematic immunotherapy (IO) has changed the landscape in advanced bladder cancer and is currently being investigated in NMIBC. Based on the hypothesis that intravesical administration will not be related with severe adverse events, we evaluated the role of intravesically administered durvalumab in NMIBC patients after BCG failure. Material(s) and Method(s): An open label, single-arm, multi-center, phase II clinical trial was conducted. A run-in phase had the objective to determine the maximum tolerated dose (MTD) of durvalumab and to exclude a detrimental effect on disease relapse by this strategy. Durvalumab was administered for a total of 6 instillations per patient at consecutive levels of 500, 750 and 1000 mg. Phase II has as primary end point the 1-year high-grade-relapse-free (HGRF)-rate. Secondary endpoints included toxicity, and high-grade progression-free rat at 1, 3 and 6 months after treatment. Result(s): Thirty patients were enrolled (run in phase: 9, phase II: 21). One patient withdrew consent prior to receiving study treatment, so 29 patients were included in efficacy and toxicity analyses. Mean age was 66.5 years. MTD of durvalumab was set at 1000 mg as no dose related toxicities (DLTs) occurred at any level studied. Three of 9 patients included in the run-in phase (33.3%) were tumor free one month after the last durvalumab instillation, therefore, the null hypothesis was rejected by the futility analysis. Western blot showed that durvalumab remained stable in urine during instillation. One patient died from Covid-19, 3 months after the last durvalumab administration. All patients concluded at least 1 year follow up. One-year HGRF rate was 34.6%. HGRF rates at 1, 3 and 6 months was 73%, 65.3% and 50% respectively. Five patients (17%) experienced a T2 or above disease relapse. Five out of the six patients who received 500mg or 750mg of durvalumab relapsed within 1 year. When efficacy analyses were restricted to patients receiving 1000mg of durvalumab, 1-year HGRF rate was 35%. Interestingly, 2 out of 2 patients with only CIS disease at baseline experienced a tumor complete response, which was durable and was maintained at least for a year. No severe adverse events were noted. The most common adverse event was Grade 1 hematuria. Conclusion(s): Intravesical IO using durvalumab was proved to be feasible with an excellent safety profile. Oncological results seem to be promising and comparable with other bladder preserving strategies in BCG failure with the advantage of a better safety profile. Further study of intravesical IO in high-risk patients with NMIBC after BCG failure is warranted.Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.
ABSTRACT
INTRODUCTION AND OBJECTIVE: Patients with non-muscleinvasive bladder cancer (NMIBC) that recurs after treatment with intravesical Bacillus Calmette-Guerin (BCG) must weigh the risk of progression of bladder cancer and loss of a window of potential cure with medical therapy against the risk of morbidity and loss of quality of life (QOL) with radical cystectomy. The CISTO Study (NCT03933826) is a pragmatic, prospective observational cohort study comparing medical therapy (i.e., intravesical therapy or systemic immunotherapy) with radical cystectomy for recurrent highrisk NMIBC. Here we report on the design and progress of the CISTO Study. METHODS: 900 patients with recurrent high-risk NMIBC that has failed first-line BCG and who have chosen to undergo standard of care treatment will be enrolled. Patient stakeholders helped determine the primary outcome: 12-month patient-reported QOL using the EORTC QLQ-C30. Secondary outcomes include urinary and sexual function, decisional regret, financial distress, healthcare utilization, return to work/normal activities, progression, and recurrence-free, metastasis-free, and overall survival. Participants will be followed for up to 3 years. RESULTS: Enrollment is active at 32 sites across the US, including 23 university-based centers and 9 community sites. As of November 1, 2021, 173 participants have been enrolled, 104 of whom chose medical therapy and 69 of whom chose radical cystectomy. The completion rate for the primary outcome of QOL at 12 months is 94% (15 out of 16 participants to date). The inclusion of electronic consent and collection of PROs allowed recruitment and follow-up to continue remotely during the COVID-19 pandemic. Significant pandemic-related challenges have included slow study start-up at sites, staffing, periods of suspension, and delays in patients obtaining care. Strategies to address these challenges include improved methods for onboarding and training sites, all-site communication, confirming study eligibility, ing EHR data, and remote monitoring while adhering to the highest study standards. CONCLUSIONS: The CISTO Study will compare patient reported outcomes for those undergoing medical therapy with radical cystectomy for recurrent high-risk NMIBC. The CISTO Study has the potential to fill critical evidence gaps and provide for personalized, patient-centered care.
ABSTRACT
INTRODUCTION AND OBJECTIVE: The COVID-19 pandemic has impacted various clinical and research processes in urologic care. As part of a pragmatic clinical trial in bladder cancer, we collected information regarding the impact of COVID-19 at participating sites, which provides insight into how the pandemic has imposed constraints on clinical bladder cancer care and research. METHODS: Starting in May 2020, we distributed a monthly survey to sites participating in CISTO (Comparison of Intravesical Therapy and Surgery as Treatment Options for Bladder Cancer, NCT0393382). The survey included questions about interruptions in routine clinical bladder cancer care, specifically assessing elective surgery restrictions, impact on radical cystectomy, TURBT, office cystoscopies, intravesical therapy, and intravesical bacillus Calmette- Guerin (BCG) supply. We report survey responses for sites that responded to > 50% of the monthly surveys from May 2020 to October 2021. RESULTS: From May 2020 through October 2021, 21 sites (66%) had > 50% monthly response rate. The time periods of greatest limitations on bladder cancer procedures (Figure 1) were May-July 2020, Dec-Jan 2020/2021, and Sept-Oct 2021, corresponding to the peak waves of COVID-19 infections. Elective surgery was most affected, with limitations or holds in those time periods at up to 76%, 38%, and 28% of CISTO sites, respectively. Most of the restrictions involved surgeries that required inpatient stays, potential intensive care unit admission, and staffing shortages. 9 sites (28%) experienced transient BCG shortages during the survey period. CONCLUSIONS: Clinical activity was most limited during the initial COVID-19 surge in Spring/Summer 2020. Despite higher COVID- 19 infection rates in subsequent waves, bladder cancer clinical activity has been maintained at CISTO sites throughout the COVID pandemic. Periodic BCG shortages continue to affect bladder cancer care across the US. (Figure Presented).
ABSTRACT
Introduction & Objectives: Intravesical instillations of GAG-layer replacement are utilised in a number of benign bladder conditions and are traditionally delivered in an outpatient setting. Our unit was considering the feasibility of an at-home service when the COVID-19 pandemic resulted in the sudden cancellation of non-essential services. This provided impetus to rapidly change service delivery so this effective therapy could continue to be available. Here we outline the implementation of an at-home intravesical therapy service & report on early patient satisfaction outcomes. Materials & Methods: The product was chosen based on local use and practical advantages. Collaboration with the company ensured optimal planning and initiation. Review of regulations & cost-effective analysis led to dispensation via a community pharmacy after appropriate tuition. Patients were identified via the unit's intravesical treatment database. Inclusion criteria were the willingness to learn intermittent catheterisation, to have the medication administered at home, and to conduct telephone review. Tuition was delivered by qualified urology nurses in a single 30-60 minute session, utilising video and diagrams. Patients that were shielding were instructed by community bladder nurses. PROMS data were collected via a unit-designed questionnaire. Clinical outcome data were collected from follow-up notes. Results: Between March 2020 and January 2021, 65 patients (mean age 50 years) commenced at-home therapy. 22 (88%) were female. The first patient was instructed 11 days after compulsory cessation of outpatient instillations. Efficacy was 65%-83% across different indications (bladder pain, recurrent UTIs, chemical cystitis, radiation cystitis & ketamine bladder). 25 patients returned the PROMS questionnaire. 20 had previously had outpatient nurse-delivered instillations, 5 were treatment naive. 20 performed self-catheterisation, 1 used the adapter, 4 received assistance from a relative/carer. Whilst some patients reported difficulty with catheter insertion, medicine instillation and/or UTI following administration, 72% completed the course at home. 11/20 experiencing both service models preferred at-home administration;9/20 preferred the hospital option. Positive feedback for at-home treatment included convenience, time saved, and privacy. Concerns were centred on technical aspects. Overall satisfaction was reported as very good, good or satisfactory by 18 (72%), and was linked to ability to continue treatment. Savings in our unit per treatment course or treatment year ranged between £180 & £470, dependent on the number of overall treatments. Conclusions: This study shows radical service change can be implemented quickly, safely and effectively. Careful patient selection and tuition enables cost-savings, freeing of outpatient space and improved patient satisfaction. We encourage other institutions to consider commencement of an at-home instillation service.