CISTO: Comparison of Intravesical Therapy and Surgery as Treatment Options for Bladder Cancer

Study Overview
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Brief Summary
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Bladder cancer is the most common urinary tract cancer and the 5th most common cancer in the US (1). Yet bladder cancer research is underfunded relative to other common cancers. As a result, bladder cancer care is prone to evidence gaps that produce decision uncertainty for both patients and clinicians. The Comparison of Intravesical Therapy and Surgery as Treatment Options (CISTO) for Bladder Cancer Study has the potential to fill these critical evidence gaps, change care pathways for the management of NMIBC (non-muscle-invasive bladder cancer), and provide for personalized, patient-centered care. The purpose of CISTO is to conduct a large prospective study that directly compares the impact of medical management versus bladder removal in recurrent high-grade NMIBC patients with BCG (Bacillus Calmette-Guerin) failure on clinical outcomes and patient and caregiver experience using standardized patient-reported outcomes (PROs).

Detailed Description
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Most bladder cancer patients (74%) present with NMIBC where the cancer is limited to the lining or support layer of the bladder. High-grade NMIBC is treated initially with endoscopic resection and intravesical immunotherapy, followed by bladder instillations of BCG. Most patients with high-risk, high-grade NMIBC are able to retain their bladders and avoid more invasive treatments. However, 24-61% of patients will have their cancers recur within 12 months of treatment with BCG (BCG failures), and they have limited treatment options. National guidelines recommend consideration between two alternatives: additional medical management and radical cystectomy (removal of the bladder). Selecting between these options involves weighing the risk of progression of bladder cancer and loss of a window of potential cure versus the risk of morbidity and loss of quality of life (QOL) with bladder removal. This complex decision-making engages patients and their caregivers, who may be impacted by the urinary, sexual, and bowel dysfunctions that can occur with NMIBC treatment. The investigators will evaluate this research question on a large scale in real world practice settings including academic and community-based practices and examine patient-centered outcomes. The investigators have engaged stakeholders with diverse perspectives relevant to this research question, including patients, caregivers, national patient advocacy organizations, national medical specialty organizations, guideline developers, health care payers, and industry. By engaging broad expertise relevant to this research question, the investigators will ensure that the study results will help NMIBC patients whose cancer recurs after BCG treatment make more informed decisions that improve the health outcomes that are important to them. CISTO is an observational study that will not affect the treatment that patients chose. Patient surveys will occur at study entry and at follow-up assessments for up to four years. There will also be a qualitative sub-study that will include interviews of approximately 50 patients and 25 caregivers recruited from the observational cohort study.

Official Title
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CISTO: Comparison of Intravesical Therapy and Surgery as Treatment Options for Bladder Cancer

Conditions
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Bladder Cancer, Cancer of the Bladder, Recurrent, Non-muscle Invasive Bladder Cancer

Participation Criteria
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Eligibility Criteria
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Patient Eligibility, Inclusion Criteria: Adult 18 years of age or older; and Presenting with high-grade NMIBC established by anatomic pathology as tumor stage classification Tis, Ta, or T1, and with: Pathology documentation from any hospital/clinic/medical center, and More than 50% urothelial carcinoma component in the specimen History of high-grade NMIBC established by anatomic pathology as tumor stage classification Tis, Ta, or T1; and Attempted or received induction BCG (at least 3 out of 6 instillations) at any point in time; and In the previous 12 months, received at least one instillation of any intravesical agent (induction or maintenance) or one administration of systemic therapy for NMIBC treatment. Patient Eligibility, Exclusion Criteria: Any plasmacytoid or small cell (neuroendocrine) component in the pathology (past or current presentation); Previous history of cystectomy or radiation therapy for bladder cancer; Previous history of muscle-invasive bladder cancer or metastatic bladder cancer; Any history of upper tract urothelial carcinoma; Incarcerated in a detention facility or in police custody (patients wearing a monitoring device can be enrolled) at baseline/screening; Contraindication to radical cystectomy (e.g., ASA of 4, patient not considered a radical cystectomy candidate due to comorbidity); Contraindication to medical therapy (i.e., intolerant of all medical therapies); Unable to provide written informed consent in English; Unable to be contacted for research surveys; Planning to participate in a Phase I or Phase II interventional clinical trial for NMIBC (unless in the control/comparator arm of a Phase II trial) or any blinded interventional trial for NMIBC.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients who have selected radical cystectomy<br>Patients with a diagnosis of recurrent high-grade NMIBC that failed first-line BCG and who have selected radical cystectomy as their second-line treatment | |
| Patients who have selected medical management<br>Patients with a diagnosis of recurrent high-grade NMIBC that failed first-line BCG and who have selected medical management as their second-line treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-reported quality of life as measured by the European Organization for Research and Treatment of Cancer Quality-of-Life-Questionnaire-Core-30 (EORTC QLQ-C30) | The primary evaluation of patient-reported quality of life, as measured by the EORTC QLQ-C30 at 12 months, will be conducted using targeted maximum likelihood estimation (TMLE) analysis. All of the subscales and single-item measures range in score from 0 to 100 and a high scale score represents a higher response level (ranging from 0 = low to 100 = high/healthy level of function; from 0 = low to 100 = high quality-of-life; from 0 = low to 100 = high level of symptomatology/problems). Subscale and global health status scores are each calculated by transforming individual item scores into a 0 to 1 scale, taking the mean, and multiplying by 100. Each subscale requires responses for at least 50% of the items in that subscale in order to be calculated. | 12 months after completion of the patient baseline assessment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-reported quality of life as measured by the European Organization for Research and Treatment of Cancer Quality-of-Life-Questionnaire-Core-30 (EORTC QLQ-C30) | The evaluation of the effect of treatment choice on the trajectory of patient-reported quality of life, as measured by the EORTC QLQ-C30 at up to 48 months, will be conducted using both mixed effects and generalized estimating equations (GEE) longitudinal models. | Up to 48 months after completion of the patient baseline assessment | 
| Patient self-reported urinary function as measured by the Bladder Cancer Index | The evaluation of the effect of treatment choice on patient-reported urinary function, as measured by the Bladder Cancer Index (BCI) at 12 months, will be conducted using TMLE analysis. The evaluation of the effect of treatment choice on the trajectory of urinary function at up to 48 months as measured by the BCI will be conducted using both mixed effects and GEE longitudinal models. The BCI consists of 36 items, with 4- or 5-point Likert response scales, covering 3 primary domains: urinary, bowel, and sexual. For each domain a summary score and two subscale scores (function and bother) are constructed. Scores are calculated by transforming item responses into a 0 to 100 scale and calculating the mean of the standardized items. Higher scores indicate better health status. To calculate a score, a minimum of 80% completed items is required. | 12 months after completion of the patient baseline assessment and up to 48 months | 
| Patient self-reported sexual function as measured by the Bladder Cancer Index | The evaluation of the effect of treatment choice on patient-reported sexual function, as measured by the BCI at 12 months, will be conducted using TMLE analysis. The evaluation of the effect of treatment choice on the trajectory of sexual function at up to 48 months as measured by the BCI will be conducted using both mixed effects and GEE longitudinal models. | 12 months after completion of the patient baseline assessment and up to 48 months | 
| Patient self-reported NMIBC treatment preferences | Patients' generic quality of life as measured in quality adjusted life years (QALY) by a series of time tradeoff (TTO) questions at 12 months post-enrollment will be modeled as a function of patient preferences, as measured by additional TTO items measuring QALY for bladder cancer-related health states, while controlling for patients' baseline quality of life, demographic and clinical characteristics using beta regression, stratified by treatment arm. | 12 months after completion of the patient baseline assessment | 
| Patient self-reported decisional regret | Patient-reported decisional regret will be measured using three items with 5-point Likert response scales which have been validated in a previous study of prostate cancer patients. These three items will be summed to yield a score from 0 to 12, with higher scores indicating greater regret. The evaluation of the effect of treatment choice on patient-reported decisional regret at 12 months will be conducted using TMLE analysis. The evaluation of the effect of treatment choice on patient-reported decisional regret at up to 48 months will be conducted using both mixed effects and GEE longitudinal models. | 12 months after completion of the patient baseline assessment and up to 48 months | 
| Patient self-reported financial distress as measured by the Comprehensive Score for Financial Toxicity (COST) | The evaluation of the effect of treatment choice on patient-reported financial distress, as measured by COST at 12-months, will be conducted using TMLE analysis. The evaluation of the effect of treatment choice on the trajectory of patient financial distress at up to 48 months will be conducted using both mixed effects and GEE longitudinal models. The COST questionnaire consists of 11 items, each scored on a 5-point Likert scale from zero to four. After reversing some items as indicated in the scoring manual (by reversing the sign on the original zero to four score and adding four), all item response scores are summed into a single financial toxicity score ranging from 0 to 44, with higher scores indicating greater financial toxicity. Each subscale requires responses for at least 50% of the items in that subscale in order to be calculated. Item nonresponse is accounted for by substituting the mean of the completed items in the subscale. | 12 months after completion of the patient baseline assessment and up to 48 months | 
| Patient self-reported healthcare utilization as measured by hospital and urology clinic days | The evaluation of the effect of treatment choice on healthcare utilization, as measured by 12-month hospital and urology clinic days, will be conducted using TMLE analysis. The evaluation of the effect of treatment choice on the trajectory of patient healthcare utilization at up to 48 months will be conducted using both mixed effects and GEE longitudinal models. | 12 months after completion of the patient baseline assessment and up to 48 months | 
| Patient self-reported return to work/normal activities | The evaluation of the effect of treatment choice on patient self-reported return to work/normal activities will be conducted using TMLE analysis. | 12 months after completion of the patient baseline assessment | 
| Patient disease-free survival | The evaluation of the effect of treatment choice on patient 12-month disease-free survival will be conducted using TMLE analysis. The evaluation of the effect of treatment choice on patient disease-free survival at up to 48 months will be conducted using TMLE-based survival analysis. | 12 months after completion of the patient baseline assessment and up to 48 months | 
| Patient metastasis-free survival | The evaluation of the effect of treatment choice on patient 12-month metastasis-free survival will be conducted using TMLE analysis. The evaluation of the effect of treatment choice on patient metastasis-free survival at up to 48 months will be conducted using TMLE-based survival analysis. | 12 months after completion of the patient baseline assessment and up to 48 months | 
| Patient progression to muscle-invasive bladder cancer | The evaluation of the effect of treatment choice on patient 12-month progression to muscle-invasive bladder cancer will be conducted using TMLE analysis. The evaluation of the effect of treatment choice on patient progression to muscle-invasive bladder cancer at up to 48 months will be conducted using TMLE-based survival analysis. | 12 months after completion of the patient baseline assessment and up to 48 months | 
| Patient bladder cancer-specific survival | The evaluation of the effect of treatment choice on patient 12-month bladder cancer-specific survival will be conducted using TMLE analysis. The evaluation of the effect of treatment choice on patient bladder cancer-specific survival at up to 48 months will be conducted using TMLE-based survival analysis. | 12 months after completion of the patient baseline assessment and up to 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pragmatic trial, Bacillus Calmette-Guerin (BCG), urinary bladder neoplasms, urogenital neoplasms, radical cystectomy, neoplasms by site, neoplasms, urinary bladder disease, immunologic factors, caregivers, physiological effects of drugs, immunologic adjuvants, urologic diseases