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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Bladder Cancer; Non-muscle Invasive Bladder Cancer; Cancer of the Bladder, Recurrent

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 572

Contacts and Locations

• Study Contact: Name: Kristin Follmer; Phone Number: 206-685-8708; Email: cistopm@uw.edu
• Study Contact Backup: Name: Erika Wolff, PhD; Phone Number: 206-221-3174; Email: cistopm@uw.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Cancer Center
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
    • Los Angeles, California, United States, 90033
      • USC/Norris Comprehensive CA Center
    • Newport Beach, California, United States, 92663
      • Hoag Memorial Hospital Presbyterian
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • LSU Healthcare Network - Multi Specialty Clinic
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University, School of Medicine
    • Hanover, Maryland, United States, 21076
      • Chesapeake Urology Research Associates
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Michigan Medicine Rogel Cancer Center
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health
    • Royal Oak, Michigan, United States, 48073
      • Comprehensive Urology -- A Division of Michigan Healthcare Professionals
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein College of Medicine
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73114
      • Stephenson Cancer Center
  • Oregon
    • Medford, Oregon, United States, 97504
      • Asante Rogue Regional Medical Center
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19122
      • Perelman Center for Advanced Medicine
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center, LLC
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37209
      • Urology Associates, P.C.
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • The University of Texas Health Science Center at San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Patients with a diagnosis of recurrent high-grade NMIBC that failed first-line BCG and who are considering second-line treatment will be approached for participation in this observational study in addition to their caregivers. Enrollment at each site will aim for a 2:1 ratio of participants selecting medical management to radical cystectomy in order to ensure adequate enrollment of radical cystectomy patients. There will also be a qualitative sub-study that will include interviews of 50 patients and 25 caregivers recruited from the observational cohort study.

Description

Patient Eligibility, Inclusion Criteria:

1. Adult 18 years of age or older; and

2. Presenting with high-grade NMIBC established by anatomic pathology as tumor stage classification Tis, Ta, or T1, and with:

   1. Pathology documentation from any hospital/clinic/medical center, and
   2. More than 50% urothelial carcinoma component in the specimen
3. History of high-grade NMIBC established by anatomic pathology as tumor stage classification Tis, Ta, or T1; and
4. Attempted or received induction BCG (at least 3 out of 6 instillations) at any point in time; and
5. 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:

1. Any plasmacytoid or small cell (neuroendocrine) component in the pathology (past or current presentation);
2. Previous history of cystectomy or radiation therapy for bladder cancer;
3. Previous history of muscle-invasive bladder cancer or metastatic bladder cancer;
4. Any history of upper tract urothelial carcinoma;
5. Incarcerated in a detention facility or in police custody (patients wearing a monitoring device can be enrolled) at baseline/screening;
6. Contraindication to radical cystectomy (e.g., ASA of 4, patient not considered a radical cystectomy candidate due to comorbidity);
7. Contraindication to medical therapy (i.e., intolerant of all medical therapies);
8. Unable to provide written informed consent in English;
9. Unable to be contacted for research surveys;
10. 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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Patients who have selected radical cystectomy; 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; 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?

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

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Patient-Centered Outcomes Research Institute
• Investigators: Principal Investigator: John L Gore, MD, University of Washington

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2019
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): March 31, 2025

Study Registration Dates

• First Submitted: April 19, 2019
• First Submitted That Met QC Criteria: April 28, 2019
• First Posted (Actual): May 1, 2019

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: caregivers; neoplasms by site; neoplasms; pragmatic trial; radical cystectomy; physiological effects of drugs; Bacillus Calmette-Guerin (BCG); urinary bladder neoplasms; urogenital neoplasms; urinary bladder disease; immunologic factors; immunologic adjuvants; urologic diseases
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urinary Bladder Neoplasms; Non-Muscle Invasive Bladder Neoplasms
• Other Study ID Numbers: SITE00001017; PCS-2017C3-9380 (Other Identifier: PCORI); RG1121143 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); NCI-2020-06082 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified study data will be shared according to the PCORI policy for data management and data sharing.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No