VA Randomized Trial of Surveillance Intervals After Transurethral Resection of High Grade Bladder Tumors

CSP #2036 - VA Randomized Trial of Surveillance Intervals After Transurethral Resection of High-Grade Bladder Tumors (VATSIT)

CSP #2036 is a pragmatic, randomized, intent-to-treat, two-arm, parallel, multicenter CSP trial. Blinding of clinical staff and participants will not be possible. However, outcomes will be adjudicated by assessors blinded to randomization arm to minimize bias. Due to the pragmatic nature of the study, treatment for bladder cancer will be at the discretion of the VA participants' clinicians, and all treatments will be recorded.

Veterans with high-grade non-muscle invasive bladder cancer who underwent biopsy or transurethral resection of a bladder tumor (TURBT) in the prior 6 months will be invited to participate. After a normal first cystoscopy after TURBT (also known as "3-month cystoscopy") and additional screening, participants will be randomized 1:1 to a program of low- vs high-intensity surveillance. Stratification by stage (2 groups: Ta only vs. any T1 / any Carcinoma in situ), and site will be done because these may influence other bladder cancer-specific care, such as the threshold of when to biopsy a possible bladder lesion and whether to administer intravesical therapy.

Outcomes will be assessed during study visits every three months for 24 months, every six months after that up to 48 months, and at 60 months. Follow-up data collection beyond 60 months will be completed by phone call or participants' health record review. This will be a 10-year study with 6 years dedicated to recruitment and a minimum of 4 years dedicated to follow-up. Thus, estimated average follow-up will be 7 years and maximum follow-up will be 10 years.

Background: This CSP study is designed to disrupt the paradigm of high-intensity surveillance with invasive cystoscopy procedures for participants with high-grade early-stage bladder cancer that has existed for more than 80 years without high-quality evidence. Bladder cancer is the third most prevalent non-cutaneous cancer in VA with approximately 30,000 Veterans living with the disease. These ~30,000 Veterans undergo regular surveillance cystoscopy procedures every 3 to 4 months - usually combined with non-invasive urine cytology testing. This makes cystoscopy the most common surgical procedure performed in VA with more than 80,000 procedures annually.

There is a significant gap in knowledge as there is no high-quality data linking high-intensity surveillance with invasive cystoscopy procedures to outcomes. While recommended in guidelines, the 3-month time interval is due to historical precedent dating back to 1936. Thus, there is an urgent need for studies to determine if low-intensity surveillance with fewer cystoscopy procedures can be employed without significantly affecting important outcomes.

Low-intensity surveillance with fewer cystoscopy procedures has a number of potential benefits. It could spare Veterans up to 60% of the currently scheduled invasive cystoscopy procedures, substantially decreasing morbidity and discomfort associated with these procedures. For the VA healthcare system, substantial cost-savings could be achieved if the number of cystoscopy procedures could be reduced without impacting outcomes that matter to participants and clinicians.

This study is the first and only study comparing high-intensity surveillance with frequent cystoscopy to low-intensity surveillance with fewer cystoscopy procedures among participants with high-grade early-stage bladder cancer. It will provide critical data on how surveillance schedules affect important outcomes. Thus, the results of the study will impact VA, national, and international guideline recommendations on surveillance cystoscopy.

Objectives:

Primary: To examine whether assignment to a low-intensity surveillance program has non-inferior overall survival compared to assignment to a high-intensity surveillance program among participants with high-grade non-muscle invasive urothelial carcinoma of the bladder. The investigators hypothesize that five-year overall survival with a low-intensity surveillance program will be no worse than with assignment to a high-intensity surveillance program with a non-inferiority margin of 5% at 5 years.

Secondary: To compare assignment to a low- vs. high-intensity surveillance program with respect to bladder cancer-specific survival and need for radical treatment. The investigators hypothesize that five-year bladder cancer-specific survival with a low-intensity surveillance program will be no worse than with a high-intensity surveillance program with a non-inferiority margin of 5% at 5 years.

The investigators hypothesize that the proportion of participants undergoing radical treatment for bladder cancer at 4 years with a low-intensity surveillance program is no worse than with a high-intensity surveillance program with a non-inferiority margin of 4%.

Tertiary: To compare assignment to a low- vs. high-intensity surveillance program with respect to bladder cancer progression, number of surgical procedures related to bladder cancer performed in the operating room under anesthesia, cumulative incidence of 30-day complications from surgical procedures, and bladder cancer-specific participant-reported quality of life. The investigators hypothesize that bladder cancer progression at 2 and 5 years is not different with low- vs high-intensity surveillance. The investigators hypothesize that the number of surgical procedures related to bladder cancer performed in the operating room under anesthesia will be significantly lower among participants randomized to a low-intensity surveillance program compared to a high-intensity surveillance program. The investigators hypothesize that the cumulative incidence of 30-day complications from surgical procedures will be significantly lower comparing participants randomized to a low- vs. high-intensity surveillance program. The investigators hypothesize that longitudinal bladder cancer-specific quality of life will be significantly better comparing participants randomized to a low- vs. high-intensity surveillance program.

Design:

CSP #2036 is a pragmatic, randomized, intent-to-treat, two-arm, parallel, multicenter CSP trial. Blinding of clinical staff and participants will not be possible. However, outcomes will be adjudicated by assessors blinded to randomization arm to minimize bias. Due to the pragmatic nature of the study, treatment for bladder cancer will be at the discretion of the VA participants' clinicians, and all treatments will be recorded.

Veterans with high-grade non-muscle invasive bladder cancer who underwent biopsy or transurethral resection of a bladder tumor (TURBT) in the prior 6 months will be invited to participate. After a normal first cystoscopy after TURBT (also known as "3-month cystoscopy") and additional screening, participants will be randomized 1:1 to a program of low- vs high-intensity surveillance. Stratification by stage (2 groups: Ta only vs. any T1 / any Carcinoma in situ), and site will be done because these may influence other bladder cancer-specific care, such as the threshold of when to biopsy a possible bladder lesion and whether to administer intravesical therapy.

Outcomes will be assessed during study visits every three months for 24 months, every six months after that up to 48 months, and at 60 months. Follow-up data collection beyond 60 months will be completed by phone call or participants' health record review. This will be a 10-year study with 6 years dedicated to recruitment and a minimum of 4 years dedicated to follow-up. Thus, estimated average follow-up will be 7 years and maximum follow-up will be 10 years.

Sample Size and Study Duration:

The sample size estimation and power analysis are based on the hypothesis testing of time to participant death, which is the primary outcome of the trial. According to analyses of data from the Corporate Data Warehouse (CDW), the investigators anticipate that Veterans with high-grade non-muscle invasive bladder cancer in the high-intensity surveillance program will have 56% survival at 5 years and 46% at 7 years. The investigators set a non-inferiority margin for overall survival of 5% at 5 years. The investigators will randomize 2,482 VA participants with 1,241 participants assigned to each arm. Based on CDW data, we anticipate an enrollment rate of one participant per month and per site. Thus, the investigators will include up to 35 sites for a recruitment period of approximately 72 months.

Population:

Key inclusion criteria: history of high-grade non-muscle invasive bladder cancer, no evidence of cancer recurrence at first follow-up visit with cystoscopy after recent resection (also known as "3-month cystoscopy"), and bladder cancer treatment in line with the VA National Oncology Program Clinical Pathway.

Key exclusion criteria: urothelial carcinoma outside the bladder, muscle-invasive or non-urothelial bladder cancer, urothelial carcinoma with predominantly (>50%) variant histology, Eastern Cooperative Oncology Group (ECOG) performance status of 3 or 4, and inability to follow-up for a planned minimum of 4 years.

Surveillance programs:

High-intensity surveillance program: Participants assigned to high-intensity surveillance will undergo cystoscopy and urine cytology testing every 3 months until month 24 after transurethral resection, then every 6 months until month 48, then annually. This is the currently accepted surveillance schedule according to national guidelines and the VA National Oncology Bladder Cancer Clinical Pathway.

Low-intensity surveillance program: Participants assigned to low-intensity surveillance will undergo cystoscopy 12 months after transurethral resection, and then annually. They will also undergo non-invasive testing in the form of urine cytology every 3 months until month 24 after transurethral resection, then every 6 months until month 48, then annually.

Participants randomized to the low-intensity surveillance program will undergo 5 surveillance cystoscopy procedures over a 5-year period, compared to 12 procedures in the high-intensity surveillance program (assuming they have no recurrences or for cause cystoscopy procedures while on trial).

Any participants who experience a positive surveillance test in the form of either an abnormal cystoscopy or a suspicious or positive cytology will be managed according to standard of care as outlined in the VA National Oncology Program Bladder Cancer Clinical Pathway. If the standard of care management reveals a recurrence of non-muscle invasive bladder cancer, this will be treated per VA National Oncology Program Bladder Cancer Clinical Pathway. After treatment, participants will continue per protocol surveillance according to the surveillance program they were randomized to. If the standard of care management reveals muscle-invasive bladder cancer, urothelial carcinoma of the upper tracts or urethra, predominantly (>50%) variant histology, or metastatic disease, the participant will be treated according to the VA National Oncology Program Bladder Cancer Clinical Pathway and no further per protocol surveillance visits will be performed. However, the investigators will follow these participants for the specified study outcomes.

Inclusion Criteria:

• VA patients with a history of high-grade non-muscle invasive urothelial carcinoma of the bladder (Inclusion of non-Veterans only allowed if they already receive clinical care at a VA medical center, e.g., via the CHAMPS program)
• Local pathology report from recent biopsy or resection confirming high-grade non-invasive urothelial carcinoma (high-grade stage Ta), high-grade urothelial carcinoma with invasion into the subepithelial connective tissue (high-grade stage T1), or carcinoma in situ (stage CIS) Note: Participants do not have to have a new diagnosis of urothelial carcinoma. Participants who had a resection of a recurrent urothelial carcinoma are eligible if they meet inclusion / exclusion criteria.
• Bladder cancer treatment since recent biopsy or resection that is in line with VA National Oncology Bladder Cancer Clinical Pathway (e.g., underwent re-resection of T1 disease, administration of intravesical therapy if indicated, or documented reason why Pathway was not followed)
• No evidence of bladder cancer recurrence at first surveillance cystoscopy after most recent resection or biopsy showing urothelial carcinoma (referred to by "3-month cystoscopy" in the protocol), defined as negative cystoscopy AND negative or atypical urine cytology

Notes:

• a re-resection TURBT performed per VA National Oncology Bladder Cancer Clinical Pathway or per local urology clinician judgement is not considered a surveillance cystoscopy. In that setting, the first cystoscopy following that re-resection TURBT will be the "3-month cystoscopy."
• atypical cytology is not of concern in this population, as it frequently can be seen secondary to instrumentation, inflammation, or bacterial colonization.
• Ability to consent in English or Spanish
• Stated willingness to comply with all study procedures

Exclusion Criteria:

• History of urothelial carcinoma of the ureter or renal pelvis status post endoscopic treatment or with evidence of current upper tract disease (inclusion allowed if status post nephroureterectomy and recurrence free at time of inclusion)
• History of urothelial carcinoma of the prostate or urethra
• History of muscle-invasive urothelial carcinoma of the bladder
• History of pure squamous cell carcinoma of the bladder
• Small cell carcinoma of the bladder
• Sarcoma of the bladder
• Urothelial carcinoma with predominantly (>50%) variant histology
• Eastern Cooperative Oncology Group (ECOG) performance status of 3 (capable of only limited selfcare; confined to bed or chair more than 50% of waking hours) or 4 (completely disabled; cannot carry out any selfcare; totally confined to bed or chair)
• Unable to follow-up for planned minimum of 5 years (e.g., pending move away from their VA site, unless planned move is to another VATSIT study site)
• Imaging concerning for metastatic urothelial carcinoma
• Anatomic constraints that make standard cystoscopy impossible (e.g., history of urethrectomy, obliterated urethra secondary to stricture)
• Known pregnancy at the time of study enrollment (routine pregnancy testing is not required)
• Dual enrollment in an interventional drug or device study