Replacing Invasive Cystoscopy with Urine Testing for Non-muscle Invasive Bladder Cancer Surveillance

There are ~800,000 bladder cancer survivors in the US, making it the fifth most prevalent cancer. This study focuses on the largest group of patients with bladder cancer, the 79% with non-muscle invasive early-stage cancer. Per current guideline recommendations, these patients undergo transurethral endoscopic resection followed by surveillance cystoscopy every 3 to 6 months, making cystoscopy common with over a million procedures per year. Cystoscopy entails direct inspection of the bladder via a cystoscope that is inserted into a patient's urethra. It can be quite uncomfortable as it is performed in non-sedated patients. In spite of this burden on patients, high-quality data on the benefits of high-intensity surveillance cystoscopy are lacking. The experts writing the guidelines recognized the unclear benefit of high-intensity surveillance and specifically stated: “There is an urgent need for studies to determine if less stringent follow-up regimens can be employed without significantly affecting oncologic outcomes in these patients.” Replacing cystoscopy with less invasive urine testing is such a less stringent follow-up regimen. Preliminary data show that the urine tests Xpert Bladder Cancer Monitor (mRNA-based) and Bladder EpiCheck (DNA methylation test) may replace cystoscopy procedures, given their high sensitivities. However, with a specificity 0.76 and 0.84, up to one out of four tests may be false positive, so many patients still have to undergo cystoscopy for positive tests. Thus, longitudinal comparative data are needed before these tests can be considered for routine care. Specifically, we need evidence that programmatic surveillance with urine tests significantly decreases the burden of surveillance for patients and has acceptable oncologic outcomes in diverse populations of bladder cancer survivors. Here, we will define the extent to which patients' burden of surveillance can be reduced with bladder cancer urine tests. We propose a three-site randomized phase 2 trial including 240 patients with early-stage bladder cancer. After a normal surveillance cystoscopy at study entry, patients will be randomized 1:1:1 to programmatic surveillance with the Xpert bladder cancer urine test, the Bladder EpiCheck urine test, or standard cystoscopy. We will (1) determine whether burden of surveillance is significantly decreased in the urine testing arms versus standard cystoscopy, (2) compare short-term safety outcomes in the urine testing arms versus standard cystoscopy at 1 and 2 years, and (3) estimate important feasibility data for a subsequent large non-inferiority comparative effectiveness trial. In summary, we will systematically study whether the burden of surveillance cystoscopy can be improved among bladder cancer survivors by replacing invasive cystoscopy with urine testing, ultimately improving their quality of life. If bladder cancer urine tests significantly decrease the burden of surveillance, our data will provide a strong justification for a subsequent comparative effectiveness trial of programmatic surveillance with urine testing versus standard cystoscopy that is large enough to be powered for oncologic outcomes.