Not surprisingly, bladder cancer is an extremely active area for clinical trials. As of April 17, 2023, active or recruiting protocols registered on clinicaltrials.gov numbered 195 for metastatic bladder cancer and 125 for non-muscle invasive bladder cancer. Within the area of non-muscle invasive bladder cancer trials, studies of ‘BCG unresponsive’ disease are heavily emphasized.
As a clinician at an academic medical center, I counsel patients with BCG unresponsive bladder cancer. Most of these patients are interested in clinical trials, and our center generally has multiple open BCG unresponsive protocols at any given time. But too often my patients are excluded from such trials even if they meet all necessary criteria for BCG unresponsive disease.
When we quantified the scope of the problem, we found that just over half of trials were not truly open to all patients with BCG unresponsive bladder cancer, for reasons like requiring that histologic carcinoma in situ (CIS) be present on that patient’s prior biopsy, or dictating that no patient with prior pelvic radiotherapy be allowed on trial, or requiring the most recent transurethral resection of bladder tumor to have occurred within the preceding 5 weeks.2 That’s even before considering comorbidity-related exclusion criteria such as strict requirements for performance status, renal function, and minimum hemoglobin and platelet count values. It is no wonder that it is so difficult for a patient to enroll in a clinical trial even when they are willing/able and meet strict disease criteria.
There is a clear tradeoff between a trial that prioritizes a positive endpoint as a path to regulatory approval versus a trial that has broad inclusion criteria that would make the results generalizable to the real-world setting, which is excellently explained by Loudon et al.’s guidance on the PRECIS-2 clinical trial tool.3 The former approach is explanatory via tightly curating an idealized setting to maximize a beneficial effect. The latter approach is pragmatic. Both approaches have different merits.
By the time someone with bladder cancer is found to have BCG unresponsive disease, that person will have traversed a very unique path, marked by signposts that may have little bearing on the biology of their disease. A diagnosis of CIS may depend on who was signing out the pathology cases that day. The time from the most recent transurethral resection may simply have been a function of complex clinic scheduling. And so on. Decreased renal function, hepatic function, anemia, and lower performance status are realities that many of our patients with bladder cancer face. As a clinician, I would like to know what the expected outcomes of the newest treatments are in my real-world clinic. This time is ripe for physicians and surgeons who treat bladder cancer to advocate for our patients and contribute to inclusive, pragmatic BCG unresponsive clinical trials.
Written by: Debasish Sundi, MD, Department of Urology, The Ohio State University Wexner Medical Center, Columbus, Pelotonia Institute for Immuno-Oncology, Columbus, OH
References:
- Schafer, E. J. et al. Disparities and Trends in Genitourinary Cancer Incidence and Mortality in the USA. Eur. Urol. (2023) doi:10.1016/j.eururo.2022.11.023.
- Chandra, M., Sundi, D., Pohar, K. S., Carson, W. E. & Li, R. Heterogeneity of BCG unresponsive bladder cancer clinical trials limits patients’ access to novel therapeutics. J. Clin. Oncol. 40, 572–572 (2022).
- Loudon, K. et al. The PRECIS-2 tool: Designing trials that are fit for purpose. BMJ 350, (2015).