Cockerill and colleagues present their retrospective experience and patient outcomes administering intravesical gemcitabine (GC) in combination with mitomycin C (MMC) in non–muscle invasive bladder cancer (NMIBC) patients recurring after prior intravesical treatments. This combination approach is based on a sound rationale of using agents with differing mechanisms of action and documented single-agent activity in NMIBC patients from prior clinical trials. While the sample size of 27 patients is small, clinical activity of the GC plus MMC combination was clearly documented. At a median follow-up of 22.1 months, 37% of patients remained recurrence free. The toxicity seemed reasonable, and only 1 patient progressed to muscle-invasive stage.
Compared with the cystectomy, a recurrence-free rate of 37% seems encouraging; however, several limitations in the study present challenges to seeing next steps forward for this combination. As is true for all retrospective studies, biases in patients selected for the GC plus MMC treatment may confound patient outcomes. Furthermore, while the authors state the usual practice pattern for recurrence surveillance in their group, the actual recurrence monitoring was at the discretion of the treating urologist. In such a setting, recurrence rates may appear higher than actual rates due simply to less frequent monitoring for recurrence. Similarly, the authors state specifically that white-light cystoscopy was utilized in follow-up. While not required in national guidelines, blue-light cystoscopy clearly is an aid in detecting disease (particularly CIS) not seen with traditional white-light cystoscopy. In most current clinical trial designs, blue-light cystoscopy is not required but is typically allowed at the urologist’s discretion. Furthermore, blue-light cystoscopy is now mentioned in NCCN guidelines as a consideration under Principles of Surgical Management. Thus, one would expect in a contemporary multisite setting the 37% recurrence-free rate would be somewhat lower. Lastly, the FDA has spent considerable time and effort to give investigators and industry partners guidance on efficacy benchmarks for NMIBC trial designs. In their initial paper in 2014, a goal of recurrence-free survival was stated in the BCG-unresponsive NMIBC population of at least 30% with 18 to 24 months of follow-up and a 95% confidence interval excluding a 20% lower bound. In the current study, formal 95% confidence intervals around the 37% recurrence-free survival rate are not provided. The authors cannot be faulted for not designing their study a priori in accordance with the recent FDA trial design guidelines not available at the time of study conduct. Given the other issues pointed out though, it is unlikely that we can exclude a lower confidence interval below 20% in the small sample size studied.
What then are we to make of the GC plus MMC combination? My take is that the regimen does have activity in intermediate- to high-risk NMIBC patients with recurrence after prior therapy. The safety of the regimen appears to be in line with other intravesical therapy options. In centers with experience giving the regimen, it seems to be a reasonable option to offer patients refusing or unfit for cystectomy. I cannot, however, recommend the GC plus MMC therapy over the many other salvage intravesical regimens which have been tried with similar “proof of concept” efficacy. In my opinion, none have separated themselves from the field. What is clear in the post-BCG NMIBC population, though is the need for novel therapy approaches. Thankfully, we are entering an exciting new era in bladder cancer therapeutics based on advances drug delivery (nanotechnologies), improved immunotherapy (checkpoint inhibitors and beyond), and new targets identified through modern gene sequencing efforts (TCGA). All of these approaches and more are rapidly entering clinical trials for all stages of bladder cancer including NMIBC. Thus, for the foreseeable future, clinical trial enrollment should be option number one whenever available.
Noah M Hahn MD