Underenrolled and Undertreated Advanced Bladder Cancer in Women: It is Time to Improve

Abstract

Female exclusion from clinical trials has been a topic of debate and discussion for well over 30 years, with an ever-growing body of literature to support ongoing disparities related to female patient enrollment, along with concerns about downstream effects on treatment efficacy and health outcomes in this patient population.1-3 Awareness of this disparity is the first step in correction. In this edition of JU Open Plus, Miyagi et al4 took a multipronged approach to assess gender representation in major urologic clinical trials, focusing on advanced bladder cancer (BC). To assess the scope of the problem, the team reviewed all trials included as evidence in the National Comprehensive Cancer Network BC guidelines on systemic therapies and found a lower percentage of female participants (20%) than would be expected based on the proportion of female patients with BC in the Surveillance, Epidemiology, and End Results database (26.9%, P < .001). There was also lower female representation in later-stage trials and randomized controlled trials. They then looked at the National Cancer Database (NCDB) to assess how these findings translated to actual patient care and found a significant difference between the proportion of male and female patients who received systemic and immunotherapy for advanced BC (42.6% vs 46% and 1.9% vs 2.8%, respectively, both P < .001). We commend the group for tackling this important and timely topic. The advanced BC management landscape has begun to shift from an almost exclusively chemotherapy-focused treatment paradigm to one that includes immunotherapy, targeted therapy, and antibody-drug conjugate-based therapies.5 A proper understanding of the state of clinical trial recruitment will allow for proactive strategy development to ensure recruitment of under-represented groups, thus ensuring adequate access to these emerging therapies. This is even more important in BC clinical trials. The Bacillus Calmette-Guerin shortage in non–muscle-invasive disease and platinum ineligibility in advanced BC each result in a larger cohort of patients who could potentially benefit from early clinical trial enrollment.6 By outlining the details of the gender disparity in one disease cohort, the authors lay the groundwork for working toward gender equality in trial recruitment. We offer some additional thoughts to build upon their analysis and discussion. Although we agree that factors influencing patient decision to participate in clinical trials should be assessed, we feel that the gender discrepancy likely extends beyond individual patient choice. The consistent and persistent finding of gender, racial, and ethnic disparities in clinical trial enrollment suggests the need for a systematic correction.7 This may come in the form of explicit differential recruitment of female participants and racial minorities with a goal of over-representation to combat historic under-representation. More dramatic adjustments to predetermined secondary or even primary end points may also need to be put in place because studies have suggested that there has not even been an upward trend in enrollment of these populations over the past 20 years.7 As new agents are offered in the second, third, and fourth-line settings, with different inclusion and exclusion criteria based on prior therapy exposure, these considerations will become increasingly important. Although the absolute difference was small, the finding that female patients were less likely to receive systemic therapy was both surprising and significant. Although data are lacking, considering various hypotheses and their implications will be key to mitigating this disparity, if truly present. Key missing data on this front include whether this difference reflects failure to deliver standard-of-care chemotherapy or ineligibility for chemotherapy. If more female patients are ineligible, then further work must be performed to understand why this is the case. This finding may reflect prior work suggesting that female patients with BC have delayed diagnosis and may present with later-stage disease more frequently.8 A previous NCDB analysis published in 2021 by Marinaro et al8 offers conflicting results. The group did not find significant gender-related treatment disparities, but did find higher female 90-day mortality and lower overall survival. Taken together, it is clear that more work must be performed, perhaps using a more diverse set of data sources, to better assess this potential trend. The scope of this study focusing only on systemic therapy for BC was appropriate, but there continue to be areas in need of further research. Little is known about disparities in clinical trial recruitment as it pertains to bladder-directed therapies in advanced BC. The previously mentioned study by Marinaro et al looked at each of the possible treatments for muscle-invasive BC and found outcome disparities without specific treatment disparities, consistent with more historical data suggesting worse outcomes for female patients with this disease.9,10 However, no analysis exists to date assessing gender representation in trials focused on cystectomy and trimodal therapy. Thus, further work must be performed to better understand and improve outcomes in female patients with BC.