Mind the gap: What is driving the survival disparity between the sexes in bladder cancer?

Bladder cancer is well known to preferentially afflict men. However, women are significantly more likely to die of the disease even when corrected for stage, tumor characteristics, and age. Although delays due to misdiagnoses and late urology referrals can certainly result in more advanced disease at the time of presentation and subsequent worse outcomes, the survival fissure among the sexes appears to be most apparent in patients with stage IV disease. In this issue of Cancer, Rose and colleagues highlighted concerning disparities in bladder cancer treatment and outcomes between the sexes. Citing little evidence in the literature to explain these varied survival outcomes even when matched for stage, Rose et al hypothesized that the lower use of chemotherapy in women was responsible for the survival gap. Indeed, with analysis of close to 24,000 patients with stage IV bladder cancer identified in the National Cancer Data Base (NCDB), the authors found that women were significantly less likely to receive systemic chemotherapy than men (45% vs 52%; adjusted relative risk, 0.91 [95% confidence interval (95% CI), 0.88-0.94]). In addition, their median overall survival was nearly 2 months lower (8 months vs 9.8 months; P<.001), which is a significant difference for patients who on average survive <1 year after the diagnosis of metastatic disease. However, when Rose et al controlled for the different rates of systemic chemotherapy, the higher risk of death in women persisted (hazard ratio [HR], 1.11 [95% CI, 1.08-1.15]), suggesting additional contributors to the outcomes gap between the sexes. Beyond their primary focus of sex disparities, there were noteworthy differences across the cohort in that, similar to women, being black, poor, and less educated correlated with receipt of less chemotherapy and a higher risk of death (Table 1). Throughout the literature, a host of precipitating factors have been proposed to account for these variable outcomes between men and women with bladder cancer. These include differences in tumor biology; sex hormones; genetics or epigenetic regulation; pharmacokinetics; metabolism; carcinogen exposure; or societal factors such as undertreatment related to access, patient preferences, or, most concerning, physician biases. Retrospective analyses are fraught with uncontrolled variables that can impact outcomes. Although useful for questions that cannot be answered prospectively, databases such as the NCDB or Surveillance, Epidemiology, and End Results (SEER) lack a level of fine detail with regard to the nuances of the personal choice of the patient or physician bias, specific chemotherapy type and dose, and direct functional status. Rose et al argued that sex is not prognostic in clinical trial populations, which supports disparities in treatment access or application in the less controlled, real-world setting as a possible explanation for the observed differences. Access to care and degree of informed care is a recognized issue that can lead to bias. For example, the low uptake of neoadjuvant cisplatin-based chemotherapy, which has been proven to enhance survival in patients with muscle-invasive bladder cancer, underscores this issue. Similarly, in other solid tumors such as colon cancer, geographical barriers such as distance from the treatment facility significantly impact the likelihood of receiving optimal adjuvant chemotherapy. The measure of chemotherapy used in the study by Rose et al was a relatively blunt instrument. The authors adjusted for the receipt of “any” chemotherapy but could not account for quality or quantity, which could have