Marcus L. Quek, MD

Persistent disparities in outcomes between men and women with bladder cancer highlight areas of needed improvement in the delivery of oncologic care. There were approximately 81,190 new cases of bladder cancer in the United States in 2018, and the majority of these cases were in men. While males are three to four times more likely to develop the disease, women tend to present with advanced stage, experience differences in quality of life following treatment, and suffer worse cancer-specific mortality (Surveillance, Epidemiology, and End Results [SEER] Program Populations [1992-2018], 

Based on Surveillance, Epidemiology, and End Results (SEER) data, women appear to have better cancer-specific mortality for most malignancies; however, this does not appear to be the case for bladder cancer 

 Epidemiologic and biologic explanations have been offered, but our incomplete understanding of the issue suggests numerous contributing factors.

In this article, we examine these factors, with a focus on current research that elucidates their role in the bladder cancer gender disparity. The table provides a summary of these research findings.

Perhaps the most evident disparity confronting female patients with bladder cancer relates to timely evaluation and diagnosis. The reasons for this are multifaceted and reflect differences in how female patients with hematuria progress through the health care system. Interpretation of hematuria in the female patient can be challenging for primary care physicians. While hematuria is certainly concerning for malignancy, it is also present in a number of benign conditions, including urinary tract infections, which are common in postmenopausal females.

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In a large population study performed by Cohn and colleagues, women presenting with hematuria who were ultimately diagnosed with bladder cancer were far more likely to be treated for a suspected urinary tract infection during initial evaluation than males 

 Similarly, evaluation of practice patterns of primary care physicians by Buteau and colleagues demonstrated that women presenting with hematuria often underwent three or more pre-referral consultations with their primary care provider for the same complaint before referral for urologic evaluation (OR: 2.31, 95% CI: 1.98–2.69) 

It is possible that these barriers are the result of conflicting guidelines regarding the evaluation of asymptomatic microscopic hematuria. While the AUA defines microscopic hematuria as greater than 3 red blood cells per high powered field as the trigger for further diagnostic evaluation, 2017 guidelines from the American College of Obstetricians and Gynecologists favor a cutoff of 25 red blood cells per high powered field for non-smoking women under 50 years of age. This may lead to confusion for primary care physicians as to when referral is appropriate. Similarly, women who present to their gynecologist for evaluation of microscopic hematuria may experience delays in urologic referral.

While individually, these factors likely play only a small role in the overall delay in evaluation, the effect is notable. Cohn and colleagues demonstrated that women were more likely to experience a delay in time to diagnosis when compared to men (85.4 days vs. 73.6 days; 

<.001) and a higher rate of >6-month delay in diagnosis (17.3% vs. 14.1%; 

 It has been well documented that delays in diagnosis translate to poorer cancer-specific outcomes 

Even after diagnosis, female patients with bladder cancer continue to suffer worse outcomes than males following definitive treatment. While it has been proposed that advanced stage presentation in women may be to blame, this does not fully explain differences in overall survival. An analysis of 5-year survival between men and women with bladder cancer found that women fared worse across all stages 

 This would suggest that gender continues to play a role even after diagnosis.

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The evidence for nonmuscle-invasive bladder cancer is mixed and somewhat limited. One single-institution series suggests that women were less likely to receive intravesical therapy for nonmuscle-invasive disease, but larger population cohorts have failed to demonstrate this 

Several studies have examined the use of treatment modalities and associated outcomes in women with muscle-invasive bladder cancer. An analysis of SEER data that examined the use of radical cystectomy or radiotherapy in patients with muscle-invasive bladder cancer revealed that while men were more likely to receive radiotherapy, there were no differences in the use of radical cystectomy between men and women 

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Similarly, it has been demonstrated that female patients do not experience significant differences in surgical margin status and lymph node count at the time of cystectomy 

 Outcomes regarding cancer-specific survival following cystectomy have unfortunately been conflicting. While older series demonstrated female gender as an independent risk factor for worse cancer-specific survival, newer series suggest the gender gap may be closing 

 While more studies are needed to confirm this new trend, it is encouraging. This may in part be due to heightened awareness of historical disparities in the diagnosis and treatment of bladder cancer in women.

Differences in urinary diversion utilization and HRQoL

Despite equivalent use of radical cystectomy between men and women, the use of continent diversions is underutilized in the female population. A recent review of radical cystectomies performed in the United States revealed that while the use of continent urinary diversions has declined, male patients still received continent diversions at more than twice the rate of female patients 

 It has been demonstrated that women suffer worse health-related quality of life outcomes following ileal conduit when compared to men 

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While patient perception of body image and the results of surgery impact a number of quality of life measures in all patients, several studies have suggested this may be improved with the use of continent diversion. In a meta-analysis performed by Cerruto et al, 65% of men who had an orthotopic neobladder following radical cystectomy showed improved quality of life measures when compared to those who received an ileal conduit 

Few studies have compared health-related quality of life measures in men and women following cystectomy. In one study of 73 female patients who underwent radical cystectomy, those who received an orthotopic neobladder were more likely to experience improvements in future perspective of their illness, perceptions of body image, and sexual function than those who received an ileal conduit 

 2018 [In press]). The factors driving the underutilization of orthotopic neobladder use in females are unclear, but may be related to gender-specific complications and adverse outcomes following urinary diversion. A study of urinary functional outcomes in women receiving an orthotopic neobladder revealed that hypercontinence rates may be as high as 44.6% in female patients 

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There is a paucity of data comparing men to women in terms of daytime incontinence, nighttime incontinence, hypercontinence, and sexual function following orthotopic diversion. Lack of standardization of questionnaires, varying definitions of continence, under-sampling of female patients, and variable assessments of sexual function are mostly to blame. Further assessment of gender differences in this area is needed.

The role of sex steroids and the hormonal axis have been investigated as a potential biologic explanation for the gender divide in bladder cancer. Population analyses have shown that bladder cancer is more common in postmenopausal women than in premenopausal women 

 This has led several investigators to assess the role of sex steroid receptors in bladder tumors.

The primary points of interest have been the expression of androgen receptor (AR) and estrogen receptor (ER) and their association with pathologic stage. In an analysis of 188 tumors, Miyamoto and colleagues showed that loss of AR and ERÎ± and increases in ERÎ² were associated with an increase in tumor grade and stage 

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It also appears that modulating estrogen receptors may inhibit the growth of urothelial cell carcinoma. In a study conducted by Sonpavde and colleagues, raloxifene (Evista), an estrogen receptor modulator, was found to inhibit the growth of urothelial cell carcinoma in an in vivo model 

 2007; 69:1221-6). The implications of androgen and estrogen receptors as drivers of tumorigenesis are profound. The role of tamoxifen (Nolvadex), a selective estrogen receptor modulator (SERM), is currently under investigation for the treatment of low- and intermediate-risk bladder cancer (NCT02197897). Further study is needed to determine the role of androgens in the treatment of bladder cancer.

Gender disparity in bladder cancer is a complex issue that likely stems from diagnostic delays, therapeutic differences, and possibly biologic factors. Each of these areas provides opportunities for improvement and for the eventual elimination of the gender divide. Partnerships with primary care providers and gynecologists should remain a priority to improve education and understanding of the importance of timely evaluation of hematuria in the female patient. Hopefully, continued understanding of the biologic drivers of urothelial carcinoma will provide novel therapeutic targets for both male and female patients with bladder cancer.

 are professors in the department of urology, Loyola University Stritch School of Medicine, Maywood, IL. 

Section Editor Christopher M. Gonzalez, MD, MBA,

 is professor and chair of the department of urology at Loyola University Chicago Stritch School of Medicine, Maywood, IL.

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Poor outcomes in women may stem from diagnostic, therapeutic, and biologic factors.

Author | Marcus L. Quek, MD

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