Many social commentators argue that we are witnessing the dawn of new age in social, political, economic, and health care equanimity. Although this may be the case, it is emphatically not so in bladder cancer care. Here, there is a striking and unexplained imbalance in outcomes by sex that is best illustrated by comparing the ratios of incidence to mortality. In males, this ratio is 3:1, whereas in females, it is decidedly lower at 2.5:1.[1-3] Simply stated, for a given patient presenting with bladder cancer, women are more likely than men to die from their disease. Moreover, this appears to be a international phenomenon engendering many profound global health care questions.
In this issue of Cancer, Cohn et al perform a retrospective population-based study examining the timing from presentation with hematuria to diagnosis of bladder cancer. They used the MarketScan databases, which includes patients from more than 100 insurance plans of 40 large US companies. The primary outcome measure was number of days from presentation with hematuria to diagnosis of bladder cancer, stratified by sex. The mean delay from presentation with hematuria to diagnosis of bladder cancer was greater in women (85.4 days versus 73.6 days, P < .001). Women were more likely to be diagnosed with urinary tract infection (odds ratio [OR] = 2.32, 95% confidence interval [CI] = 2.07-2.59) and less likely to undergo abdominal or pelvic imaging (OR = 0.80, 95% CI = 0.71-0.89). Female patients were 15% and 25% more likely to experience a delay in diagnosis > 6 months and > 9 months, respectively.
The study provides data on an important clinical question; namely, what is the typical delay from presentation with hematuria to diagnosis of bladder cancer? Surprisingly, both sexes demonstrate lengthy intervals between presentation and diagnosis (2-3 months). This is a longer interval than a prior Surveillance, Epidemiology and End Results (SEER) database study, in which 24% of patients had a ≥ 3 month delay in diagnosis. The difference in overall delay to diagnosis between sexes in the current study, although statistically significant, is modest. In addition, the study is somewhat limited by the MarketScan database, which does not include patients older than 65 years. The authors correctly address their finding that as patient age increases, the likelihood of delay in diagnosis decreases. Thus, perhaps the findings may be more generalizable to younger patient cohorts.
Differences by sex in bladder cancer patient outcomes have been well described. Mungan and colleagues looked at patients with bladder cancer from the United States (SEER data) stratified by sex. Across all stages of presentation, female patients had lower 5-year survival rates across all stages of presentation than their male counterparts (79.5% versus 73.1%, P<0.05). The male versus female 5-year survival rate among stages I, II, III, and IV were 96.5% versus 93.7%, 65.5% versus 59.6%, 58.8% versus 49.6%, and 27.1% versus 15.2%, respectively.
The finding that females fare worse than males in bladder cancer is unusual in the cancer landscape. Several reasons for sex discrepancies in bladder cancer have been proposed including: tobacco use, occupational exposure, sex hormone milieu, and delays in diagnosis. Although sex differences in bladder cancer incidence and mortality were historically attributed to differences in carcinogen exposure (eg, smoking, occupational exposure), the impact of these epidemiologic factors has recently been quiesced.
Another explanation for the sex discrepancy in bladder cancer incidence to mortality centers on differences in sex hormone exposure between men and women. Differential hormonal receptor expression has been demonstrated at the basic science level.[10, 11] Population-based studies, however, have produced disparate conclusions. In the US Nurses Health Study, early (age ≤ 45 years) compared with late (≥ 50 years) age at menopause was associated with significantly increased risk of bladder cancer (incidence rate ratio = 1.63, 95% CI = 1.2-2.23). Age at menarche, parity, age at first birth, and exogenous hormone therapy were not associated with bladder cancer incidence. The authors concluded that menopausal status and age at menopause might play a role in bladder cancer risk among women. In contrast, Cantwell and colleagues looked at bladder cancer incidence in the Breast Cancer Detection Demonstration Project and found no relationship between age at menopause, parity, age at menarche, age at first birth, and oral contraceptive use.
Differential treatment-related factors are other proposed explanations for the observed sex discrepancy in bladder cancer survival rates.[14, 15] A recent study examined delays in diagnosis of bladder cancer between sexes in a European cohort. Lyratzopoulos and colleagues looked at 920 patients with bladder cancer and subdivided them into patients with 3 or more prereferral consultations, number of days from first presentation to referral, number presenting with gross hematuria, and number of patients investigated in primary care. Women required more physician appointments prior to specialist referral and experienced a greater number of days from presentation to referral. The authors concluded that there are notable sex inequalities in the timeliness of diagnosis in patients with bladder carcinoma.
The significance of delay in diagnosis of bladder cancer is not trivial. Hollenbeck and colleagues showed data supporting that patients with a delay of 9 months were more likely to die from bladder cancer compared to patients diagnosed within 3 months (hazard ratio = 1.34, 95% CI = 1.20-1.50). Moreover, several studies have documented worse clinical outcomes when radical cystectomy is delayed > 3 months after diagnosis of muscle-invasive bladder cancer.[17, 18] Given that 33% of patients undergoing radical cystectomy will experience disease recurrence at 10 years, perhaps the best opportunity for cure exists in expediting time from presentation to diagnosis.
Differences in sex, race, occupational exposure, and socioeconomic status all influence health care outcomes. In a homogenized population, perhaps this would be surprising; however, in our profoundly diverse world, it is less so. The study by Cohn and colleagues provides important insight to the sex disparity in bladder cancer outcomes. Yet, it does not completely explain why female patients present with more advanced disease and have worse outcomes stage-for-stage. Similar to most medical phenomena, a multifactorial interaction among tumor biology, sex hormones, acute differences in time to diagnosis, and access to care define the problem and the solution.