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Gender, racial and age differences in bladder cancer incidence and mortality
Urologic Oncology: Seminars and Original Investigations 22 (2004) 86 –92
Review article
Gender, racial and age differences in bladder cancer incidence and mortality Ralph Madeb, M.D., Edward M. Messing, M.D.* Department of Urology, Strong Memorial Hospital University of Rochester Medical Center, Rochester, NY, USA Received 20 May 2003; received in revised form 12 August 2003; accepted 20 August 2003
Abstract Bladder cancer is the fourth most commonly diagnosed cancer in men and the eighth most common in women in the United States. While clinicians who diagnose and treat the disease recognize that bladder cancer has a unique demographic profile, the influence of such factors as age, gender and race on incidence, prognosis, and survival of patients is poorly understood, and has not been the subject of intense investigation. Both through analysis of the population-based databases of bladder cancer in the United States and Europe, as well as epidemiological studies, some of the effects of gender, race and age on this disease have begun to be explained. In this manuscript we review the current literature and epidemiological studies on the affects of gender, race and age on incidence and mortality of bladder cancer. © 2004 Elsevier Inc. All rights reserved. Keywords: Gender; Race; Bladder cancer; Epidemiology; Risk factors
1. Introduction Bladder cancer is the fourth most commonly diagnosed cancer in men and the eighth most common in women in the United States. An estimated 56,500 new cases of bladder cancer were diagnosed in 2002 and an estimated 12,600 patients died of this disease [1]. Epidemiological and experimental evidence favors a strong role for chemical carcinogens in the etiology of bladder cancer, but many cases arise with no obvious exposure to known carcinogens [2– 4]. Similarly, while most clinicians who diagnose and treat the disease recognize that bladder cancer has a unique demographic profile, the influence of such factors as age, gender and race on incidence, prognosis, and survival of patients is poorly understood, and has not been the subject of intense investigation. Both through analysis of the population-based databases of bladder cancer in the United States and Europe, as well as epidemiological studies, some
* Corresponding author. Tel.: ⫹1-585-275-3345; fax: ⫹1-585-2731068. E-mail address: [email protected] (E.M. Messing). 1078-1439/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/S1078-1439(03)00139-X
of the effects of gender, race and age on this disease have begun to be explained. Herein, we review the current literature in this field.
2. Incidence and prevalence In Western countries, bladder cancer is 2.5 to 4 times more common among men than women [2– 8]. Between 1985 and 2000 the number of bladder cancers diagnosed annually in the United States increased by 33%, at roughly the same rate in both genders [1,9]. The relatively equal rise in incidence cases in men and women is perplexing in a number of ways. Bladder cancer is virtually never recognized incidentally at autopsy [10 –11]. This coupled with the consistent method by which bladder cancer has been diagnosed (cystoscopy and biopsy) over the last six decades, indicates that the increase in bladder cancer cannot be attributed to technological innovations or major changes in the delivery of medical care. As a result, the reported differences in incidence rates between the genders (as well as races and ages, see below) cannot be simply explained by a failure to diagnose the disease in particular groups. Moreover, because bladder cancers incidence increases with age
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in both genders, the relatively equal rise in incidence in men and women seems contrary to what one would expect in view of the longer female life expectancy (roughly 5 years or longer) in most industrialized countries [12,13]. That the number of new bladder cancer cases has risen similarly remains particularly surprising because during the last three decades, women have joined the male workplace and have changed social habits which expose them to both industrial and environmental carcinogens (i.e., cigarette smoking) from which they once had been relatively protected. One would have expected that these social factors should have resulted in a disproportionate increase in women as has been seen with lung cancer during this interval [1]. It is quite possible that genetic, hormonal and/or anatomic factors may eventually answer this puzzling trend. Race also has a significant influence on bladder cancer incidence. Bladder cancer is twice as common among American Caucasian men as among African American men and roughly 1.5 times more common among White American women than African American women [2– 4,14]. Alternatively, the incidence of bladder cancer in Hispanic Americans and Native Americans is one-half and one-sixth, respectively, that of Whites of each gender [14]. The Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute (NCI) collects and publishes cancer incidence and survival data from 11 population-based cancer registries and three supplemental registries covering approximately 14% of the US population [14]. The lifetime risk of being diagnosed with bladder cancer in the 11 SEER areas in 1995 through 1997 was 3.7% for a White male, which is roughly three times the likelihood that a White female (1.2%) or a African American male (1.3%) has, and over 4.5 times the likelihood that an African American female has (0.8%) [14 –15]. This was also shown in a recent study by Prout et al. [16], who used population-based tumor registries in 3 major states of the United States and found higher stages of bladder cancer in blacks. Interestingly, in their epidemiological study it was found that African Americans were twice as likely to have invasive cancers at diagnosis and among patients with invasive cancer, they were 2.2 times more likely to have muscle invasive disease [16]. As with gender and race, there is an unequal distribution of the incidence of bladder cancer with age. Although, bladder cancer can occur at any age, it is primarily a disease of the elderly with the median ages at diagnosis for transitional cell carcinoma being 69 years in males and 71 years in females in the United States. Trends in the SEER database reveal that the incidence of bladder cancer increases directly with age—from roughly 142 per 100,000 men and 33 per 100,000 women age 65 to 69 years to 296 per 100,000 men and 74 per 100,000 women 85 years old or older [14]. Bladder cancer is uncommon below the age of 50.
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3. Mortality and survival It is estimated that in 2002 there were 12,600 bladder cancer deaths in the United States; 8,600 in men and 4000 in women [1]. Bladder cancer accounts for 3% of all cancer deaths in men and 1.5% in woman, making it the seventh most common cause of cancer deaths in American men [1]. Between 1973 and 1999 there has been a 33% decline in bladder cancer mortality [14]. Whether this is attributable to a fundamental change in the biology of this disease, alteration in risk factors for different phenotypic variants, better treatments, earlier diagnoses, or a combination of these factors is uncertain. However, the reduction in mortality has primarily been seen in men. Males have a higher 5-year survival rate than women (overall 83% vs. 74% in SEER [14]; 65% vs. 60% in EUROCARE data [13]) with the gender breakdown of White males, African American males, White females and African American females being 84%, 67%, 76% and 58%, respectively (SEER). In other words, in the United States, women have a 30% (in African Americans) to 50% (in Whites) greater chance of dying from bladder cancer if they develop it than men of their respective races. Whatever the explanations, women account for a disproportionately high percentage of lives lost from this disease. This is confirmed by the relatively striking changes in age-adjusted mortality from bladder cancer for the most recent 10 years reported in the SEER database: ⫺0.4% change annually in men with an annual ⫹0.1% change increase in women. Similar trends have also been seen in other databases including the Finnish Cancer registry from 1985–1994 [17,18]. The age-adjusted mortality trends, as well as the increase in incidence in men compared to women suggests differences in bladder cancer diagnosis, treatment, and/or disease characteristics between the sexes rather than the longer female life expectancy are responsible for these mortality data.
4. Gender differences in mortality One explanation for the higher mortality in women would be if they had more advanced disease at diagnosis than men. According to SEER data, women with bladder cancer had a 3 to 12% 5-year survival disadvantage in Stages I-IV(I, II-localized, III-regional, IV-metastatic), respectively [14]. Additionally, using the population basedregistry in Netherlands (1975–1989), Kiemeney et al. showed that males were diagnosed with lower staged disease with 28% of males vs. 43% of females being diagnosed with Stage III or IV disease at diagnosis [19]. In the Unites States, Fleshner et al. [20] presented the National Cancer Data Base Report on bladder carcinoma. With a total of 40,659 known cases of bladder carcinoma evaluated between 1985 and 1993, women were more likely to be diagnosed with advanced stages (33.1% vs. 27.7%) [20]. Finally, using the Netherlands Cancer Registry, Mungan et al.
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[21] have also recently shown that females had a higher percentage than men of invasive transitional cell carcinoma of the bladder and upper urinary tract at first presentation. In their study, males had a 32% better chance of being diagnosed with superficial disease than females [21]. Stage at diagnosis clearly predicts outcome. Therefore, it has been suggested that one reason for the worse survival among women with bladder cancer is the difference in stage distribution at the time of diagnosis. One must be cautious when evaluating the stages of bladder cancer reported in the SEER database. The main problem is that this database only crudely stratifies stage as localized, regional, distant and unstaged that does not allow accurate analysis according to the TNM staging system. Specifically, because metastases almost never occur without concomitant or preexistent invasion of the muscularis propria [22,23], the distinction between Ta, T1 (“superficial”) and T2 (“invasive”) disease is critical, yet both are categorized as “localized” in SEER reports. Furthermore, the lack of pathological details such as depth of invasion and the presence or absence of subepithelial and/or muscularis propria tissues in examined specimens prevent sufficiently accurate assessment of stage. Additionally, varying reports on in situ cancer, which in the case of urothelial neoplasia can be a very aggressive phenotype, further confound the accuracy of pathologic information in the SEER database. Despite these limitations, there almost certainly is a difference between the genders in stages at diagnosis. The following has been proposed as explanations: A. Delay in Diagnosis: An initial symptom in more than 80% of men and 70% of women with bladder cancer is painless hematuria (often grossly visible). As urinary infection is far more common in women, misinterpretation of hematuria and irritative voiding (the next most common symptom of bladder cancer) for bacterial cystitis, will cause a delay in diagnosis in females, perhaps resulting in a more advanced stage at the time of diagnosis. Mommsen [24] and Mansson [25] and their respective colleagues, have shown that doctors’ delays were strongly influenced by the presenting symptom. The lag time was shorter when hematuria alone was the presenting symptom than when urgency was. However, there was estimated to be, on the average, a 3-month longer interval to diagnosis of bladder cancer in women once medical attention was sought than in men in relatively universal health access systems. While bladder cancer in women is primarily a postmenopausal disease, which men can observe hematuria more readily than women based on anatomic differences is almost certainly the case, as well. This difference between the genders would normally be added to the physician related delay. Interestingly, two different groups have recently reported that at least with muscle invasive bladder cancer, a delay from diagnosis to definitive
treatment of more than 3 months was associated with a significantly worse outcome [26,27]. Thus, this delay in diagnosis in women may in part explain their poorer prognosis. B. Cultural: Culture-mediated factors may influence differences in illness behavior and health awareness between women and men resulting in differences in the perception and/or acceptance of the disease, readiness to use available health services and interventions, and delay in treatment [28 –32]. However, all of the factors would normally favor an earlier diagnosis and treatment in women, which of course, is the reverse of what is seen. C. Biological: There are epidemiologic and laboratory studies indicating that there might be differences between the genders in exposure to potential carcinogens and that men and women might metabolize carcinogens differently [2– 4,6]. While for the two most commonly described carcinogens, cigarette smoking and industrial exposures, no predilection for high or low risk bladder cancer has been reported [33], it is possible that subtle differences could have been overlooked in reported studies, which when combined with the aforementioned delays, could lead to more advanced stages at diagnosis in women. D. Anatomical: In addition to the easier detection of gross hematuria in men, other anatomic differences between the middle aged and elderly female and male bladder have been postulated as reasons for the disparate mortalities between genders. Male bladders have a thicker detrusor probably because of the need to void at higher intravesical pressures to overcome outflow resistance caused by the hyperplastic prostate gland. The thicker muscle may delay extravesical extension, and perhaps retard the development of metastases. Another anatomic difference that may affect disease progression is that the prostate may influence the surrounding lymphatic channels and pathways of spread. Maralani et al. [34] have shown that there is an increased incidence of urethral involvement in female bladder cancer. The patterns of urethral invasion identified were via the vascular or lymphatic channels in the periurethral tissue. The replacement of periurethral tissue in men by the prostate gland and its capsule may block the angiolymphatic extension of the tumor that is seen in women [21,34]. These anatomic factors could contribute to the higher stages of bladder cancer that occur in females. Although the abovementioned explanations for the advanced stage of females at the time of diagnosis are each plausible, recent stage-adjusted studies by Fleshner et al. [20] and Mungan et al. [35] indicate that women still fared worse after survival analyses were stratified by disease stage. While to some degree a migration to more invasive
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disease within given pathologic stages may in part explain this observation (e.g., pT2b vs. pT2a) there are probably additional factors that are unknown currently, which cause a higher likelihood of women dying from bladder cancer than men.
5. Racial differences in mortality African Americans, especially women, have a 60 to 100% higher mortality from bladder cancer than do their White counterparts ([14]; see above). There is some evidence to suggest that the reduced risk for whites is primarily limited to noninvasive bladder cancers, implying a later diagnosis and/or more aggressive tumor phenotype in African Americans [15–16]. Whatever the explanation, a lower percentage of African Americans (61%) and females (49%) compared to White males (76%) and females (70%) diagnosed with transitional cell carcinoma have disease confined to the bladder [14]. Several studies have tried to explain the differences in the stage distribution of bladder cancer among the races. The following theories have been proposed: 5.1. More aggressive disease Recent genetic and epidemiological evidence indicates that African Americans may often have a more aggressive form of other cancers such as those of the breast and prostate [36]. This has gained prominence after the NCI sponsored a Black-White Cancer Survival Study (BWCSS), which compared the survival for blacks and whites with cancers of the bladder, breast, colon and uterus [37– 40]. Blacks had a poorer survival with all four cancers even after the adjustment for clinical stage and socioeconomic characteristics. Data show that breast cancer in the AfricanAmerican population is biologically more aggressive and more likely to be poorly differentiated with high grade atypia and less estrogen receptor positivity [38,41– 43]. Similar data are currently not yet available to determine if African Americans have a greater proportion of high grade bladder cancers, and/or of unfavorable histologies, and/or of tumors with molecular markers of poor prognosis than Caucasians have. Indeed Prout et al. have reported blacks had a predominance of cell types other than transitional cell cancers including squamous cell and adenocarcinomas [16], which generally have more aggressive phenotypes than, at least, well and moderately differentiated urothelial (transitional cell) cancers. This could contribute to the tendency towards more advanced stages at diagnosis and worse outcomes found in African Americans. 5.2. Socioeconomic status Several studies have shown that low socioeconomic status (SES), which includes variables such as low income,
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minimal education, no private health insurance or lack of access to health care, and residing in a neighborhood of high population density is associated with less cancer screening, delay in diagnosis, advanced tumor stage and poorer survival from most cancers [44]. Although the SEER program does not report SES, epidemiologists have tried to estimate the influence that SES has on the racial differences in survival. Studies have shown higher survival rates in populations of higher SES [45,46]. For breast carcinoma, higher SES correlated with a more favorable stage at first diagnosis because of greater rates of mammography use and less risky behaviors [44]. Therefore, SES may explain, in part, racial differences in cancer mortality rates between African Americans and Whites. This may be assessed more directly by knowing outcomes in relatively equal health access settings, such as the military, which may in part control for SES. Moreover, since other groups with lower SES, including Hispanics and Native Americans, do not share with AfricanAmericans a higher mortality from bladder cancer (see below), the influence of SES on racial differences in mortality is likely not to be great. 5.3. Elapsed time from symptoms to onset of treatment Whether it is biologic factors, nonbiologic factors or both that cause an advanced stage at the time of diagnosis, elapsed time from symptoms to onset of treatment has been shown to be associated with decreased survival [24]. This has not been studied intensively in explaining racial differences in stages at diagnosis, but well may be a fruitful area of investigation. 5.4. Occupational exposures, smoking, and differences in metabolism of toxic substances There may be genetic differences between blacks and whites that contribute to underlying molecular origins and pathophysiology of the disease. For example, these factors may affect the host response to different carcinogens and occupational exposures [2– 4]. Again, this has not yet been studied intensively in terms of explaining racial differences in susceptibility and prognosis. If these (either the exposures or how carcinogens are metabolized) occur disproportionately in the African-American population then there will be an increased tendency towards invasive disease, a more advanced stage at presentation and poorer survival. Insufficient evidence is available to assess these possibilities. In addition to 5-year survival disparity, survival by stage is also more favorable in whites [14,20]. This may not only reflect more advanced or more aggressive disease within stage categories at diagnosis, but also less adequate access to healthcare, with a delay in diagnosis and/or acceptance of optimal therapies in the African American population. Moreover, the discrepancies are greatest in the localized and regional stages, which are the stages where aggressive therapy has been shown to be of the most benefit. Previous
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studies for other malignancies have shown that later diagnoses among the black population appear to be because of beliefs that cancer is not preventable, deficits in knowledge about screening, and less availability of screening tests. All contribute to a later stage at diagnosis [47,48]. Other explanations for the stage-specific racial disparity include differences in tolerating or accepting follow-up and adjuvant therapies, use of different providers, and the possibility of an inherently more aggressive disease [49].
6. Mortality in Hispanic Americans Another puzzling trend that warrants further attention is the incidence and mortality of bladder cancer among Hispanic Americans. As mentioned earlier, Hispanic Americans have incidence rates that closely mirror that of African Americans with 5 year survival rates that, particularly for invasive and more advanced disease, surpass those of Whites [14,50]. Hence, Hispanic Americans, being one the largest minority groups in the Unites States, have lower incidence and mortality rates when compared to other ethnic groups. Although very little research has been reported on the Hispanic ‘riddle’, these data cast serious doubt on whether low SES or inadequate health care access can explain the worse outcome in African Americans. However, one possible explanation for the decreased mortality and lower incidence in Hispanics could be their lower rate of tobacco use as a whole. It is well known that cigarette smoking is the most significant environmental risk for bladder cancer and another factor associated with survival. Active smokers have a fourfold higher incidence over people who never smoked [51] and risk correlates with number of cigarettes, duration of smoking, and degree of inhalation [23]. Former smokers have a 30 to 60% lower risk of bladder cancer [52]. For those who quit, the risk decreases over 10 to 20 years of abstinence. According to the 1994 – 1996 National Health Interview Survey, the average annual prevalence of cigarette smoking was approximately 50% lower among Hispanic Americans than Whites [50,53]. This was true for both males and females and for comparisons at all income levels. This in part, could explain the lower incidence and mortality among Hispanic Americans with bladder cancer, but there is a need for further epidemiological and possibly biological investigation in this area, as well.
7. Mortality in the elderly As with incidence, mortality from bladder cancer is also higher in elderly people. For instance, the ratio of diseaserelated mortality to incidence rates for men and women in the United States age 65 to 69 years is 14% and 18%, respectively, whereas for men and women age 80 to 84 years it is 30% and 37%, respectively (SEER, 1973–1997)
[14]. The higher mortality in the elderly has several explanations. In patients under the age of 40, bladder cancers tend to express well-differentiated histologies and behave in a more indolent fashion, and in contrast to those that occur in older individuals, these tend not to recur [54 –56]. Furthermore, the molecular and genetic aberrations in bladder cancers in this population do not share the fairly close correlation with histologic grade and clinical behavior that is seen in urothelial cancers in the middle-aged and elderly populations [56]. This may indicate that bladder cancer usually occurs from a series of molecular aberrations, many of which are present as part of a background of genetic instability that occurs with aging, upon which, signature genetic abnormalities that have been well described (e.g., mutations inactivating p53) arise. When these signature events occur in isolation without the other cumulative genetic abnormalities, low grade and indolent tumors occur without progression or field effect patterns of recurrence. At advanced age, the background genetic aberrations are greater, resulting in more aggressive tumors when signature genetic events occur. Another explanation is that the diagnosis of bladder cancer in the elderly is likely to be delayed more often than in younger patients, which is probably both physician and patient related [57]. The elderly also have multiple comorbidities which may interfere with a decision for offering (by medical care providers), or receiving (by patients) more effective, but often more strenuous treatments [57,58]. Additionally, elderly patients have a more unfavorable survival within a given stage which ultimately may be a reflection of decreased host immunologic and other defense factors, more aggressive tumor patterns and greater resistance to treatment. It is likely that all the above factors play a role in the increased disease related mortality and decreased survival exhibited by the elderly with bladder cancer. Despite this, there has been growing recognition that the changes in the aging population have far reaching effects on oncologic care and cancer research. As the elderly are the largest growing segment of the population [59,60], understanding reasons for the increased mortality from bladder cancer is critical and needs further investigation.
8. Conclusion The potential effects of gender, race and age on the development of and outcome from bladder cancer have not been sufficiently investigated. Delays in diagnosis and institution of appropriate therapy are likely to play a role in patients (particularly women and African Americans) who are diagnosed at later stages and exhibit poorer survivals. Moreover, particularly with muscle invading and more advanced bladder cancer, outcome is clearly related to the timing of therapeutic intervention. Preliminary studies show that a delay in 12 weeks or greater is associated with advanced pathologic stage and decreased survival [26,27].
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Additionally, when survival was compared after early versus delayed cystectomy in patients with recurrent high-risk nonmuscle invading bladder cancers, it was found that early cystectomy results in better survival than delayed cystectomy or continued bladder-sparing procedures [61]. These data suggest that delay of intervention, especially cystectomy, is an independent adverse predictor of survival. Hence, the ability to diagnose bladder cancer earlier, especially in females and African Americans, should eventually improve their survival from bladder cancer. Another important stride is improving the reporting and classification of bladder cancer in the SEER database to include precise stage, grade and other histopathological information at the time of presentation. This should enable far better stage-adjusted analyses, and conclusions to be drawn about this disease, its biologic behavior, epidemiology, and the appropriateness of its management in various demographic groups. It should be understood that these factors alone may not account fully for the poorer outlook in some demographic groups as it is possible that genetic characteristics and environmental exposures, and their complex interactions probably influence bladder cancer development and prognosis as well. Future studies and should investigate how demographic risk factors, environmental exposures, and constitutional factors interact to affect prognosis. These studies should help us understand and eventually minimize disparities in disease outcome, and highlight target populations for early detection and prevention efforts. References [1] Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin 2002;52(1):23– 47. [2] Aben KK, Kiemeney LA. Epidemiology of bladder cancer. Eur Urol 1999;36(6):660 –72. [3] Brauers A, Jakse G. Epidemiology and biology of human urinary bladder cancer. J Cancer Res Clin Oncol 2000;126(10):575– 83. [4] Cohen SM, Shirai T, Steineck G. Epidemiology and etiology of premalignant and malignant urothelial changes. Scand J Urol Nephrol 2000;205(Suppl):105–15. [5] Goldstein MM, Messing EM. Prostate and bladder cancer screening. J Am Coll Surg 1998;86(1):63–74. [6] Lee R, Droller MJ. The natural history of bladder cancer: Implications for therapy. Urol Clin North Am 2000;27(1):1–13. [7] Cheng L, Weaver AL, Leibovich BC, et al. Predicting the survival of bladder carcinoma patients treated with radical cystectomy. Cancer 2000;88(10):2326 –32. [8] Thrasher JB, Frazier HA, Robertson JE, Dodge RK, Paulson DF. Clinical variables which serve as predictors of cancer-specific survival among patients treated with radical cystectomy for transitional cell carcinoma of the bladder and prostate. Cancer 1994;73(6):1708 – 15. [9] Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;51(1):15–36. [10] Marshall VF. Current clinical problems regarding bladder tumors. Cancer 1956;3:543–50. [11] Kishi K, Hirota T, Matsumoto K, Kakizoe T, Murase T, Fujita J. Carcinoma of the bladder: a clinical and pathological analysis of 87 autopsy cases. J Urol 1981;125(1):36 –9.
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[48] Robinson RG, Kessler LG, Naughton MD. Cancer awareness among African Americans: a survey assessing race, social status, and occupation. J Natl Med Assoc 1991;83(6):491–7. [49] Potosky AL, Harlan LC, Kaplan RS, Johnson KA, Lynch CF. Age, sex, and racial differences in the use of standard adjuvant therapy for colorectal cancer. J Clin Oncol 2002;20(5):1192–202. [50] Canto MT, Chu KC. Annual cancer incidence rates for Hispanics in the United States: surveillance, epidemiology, and end results, 1992– 1996. Cancer 2000;88(11):2642–52. [51] Droller MJ. Bladder cancer: state of the art care. CA Cancer J Clin 1998;48:269 – 84. [52] Silverman DT, Morrison AS, Devesa SS. Bladder Cancer. In: Schottenfeld D, editor. Cancer epidemiology and prevention. New York: Oxford University Press, 1996. p. 1156 –79. [53] Pamuk E, Makuc D, Heck K, Reuben C, Lochner K. Socioeconomic status and health chartbook. Health, United States. U. S. department of Health and Human Services publication number (PHS): 98 –1232. Hyattsville, MD: National Center for Health Statistics, 1998. [54] Benson RC Jr., Tomera KM, Kelalis PP. Transitional cell carcinoma of the bladder in children and adolescents. J Urol 1983;130(1):54 –5. [55] Fitzpatrick JM, Reda M. Bladder carcinoma in patients 40 years old or less. J Urol 1986;135(1):53– 4. [56] Linn JF, Sesterhann I, Mostofi FK, Schoenberg M. The molecular characteristics of bladder cancer in young patients. J Urol 1998;159:1493. [57] Wymenga AN, Slaets JP, Sleijfer DT. Treatment of cancer in old age, shortcomings and challenges. Neth J Med 2001;59(5):259 – 66. [58] Miller DC, Taub DA, Dunn RL, Montie JE, Wei JT. The impact of co-morbid disease on cancer control and survival following radical cystectomy. J Urol 2003;169(1):105–9. [59] Edwards BK, Howe HL, Ries LA, et al. Annual report to the nation on the status of cancer, 1973–1999, featuring implications of age and aging on U.S. cancer burden. Cancer 2002;94(10):2766 –92. [60] Yancik R, Ries LA. Aging and cancer in America: Demographic and epidemiologic perspectives. Hematol Oncol Clin North Am 2000; 14(1):17–23. [61] Herr HW. Does early cystectomy improve survival of patients with high-risk nonmuscle invasive bladder tumors. J Urol 2001;165(Suppl 5):1061 [abstr].
Review article
Gender, racial and age differences in bladder cancer incidence and mortality Ralph Madeb, M.D., Edward M. Messing, M.D.* Department of Urology, Strong Memorial Hospital University of Rochester Medical Center, Rochester, NY, USA Received 20 May 2003; received in revised form 12 August 2003; accepted 20 August 2003
Abstract Bladder cancer is the fourth most commonly diagnosed cancer in men and the eighth most common in women in the United States. While clinicians who diagnose and treat the disease recognize that bladder cancer has a unique demographic profile, the influence of such factors as age, gender and race on incidence, prognosis, and survival of patients is poorly understood, and has not been the subject of intense investigation. Both through analysis of the population-based databases of bladder cancer in the United States and Europe, as well as epidemiological studies, some of the effects of gender, race and age on this disease have begun to be explained. In this manuscript we review the current literature and epidemiological studies on the affects of gender, race and age on incidence and mortality of bladder cancer. © 2004 Elsevier Inc. All rights reserved. Keywords: Gender; Race; Bladder cancer; Epidemiology; Risk factors
1. Introduction Bladder cancer is the fourth most commonly diagnosed cancer in men and the eighth most common in women in the United States. An estimated 56,500 new cases of bladder cancer were diagnosed in 2002 and an estimated 12,600 patients died of this disease [1]. Epidemiological and experimental evidence favors a strong role for chemical carcinogens in the etiology of bladder cancer, but many cases arise with no obvious exposure to known carcinogens [2– 4]. Similarly, while most clinicians who diagnose and treat the disease recognize that bladder cancer has a unique demographic profile, the influence of such factors as age, gender and race on incidence, prognosis, and survival of patients is poorly understood, and has not been the subject of intense investigation. Both through analysis of the population-based databases of bladder cancer in the United States and Europe, as well as epidemiological studies, some
* Corresponding author. Tel.: ⫹1-585-275-3345; fax: ⫹1-585-2731068. E-mail address: [email protected] (E.M. Messing). 1078-1439/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/S1078-1439(03)00139-X
of the effects of gender, race and age on this disease have begun to be explained. Herein, we review the current literature in this field.
2. Incidence and prevalence In Western countries, bladder cancer is 2.5 to 4 times more common among men than women [2– 8]. Between 1985 and 2000 the number of bladder cancers diagnosed annually in the United States increased by 33%, at roughly the same rate in both genders [1,9]. The relatively equal rise in incidence cases in men and women is perplexing in a number of ways. Bladder cancer is virtually never recognized incidentally at autopsy [10 –11]. This coupled with the consistent method by which bladder cancer has been diagnosed (cystoscopy and biopsy) over the last six decades, indicates that the increase in bladder cancer cannot be attributed to technological innovations or major changes in the delivery of medical care. As a result, the reported differences in incidence rates between the genders (as well as races and ages, see below) cannot be simply explained by a failure to diagnose the disease in particular groups. Moreover, because bladder cancers incidence increases with age
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in both genders, the relatively equal rise in incidence in men and women seems contrary to what one would expect in view of the longer female life expectancy (roughly 5 years or longer) in most industrialized countries [12,13]. That the number of new bladder cancer cases has risen similarly remains particularly surprising because during the last three decades, women have joined the male workplace and have changed social habits which expose them to both industrial and environmental carcinogens (i.e., cigarette smoking) from which they once had been relatively protected. One would have expected that these social factors should have resulted in a disproportionate increase in women as has been seen with lung cancer during this interval [1]. It is quite possible that genetic, hormonal and/or anatomic factors may eventually answer this puzzling trend. Race also has a significant influence on bladder cancer incidence. Bladder cancer is twice as common among American Caucasian men as among African American men and roughly 1.5 times more common among White American women than African American women [2– 4,14]. Alternatively, the incidence of bladder cancer in Hispanic Americans and Native Americans is one-half and one-sixth, respectively, that of Whites of each gender [14]. The Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute (NCI) collects and publishes cancer incidence and survival data from 11 population-based cancer registries and three supplemental registries covering approximately 14% of the US population [14]. The lifetime risk of being diagnosed with bladder cancer in the 11 SEER areas in 1995 through 1997 was 3.7% for a White male, which is roughly three times the likelihood that a White female (1.2%) or a African American male (1.3%) has, and over 4.5 times the likelihood that an African American female has (0.8%) [14 –15]. This was also shown in a recent study by Prout et al. [16], who used population-based tumor registries in 3 major states of the United States and found higher stages of bladder cancer in blacks. Interestingly, in their epidemiological study it was found that African Americans were twice as likely to have invasive cancers at diagnosis and among patients with invasive cancer, they were 2.2 times more likely to have muscle invasive disease [16]. As with gender and race, there is an unequal distribution of the incidence of bladder cancer with age. Although, bladder cancer can occur at any age, it is primarily a disease of the elderly with the median ages at diagnosis for transitional cell carcinoma being 69 years in males and 71 years in females in the United States. Trends in the SEER database reveal that the incidence of bladder cancer increases directly with age—from roughly 142 per 100,000 men and 33 per 100,000 women age 65 to 69 years to 296 per 100,000 men and 74 per 100,000 women 85 years old or older [14]. Bladder cancer is uncommon below the age of 50.
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3. Mortality and survival It is estimated that in 2002 there were 12,600 bladder cancer deaths in the United States; 8,600 in men and 4000 in women [1]. Bladder cancer accounts for 3% of all cancer deaths in men and 1.5% in woman, making it the seventh most common cause of cancer deaths in American men [1]. Between 1973 and 1999 there has been a 33% decline in bladder cancer mortality [14]. Whether this is attributable to a fundamental change in the biology of this disease, alteration in risk factors for different phenotypic variants, better treatments, earlier diagnoses, or a combination of these factors is uncertain. However, the reduction in mortality has primarily been seen in men. Males have a higher 5-year survival rate than women (overall 83% vs. 74% in SEER [14]; 65% vs. 60% in EUROCARE data [13]) with the gender breakdown of White males, African American males, White females and African American females being 84%, 67%, 76% and 58%, respectively (SEER). In other words, in the United States, women have a 30% (in African Americans) to 50% (in Whites) greater chance of dying from bladder cancer if they develop it than men of their respective races. Whatever the explanations, women account for a disproportionately high percentage of lives lost from this disease. This is confirmed by the relatively striking changes in age-adjusted mortality from bladder cancer for the most recent 10 years reported in the SEER database: ⫺0.4% change annually in men with an annual ⫹0.1% change increase in women. Similar trends have also been seen in other databases including the Finnish Cancer registry from 1985–1994 [17,18]. The age-adjusted mortality trends, as well as the increase in incidence in men compared to women suggests differences in bladder cancer diagnosis, treatment, and/or disease characteristics between the sexes rather than the longer female life expectancy are responsible for these mortality data.
4. Gender differences in mortality One explanation for the higher mortality in women would be if they had more advanced disease at diagnosis than men. According to SEER data, women with bladder cancer had a 3 to 12% 5-year survival disadvantage in Stages I-IV(I, II-localized, III-regional, IV-metastatic), respectively [14]. Additionally, using the population basedregistry in Netherlands (1975–1989), Kiemeney et al. showed that males were diagnosed with lower staged disease with 28% of males vs. 43% of females being diagnosed with Stage III or IV disease at diagnosis [19]. In the Unites States, Fleshner et al. [20] presented the National Cancer Data Base Report on bladder carcinoma. With a total of 40,659 known cases of bladder carcinoma evaluated between 1985 and 1993, women were more likely to be diagnosed with advanced stages (33.1% vs. 27.7%) [20]. Finally, using the Netherlands Cancer Registry, Mungan et al.
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[21] have also recently shown that females had a higher percentage than men of invasive transitional cell carcinoma of the bladder and upper urinary tract at first presentation. In their study, males had a 32% better chance of being diagnosed with superficial disease than females [21]. Stage at diagnosis clearly predicts outcome. Therefore, it has been suggested that one reason for the worse survival among women with bladder cancer is the difference in stage distribution at the time of diagnosis. One must be cautious when evaluating the stages of bladder cancer reported in the SEER database. The main problem is that this database only crudely stratifies stage as localized, regional, distant and unstaged that does not allow accurate analysis according to the TNM staging system. Specifically, because metastases almost never occur without concomitant or preexistent invasion of the muscularis propria [22,23], the distinction between Ta, T1 (“superficial”) and T2 (“invasive”) disease is critical, yet both are categorized as “localized” in SEER reports. Furthermore, the lack of pathological details such as depth of invasion and the presence or absence of subepithelial and/or muscularis propria tissues in examined specimens prevent sufficiently accurate assessment of stage. Additionally, varying reports on in situ cancer, which in the case of urothelial neoplasia can be a very aggressive phenotype, further confound the accuracy of pathologic information in the SEER database. Despite these limitations, there almost certainly is a difference between the genders in stages at diagnosis. The following has been proposed as explanations: A. Delay in Diagnosis: An initial symptom in more than 80% of men and 70% of women with bladder cancer is painless hematuria (often grossly visible). As urinary infection is far more common in women, misinterpretation of hematuria and irritative voiding (the next most common symptom of bladder cancer) for bacterial cystitis, will cause a delay in diagnosis in females, perhaps resulting in a more advanced stage at the time of diagnosis. Mommsen [24] and Mansson [25] and their respective colleagues, have shown that doctors’ delays were strongly influenced by the presenting symptom. The lag time was shorter when hematuria alone was the presenting symptom than when urgency was. However, there was estimated to be, on the average, a 3-month longer interval to diagnosis of bladder cancer in women once medical attention was sought than in men in relatively universal health access systems. While bladder cancer in women is primarily a postmenopausal disease, which men can observe hematuria more readily than women based on anatomic differences is almost certainly the case, as well. This difference between the genders would normally be added to the physician related delay. Interestingly, two different groups have recently reported that at least with muscle invasive bladder cancer, a delay from diagnosis to definitive
treatment of more than 3 months was associated with a significantly worse outcome [26,27]. Thus, this delay in diagnosis in women may in part explain their poorer prognosis. B. Cultural: Culture-mediated factors may influence differences in illness behavior and health awareness between women and men resulting in differences in the perception and/or acceptance of the disease, readiness to use available health services and interventions, and delay in treatment [28 –32]. However, all of the factors would normally favor an earlier diagnosis and treatment in women, which of course, is the reverse of what is seen. C. Biological: There are epidemiologic and laboratory studies indicating that there might be differences between the genders in exposure to potential carcinogens and that men and women might metabolize carcinogens differently [2– 4,6]. While for the two most commonly described carcinogens, cigarette smoking and industrial exposures, no predilection for high or low risk bladder cancer has been reported [33], it is possible that subtle differences could have been overlooked in reported studies, which when combined with the aforementioned delays, could lead to more advanced stages at diagnosis in women. D. Anatomical: In addition to the easier detection of gross hematuria in men, other anatomic differences between the middle aged and elderly female and male bladder have been postulated as reasons for the disparate mortalities between genders. Male bladders have a thicker detrusor probably because of the need to void at higher intravesical pressures to overcome outflow resistance caused by the hyperplastic prostate gland. The thicker muscle may delay extravesical extension, and perhaps retard the development of metastases. Another anatomic difference that may affect disease progression is that the prostate may influence the surrounding lymphatic channels and pathways of spread. Maralani et al. [34] have shown that there is an increased incidence of urethral involvement in female bladder cancer. The patterns of urethral invasion identified were via the vascular or lymphatic channels in the periurethral tissue. The replacement of periurethral tissue in men by the prostate gland and its capsule may block the angiolymphatic extension of the tumor that is seen in women [21,34]. These anatomic factors could contribute to the higher stages of bladder cancer that occur in females. Although the abovementioned explanations for the advanced stage of females at the time of diagnosis are each plausible, recent stage-adjusted studies by Fleshner et al. [20] and Mungan et al. [35] indicate that women still fared worse after survival analyses were stratified by disease stage. While to some degree a migration to more invasive
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disease within given pathologic stages may in part explain this observation (e.g., pT2b vs. pT2a) there are probably additional factors that are unknown currently, which cause a higher likelihood of women dying from bladder cancer than men.
5. Racial differences in mortality African Americans, especially women, have a 60 to 100% higher mortality from bladder cancer than do their White counterparts ([14]; see above). There is some evidence to suggest that the reduced risk for whites is primarily limited to noninvasive bladder cancers, implying a later diagnosis and/or more aggressive tumor phenotype in African Americans [15–16]. Whatever the explanation, a lower percentage of African Americans (61%) and females (49%) compared to White males (76%) and females (70%) diagnosed with transitional cell carcinoma have disease confined to the bladder [14]. Several studies have tried to explain the differences in the stage distribution of bladder cancer among the races. The following theories have been proposed: 5.1. More aggressive disease Recent genetic and epidemiological evidence indicates that African Americans may often have a more aggressive form of other cancers such as those of the breast and prostate [36]. This has gained prominence after the NCI sponsored a Black-White Cancer Survival Study (BWCSS), which compared the survival for blacks and whites with cancers of the bladder, breast, colon and uterus [37– 40]. Blacks had a poorer survival with all four cancers even after the adjustment for clinical stage and socioeconomic characteristics. Data show that breast cancer in the AfricanAmerican population is biologically more aggressive and more likely to be poorly differentiated with high grade atypia and less estrogen receptor positivity [38,41– 43]. Similar data are currently not yet available to determine if African Americans have a greater proportion of high grade bladder cancers, and/or of unfavorable histologies, and/or of tumors with molecular markers of poor prognosis than Caucasians have. Indeed Prout et al. have reported blacks had a predominance of cell types other than transitional cell cancers including squamous cell and adenocarcinomas [16], which generally have more aggressive phenotypes than, at least, well and moderately differentiated urothelial (transitional cell) cancers. This could contribute to the tendency towards more advanced stages at diagnosis and worse outcomes found in African Americans. 5.2. Socioeconomic status Several studies have shown that low socioeconomic status (SES), which includes variables such as low income,
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minimal education, no private health insurance or lack of access to health care, and residing in a neighborhood of high population density is associated with less cancer screening, delay in diagnosis, advanced tumor stage and poorer survival from most cancers [44]. Although the SEER program does not report SES, epidemiologists have tried to estimate the influence that SES has on the racial differences in survival. Studies have shown higher survival rates in populations of higher SES [45,46]. For breast carcinoma, higher SES correlated with a more favorable stage at first diagnosis because of greater rates of mammography use and less risky behaviors [44]. Therefore, SES may explain, in part, racial differences in cancer mortality rates between African Americans and Whites. This may be assessed more directly by knowing outcomes in relatively equal health access settings, such as the military, which may in part control for SES. Moreover, since other groups with lower SES, including Hispanics and Native Americans, do not share with AfricanAmericans a higher mortality from bladder cancer (see below), the influence of SES on racial differences in mortality is likely not to be great. 5.3. Elapsed time from symptoms to onset of treatment Whether it is biologic factors, nonbiologic factors or both that cause an advanced stage at the time of diagnosis, elapsed time from symptoms to onset of treatment has been shown to be associated with decreased survival [24]. This has not been studied intensively in explaining racial differences in stages at diagnosis, but well may be a fruitful area of investigation. 5.4. Occupational exposures, smoking, and differences in metabolism of toxic substances There may be genetic differences between blacks and whites that contribute to underlying molecular origins and pathophysiology of the disease. For example, these factors may affect the host response to different carcinogens and occupational exposures [2– 4]. Again, this has not yet been studied intensively in terms of explaining racial differences in susceptibility and prognosis. If these (either the exposures or how carcinogens are metabolized) occur disproportionately in the African-American population then there will be an increased tendency towards invasive disease, a more advanced stage at presentation and poorer survival. Insufficient evidence is available to assess these possibilities. In addition to 5-year survival disparity, survival by stage is also more favorable in whites [14,20]. This may not only reflect more advanced or more aggressive disease within stage categories at diagnosis, but also less adequate access to healthcare, with a delay in diagnosis and/or acceptance of optimal therapies in the African American population. Moreover, the discrepancies are greatest in the localized and regional stages, which are the stages where aggressive therapy has been shown to be of the most benefit. Previous
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studies for other malignancies have shown that later diagnoses among the black population appear to be because of beliefs that cancer is not preventable, deficits in knowledge about screening, and less availability of screening tests. All contribute to a later stage at diagnosis [47,48]. Other explanations for the stage-specific racial disparity include differences in tolerating or accepting follow-up and adjuvant therapies, use of different providers, and the possibility of an inherently more aggressive disease [49].
6. Mortality in Hispanic Americans Another puzzling trend that warrants further attention is the incidence and mortality of bladder cancer among Hispanic Americans. As mentioned earlier, Hispanic Americans have incidence rates that closely mirror that of African Americans with 5 year survival rates that, particularly for invasive and more advanced disease, surpass those of Whites [14,50]. Hence, Hispanic Americans, being one the largest minority groups in the Unites States, have lower incidence and mortality rates when compared to other ethnic groups. Although very little research has been reported on the Hispanic ‘riddle’, these data cast serious doubt on whether low SES or inadequate health care access can explain the worse outcome in African Americans. However, one possible explanation for the decreased mortality and lower incidence in Hispanics could be their lower rate of tobacco use as a whole. It is well known that cigarette smoking is the most significant environmental risk for bladder cancer and another factor associated with survival. Active smokers have a fourfold higher incidence over people who never smoked [51] and risk correlates with number of cigarettes, duration of smoking, and degree of inhalation [23]. Former smokers have a 30 to 60% lower risk of bladder cancer [52]. For those who quit, the risk decreases over 10 to 20 years of abstinence. According to the 1994 – 1996 National Health Interview Survey, the average annual prevalence of cigarette smoking was approximately 50% lower among Hispanic Americans than Whites [50,53]. This was true for both males and females and for comparisons at all income levels. This in part, could explain the lower incidence and mortality among Hispanic Americans with bladder cancer, but there is a need for further epidemiological and possibly biological investigation in this area, as well.
7. Mortality in the elderly As with incidence, mortality from bladder cancer is also higher in elderly people. For instance, the ratio of diseaserelated mortality to incidence rates for men and women in the United States age 65 to 69 years is 14% and 18%, respectively, whereas for men and women age 80 to 84 years it is 30% and 37%, respectively (SEER, 1973–1997)
[14]. The higher mortality in the elderly has several explanations. In patients under the age of 40, bladder cancers tend to express well-differentiated histologies and behave in a more indolent fashion, and in contrast to those that occur in older individuals, these tend not to recur [54 –56]. Furthermore, the molecular and genetic aberrations in bladder cancers in this population do not share the fairly close correlation with histologic grade and clinical behavior that is seen in urothelial cancers in the middle-aged and elderly populations [56]. This may indicate that bladder cancer usually occurs from a series of molecular aberrations, many of which are present as part of a background of genetic instability that occurs with aging, upon which, signature genetic abnormalities that have been well described (e.g., mutations inactivating p53) arise. When these signature events occur in isolation without the other cumulative genetic abnormalities, low grade and indolent tumors occur without progression or field effect patterns of recurrence. At advanced age, the background genetic aberrations are greater, resulting in more aggressive tumors when signature genetic events occur. Another explanation is that the diagnosis of bladder cancer in the elderly is likely to be delayed more often than in younger patients, which is probably both physician and patient related [57]. The elderly also have multiple comorbidities which may interfere with a decision for offering (by medical care providers), or receiving (by patients) more effective, but often more strenuous treatments [57,58]. Additionally, elderly patients have a more unfavorable survival within a given stage which ultimately may be a reflection of decreased host immunologic and other defense factors, more aggressive tumor patterns and greater resistance to treatment. It is likely that all the above factors play a role in the increased disease related mortality and decreased survival exhibited by the elderly with bladder cancer. Despite this, there has been growing recognition that the changes in the aging population have far reaching effects on oncologic care and cancer research. As the elderly are the largest growing segment of the population [59,60], understanding reasons for the increased mortality from bladder cancer is critical and needs further investigation.
8. Conclusion The potential effects of gender, race and age on the development of and outcome from bladder cancer have not been sufficiently investigated. Delays in diagnosis and institution of appropriate therapy are likely to play a role in patients (particularly women and African Americans) who are diagnosed at later stages and exhibit poorer survivals. Moreover, particularly with muscle invading and more advanced bladder cancer, outcome is clearly related to the timing of therapeutic intervention. Preliminary studies show that a delay in 12 weeks or greater is associated with advanced pathologic stage and decreased survival [26,27].
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Additionally, when survival was compared after early versus delayed cystectomy in patients with recurrent high-risk nonmuscle invading bladder cancers, it was found that early cystectomy results in better survival than delayed cystectomy or continued bladder-sparing procedures [61]. These data suggest that delay of intervention, especially cystectomy, is an independent adverse predictor of survival. Hence, the ability to diagnose bladder cancer earlier, especially in females and African Americans, should eventually improve their survival from bladder cancer. Another important stride is improving the reporting and classification of bladder cancer in the SEER database to include precise stage, grade and other histopathological information at the time of presentation. This should enable far better stage-adjusted analyses, and conclusions to be drawn about this disease, its biologic behavior, epidemiology, and the appropriateness of its management in various demographic groups. It should be understood that these factors alone may not account fully for the poorer outlook in some demographic groups as it is possible that genetic characteristics and environmental exposures, and their complex interactions probably influence bladder cancer development and prognosis as well. Future studies and should investigate how demographic risk factors, environmental exposures, and constitutional factors interact to affect prognosis. These studies should help us understand and eventually minimize disparities in disease outcome, and highlight target populations for early detection and prevention efforts. References [1] Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin 2002;52(1):23– 47. [2] Aben KK, Kiemeney LA. Epidemiology of bladder cancer. Eur Urol 1999;36(6):660 –72. [3] Brauers A, Jakse G. Epidemiology and biology of human urinary bladder cancer. J Cancer Res Clin Oncol 2000;126(10):575– 83. [4] Cohen SM, Shirai T, Steineck G. Epidemiology and etiology of premalignant and malignant urothelial changes. Scand J Urol Nephrol 2000;205(Suppl):105–15. [5] Goldstein MM, Messing EM. Prostate and bladder cancer screening. J Am Coll Surg 1998;86(1):63–74. [6] Lee R, Droller MJ. The natural history of bladder cancer: Implications for therapy. Urol Clin North Am 2000;27(1):1–13. [7] Cheng L, Weaver AL, Leibovich BC, et al. Predicting the survival of bladder carcinoma patients treated with radical cystectomy. Cancer 2000;88(10):2326 –32. [8] Thrasher JB, Frazier HA, Robertson JE, Dodge RK, Paulson DF. Clinical variables which serve as predictors of cancer-specific survival among patients treated with radical cystectomy for transitional cell carcinoma of the bladder and prostate. Cancer 1994;73(6):1708 – 15. [9] Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;51(1):15–36. [10] Marshall VF. Current clinical problems regarding bladder tumors. Cancer 1956;3:543–50. [11] Kishi K, Hirota T, Matsumoto K, Kakizoe T, Murase T, Fujita J. Carcinoma of the bladder: a clinical and pathological analysis of 87 autopsy cases. J Urol 1981;125(1):36 –9.
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