Curr Urol Rep (2014) 15:409 DOI 10.1007/s11934-014-0409-2

UROTHELIAL CANCER (A SAGALOWSKY, SECTION EDITOR)

Contemporary Gender-Specific Outcomes in Germany After Radical Cystectomy for Bladder Cancer Marianne Schmid & Shahrokh F. Shariat & Armin Soave & Oliver Engel & Margit Fisch & Michael Rink

Published online: 23 April 2014 # Springer Science+Business Media New York 2014

Abstract In 2008, urothelial carcinoma of the bladder (UCB) was the 8th most common cause of death in Germany. An increasing body of evidence suggests differences in the presentation and prognosis of UCB between genders. Large population-based and multi-institutional studies have found a higher incidence of UCB in men, while women treated with radical cystectomy (RC) have shown unfavorable outcomes compared to their male counterparts. Indeed, it is important to note that UCB incidence and outcomes have regional and country-specific variability. These distinct country and genderspecific differences must be considered in patient counseling, treatment decisions, and UCB management. This review summarizes the contemporary literature regarding the impact of gender on UCB outcomes, focusing on patients treated with RC in Germany. We evaluated the most current literature regarding gender-specific differences in UCB incidence, treatment patterns, and oncological outcomes, including pathological stage distribution and survival. Keywords Urothelial carcinoma . Bladder cancer . Gender . Outcome . Prognosis

Introduction Urothelial carcinoma of the bladder (UCB) represents one of the major causes of cancer morbidity and mortality worldwide. This article is part of the Topical Collection on Urothelial Cancer M. Schmid : A. Soave : O. Engel : M. Fisch : M. Rink (*) Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany e-mail: [email protected] S. F. Shariat Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria

UCB is the fourth most common cancer in men and 12th most common cancer in women, with 72,570 estimated new cases in the United States in 2013 [1]. In Europe, over 110,000 men and 70,000 women are newly diagnosed annually with UCB and over 38,000 patients in Europe die from UCB each year [2, 3]. At initial diagnosis, approximately 25 % of patients present with muscle-invasive bladder cancer (MIBC) and are subsequently treated with radical cystectomy (RC) and bilateral lymph node dissection (LND), the gold standard of treatment for patients with high-risk non-muscle-invasive disease and those with muscle-invasive UCB [4]. However, despite advances in surgical techniques, imaging, perioperative management, and systemic chemotherapy, approximately 50 % of patients develop metastases and die from their disease within five years of surgery [5–7]. In 2008, UCB was the eighth most common cause of death in Germany for both genders [3]. Gender is an important factor in clinical decision-making regarding UCB management [8] and is implemented in prediction tools as a strong prognosticator of UCB outcomes for patients undergoing RC [9–11]. Population-based and international multi-institutional studies have reported distinct gender-specific disparities, with women presenting more advanced disease and having worse survival [12–15, 16••, 17]. Although recent reviews have underscored the importance of gender-adjusted evidence-based guidelines and specific care for female UCB patients [8, 18], the association and impact of gender on UCB outcomes is still poorly understood. Gender-specific differences in general health and disease outcomes appear to be multifactorial. In addition to individual genetic and physiological constitutions, individual interaction with environmental factors and occupational and lifestyle exposure seem to be of particular importance [19]. Variable evidence for regional and country-specific differences regarding UCB incidence is provided by several national studies [20–23]. Furthermore, variations concerning bladder cancer

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registration among different countries must be taken into account [24]. Therefore, it is important to focus on local/ regional cancer registries when providing recommendations for patient counseling and tailored decision-making. In this manuscript, we review the contemporary literature regarding the impact of gender on UCB outcomes, with particular emphasis on patients treated with RC in Germany.

Data Acquisition This review will summarize new gender-specific UCB outcome findings from the past three years, with a focus on Germany. We performed a non-systematic PubMed/MEDLINE literature search to identify original articles, review articles, and editorials for the keywords “bladder cancer,” “urothelial carcinoma,” “transitional cell carcinoma,” “gender,” “radical cystectomy,” “recurrence and progression,” and “outcome and prognosis” between January 2010 and October 2013 [25]. Cited references from selected studies and relevant review articles were also retrieved. Searches were limited to English and German language. Articles with the highest level of evidence were selected and reviewed, with the consensus of all of the authors of this paper. In addition, we reviewed UCB data from the German Robert Koch Institute (RKI) [26]. The RKI is part of the Federal Ministry of Health of the German government responsible for disease control and prevention. The RKI provides health monitoring as well as maintenance of cancer registries. Each German federal state transfers its population-based cancer databases to the German Center for Cancer Registry Data (ZfKD), where data are periodically quality-checked, analyzed, and evaluated [26].

Results General Gender-Specific UCB Outcomes Gender is increasingly recognized as an important factor of outcome in bladder cancer [27]. Men are three to four times more likely to develop UCB than women [18]. During the past two decades, the incidence of annually diagnosed UCB in the U.S. increased by 50 %, and at a 25 % faster rate in men than in women [28]. Inferior UCB survival rates among women, however, appear to be significantly related to differences in stage distribution in which women present more advanced disease [14, 15, 29]. The association of female gender with worse clinical outcome after RC [30] may be related to differences in sociodemographic characteristics [31]. Additionally, several studies observed that female gender was associated with a higher rate

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of disease recurrence and cancer-specific mortality (CSM) [32–34]. UCB is primarily considered a disease of the elderly, and women have a higher life expectancy than their male counterparts. Indeed, age-adjusted analyses did not observe differences between genders. Gender-specific differences in UCB diagnosis, treatment, and disease characteristics appear to be responsible for the variability in mortality rates [35]. Data Quality in Germany The accuracy of epidemiologic data collected in cancer registries is highly dependent upon complete data acquisition. Development and utilization of the cancer registry has improved since the beginning of cancer registration in Germany [36]. Although East and West Germany were reunited in October of 1990, differences still remain between the eastern and western states, including the monitoring of UCB. This has resulted in heterogeneity of data systems among the individual German federal states. For example, implementation of continuous statewide registration has ranged from 1967 (Saarland) to 2009 (Baden-Würtemberg). The ZfKD regularly estimates the degree of completeness for the population-based cancer registries, which has increased considerably within the last 6–8 years. According to the latest evaluation (2008), of the total 16 German federal states, 10 states and four of the five administrative districts of North Rhine-Westphalia (NRW) had reached an estimated completeness level of at least 90 %, and of these, eight federal states and the eastern part of NRW had reached over 95 % completeness (Fig. 1). UCB Incidence and Mortality in Germany In 2008, approximately 16,000 patients in Germany were diagnosed with MIBC, and approximately one-quarter (4,510) of newly diagnosed UCB cases were female [26]. In addition, a further 12,000 patients presenting in situ carcinomas (Cis) and unspecified neoplasms are accounted for in the registry (Table 1). Although cancer registries in other countries have reported stable or even decreasing UCB incidence and mortality rates [37, 38], the RKI found a general increase of newly diagnosed UCB in both genders across all age groups between 1999 and 2008. The increased incidence of UCB was particularly notable in the older population, with over 80 % of patients over 65 years of age at diagnosis (Fig. 2). While the total incidence of UCB in German men is increasing due to the aging population, the age-adjusted morbidity rates are falling. In 2012, the age-adjusted incidence rate of UCB was estimated at 18.5 %, compared to 20.1 % in 2008. Moreover, ageadjusted mortality rates are decreasing. Changes in lifestyle such as drinking and smoking habits as well as a reduction in

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Fig. 1 Estimated integrity of German cancer register in 2008, separated by states and regions (reprinted with permission of Robert-Koch Institute, Berlin, Germany) [36]

occupational carcinogen exposure are thought to be the major reasons for this observation. Conversely, the total and age-adjusted UCB incidence rates in German women are increasing. The age-adjusted UCB incidence rate rose slightly, from 5.6 % in 2008 to 5.7 % in 2012, although mortality rates in women decreased slightly (Fig. 3). According to RKI data, smoking still represents the major risk factor in Germany for developing UCB development. Interestingly, in contrast to their male counterparts, the number of female smokers in Germany has increased since the 1980s [39], which may explain the difference in UCB incidence rates. It is important to note that UCB-related morbidity and mortality rates for both genders are higher in the eastern part of Germany.

Gender-Specific Radical Cystectomy, Urinary Diversion, and Perioperative Outcomes in Germany The data indicate that treatment with RC is more common in men than women. An analysis of 812 UCB patients admitted to a German rehabilitation clinic after surgical treatment found that men were significantly more likely to undergo RC than women (Odds ratio (OR): 2.9, p=0.03) [40]. However, the number of women in Germany treated with RC has increased significantly over time. Otto et al. observed that the rate of women undergoing RC has doubled over time (18 % in 1989– 1996 to 44.4 % in 2003–2008) [16••]. Women are more likely than men to receive incontinent urinary diversion. A recent study found that conduit (70 %)

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Table 1 UCB incidence, mortality, and survival rates 2007, 2008, and 2012 (estimated) 2007

Total incidence/year # Crude incidence rate*,# Standardised incidence rate*,+,# Median age at UCB diagnosis ∞,# Mortality Crude mortality rate* Standardised mortality rate*,+ 5-year prevalence Absolute 5-year survival rate (2007–2008)⌃ Relative 5-year survival rate (2007–2008)⌃

2008

2012 (est.)

Men

Women

Men

Women

Men

Women

11,090 (20,470) 27.5 (50.7) 19.8 (36.7) 73 (72) 3,639 9.0 6.5 32,300

4,310 (7,040) 10.3 (16.7) 5.4 (9.4) 77 (75) 1,965 4.7 2.1 10,400

11,460 (20,850) 28.5 (52.4) 20.1(37.1) 73 (72) 3,611 9.0 6.2 32,900 48 (38–57) 60 (50–69)

4,510 (7,490) 10.8 (17.8) 5.6 (9.9) 77 (74) 1,921 4.6 2.0 10,700 40 (31–51) 49 (39–62)

11,500 28.9 18.5

4,700 11.4 5.7

33,500

11,400

* per 100,000 persons; + standardized to age (old European population); ∞ median; ⌃ percentage (lowest and highest value of the included states); # values including Cis and tumor of unknown specificity (D09.0, D41.4) (Adapted with permission from Robert-Koch Institute, Berlin, Germany) [26]

or pouch (15 %) urinary diversion was more common in women, whereas men received conduit (50 %) or orthotopic neobladder (49 %) (p

Contemporary gender-specific outcomes in Germany after radical cystectomy for bladder cancer.

In 2008, urothelial carcinoma of the bladder (UCB) was the 8th most common cause of death in Germany. An increasing body of evidence suggests differen...
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