Trends in corpus uteri cancer mortality in member states of the European Union

European Journal of Cancer (2014) 50, 1675– 1684

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Trends in corpus uteri cancer mortality in member states of the European Union q Elisabete Weiderpass a,b,c,d,⇑, Jerome Antoine e, Freddie I. Bray f, Jin-Kyoung Oh b,g, Marc Arbyn e a

Cancer Registry of Norway, Oslo, Norway Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden c Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway d Department of Genetic Epidemiology, Folkha¨lsan Research Center, Helsinki, Finland e Unit of Cancer Epidemiology, Scientific Institute of Public Health, Brussels, Belgium f International Agency for Research on Cancer, Lyon, France g Risk Appraisal and Prevention Branch, National Cancer Center, Goyang, Republic of Korea b

Received 9 December 2013; received in revised form 11 February 2014; accepted 13 February 2014 Available online 20 March 2014

KEYWORDS Corpus uteri cancer Endometrial cancer Mortality Europe European Union Trends Epidemiology Women Age period cohort

Abstract Objectives: The burden of corpus uteri cancer varies in the European Union (EU). We analysed trends in corpus uteri cancer mortality in 26 EU member states from 1970 onward. Methods: Population numbers and number of uterine cancer deaths were extracted from the World Health Organisation mortality database. Corpus uteri cancer mortality rates were corrected for certification problems using different reallocation rules for deaths registered as uterine cancer not otherwise specified, or using mixed disease codes. Join point regression was used to study the annual percentage change of age-standardised corpus uteri cancer mortality rates. Changes in corpus uteri cancer mortality rates by calendar period and standardised cohort mortality ratios were also estimated. Results: In 2008, 12,903 women died from corpus uteri cancer in the EU. Corrected age-standardised corpus uteri cancer mortality rates have decreased significantly over the past decades in most member states, with exception of Malta and Bulgaria, where rates increased; Greece, where rates remained low but stable; and Sweden, where rates have been stable since 1970.

Sources of support: Supported by the Cancer Registry of Norway and the Belgian Foundation Against Cancer. ⇑ Corresponding author at: Cancer Registry of Norway, Postbox 5313 Majorstuen, 0304 Oslo, Norway. Tel.: +358 408453406; fax: + 358 919125727. E-mail address: [email protected] (E. Weiderpass). http://dx.doi.org/10.1016/j.ejca.2014.02.020 0959-8049/Ó 2014 Elsevier Ltd. All rights reserved.

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Original member states showed a steeper decrease than newer member states. The standardised cohort mortality ratios indicated that corpus uteri cancer mortality does not decrease further, nor does it increase, among women born after 1940, although these birth cohorts may still be too young for corpus uteri cancer incidence to be fully evaluated. Conclusion: Our corrected corpus uteri cancer mortality rates showed a decrease in most EU member states among women born before 1940. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction Corpus uteri cancer is the sixth most common incident cancer in women worldwide, and the second most common gynaecological cancer, with an estimated 288,387 new cases and 73,854 deaths in 2008 [1]. North America and Western Europe have the highest incidence of corpus uteri cancer (age-standardised rate, ASR, greater than 10 per 100,000), with the lowest incidence occurring in Asia and Africa (ASR less than 10 per 100,000) (Supplementary Fig. 1) [1]. The estimated cumulative risk of corpus uteri cancer is 0.96%, with a corresponding mortality risk of 0.23%. This yields a mortality-to-incidence ratio of 0.24, which is lower than that for breast cancer (0.32), ovarian cancer (0.63) and cervix uteri cancer (0.55) (Supplementary Table 1). Corpus uteri cancer is the most common gynaecological malignancy in the European Union (EU), where an estimated 55,941 women developed corpus uteri cancer in 2008 (ASR 16.2) and 12,903 died from the disease (ASR 3.0; mortality-to-incidence ratio 0.18) (Supplementary Fig. 2) [2]. Trend analyses of corpus uteri cancer mortality are often hampered by certification problems, i.e. a cause of death recorded as uterine cancer not otherwise specified (NOS) instead of determining the origin of the cancer, be it the cervix uteri or the corpus uteri [3,4]. Indeed, in many countries a substantial fraction of uterine cancer deaths are recorded as NOS, a complication compounded by the fact that the International Classification of Diseases Revision 8 (ICD-8) combined corpus uteri cancer and NOS into a single three-digit code. The present report shows corpus uteri cancer mortality rates in the EU corrected for certification problems using different reallocation rules for deaths recorded as NOS, or using mixed disease codes, building upon previously published methods [4,5].

calendar year, 5-year age group (from 40–44 years to P85 years) and member state. EU member states were categorised into the 15 original member states (Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Portugal, Spain, Sweden, the Netherlands and the United Kingdom) and the 11 newer member states that joined in 2004 or later (Bulgaria, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Malta, Poland, Romania, Slovakia and Slovenia). Cyprus was not included as data were only available from 2000 onwards, which did not allow for a meaningful analysis. In the present study, uterine cancers were categorised as cervix uteri cancer, corpus uteri cancer, NOS, or other rare cancers such as placental cancer. Cervix uteri cancer was identified using ICD-8 and ICD-9 code 180, and ICD-10 code C53. Corpus uteri cancer and NOS had separate codes in ICD-9 and ICD-10 (corpus uteri cancer: 182 and C54, respectively; NOS: 179 and C55, respectively). However, in ICD-8, code 182 was used for both corpus uteri cancer and NOS. Other cancers included ICD-8 and ICD-9 code 181, and ICD-10 code C57/C58. 2.2. Reallocation rules Three different reallocation rules were used to correct corpus uteri cancer mortality rates for certification problems, i.e. to re-allocate the portions of NOS that probably originated from the cervix uteri and the corpus uteri; all presented information on corpus uteri cancer mortality in the present report was corrected [3,7]. To estimate the corrected number of corpus uteri cancer (corCRP), we first subtracted the corrected number of cervix uteri cancers (corCVX) from the total number of uterine cancers as follows: corCRPij = UTij corCVXij, where UT is the total number of uterine cancers and i and j correspond to age group and year of death, respectively.

2. Materials and methods 2.1. Source of data The number of uterine cancer deaths and the number of women in the general population in EU member states were obtained from the World Health Organisation’s mortality database [6]. Data were aggregated by

2.2.1. Reallocation rule 1 According to Loos et al. [4], when the proportion of NOS (pNOS) of all uterine cancer is less than 25%, adjustments can be made using the following reallocation rule, which assumes that the cause of death NOS was allocated at random: corCVXij = CVXij + NOSij * [CVXij/(CVXij + CRPij)].

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2.2.2. Reallocation rule 2 When reallocation rule 1 could not be applied because pNOS was more than 25% or NOS was not available as a separate ICD code, reallocation rule 2 was used. This consisted of using linear regression to impute [8–10] the age-specific proportion of corCVX (pcorCVXij = corCVXij/UTij) in a relevant target period other than that used in reallocation rule 1 (containing an age  year interaction) [3]. 2.2.3. Reallocation rule 3 When neither reallocation rule 1 or 2 could be applied to a member state, reallocation rule 3 was used to assign a corresponding ‘template country’. A template country was a country in which either reallocation rule 1 or 2 had already been applied. These template countries took the place of member states to which the first two reallocation rules could not be applied (Table 1): corCVXijc = UTijc  pcorCVXijt, where c refers to a given country and t to its corresponding template country. 2.3. Presented trends Age-standardisation was performed using the world standard population [11]. The last period considered did not always span 5 years for all member states due to the availability of data. For Germany, data were added from East and West Germany from 1973 to 1989, and thereafter data from the unified Germany were used. For the United Kingdom (UK), data from England, Wales, Northern Ireland and Scotland were combined. Join point regression [12] was used to analyse trends in age-standardised corpus uteri cancer mortality rates, as a linear function of year of death for all member states with available data. Join point regression identifies periods with distinct linear slopes that can be separated by join points, where the slope of the trend changes significantly [13,14]. Join point regression is Table 1 List of template countries used to correct data from countries where reallocation rules 1 and 2 did not apply. Template countries

Countries where reallocation rules 1 and 2 did not apply

Finland Hungary Lithuania The Netherlands

Sweden Bulgaria, Romania, Slovenia Estonia, Latvia Austria, Belgium, France, Germany, Greece, Italy, Luxemburg, Malta, Portugal, Spain Ireland, Northern Ireland, Scotland

England and Wales

Countries with >25% NOS or mixed codes (CRPNOS, CRPNOSTH). NOS: uterine cancer not otherwise specified (NOS). CRPNOS: combination of NOS and corpus uteri cancer. CRPNOSTH: combination of CRPNOS and other rare uterine cancers.

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not well suited to data with an autoregressive structure or periodic fluctuations, but is appropriate to identify abrupt or non-cyclical changes, which is the purpose of the current analysis. The maximum number of join points was set at three. For each linear segment, the average annual percentage of change and corresponding 95% confidence intervals (CIs) were calculated. Corpus uteri cancer mortality rates for 1970–1974 and 2000–2004 were compared. The period 1970–1974 was chosen because of the availability of data and the plausibility of the reallocation rules, both of which were more questionable before 1970. We plotted age-specific trends by 5-year period and the standardised cohort mortality ratio. The standardised cohort mortality ratio represents the relative risk of a certain birth cohort of dying from corpus uteri cancer compared to the mean mortality rate of all generations together [15]. It consists of the ratio of the number of observed deaths in a given cohort, k, over the number of expected deaths if the average age-specific mortality rates are applied to the respective age segments of the population in cohort k. The trends by birth cohort were plotted on a logarithmically (log10) scaled y-axis [16]. Corpus uteri cancer mortality rates that changed at a constant percentage by birth cohort are presented by a straight line on a log scale. 3. Results Fig. 1 shows the join point regression plots for the corrected age-standardised mortality rates. A substantial variation in these rates was observed across the EU member states considered. This variation was more evident in member states with data available from earlier periods (1950 and 1960), with a fourfold difference between Greece and Spain (which have low corpus uteri cancer mortality rates) and Austria, Hungary and Romania (which have high corpus uteri cancer mortality rates). Corpus uteri cancer mortality rates have been decreasing over time throughout the EU, with exception of Malta and Bulgaria, where rates increased; Greece where they have been stable throughout the study period; and Sweden, where they have been stable for the last 30 years, after a period of decrease. However, the magnitude of the decrease differed between member states, and was not linear in all of them. At the end of our study period (2005) corpus uteri cancer mortality rates approached 2 per 100,000 women in Austria, Belgium, Denmark, Finland, France, Germany, Hungary, Italy, Greece, Ireland, Luxembourg, the Netherlands, Slovenia, Spain and the UK. In other member states corpus uteri cancer mortality rates were twice as high, about 4 per 100,000 in several Eastern European countries and the Balkans, namely the Czech Republic, Estonia, Latvia, Lithuania, Poland, Romania, Slovakia; as well as – surprisingly – Sweden. Finally, Bulgaria, Malta and Portugal had a corpus uteri cancer mortality rate of between 2 and 4 per 100,000 (Fig. 1).

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Fig. 1. Corrected, world-age-standardised corpus uteri cancer mortality rates in 26 member states of the European Union. Dots represent annual rates; lines represent linear trends obtained by join point regression.

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During the study period, only Italy and the Netherlands showed a trend of linear decrease in corrected corpus uteri cancer mortality rates. Austria, Bulgaria, Germany, Hungary, Romania and Sweden presented a decrease–increase–decrease trend in corpus uteri cancer mortality rates. After a period of decreasing corpus uteri cancer mortality rates, Belgium and Finland showed increasing rates (Table 2). Fig. 2 shows the corrected age-standardised corpus uteri cancer mortality rates in 1970–1974 and 2000– 2004 (unless otherwise specified). Member states are ranked by decreasing corpus uteri cancer mortality rates in 2000–2004. When comparing the two time periods, corpus uteri cancer mortality rates decreased in all member states, with exception of Malta and Bulgaria where rates increased (from 2.3 to 3.1 per 100,000 and from 2.9 to 3.3 per 100,000, respectively). In 1970–1974, there was a threefold difference between the member states with the lowest and highest corpus uteri cancer mortality rates (6.9 in Romania compared to 2.0 in Greece). In 2000–2004, this difference was slightly narrower (4.8 per 100,000 in Romania and Slovakia compared to 1.7 in Ireland). It is remarkable that corpus uteri cancer mortality rates remained basically unchanged in Sweden (3.7 in 1970–1974 and 3.6 in 2000–2004) (Fig. 2). Fig. 3 shows standardised cohort mortality ratio plots for the corrected age-specific corpus uteri cancer mortality ratio by birth cohort. Corpus uteri cancer mortality decreased in all member states, although to different degrees, for all birth cohorts before 1940. There seemed to be a breaking point around 1940, after which trends in corpus uteri cancer mortality either became flat, or continued to decrease (Bulgaria, Hungary, Poland, Romania, Denmark, the UK, Ireland, Lithuania, Sweden, Greece, Italy, Malta, Portugal, Spain, Austria, Belgium, France, Germany, Luxemburg and the Netherlands), or began to rise (the Czech Republic, Slovakia, Estonia, Finland, Latvia and Slovenia) after remaining relatively flat for a few birth cohorts.

Table 2 Join points, i.e. years with distinct changes in linear trends, and corresponding 95% confidence intervals (CIs), and average annual percentage of change in each linear segment and its corresponding 95% CI. Region/country Eastern Europe Bulgaria

Join points

Annual percent change (95% CI)

1982 (1978–1988) 0.5 ( 1.4 to 0.4) 1993 (1986–2000) 3.3* (1.4 to 5.2) 1.4* ( 2.6 to 0.1)

Czech Republic

1998 (1995–2001) 0.8 ( 0.3 to 1.9) 3.2* ( 4.6 to 1.8)

Hungary

1990 (1983–1996) 2.2* ( 2.5 to 2.0) 1999 (1996–2001) 0.6 ( 1.5 to 2.6) 7.5* ( 10.7 to 4.1)

Poland

1965 (1962–1969) 7.1* (2.6 to 11.8) 1982 (1974–1987) 2.4* ( 3.2 to 1.5) 0.6* ( 1.0 to 0.2)

Romania

1986 (1981–1992) 2.6* ( 3.0 to 2.2) 2002 (1996–2005) 0.6 ( 0.4 to 1.7) 6.3* ( 10.1 to 2.4)

Slovakia

–

1.5* ( 2.8 to

0.2)

Northern Europe Denmark 1961 (1954–1966) 0.4 ( 1.7 to 2.6) 1967 (1963–1973) 5.2 ( 10.6 to 0.6) 0.8* ( 1.1 to 0.5) United Kingdom 1991 (1985–1993) 1994 (1993–1997)

1.7* (1.8 to 1.5) 8.5 ( 21.8 to 7.1) 3.0* (2.2 to 3.8)

Estonia

1993 (1991–1998) 2.0* (0.4 to 3.6) 2003 (1998–2006) 6.2* ( 8.4 to 3.8) 5.6 ( 0.9 to 12.5)

Finland

1986 (1981–1991)

1.7* ( 2.0 to 1.3) 0.8* (0.1 to 1.4)

Ireland

1975 (1969–1983) 2004 (1996–2005)

1.0* ( 1.5 to 0.5) 2.8* ( 3.3 to 2.4) 16.5* (0.6 to 34.8)

Latvia

–

0.1 ( 0.6 to 0.4)

Lithuania

–

1.0* ( 1.5 to

Sweden

4. Discussion Mortality statistics have been compiled for virtually all EU member states for several decades [6]. Mortality statistics are in general more comprehensive and complete than cancer incidence data reported by cancer registries. Furthermore, statistics on corpus uteri cancer incidence before 1970 may be inflated by the inclusion of endometrial hyperplasia and borderline endometrial lesions. These lesions were frequent, probably due to the use of unopposed oestrogens as hormone replacement therapy in several countries by a substantial number of peri- and postmenopausal women, notably in the original EU member states.

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0.5)

*

1967 (1964–1969) 5.4 ( 7.7 to 3.1) 1970 (1968–1975) 18.8 ( 30.6 to 103.5) 0.2 ( 0.7 to 0.4)

Southern Europe Greece 1978 (1972–1991) 0.2 ( 0.7 to 1.0) 1995 (1987–2001) 1.7* ( 2.5 to 0.8) 0.8 ( 0.3 to 1.8) 0.7* ( 1.0 to 3.5* ( 4.5 to 1.4* ( 2.6 to

0.4) 2.4) 0.2)

Italy

1978 (1960–1985) 1991 (1964–2001)

Malta

–

0.3 ( 0.6 to 1.1)

Portugal

1970 (1965–1978) 1990 (1983–1994)

0.2 ( 1.0 to 0.6) 2.2* ( 2.7 to 1.6) 0.4 ( 0.5 to 1.3)

Slovenia

1997 (1995–2001) 1.2 ( 0.5 to 3.0) 4.5* ( 6.3 to 2.6) (Continued on the next page)

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Table 2 (Continued) Region/country

Join points

Annual percent change (95% CI)

Spain

1973 (1966–1979) 0.6* (0.1 to 1.1) 1991 (1984–1996) 2.1* ( 2.8 to 1.5) 0.2 ( 0.6 to 1.1)

Western Europe Austria 1962 (1959–1963) 4.6* ( 6.6 to 2.6) 1965 (1963–1968) 5.4 ( 10.6 to 24.3) 2.2* ( 2.3 to 2.0) Belgium

1991 (1968–1996)

2.0* ( 2.2 to 1.8) 0.5 ( 1.9 to 3.0)

France

1983 (1973–1989) 1991 (1987–1996)

1.1* ( 1.4 to 0.9) 3.1* ( 5.5 to 0.7) 0.3 ( 0.5 to 1.0)

Germany

1961 (1954–1973) 1.9 ( 4.7 to 1.0) 1975 (1971–1980) 2.3* (0.8 to 3.8) 1.7* ( 2.1 to 1.3)

Luxembourg

–

The Netherlands 1969 (1962–1984) 1992 (1983–1997)

1.8* ( 2.3 to

1.2)

0.6 ( 1.2 to 0.0) 1.9* ( 2.4 to 1.5) 0.1 ( 0.8 to 0.6)

* Indicates that the magnitude of the annual percent change is statistically significantly different from zero (p < 0.05).

As corpus uteri cancer is mainly a postmenopausal disease, with a relatively high median age at diagnosis (around 66 years) and relatively good 5-year survival, it is probable that the full effect of the disease in cohorts born after 1940 has yet to be observed. This may also explain why trends in corpus uteri cancer mortality rates in some birth cohorts seem relatively unstable. Trends in corpus uteri cancer mortality rates are determined by corpus uteri cancer incidence and case fatality rate. Corpus uteri cancer survival is strongly influenced by tumour histology, stage, grade, age of the patient at the time of diagnosis [17] and probably by the capacity of the health care systems to diagnose and treat corpus uteri cancer in its early stages. The observed trends in corrected corpus uteri cancer mortality rates can be tentatively explained by changes in exposure to risk factors and the impact of treatment on survival. Most corpus uteri cancer are endometrial cancers; uterine sarcomas (leiomyosarcoma which originates from myometrial muscle, and mesodermal or Mu¨llerian and stromal sarcomas, both originating from the endometrial epithelium) represent less than 8% of all corpus uteri cancer [17]. Endometrial cancer has been broadly classified into two groups, based on somatic mutations that can be observed after histological examination. These mutations indicate different aetiologies, which can help to determine the pathogenesis and outcomes of the disease. Type 1 endometrial cancer is the most common, accounting for about 90% of cases; mainly adenocarcinomas of endometrioid origin. Type 1 endometrial cancer is considered to be

hormone-dependent, is usually diagnosed in early stages and has a relatively good prognosis. The main aetiology of type 1 endometrial cancer is increased levels of circulating oestrogens after menopause, which may be caused by overweight and obesity, as fat tissue acts as an oestrogen-producing organ. Other causes include use of exogenous hormones, in particular oestrogens unopposed by progestins in the peri- and postmenopausal period (common until the 1970s), type 2 diabetes mellitus and nulliparity. The association between lack of physical activity and endometrial cancer is probable, although it may be at least partially explained by the effect of physical inactivity on obesity [18]. Family history of endometrial cancer and some specific genetic predisposition traits are also associated with increased endometrial cancer risk. On the other hand, the risk of type 1 endometrial cancer decreases substantially with the use of oral contraceptives [19,20], increasing parity [21], late age at last birth [22] and coffee drinking, as coffee contains strong antioxidant properties [18]. Incidence of type 1 endometrial cancer in a population may vary according to the presence of risk factors, such as reproductive patterns, and the prevalence of overweight and obesity in postmenopausal women. Type 2 endometrial cancer (about 10% of all endometrial tumours) of non-endometrioid origin (including serous, clear cell and squamous cell carcinomas) is considered less hormone-dependent, is usually diagnosed in later stages, is generally more aggressive and has a poorer prognosis than type 1 endometrial cancer. Type 2 endometrial cancer shares many aetiological factors (increasing parity, oral contraceptive use, cigarette smoking, age at menarche and diabetes) with type 1 endometrial cancer [23]. Relative survival for these uncommon epithelial endometrial carcinomas and uterine sarcomas has not improved over past decades [24]. The decrease in corpus uteri cancer mortality rates in the EU during the last decades may be explained by a combination of factors affecting the incidence of type 1 endometrial cancer, mainly an increase in the use of oral contraceptives, a decrease in the use of unopposed oestrogen replacement therapy [25] and increasing access to early diagnosis and treatment. On the other hand, the increase of overweight and obesity in the general female population in the EU, and the decrease in levels of physical activity [26,27] and parity [28] should have increased these rates. However, as most endometrial cancer mortality is due to type 2 endometrial cancer, it is plausible that access to health care – both diagnostic services and treatment – is responsible for decreasing mortality rates. Endometrial cancer most commonly occurs after menopause. In the majority of women, postmenopausal bleeding leads to clinical investigation, and – in most cases – diagnosis of endometrial cancer in its early stages

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Fig. 2. Corrected, world-age-standardised corpus uteri cancer mortality rates in the European Union in 1970–1974 and 2000–2004 unless otherwise specified.

when surgical treatment is curative. This may explain the relatively low corpus uteri cancer mortality rates observed in the present study when compared to corpus uteri cancer incidence [17], which is showing increasing trend [29]. However, when diagnosed at advanced stages 5-year corpus uteri cancer mortality is high, comparable to pancreatic cancer, among others [17]. Improved cancer treatment has resulted in better survival in most European countries [30], and has contributed to the decrease in endometrial cancer mortality. Endometrial cancer is chemosensitive [31], and the more frequent use of chemotherapy, in particular in patients in advanced stages, has resulted in better survival. Moreover, progress in anaesthesiology may have led to more and safer surgery, especially in old and frail patients.

Endometrial cancer has very recently been reclassified into four categories by integrated genomic, transcriptomic and proteomic characteristics: POLE ultramutated, microsatellite instability hypermutated, copy-number low and copy-number high [32]. This integrated analysis provides key molecular insights into disease biology and diagnostic classification, which may orient treatment recommendations for patients, and provides opportunities for genome-guided clinical trials and drug development. Currently, endometrial cancer screening in the general population is not recommended, as the disease is relatively rare and generally occurs in older women. Another reason is that screening methods such as ultrasonography have a very low specificity and therefore cannot be used in asymptomatic populations [33,34].

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Fig. 3. Corrected corpus uteri cancer mortality in the European Union: standardised cohort mortality ratio (SCMR) by birth cohort with 95% confidence interval (interrupted line).

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In some countries, particularly in North America, hysterectomy is relatively common, and up to 30% of postmenopausal women may have had their uterus removed for a variety of reasons, including benign tumours or endometrial hyperplasia [35]. In the EU, hysterectomy rates vary by country (e.g. 1.8 in Denmark, 2.1 in Sweden, 3.6 in Germany, and 4.1 in Finland per 1000 women) and by calendar period [36–39], though they are substantially lower than those in the United States (5.5 per 1000 women, between 2000 and 2004) [35]. Hysterectomy rates before endometrial cancer diagnosis were not available for all EU member states, and therefore we cannot rule out underestimation of the true corpus uteri cancer mortality rates in the EU (as our denominator included a small proportion of women who were hysterectomised, and thus not at risk for endometrial cancer). In conclusion, corpus uteri cancer mortality rates are decreasing in the EU. The decrease is most evident for pre-1940 birth cohorts. Conflict of interest statement

[5]

[6]

[7]

[8]

[9] [10] [11]

[12]

[13]

None declared. [14]

Acknowledgements [15]

This study was supported by the Cancer Registry of Norway and the Belgian Foundation Against Cancer. The study sponsor had no role in the study design, in the collection analysis and interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication. The authors would like to thank to Mrs Margrethe Meo, Cancer Registry of Norway, for secretarial assistance, and Mrs Trudy Perdrix-Thoma for editorial help. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/ 10.1016/j.ejca.2014.02.020.

[16] [17]

[18]

[19] [20]

[21]

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