According to estimates by the International Agency for Research on Cancer (Ferlay et al., 2010), ovarian cancer ranks as the seventh most common cancer in women for both incidence and mortality worldwide, with an estimated (age-standardized) incidence of 6.3/100 000 women (225 000 new cases per year) and a mortality of 3.8/100 000 women (140 000 deaths per year) globally in 2008. The burden of ovarian cancer is more severe in developed countries, including Germany, where ovarian cancer ranks as the sixth most common cancer in women, with an incidence of 10.0/100 000 women (8711 new cases in 2008), and as the fifth most common cause of cancer death in women, with a mortality of 5.0/100 000 women (5486 deaths in 2008; Ferlay et al., 2010).
Ovarian cancer is associated with a fairly poor prognosis. Five-year RS estimates in the range of 31–42 and 16–51% have been reported for developed countries and developing countries, respectively (Sankaranarayanan and Ferlay, 2006). The prognosis of ovarian cancer has been shown to decrease markedly with age (Kosary, 1994; Gatta et al., 1998; Gondos et al., 2007). In addition, there are a number of factors specific to ovarian cancer that may have a major impact on prognosis. First, ovarian cancer comprises a heterogeneous group of tumors with more than 10 histologic subtypes (Lee et al., 2003; Kosary, 2007). Nevertheless, population-based studies providing survival data by histology have been sparse. Second, malignant ovarian carcinoma often occurs bilaterally (Boger-Megiddo and Weiss, 2005), but little is known about the prognosis of ovarian cancer patients according to laterality, especially when stratified by histology. Third, ovarian carcinoma is often diagnosed at an advanced stage and patients with distant metastases have a much worse prognosis compared with those diagnosed at a localized stage (Kosary, 2007; Hannibal et al., 2008; Hamidou et al., 2010).
To our knowledge, there is no population-based study providing survival estimates for ovarian cancer stratified by histology, laterality, and stage, as most studies, including the Surveillance, Epidemiology and End Results (SEER) Survival Monograph published in 2007 (Kosary, 2007), did not provide survival estimates stratified by laterality. Population-based survival data have been particularly sparse for Germany as they mostly relied on data from the Saarland Cancer Registry, covering only 1.3% of the total German population (Brenner et al., 2005).
In this article, we provide detailed (stratified by age, histology, laterality, and stage) population-based survival estimates of ovarian cancer patients in Germany based on a pooled German national database from 11 population-based cancer registries, covering 33 million inhabitants. Furthermore, we used standard and model-based period analysis (Brenner and Gefeller, 1996; Brenner et al., 2004; Brenner and Hakulinen, 2006; Gondos et al., 2008) to provide the most up-to-date estimates and trends of survival in the early 21st century.
Materials and methods
This analysis is based on a pooled German national dataset described in detail previously (Hiripi et al., 2012). Briefly, data from 11 German cancer registries (covering a population of 33 million residents) with estimated completeness greater than 90% in the period 2004–2006 were combined. Patients aged 15 years or older and diagnosed with malignant tumors during 1997–2006 were included. Follow-up with respect to vital status was performed until the end of December 2006.
The current analysis focuses on patients diagnosed with ovarian cancer (ICD-10 code: C56). According to the International Classification of Diseases for Oncology (Fritz et al., 2000) and the SEER Survival Monograph (Kosary, 2007), cancers were grouped into four major histologic groups: adenocarcinoma, carcinoma not otherwise specified (NOS), nonepithelial ovarian cancer (NEOC), and others (mixture). Adenocarcinoma can be further divided into 10 subtypes (adenocarcinoma NOS, papillary, clear cell, endometrioid, serous cystadenocarcinoma, cystadenocarcinoma, papillary serous cystadenocarcinoma, mucinous adenocarcinoma, mucinous cystadenocarcinoma, and other adenocarcinoma). NEOC can be further divided into two subtypes (stromal cell and germ cell). For more details about the histology and morphology codes and their frequencies in the analyzed dataset, please contact the corresponding author.
Laterality was divided into three categories (unilateral, bilateral, and unknown). Staging was formulated according to the recommendation of the International Federation of Gynecology and Obstetrics (FIGO; Kosary, 2007; http://en.wikipedia.org/wiki/Ovarian_cancer) using a variable indicating the grouped clinical stage with five categories, that is I (localized), II (local spread to the pelvic region), III (regional spread to the abdomen), IV (distant metastasis), and unknown. As the subgroup stage II included only 603 patients, FIGO stages I and II were combined into one group (I and II), equivalent to the stage of localized/local spread.
Period analysis (Brenner and Gefeller, 1996; Brenner et al., 2004) was used to derive the 5-year RS point estimates for 2002–2006. Period analysis provides more up-to-date survival estimates than the traditional cohort-based survival analysis by focusing exclusively on survival experience during the most recent time period for which data are available. This is achieved by left truncation of observations at the beginning of the period of interest. It has been shown by extensive empirical evaluations that period estimates of 5-year survival for a specific period closely predict 5-year survival later observed for patients diagnosed during that period (Brenner et al., 2002; Brenner and Hakulinen, 2002). Relative survival was calculated as the ratio of the observed survival in the group of ovarian cancer patients divided by the expected survival of a comparable group from the general population (Ederer et al., 1961). Expected survival was derived from life tables stratified by age, sex, calendar period, and federal states using the Ederer II method (Ederer and Heise, 1959).
Five-year RS was calculated by histologic subtypes for three major age groups (15–49, 50–69, and 70+ years) in analogy with the SEER Survival Monograph published in 2007 (Kosary, 2007). RS estimates were not reported if the standard errors exceeded 5 percent units. In addition, the age-adjusted 5-year RS was calculated for patient subgroups jointly defined by histology, laterality, and stage.
In addition to the ‘standard’ period analysis (Brenner et al., 2004), model-based period analysis (Brenner and Hakulinen, 2006; Gondos et al., 2008) was used to assess recent trends within the 2002–2006 period. Briefly, after calculating age group-specific numbers of patients at risk and of deaths by the year of follow-up for each single year between 2002 and 2006, a Poisson regression model for RS was fitted for the period between 2002 and 2006, in which the logarithm of the excess number of deaths was modeled as a function of the year of follow-up, age (categorical variables), and calendar year (numerical variable), using the logarithm of the person–years at risk as the offset (Brenner and Hakulinen, 2006; Gondos et al., 2008). Model-based estimates of 5-year RS for the first (2002) and the last year (2006) of the period and a P-value for the trend in RS between 2002 and 2006 were derived. An α-value of 0.05 was used as the level of significance for trend tests. Standard errors of the model-based 5-year RS estimates were calculated using the delta method.
Age adjustment for both the standard and the model-based period analysis was performed by deriving the weighted averages of age-specific 5-year RS estimates using the weights of five age groups (15–44, 45–54, 55–64, 65–74, and 75+ years) according to the International Cancer Survival Standards (Corazziari et al., 2004).
All calculations were performed using the SAS statistical software package (version 9.2; SAS Institute Inc., Cary, North Carolina, USA) using special macros for the period analysis as described in detail elsewhere (Brenner et al., 2002; Brenner and Hakulinen, 2006).
The basic characteristics of the dataset used in the current period analysis for ovarian cancer patients diagnosed in Germany from 1997 to 2006 are presented in Table 1. After the exclusion of 4681 patients (17.8%) notified by death certificate only (DCO) or by autopsy only and five patients (0.02%) without dates of diagnosis or death, 21 651 patients with a median age at diagnosis of 65 years were included in the analysis. In total, 94% of cases were microscopically confirmed. In terms of histologic subtypes, the majority of cancers (82%) were adenocarcinomas, and only 3% (602 cases) were NEOC. The distribution of histologic subtypes is generally similar among 11 registries, but larger proportions (>20%) in carcinoma NOS were reported from two registries (Hamburg and North Rhine-Westphalia). As the high percentage of cases without histologic confirmation in one cancer registry (Lower Saxony) and the high proportion of NOS carcinomas in two registries (Hamburg and North Rhine-Westphalia) may raise concerns on the validity of survival estimates, we carried out careful sensitivity analyses in which all survival analyses were repeated after the exclusion of these three registries. However, as the results remained essentially unchanged by these exclusions, all results are reported for analyses including all registries.
Table 2 shows the age-adjusted and age group-specific 5-year RS for the period 2002–2006 by histologic subtypes. Overall, the age-adjusted 5-year RS in 2002–2006 was 40.7%. Prognosis varied markedly by histology, with the age-adjusted 5-year RS ranging from 25.2% (carcinoma NOS) to 80.9% (stromal cell cancers). Overall, a strong age gradient was observed, with the 5-year RS decreasing from 66.9% in the age group 15–49 years to 28.4% in the age group 70+ years. Patients with NEOC had the best prognosis among all the age groups, with the 5-year RS close to 90% in the age group 15–49 years and greater than 80% in the age group 50–69 years. Patients with endometrioid and mucinous adenocarcinoma had more favorable survival than those with other subtypes of adenocarcinoma in all age groups.
Prognosis also varied markedly by laterality, with the overall age-adjusted 5-year RS reaching 45.7% for unilateral cancer and 31.6% for bilateral cancer (Table 3). For all histologic subtypes, survival of patients with unilateral cancer was superior to that of patients with bilateral cancer. Among patients with unilateral cancer, patients with stromal cell cancer had the best prognosis (84%), whereas those with adenocarcinoma NOS, papillary adenocarcinoma, and carcinoma NOS had a poor prognosis (5-year RS ranging from 29 to 35%); among adenocarcinomas, clear cell, endometrioid, and mucinous adenocarcinomas were associated with the most favorable prognosis (5-year RS around 60%). Among patients with bilateral cancers, a similar variation in prognosis by histologic subtypes was observed, albeit at substantially lower levels of 5-year RS.
The age-adjusted 5-year RS by histology and stage is presented in Table 4. Among the restricted dataset with complete information on stage (9192 cases), 39% of the patients were diagnosed with FIGO stage IV (distant metastasis). The prognosis varied markedly by stage, with the age-adjusted 5-year RS reaching 82.3% for FIGO stages I and II, 36.1% for FIGO stage III, and 17.5% for FIGO stage IV. The gradient in prognosis by tumor stage was less pronounced for patients with serous adenocarcinoma. In contrast to other histologic types, larger proportions in FIGO stages I and II and smaller proportions in FIGO stage IV were noted for both endometrioid and mucinous adenocarcinomas.
Table 5 shows the model-based age-specific 5-year RS in 2002 and 2006. Overall, we observed no improvement in survival between 2002 and 2006, with the 5-year RS reaching 43.3% in 2002 and 42.6% in 2006. Furthermore, no statistically significant improvement between 2002 and 2006 was observed in any of the age groups. For both calendar years, a similarly strong age gradient in the 5-year RS was observed.
Model-based age-adjusted 5-year RS estimates in 2002 and 2006 by histology, laterality, and stage are presented in Table 6. Significant improvement in the 5-year RS was not observed within the recent period between 2002 and 2006 for any of the subgroups assessed.
In this manuscript, we provide the most comprehensive analysis of survival for patients with ovarian cancer for Germany available to date. Overall, the age-adjusted 5-year RS in 2002–2006 was 40.7%. A strong age gradient was observed, with the 5-year RS decreasing from 66.9% in the age group 15–49 years to 28.4% in the age group 70+ years. Furthermore, the prognosis varied markedly with histologic subtypes, laterality, and stage, with the age-adjusted 5-year RS ranging from 25.2% (for carcinoma NOS) to 80.9% (for stromal cell carcinoma), reaching 45.7% for unilateral carcinoma and 31.6% for bilateral carcinoma and reaching 82.3% for FIGO stages I and II, 36.1% for FIGO stage III, and 17.5% for FIGO stage IV. No improvement in survival was observed within the 5-year period under investigation.
Our observation of a lack of improvement in the survival of ovarian cancer patients for the recent short period between 2002 and 2006 in Germany is consistent with the results from two large international studies with data from population-based cancer registries (Gondos et al., 2008; Coleman et al., 2011), which, similarly, did not show improvements in survival in the early 21st century. In the first study, no significant improvement in survival between 2000 and 2004 was observed in any of the 12 European countries under investigation. However, strong between-country variation was observed, with the 5-year RS ranging from 30 to 47% in 2004 (Gondos et al., 2008). The other study published in 2011 (Coleman et al., 2011) showed that survival remained rather stable (from the period 2000–2002 to the period 2005–2007) in Norway and Australia, although small increments in the 5-year RS (about 2 percent points) were observed in Denmark, UK, and Canada. Furthermore, no improvement in survival was also found in the USA in the period between 1998 and 2003 (Brenner et al., 2007). These recent trends are in contrast to observations from earlier periods. For example, according to the last comprehensive survival analysis for ovarian cancer patients from Germany (Brenner et al., 1999), the 5-year RS increased continuously from 28.8% in the period 1976–1980 to 39.4% in the period 1991–1995. For similar time periods, supporting evidence for an improvement in survival has also been reported from the SEER program in the USA (Barnholtz-Sloan et al., 2003). In addition, steady improvements in survival have also been reported for earlier decades (the 1950s–1980s) for other European countries (Balvert-Locht et al., 1991; Levi et al., 1993; Bjorge et al., 1998), which have generally been attributed to advances in therapy (e.g. debulking surgery, adjuvant platinum-based chemotherapy) and a trend toward earlier diagnosis because of the introduction of ultrasonography in the early 1980s (Balvert-Locht et al., 1991; Levi et al., 1993; Bjorge et al., 1998; Brenner et al., 1999).
Although explanations for the lack of improvement in survival for the recent period in the early 21st century cannot be derived from our study, it is plausible to assume that innovations in therapy for ovarian cancer in the early 21st century have not been translated into increasing survival at the population level yet. Furthermore, limited centralization of medical care during the period of investigation could be another reason (Cress et al., 2003; Du et al., 2005; Chan et al., 2008) as centralization of care has been shown to be an important prognostic factor (Tingulstad et al., 2003; Vernooij et al., 2007). In addition, unlike colorectal cancer and breast cancer (Gondos et al., 2007), so far, effective screening programs for ovarian cancer are not yet available (Bast et al., 2007; Buys et al., 2011).
Our observation of a strong declining survival with advancing age at diagnosis is consistent with the established literature (Kosary, 1994; Gatta et al., 1998; Brenner and Arndt, 2004; Gondos et al., 2007; Quaglia et al., 2009). The poor survival rates for ovarian cancer in the elderly might be attributable in part to less aggressive treatment (e.g. chemotherapy; Cress et al., 2003; Du et al., 2005), less utilization of specialist care (Carney et al., 2002), and a larger proportion of patients at an advanced stage on diagnosis (Kosary, 2007). In addition, elderly patients present a larger proportion of histologic subtypes with an unfavorable diagnosis (e.g. carcinoma NOS and adenocarcinoma NOS), as shown in our data. On comparing our results with data from the SEER Survival Monograph published in 2007 (Kosary, 2007), the overall 5-year RS estimates in all three age groups are lower in Germany than in the USA, and the differences between the two countries are more pronounced in the youngest age group (Kosary, 2007).
Our observation of a strong variation in survival by histologic subtypes is in agreement with findings of other studies (Kosary, 1994; Bjorge et al., 1998; Kosary, 2007; Hannibal et al., 2008), suggesting that ovarian cancer survival is related to histologic subtypes that have a distinct etiology. Although the etiology of ovarian cancer is not completely understood, the main underlying biological mechanism points to the changes in endogenous hormones (sex steroids and gonadotropins), especially during the perimenopausal period and after menopause (Gadducci et al., 2004; Lukanova and Kaaks, 2005). In addition, we observed that endometrioid and mucinous types had a better prognosis than serous types (serous cystadenocarcinoma and papillary serous cystadenocarcinoma), in agreement with findings of other studies (Levi et al., 1993; Kosary, 1994). Our finding of a favorable prognosis (overall 5-year RS of 56%) for patients with clear cell adenocarcinomas is also comparable with findings of previous studies from the USA based on the SEER database, showing an overall 5-year RS ranging from 51 to 64% (Kosary, 1994; Chan et al., 2008).
To our knowledge, this is the first population-based study to present survival estimates of ovarian cancer stratified concurrently by histology and laterality. Although two studies have addressed differences in survival by laterality (Roychoudhuri et al., 2006; Mahdi et al., 2011), one study was limited to germ cell cancers (Mahdi et al., 2011) and the other did not provide information on histology (Roychoudhuri et al., 2006). For all histologic subtypes, we observed a better survival in unilateral than in bilateral ovarian cancers, in agreement with the study (Mahdi et al., 2011) showing bilateral germ cell cancers to be more often associated with poor survival compared with unilateral ones.
We observed that patients in FIGO stages I and II had a much better prognosis than those in FIGO stage IV (82.3 vs. 17.5%), in agreement with the established literature (Brenner et al., 2007; Kosary, 2007; Hannibal et al., 2008; Hamidou et al., 2010). For endometrioid cancers, a favorable overall prognosis (56.0%) is likely because of their larger proportion (66.3%) in the localized stage, as supported by findings of other studies (Bjorge et al., 1998; Kosary, 2007). Furthermore, our observation of a 43.8% proportion in FIGO stages I and II is in agreement with findings of other studies (Carney et al., 2002), indicating that, theoretically, there may be a large potential for the detection of ovarian cancer at an earlier stage if reliable methods for early detection can be identified and established.
Our study has a number of strengths. First, to our knowledge, this is the first population-based study to present survival estimates of ovarian cancer patients stratified concurrently by histology and laterality. Second, this study was based on a large pooled German national dataset with a high degree of completeness of information on histology and laterality from 11 population-based cancer registries covering 33 million inhabitants. Third, this study provided the most up-to-date and comprehensive survival estimates of ovarian cancer in the early 21st century, using the techniques of standard and model-based period analyses.
The limitations of this study are mainly related to limited staging information. Although all registries provided staging information, there were 9192 cases (42.5%) with complete stage information. Thus, limited staging information in our study precluded further analysis stratified by stage and histology because of unstable point estimates for some histologic subtypes. Another limitation is that we did not have sufficiently detailed documentation of therapy to carry out additional analyses. This is a common limitation of data from epidemiological cancer registries as treatment details are seldom available in population-based cancer registries. Furthermore, the high proportion of NOS carcinomas in two registries and the high percentage of cases without histologic confirmation in one registry raise questions on the quality of data. However, sensitivity analyses showed that none of the results changed to any relevant extent after the exclusion of these three registries. Finally, the exclusion of cases with DCO may lead to overestimation of the 5-year RS estimates as DCO cases are known to have a poor prognosis and the inclusion of these cases results in reductions in the 5-year RS estimates, particularly for older patients and those with fatal cancers (Holleczek and Brenner, 2012).
Despite its limitations, our study provides the most comprehensive information on the 5-year RS of ovarian cancer patients in Germany reported so far, indicating that prognosis of ovarian cancer varied markedly by age, histology, laterality, and stage. In addition, we show that the improvement in the 5-year RS of ovarian cancer patients has been stagnating in the early 21st century. Optimization of the structure of medical care, more timely translation and dissemination of advances in therapeutic oncology to the population level, in particular including older patients, as well as progress in methods for early detection might potentially lead to an improvement in ovarian cancer survival in the 21st century.
Members of the GEKID Cancer Survival Working Group: Karla Geiss, Martin Meyer (Cancer Registry of Bavaria), Andrea Eberle, Sabine Luttmann (Cancer Registry of Bremen), Roland Stabenow (Cancer Registry of Berlin and the New Federal States), Stefan Hentschel, Alice Nennecke (Hamburg Cancer Registry), Joachim Kieschke, Eunice Sirri (Cancer Registry of Lower Saxony), Bernd Holleczek (Saarland Cancer Registry), Katharina Emrich (Cancer Registry of Rhineland-Palatinate), Hiltraud Kajüter, Volkmar Mattauch (Cancer Registry of North Rhine-Westphalia), Alexander Katalinic (Cancer Registry of Schleswig-Holstein), Klaus Kraywinkel (Robert Koch Institute, Berlin), Hermann Brenner, Lina Jansen, Adam Gondos (DKFZ).
This study was funded by German Cancer Aid (Deutsche Krebshilfe), 108257. Tianhui Chen’s work was supported in part by the Fundamental Research Funds for the Central Universities, China. The sponsor had no role in the study design, collection, analysis, or interpretation of data.
Conflicts of interest
There are no conflicts of interest.
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