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Trends in breast cancer survival in Germany from 1976 to 2008—A period analysis by age and stage
Cancer Epidemiology 35 (2011) 399–406
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Trends in breast cancer survival in Germany from 1976 to 2008—A period analysis by age and stage Bernd Holleczek a,*, Volker Arndt b, Christa Stegmaier a, Hermann Brenner b a b
Saarland Cancer Registry, Pra¨sident Baltz-Straße 5, 66119 Saarbru¨cken, Saarland, Germany German Cancer Research Center, Division for Clinical Epidemiology and Aging Research, Bergheimer Straße 20, 69115 Heidelberg, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 November 2010 Received in revised form 10 January 2011 Accepted 18 January 2011 Available online 5 April 2011
Background: Implementation of mammography screening and advances in breast cancer treatment are considered as main reasons for the decline in breast cancer mortality observed in many industrialized countries during the past two decades. The purpose of this study was to provide a comprehensive assessment of trends in breast cancer incidence, mortality and survival by age and stage in Germany. Methods: Data from the population based Saarland Cancer Registry including patients diagnosed with breast cancer from 1972 to 2007 were used. Period analysis methods were employed to calculate 5-year relative survival and its trends. Results: Mortality started to decline during the 1990s, and a previous increase in incidence levelled off in the early 21st century. Overall age-standardized 5-year relative survival of invasive breast cancer steadily increased during the past three decades to 83% in 2004–2008. This increase was mostly due to an increase in survival for patients with localized cancers and locally or regionally spread tumours (increase of age-standardized 5-year relative survival from 92% to 98% and from 65% to 80%, respectively, between 1992 and 2008), whereas age-standardized 5-year relative survival essentially remained unchanged at levels close to 21% in patients with metastasized cancer. For women aged 70 years or older 5-year relative survival and its increase over time were inferior compared to younger patients. Conclusions: The observed trends in population based survival suggest that advances in treatment of early breast cancer have substantially contributed to the gain in prognosis. The poor prognosis of metastasized breast cancer patients and the increasing age gradient in 5-year relative survival call for enhanced efforts for early detection and more rigorous treatment of elderly patients. ß 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Survival Population based cancer registry Screening Treatment
1. Introduction Breast cancer (BRC) is the most frequent cancer in women. Overall, 421,000 new cases and 129,000 deaths were estimated for Europe in 2008 [1]. Whereas BRC incidence has increased in industrialized countries during recent decades, mortality has declined over the past two decades [2], most probably as a result of screening activities and improved treatment [3,4]. Likewise, population based studies on BRC survival from Germany, other European countries and the US have demonstrated ongoing improvement of 5-year relative survival during the past two decades [5,6]. Prolongation of cancer survival may have two principal causes: firstly anticipation of tumour diagnosis (resulting in earlier stages with more effective treatment options available) and secondly, improved survival as a result of advances in cancer treatment. To better understand the underlying mechanisms for the observed improvements in cancer survival, close monitoring of
population-based stage specific survival analysis is essential. However, to our knowledge stage specific survival has been reported only for singular calendar periods [7,8]. Given the demographic aging observed in many developed countries, it is also relevant to assess whether all age groups benefit from the aforementioned progress in cancer care as age related differences in cancer care with subsequent inferior outcome for older cancer patients have been reported for many countries [9–11]. In this article, we aimed to assess most recent 5-year relative survival of patients with invasive BRC and precedent trends stratified by age and tumour stage in Saarland (Germany). Patterns are discussed along with BRC incidence (including in situ tumours) and mortality in the context of screening activities and advances in treatment of primary invasive BRC. 2. Materials and methods 2.1. Database
* Corresponding author. Tel.: +49 681 501 5805; fax: +49 681 501 5998. E-mail address: [email protected] (B. Holleczek). 1877-7821/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2011.01.008
This study used data from the population based Saarland Cancer Registry and included all female patients aged 15 years and older
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diagnosed with a first invasive BRC (ICD-10 code: C50) between 1972 and 2007 (n = 23,245). Incidence data of in situ tumours of the breast (ICD-10 code: D05) were provided after 1988 (n = 817). The registry covers the population of the Saarland, a federal state (1.04 million inhabitants) in South-Western Germany. The incidence data are based on notifications from pathology laboratories, hospitals, radiotherapy departments, outpatient clinics and general practitioners. Population data for calculating incidence and mortality, as well as mortality follow-up of cancer patients for calculating survival, including date and cause of death based on information from death certificates, were provided by the state statistical office. Mortality follow-up was available until December 31, 2008. To correct follow-up information for missed deaths and migration out of the registry area, linkage with administrative population registries was carried out for all patients considered survivors at the end of 2008. Patients for whom such linkage was not successful were categorized as lost to follow-up and excluded from survival analyses. The following items were used for survival analysis: month and calendar year of diagnosis, age, summary stage of cancer at diagnosis (categories: ‘localized’ (T1-3N0M0 tumours), ‘local/regional spread’ (nodal positive and T4 tumours without involvement of distant sites), ‘distant metastasis’ (any metastasized tumour), ‘unknown extent’ (if staging information was incomplete)) based on reported summary stage or available TNM categories (5th revision) and information whether a cancer was notified by ‘death certificate only’ (DCO). Clinical extent of disease was used if there was no pathological stage available. Patients were grouped into three age categories (15–49, 50–69 and 70 years and above). 2.2. Statistical analyses Age-standardized rates (ASR) and truncated age-standardized rates (TASR; age categories 15–49, 50–69 and 70 years or older) using the Europe standard population were derived for incidence of invasive and in situ tumours and BRC mortality for successive calendar periods of four years until 2007.
Descriptive analyses of patients with invasive BRC were performed for subsequent calendar periods of four years between 1972 and 2007 with regard to age, size of primary tumour and summary stage, microscopic confirmation, follow-up status and number of DCO cases. Relative survival, which does not require knowledge of the cause of death and which may be interpreted as disease specific survival within a cancer patient population was derived as ratio of observed survival and expected survival for persons in the general population similar to the cancer patients with respect to sex, age and calendar period of observation [12]. Counts of deaths and populations up to the age of 89 years since 1970 were used to build life tables [13] to obtain expected survival probabilities by age for successive calendar periods of 5 years. Survival probabilities for patients aged from 90 to 99 years were projected using the Coale–Kisker model for mortality rates at high ages [14,15]. Expected survival was calculated according to the Ederer II method [16]. All estimates of relative survival are period estimates, which are derived from survival of cancer patients observed within defined calendar periods [17]. Period estimates have shown to closely predict survival observed for patients diagnosed in the period of investigation [18,19]. As follow-up was more up-to-date than registration of incident cases, a modified period analysis approach, called hybrid analysis was used [20]. Estimates of 5-year relative survival were derived for successive calendar periods of four years by age category (starting 1976) and extent of disease (starting 1992; stage information was reasonably complete (>70%) since 1988). Fig. 1 shows data used for 5-year relative survival estimation by calendar year of diagnosis and follow-up. In addition to crude estimates, agestandardized relative survival using weights from the International Cancer Survival Standards (ICSS) [21,22] and stage-mix adjusted relative survival (weights derived from all patients diagnosed between 1988 and 2007 based on stage categories used) were calculated. Standard errors of survival estimates are based on Greenwood’s formula [23,24]. Average annual percentage change
Fig. 1. Data use for estimating 5-year relative survival using a hybrid period analysis approach. The numbers within the cells indicate the years of follow-up since diagnosis.
B. Holleczek et al. / Cancer Epidemiology 35 (2011) 399–406
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Fig. 2. Trends of age-standardized breast cancer incidence (ICD-10: C50 and D05) and mortality (ICD-10: C50) in women in Saarland from 1976 to 2007. The Europe standard population was used for age standardized (ASR) and truncated age-standardized rates (TASR).
(AAPC) of 5-year relative survival was estimated. 619 patients lost to follow-up were excluded from the survival analyses, as were 615 DCO cases. To test for linear trend in relative survival, Poisson regression models for relative survival were fitted modelling the logarithm of the excess number of deaths as a linear function of follow-up year (categorical variable), age group (categorical variable) and calendar period (numeric variable) including the logarithm of person time as offset [25,26]. The reported p-value is based on the Wald test for inclusion of calendar period as explanatory variable. For data preparation and analysis, the R Language and Environment for Statistical Computing (release 2.8.0; R Foundation for Statistical Computing, Vienna, 2009) and add-on package ‘periodR’ (release 1.0-5) [27] were used. 3. Results Trends of BRC incidence (invasive and in situ tumours) and mortality are plotted in Fig. 2. During the study period, incidence of invasive BRC has increased by approximately 50%, but levelled off during the last two calendar periods (in 2004–2007 ASR and TASR were 111 (all ages), 55 (age 15–49 years), 282 (age 50–69 years) and 314 (age 70 years or older) new cases per 100,000 person years respectively; left plot). The median age at diagnosis has increased from 61 to 64 years since 1976. Incidence of in situ tumours has almost tripled since the 1990s with strongest increase seen for women aged 50–69 years (most recent ASR and TASR were 8 (all ages), 6 (15–49 years), 19 (50–69 years) and 14 (70 years or older) cases per 100,000 person years respectively; plot in the centre). BRC mortality started to decrease slightly for all age groups in the mid 1990s (most recent ASR and TASR were 29 (all ages), 7 (15–49 years), 70 (50–69 years), 148 (70 years or older) deaths per 100,000 person years; right plot). The median age at death increased from 65 years to 71 years. The overall number of patients with invasive BRC has almost doubled over the study period (Table 1). Most recently, 19% of the patients were younger than 50 years, 47% were 50–69 years old
and 34% were 70 years or over. Between 1972 and 2007, the proportion of patients with incomplete staging information decreased from 45% to 23%. In 2004–2007, the proportions of patients with cancers staged ‘localized’, ‘local/regional spread’ and ‘distant metastasis’ were 49%, 42% and 9% respectively. The proportion of T1 tumours increased from 33% in 1988–1992 to 46% in the most recent calendar period (T2: 40%, T3: 6%, T4: 8%; proportions among cancers with known tumour size). Almost all cancers were microscopically verified. The overall proportion of patients lost to follow-up was 3% (increasing with time since diagnosis) and 3% of the registered cancers were DCO cases. Overall and age group specific 5-year relative survival has steadily increased since 1976 by approximately 20% points (pvalues <0.001; Table 2). Overall age-standardized 5-year relative survival was 83% in 2004–2008, but survival remained inferior for patients aged 70 years or older (75%) compared to younger patients (88%). This difference has grown to 13% points and almost doubled since the 1990s. Five-year relative survival stratified by stage and age and adjusted for stage-mix between 1992 and 2008 is presented in Table 3. Most recent age-standardized 5-year relative survival for localized, locally/regionally spread and metastasized BRC was 98%, 80% and 22% respectively. The overall increase of survival was highest for patients with locally/regionally spread cancers (15% points; AAPC 1.8%; p-value <0.001) and intermediate for localized tumours (6% units; AAPC 0.6%; p-value <0.001), If localized cancers were subdivided into T1 and T2–3 tumours, age-standardized 5year relative survival was 104% for tumours equals or less than 2 cm in greatest dimension in the most recent calendar period (increase of 6% points; AAPC 0.5%) and 92% for tumours with more than 2 cm in greatest dimension (increase of 4% points; AAPC 0.3%; p-value 0.008). No improvement was observed for patients with metastasized BRC (1% unit; p-value 0.366). Stage-mix adjusted survival increased from 74% to 83% (p-value <0.001) and was almost identical to crude and age-standardized overall survival. Survival of elderly patients (70 years or older) with nonmetastasized BRC improved to a lesser extent compared to
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Table 1 Characteristics of female breast cancer patients (ICD-10: C50) from Saarland diagnosed between 1972 and 2007 for successive calendar periods. Category
Age 15–49 years 50–69 years 70 years
1972–1975
1976–1979
1980–1983
1984–1987
1988–1991
1992–1995
1996–1999
2000–2003
n
n
n
n
n
n
n
n
%
1848
450 974 424
%
1966
24.4 52.7 22.9
435 994 537
%
2090
22.1 50.6 27.3
473 942 675
%
2218
22.6 45.1 32.3
484 958 776
%
2497
21.8 43.2 35.0
Tumour size Available T1a T2a T3a T4a
%
2785
%
3081
%
3348
2004–2007 n
%
3412
502 1176 819
20.1 47.1 32.8
544 1256 985
19.5 45.1 35.4
603 1398 1080
19.6 45.4 35.1
601 1592 1155
18.0 47.6 34.5
646 1611 1155
18.9 47.2 33.9
1881 614 889 122 256
75.3 32.6 47.3 6.5 13.6
2362 854 1054 141 313
84.8 36.2 44.6 6.0 13.3
2791 1061 1244 165 321
90.6 38.0 44.6 5.9 11.5
3121 1305 1285 171 360
93.2 41.8 41.2 5.5 11.5
3014 1387 1211 171 245
88.3 46.0 40.2 5.7 8.1
Extent of disease Available Localizeda Local/regional spreada Distant metastasisa
1021 275 575 171
55.2 26.9 56.3 16.7
967 243 559 165
49.2 25.1 57.8 17.1
1420 487 719 214
67.9 34.3 50.6 15.1
1253 414 657 182
56.5 33.0 52.4 14.5
1755 670 876 209
70.3 38.2 49.9 11.9
2224 967 1031 226
79.9 43.5 46.4 10.2
2547 1161 1141 245
82.7 45.6 44.8 9.6
2960 1458 1223 279
88.4 49.3 41.3 9.4
2636 1284 1118 234
77.3 48.7 42.4 8.9
Microscopical confirmation Lost to follow-up DCO notified
1726 114 63
93.4 6.2 3.4
1820 114 85
92.6 5.8 4.3
1960 46 73
93.8 2.2 3.5
2112 44 52
95.2 2.0 2.3
2339 58 88
93.7 2.3 3.5
2656 45 69
95.4 1.6 2.5
2984 65 52
96.9 2.1 1.7
3249 77 48
97.0 2.3 1.4
3312 56 85
97.1 1.6 2.5
Annotations/abbreviations: DCO, death certificate only. a Proportions among patients with available information.
B. Holleczek et al. / Cancer Epidemiology 35 (2011) 399–406
Overall
Calendar period of diagnosis
1.0 1.0 0.9 1.1 1.0 1.0
AAPC
0.9 1.0 1.4 1.0 0.8 2.1 Annotations/abbreviations: RS, relative survival (period estimate); SE, standard error; AAPC, average annual percentage change. a Difference in percentage points between last and first calendar period. b Using weights from the International Cancer Survival Standards [22].
SE RS
84.1 82.9 87.8 88.4 88.3 74.7 0.9 1.0 1.6 1.1 0.9 2.1 1.0 1.1 1.8 1.3 1.0 2.2 77.1 76.3 78.8 79.1 79.0 73.4 1.1 1.2 2.0 1.4 1.2 2.5 73.2 72.5 75.6 74.5 74.8 69.7 1.2 1.3 2.1 1.5 1.2 2.7 71.4 71.0 75.2 71.7 72.7 68.4 1.2 1.4 2.1 1.7 1.3 2.8 69.4 69.3 72.7 68.3 69.8 68.9 1.3 1.6 2.3 1.8 1.4 3.2 65.5 64.5 70.8 65.2 67.1 61.6 1.3 1.7 2.4 1.7 1.4 3.6 63.8 61.4 66.5 65.9 66.0 55.7 Crude Age-standardizedb 15–49 years 50–69 years 15–69 years 70 years
SE
4. Discussion
79.6 78.7 83.5 81.5 82.0 74.3
SE
2000/1–2004
RS SE
1996/7–2000
RS SE
1992/3–1996
RS SE
1988/9–1992
RS SE
1984/5–1988
RS RS
SE
1980/1–1984 1976/7–1980
RS
2004/5–2008
20.3 21.4 21.2 22.5 22.2 19.0
Differencea Calendar period Age
Table 2 Five-year relative survival of female breast cancer patients (ICD-10: C50) from Saarland by age for successive calendar periods between 1976 and 2008.
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younger patients (differences in increase of survival were 6 and 9% points respectively for localized and locally/regionally spread BRC; AAPC: 0.2 and 1.2%; p-values 0.312 and 0.080). The differences in 5year relative survival between elderly patients and younger ones thus increased to 2 and 14% points in the most recent calendar period. Among patients with metastasized BRC, a substantial increase in survival was observed only for patients below the age of 50 years. Their survival increased by 14%26% in 2004–2008 (AAPC 6.9%; pvalue 0.058). For patients older than 50 years no improvement was seen (relative survival was 25% and 15% respectively in the most recent calendar period; p-values 0.547 and 0.986). Age-standardized 5-year relative survival of patients for whom stage information was incomplete was 84% in 2004–2008, with an increase of 6% points since 1992 (AAPC 0.3%; p-value 0.081). Among these patients, a substantial improvement in survival was only observed for patients below the age of 50 years (increase by 18% units to 97%; AAPC 2.0%; p-value 0.013).
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001
p-Value
B. Holleczek et al. / Cancer Epidemiology 35 (2011) 399–406
In this population based study from Germany, age-standardized overall 5-year relative survival of BRC patients has steadily increased since 1976 (increase of 21% points to 83% in 2004– 2008). Prognosis was most favourable for localized BRC (overall increase of 6% points since 1992–1998%). Most overall improvement was observed for locally or regionally spread BRC (increase of 15% units to 80%). No improvement was observed for metastasized BRC (survival was 22% in 2004–2008). For women aged 70 years or older both most recent 5-year relative survival and its increase over time were inferior compared to younger patients. Compared to other European countries, Saarland was ranking middle in terms of overall BRC survival and its improvement between 1990 and 2004 (overall range of 5-year relative survival across 11 European countries in 2000–2004: 70–87% vs. 80% in Saarland) [6,28]. In a recent comparison of BRC survival between the US population covered by SEER registries and Saarland, higher 5year relative survival was found for the US during 2000–2002 (crude survival in the US was 99, 83 and 28% respectively for patients with localized, locally/regionally spread and distant BRC) [7]. The increase of BRC survival seen during the past decades has been primarily attributed to introduction of mammography screening and advances in adjuvant treatment [3,4]. During the study period, only opportunistic screening was available (organised screening started in Saarland at the end of 2006). Besides its effect on stage distribution and survival, mammography screening should also affect incidence and mortality. Widespread adoption of mammography screening correlates with an increase of incidence of in situ tumours [29–31]. The ASR of in situ tumours increased by 180% points since end of the 1990s and a major rise was observed for the target group for screening (women aged 50–69 years). The overall proportion of in situ neoplasms among all BRC increased from 3% to 6% (data not shown in tables). Our data further demonstrated a continuous increase of the proportion of T1 tumours from 33% to 46% (among cancers with available information on tumour size) since the 1990s. This shift towards smaller tumours could be interpreted as visible effect from improved BRC early detection (resulting from not only screening activities, but also improved diagnostic processes and raised BRC awareness in the population). The observed incidence trends of invasive BRC most probably reflect an interaction of trends in ‘traditional’ risk factors and effects of opportunistic mammography screening [2]. Most recently, the incidence rates have levelled off or even dropped, possibly a result from changes in prescription of hormone replacement therapy [32–34].
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Table 3 Five-year relative survival of female breast cancer patients (ICD-10: C50) from Saarland by age and stage for successive calendar periods between 1992 and 2008. Stage
Age
Differencea
Calendar period 1992/3–1996
1996/7–2000
2000/1–2004
2004/5–2008
RS
SE
RS
SE
RS
SE
RS
AAPC
p-Value
SE
Crude Age-standardizedb Stage-mix adjustedc
73.2 72.5 74.3
1.1 1.2 1.1
77.1 76.3 77.5
1.0 1.1 1.0
79.6 78.7 78.9
0.9 1.0 1.0
84.1 82.9 83.3
0.9 1.0 0.9
11.0 10.3 9.0
1.1 1.1 0.9
<0.001 <0.001 <0.001
Localized
Crude Age-standardizedb 15–49 years 50–69 years 15–69 years 70 years T1 tumours age-standardizedb T2–3 tumours age-standardizedb
91.0 91.8 87.3 91.8 90.3 93.7 97.5 88.7
1.5 2.1 2.5 1.8 1.5 4.6 3.3 3.3
93.3 94.4 91.9 91.8 91.8 98.7 98.7 94.1
1.2 1.7 1.9 1.5 1.2 3.6 2.4 2.9
95.7 96.7 93.1 95.2 94.6 99.3 99.2 93.6
1.0 1.4 1.6 1.2 0.9 2.9 2.2 2.2
97.7 98.2 95.5 99.3 98.2 95.8 103.5 92.3
0.9 1.3 1.4 0.9 0.7 3.0 1.6 2.3
6.7 6.4 8.1 7.4 7.9 2.1 6.0 3.6
0.6 0.6 0.7 0.7 0.7 0.2 0.5 0.3
0.002 <0.001 0.012 0.001 <0.001 0.312 – 0.008
Local/regional spread
Crude Age-standardizedb 15–49 years 50–69 years 15–69 years 70 years
65.4 64.7 70.7 65.4 67.0 61.8
1.9 2.1 3.4 2.5 2.0 4.1
70.7 70.1 71.8 72.2 72.0 67.8
1.7 1.9 3.1 2.2 1.8 3.7
76.2 75.0 80.1 77.7 78.4 70.2
1.5 1.8 2.7 1.9 1.6 3.7
81.7 79.8 82.4 86.9 85.6 71.7
1.5 1.7 2.7 1.7 1.4 3.6
16.3 15.1 11.7 21.6 18.7 9.9
1.9 1.8 1.4 2.4 2.1 1.2
<0.001 <0.001 0.006 <0.001 <0.001 0.080
Distant metastasis
Crude Age-standardizedb 15–49 years 50–69 years 15–69 years 70 years
20.4 20.6 11.5 25.0 21.9 17.6
3.1 3.0 5.8 4.4 3.7 6.1
21.8 21.7 17.8 24.4 23.7 19.4
3.0 2.9 8.9 4.3 3.9 4.7
18.4 18.2 23.1 20.9 21.5 13.5
2.6 2.5 7.2 3.8 3.4 3.8
20.8 21.6 25.8 25.3 25.3 14.6
2.9 2.8 9.3 4.4 4.0 4.0
0.4 1.0 14.3 0.3 3.4 2.9
0.3 0.1 6.9 0.3 0.9 2.2
0.372 0.366 0.058 0.574 0.180 0.986
Unknown extent of disease
Crude Age-standardizedb 15–49 years 50–69 years 15–69 years 70 years
78.2 78.2 78.5 83.7 82.3 73.7
2.5 2.4 4.7 3.2 2.6 4.5
81.9 82.7 78.0 92.8 88.0 76.3
2.7 2.5 5.2 2.8 2.6 4.8
75.0 75.8 92.2 79.8 82.8 69.9
3.5 3.1 5.1 4.7 3.8 5.1
82.8 83.9 96.8 87.8 90.4 74.8
2.6 2.2 2.1 2.7 2.1 4.5
4.6 5.6 18.3 4.1 8.1 1.1
0.2 0.3 2.0 0.0 0.6 0.1
0.227 0.081 0.013 0.673 0.090 0.599
Annotations/abbreviations: RS, relative survival (period estimate); SE, standard error; AAPC, average annual percentage change. a Difference of relative survival in percentage points between last and first calendar period. b Using weights from the International Cancer Survival Standards (ICSS) [22]. c Weights derived from all cancer patients diagnosed 1988–2007.
B. Holleczek et al. / Cancer Epidemiology 35 (2011) 399–406
Overall
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Due to lack of detailed information on the method of first detection, the effect of screening on BRC survival could not be assessed directly from the data. However, the steady and similar increase of 5-year relative survival observed across all strata of age and stage, the similarity of the increase in crude, age-standardized and stage-mix adjusted survival and improvements found for localized T1 and T2–3 tumours do suggest substantial effects of improved treatment on BRC survival. Major advances in BRC treatment during the study period included propagation of breast conserving surgery followed by radiotherapy as effective local treatment for early stage BRC, sentinel node dissection, new agents for chemotherapy and antiestrogen treatment, introduction of targeted biologic agents (e.g. trastruzumab) and combination of these agents according to the patient’s risk of recurrence. Treatments have also become available for a broader range of patients who before had fewer treatment options. Due to lack of therapy data in routine population-based cancer registration, the impact of specific treatments on increases in survival could not be observed directly. The gap and the less pronounced increase in survival among elderly patients [28,35,36] may be explained by co-morbidity and differences in the delivery of cancer care (e.g. delay in seeking medical care and impact of co-morbidity on selection of cancer treatments [11], lower likelihood of receiving adjuvant radiotherapy and systemic chemotherapy compared to younger patients, even when diagnosed with less advanced tumours [10,37,38]). It is striking that overall 5-year relative survival of patients with metastasized BRC has not improved since the 1990s. Interim changes in the treatment of metastasized BRC (mainly systemic treatment options) which have become more and more costly [39,40] are not reflected on a population level. Only patients younger than 50 years have benefited from a substantial improvement of prognosis. Here, reasons might be differences in tumour characteristics as well as provision of palliative treatment. This population based study has a number of strengths and limitations. The strengths include use of incidence data with a high level of completeness and validity of case ascertainment, cancer diagnosis and follow-up which were available for a period of more than 30 years. The completeness of registration of the registry is estimated above 95% [41]. Almost all tumours were microscopically verified. The proportion of DCO cases was rather small (overall 3%) due to trace-back activities to obtain clinical information for death certificate notified cases. Linkage of all patients considered to be survivors at the end of 2008 with administrative population registries ensured complete mortality follow-up. Limitations are mainly related to the limited availability of clinical data. Stage information was incomplete for more than 40% of the patients prior to 1987. We restricted stage stratified analyses to the time after 1992, as stage information was available for at least 77% of the patients diagnosed since 1988. The somewhat increased proportion of missing values in the most recent calendar period was probably due to delay in reporting from clinical sources. Data on the usage of opportunistic mammography screening over time were not available for individual patients or on a population level. Although rather crude, the staging scheme used allowed firstly to analyze the prognosis of three rather distinct groups of BRC patients with regard to treatment options and secondly best possible use of available information on stage. We additionally categorized localized cancers as either T1 or T2–3 (for calendar years right after 1992 not all localized cancers could be categorized this way as for some only a summary stage was available) and provided trends of agestandardized 5-year relative survival for patients with these cancers to account for stage shift. Survival of each of these patient groups improved over time possibly resulting from better treatment, but improved early detection and screening and stage shifts even within those categories could still have made some contribution to the
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observed trends. The fact that relative survival exceeded 100% for T1 cancer patients in the most recent period, which indicates lower mortality for this group of patients than in women from the general population also points to potential overrepresentation of more health conscious women with increased awareness and utilization of breast cancer early detection in this group. Along with increased registration of stage information, its accuracy might have improved as well due to more sensitive diagnostic methods. In the interpretation of stage specific survival trends, the possibility of stage migration, i.e. a shift of classification towards more advanced stages as a result of more sensitive diagnostic procedures has to be kept in mind [42]. Due to the restricted collection of clinical information, the analyses could not include further determinants of prognosis beyond age and stage such as the method of first detection or differences in the provision of cancer care, socio-economic status or co-morbidity. Despite its limitations, the study disclosed patterns of 5-year relative survival of BRC patients which allow to judge progress that has been reached so far. Although improved early detection in general and increased use of mammography screening in particular have certainly contributed to the increase of survival, the observed trends suggest advances in BRC treatment as an important cause for the gain in prognosis. Our findings have a number of important implications. In contrast to localized and locally or regionally spread BRC, patients with metastasized BRC aged 50 years or older did not benefit from improved survival despite interim advances in treatment options. For these patients, the health care systems are faced with an increasing discrepancy between rapidly increasing expenditures on late stage BRC treatment and its impact on survival on the population level. A further shift towards earlier stages with more effective treatment options and further reduction in mortality will hopefully be reached with implementation and widespread use of effective screening. Widening age gradients in relative BRC survival indicate discrepancies in the provision of cancer care among elderly patients who did not benefit from advances in BRC treatment to the same extent as younger ones. Clinicians, researchers and politics need to address these issues, i.e. continue implementation of effective early detection programs and combat inequalities in delivery of BRC care – an issue which will become even more salient with ongoing demographic changes. Conflicts of interest None declared. Acknowledgements This work was supported in part by the German Cancer Aid (grants 70-3166-Br 5, 108257 and 108761). The German Cancer Aid had no role in the design, the data collection, the analysis, the interpretation of the results, the writing of the manuscript, or in the decision to submit the manuscript. References [1] Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010;46(4):765–81. [2] Botha JL, Bray F, Sankila R, Parkin DM. Breast cancer incidence and mortality trends in 16 European countries. Eur J Cancer 2003;39(12):1718–29. [3] Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005;353(17):1784–92. [4] Elmore JG, Armstrong K, Lehman CD, Fletcher SW. Screening for breast cancer. JAMA 2005;293(10):1245–56. [5] Sant M, Allemani C, Berrino F, Coleman MP, Aareleid T, Chaplain G, et al. Breast carcinoma survival in Europe and the United States. Cancer 2004;100(4):715–22.
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Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Trends in breast cancer survival in Germany from 1976 to 2008—A period analysis by age and stage Bernd Holleczek a,*, Volker Arndt b, Christa Stegmaier a, Hermann Brenner b a b
Saarland Cancer Registry, Pra¨sident Baltz-Straße 5, 66119 Saarbru¨cken, Saarland, Germany German Cancer Research Center, Division for Clinical Epidemiology and Aging Research, Bergheimer Straße 20, 69115 Heidelberg, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 November 2010 Received in revised form 10 January 2011 Accepted 18 January 2011 Available online 5 April 2011
Background: Implementation of mammography screening and advances in breast cancer treatment are considered as main reasons for the decline in breast cancer mortality observed in many industrialized countries during the past two decades. The purpose of this study was to provide a comprehensive assessment of trends in breast cancer incidence, mortality and survival by age and stage in Germany. Methods: Data from the population based Saarland Cancer Registry including patients diagnosed with breast cancer from 1972 to 2007 were used. Period analysis methods were employed to calculate 5-year relative survival and its trends. Results: Mortality started to decline during the 1990s, and a previous increase in incidence levelled off in the early 21st century. Overall age-standardized 5-year relative survival of invasive breast cancer steadily increased during the past three decades to 83% in 2004–2008. This increase was mostly due to an increase in survival for patients with localized cancers and locally or regionally spread tumours (increase of age-standardized 5-year relative survival from 92% to 98% and from 65% to 80%, respectively, between 1992 and 2008), whereas age-standardized 5-year relative survival essentially remained unchanged at levels close to 21% in patients with metastasized cancer. For women aged 70 years or older 5-year relative survival and its increase over time were inferior compared to younger patients. Conclusions: The observed trends in population based survival suggest that advances in treatment of early breast cancer have substantially contributed to the gain in prognosis. The poor prognosis of metastasized breast cancer patients and the increasing age gradient in 5-year relative survival call for enhanced efforts for early detection and more rigorous treatment of elderly patients. ß 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Survival Population based cancer registry Screening Treatment
1. Introduction Breast cancer (BRC) is the most frequent cancer in women. Overall, 421,000 new cases and 129,000 deaths were estimated for Europe in 2008 [1]. Whereas BRC incidence has increased in industrialized countries during recent decades, mortality has declined over the past two decades [2], most probably as a result of screening activities and improved treatment [3,4]. Likewise, population based studies on BRC survival from Germany, other European countries and the US have demonstrated ongoing improvement of 5-year relative survival during the past two decades [5,6]. Prolongation of cancer survival may have two principal causes: firstly anticipation of tumour diagnosis (resulting in earlier stages with more effective treatment options available) and secondly, improved survival as a result of advances in cancer treatment. To better understand the underlying mechanisms for the observed improvements in cancer survival, close monitoring of
population-based stage specific survival analysis is essential. However, to our knowledge stage specific survival has been reported only for singular calendar periods [7,8]. Given the demographic aging observed in many developed countries, it is also relevant to assess whether all age groups benefit from the aforementioned progress in cancer care as age related differences in cancer care with subsequent inferior outcome for older cancer patients have been reported for many countries [9–11]. In this article, we aimed to assess most recent 5-year relative survival of patients with invasive BRC and precedent trends stratified by age and tumour stage in Saarland (Germany). Patterns are discussed along with BRC incidence (including in situ tumours) and mortality in the context of screening activities and advances in treatment of primary invasive BRC. 2. Materials and methods 2.1. Database
* Corresponding author. Tel.: +49 681 501 5805; fax: +49 681 501 5998. E-mail address: [email protected] (B. Holleczek). 1877-7821/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2011.01.008
This study used data from the population based Saarland Cancer Registry and included all female patients aged 15 years and older
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diagnosed with a first invasive BRC (ICD-10 code: C50) between 1972 and 2007 (n = 23,245). Incidence data of in situ tumours of the breast (ICD-10 code: D05) were provided after 1988 (n = 817). The registry covers the population of the Saarland, a federal state (1.04 million inhabitants) in South-Western Germany. The incidence data are based on notifications from pathology laboratories, hospitals, radiotherapy departments, outpatient clinics and general practitioners. Population data for calculating incidence and mortality, as well as mortality follow-up of cancer patients for calculating survival, including date and cause of death based on information from death certificates, were provided by the state statistical office. Mortality follow-up was available until December 31, 2008. To correct follow-up information for missed deaths and migration out of the registry area, linkage with administrative population registries was carried out for all patients considered survivors at the end of 2008. Patients for whom such linkage was not successful were categorized as lost to follow-up and excluded from survival analyses. The following items were used for survival analysis: month and calendar year of diagnosis, age, summary stage of cancer at diagnosis (categories: ‘localized’ (T1-3N0M0 tumours), ‘local/regional spread’ (nodal positive and T4 tumours without involvement of distant sites), ‘distant metastasis’ (any metastasized tumour), ‘unknown extent’ (if staging information was incomplete)) based on reported summary stage or available TNM categories (5th revision) and information whether a cancer was notified by ‘death certificate only’ (DCO). Clinical extent of disease was used if there was no pathological stage available. Patients were grouped into three age categories (15–49, 50–69 and 70 years and above). 2.2. Statistical analyses Age-standardized rates (ASR) and truncated age-standardized rates (TASR; age categories 15–49, 50–69 and 70 years or older) using the Europe standard population were derived for incidence of invasive and in situ tumours and BRC mortality for successive calendar periods of four years until 2007.
Descriptive analyses of patients with invasive BRC were performed for subsequent calendar periods of four years between 1972 and 2007 with regard to age, size of primary tumour and summary stage, microscopic confirmation, follow-up status and number of DCO cases. Relative survival, which does not require knowledge of the cause of death and which may be interpreted as disease specific survival within a cancer patient population was derived as ratio of observed survival and expected survival for persons in the general population similar to the cancer patients with respect to sex, age and calendar period of observation [12]. Counts of deaths and populations up to the age of 89 years since 1970 were used to build life tables [13] to obtain expected survival probabilities by age for successive calendar periods of 5 years. Survival probabilities for patients aged from 90 to 99 years were projected using the Coale–Kisker model for mortality rates at high ages [14,15]. Expected survival was calculated according to the Ederer II method [16]. All estimates of relative survival are period estimates, which are derived from survival of cancer patients observed within defined calendar periods [17]. Period estimates have shown to closely predict survival observed for patients diagnosed in the period of investigation [18,19]. As follow-up was more up-to-date than registration of incident cases, a modified period analysis approach, called hybrid analysis was used [20]. Estimates of 5-year relative survival were derived for successive calendar periods of four years by age category (starting 1976) and extent of disease (starting 1992; stage information was reasonably complete (>70%) since 1988). Fig. 1 shows data used for 5-year relative survival estimation by calendar year of diagnosis and follow-up. In addition to crude estimates, agestandardized relative survival using weights from the International Cancer Survival Standards (ICSS) [21,22] and stage-mix adjusted relative survival (weights derived from all patients diagnosed between 1988 and 2007 based on stage categories used) were calculated. Standard errors of survival estimates are based on Greenwood’s formula [23,24]. Average annual percentage change
Fig. 1. Data use for estimating 5-year relative survival using a hybrid period analysis approach. The numbers within the cells indicate the years of follow-up since diagnosis.
B. Holleczek et al. / Cancer Epidemiology 35 (2011) 399–406
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Fig. 2. Trends of age-standardized breast cancer incidence (ICD-10: C50 and D05) and mortality (ICD-10: C50) in women in Saarland from 1976 to 2007. The Europe standard population was used for age standardized (ASR) and truncated age-standardized rates (TASR).
(AAPC) of 5-year relative survival was estimated. 619 patients lost to follow-up were excluded from the survival analyses, as were 615 DCO cases. To test for linear trend in relative survival, Poisson regression models for relative survival were fitted modelling the logarithm of the excess number of deaths as a linear function of follow-up year (categorical variable), age group (categorical variable) and calendar period (numeric variable) including the logarithm of person time as offset [25,26]. The reported p-value is based on the Wald test for inclusion of calendar period as explanatory variable. For data preparation and analysis, the R Language and Environment for Statistical Computing (release 2.8.0; R Foundation for Statistical Computing, Vienna, 2009) and add-on package ‘periodR’ (release 1.0-5) [27] were used. 3. Results Trends of BRC incidence (invasive and in situ tumours) and mortality are plotted in Fig. 2. During the study period, incidence of invasive BRC has increased by approximately 50%, but levelled off during the last two calendar periods (in 2004–2007 ASR and TASR were 111 (all ages), 55 (age 15–49 years), 282 (age 50–69 years) and 314 (age 70 years or older) new cases per 100,000 person years respectively; left plot). The median age at diagnosis has increased from 61 to 64 years since 1976. Incidence of in situ tumours has almost tripled since the 1990s with strongest increase seen for women aged 50–69 years (most recent ASR and TASR were 8 (all ages), 6 (15–49 years), 19 (50–69 years) and 14 (70 years or older) cases per 100,000 person years respectively; plot in the centre). BRC mortality started to decrease slightly for all age groups in the mid 1990s (most recent ASR and TASR were 29 (all ages), 7 (15–49 years), 70 (50–69 years), 148 (70 years or older) deaths per 100,000 person years; right plot). The median age at death increased from 65 years to 71 years. The overall number of patients with invasive BRC has almost doubled over the study period (Table 1). Most recently, 19% of the patients were younger than 50 years, 47% were 50–69 years old
and 34% were 70 years or over. Between 1972 and 2007, the proportion of patients with incomplete staging information decreased from 45% to 23%. In 2004–2007, the proportions of patients with cancers staged ‘localized’, ‘local/regional spread’ and ‘distant metastasis’ were 49%, 42% and 9% respectively. The proportion of T1 tumours increased from 33% in 1988–1992 to 46% in the most recent calendar period (T2: 40%, T3: 6%, T4: 8%; proportions among cancers with known tumour size). Almost all cancers were microscopically verified. The overall proportion of patients lost to follow-up was 3% (increasing with time since diagnosis) and 3% of the registered cancers were DCO cases. Overall and age group specific 5-year relative survival has steadily increased since 1976 by approximately 20% points (pvalues <0.001; Table 2). Overall age-standardized 5-year relative survival was 83% in 2004–2008, but survival remained inferior for patients aged 70 years or older (75%) compared to younger patients (88%). This difference has grown to 13% points and almost doubled since the 1990s. Five-year relative survival stratified by stage and age and adjusted for stage-mix between 1992 and 2008 is presented in Table 3. Most recent age-standardized 5-year relative survival for localized, locally/regionally spread and metastasized BRC was 98%, 80% and 22% respectively. The overall increase of survival was highest for patients with locally/regionally spread cancers (15% points; AAPC 1.8%; p-value <0.001) and intermediate for localized tumours (6% units; AAPC 0.6%; p-value <0.001), If localized cancers were subdivided into T1 and T2–3 tumours, age-standardized 5year relative survival was 104% for tumours equals or less than 2 cm in greatest dimension in the most recent calendar period (increase of 6% points; AAPC 0.5%) and 92% for tumours with more than 2 cm in greatest dimension (increase of 4% points; AAPC 0.3%; p-value 0.008). No improvement was observed for patients with metastasized BRC (1% unit; p-value 0.366). Stage-mix adjusted survival increased from 74% to 83% (p-value <0.001) and was almost identical to crude and age-standardized overall survival. Survival of elderly patients (70 years or older) with nonmetastasized BRC improved to a lesser extent compared to
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Table 1 Characteristics of female breast cancer patients (ICD-10: C50) from Saarland diagnosed between 1972 and 2007 for successive calendar periods. Category
Age 15–49 years 50–69 years 70 years
1972–1975
1976–1979
1980–1983
1984–1987
1988–1991
1992–1995
1996–1999
2000–2003
n
n
n
n
n
n
n
n
%
1848
450 974 424
%
1966
24.4 52.7 22.9
435 994 537
%
2090
22.1 50.6 27.3
473 942 675
%
2218
22.6 45.1 32.3
484 958 776
%
2497
21.8 43.2 35.0
Tumour size Available T1a T2a T3a T4a
%
2785
%
3081
%
3348
2004–2007 n
%
3412
502 1176 819
20.1 47.1 32.8
544 1256 985
19.5 45.1 35.4
603 1398 1080
19.6 45.4 35.1
601 1592 1155
18.0 47.6 34.5
646 1611 1155
18.9 47.2 33.9
1881 614 889 122 256
75.3 32.6 47.3 6.5 13.6
2362 854 1054 141 313
84.8 36.2 44.6 6.0 13.3
2791 1061 1244 165 321
90.6 38.0 44.6 5.9 11.5
3121 1305 1285 171 360
93.2 41.8 41.2 5.5 11.5
3014 1387 1211 171 245
88.3 46.0 40.2 5.7 8.1
Extent of disease Available Localizeda Local/regional spreada Distant metastasisa
1021 275 575 171
55.2 26.9 56.3 16.7
967 243 559 165
49.2 25.1 57.8 17.1
1420 487 719 214
67.9 34.3 50.6 15.1
1253 414 657 182
56.5 33.0 52.4 14.5
1755 670 876 209
70.3 38.2 49.9 11.9
2224 967 1031 226
79.9 43.5 46.4 10.2
2547 1161 1141 245
82.7 45.6 44.8 9.6
2960 1458 1223 279
88.4 49.3 41.3 9.4
2636 1284 1118 234
77.3 48.7 42.4 8.9
Microscopical confirmation Lost to follow-up DCO notified
1726 114 63
93.4 6.2 3.4
1820 114 85
92.6 5.8 4.3
1960 46 73
93.8 2.2 3.5
2112 44 52
95.2 2.0 2.3
2339 58 88
93.7 2.3 3.5
2656 45 69
95.4 1.6 2.5
2984 65 52
96.9 2.1 1.7
3249 77 48
97.0 2.3 1.4
3312 56 85
97.1 1.6 2.5
Annotations/abbreviations: DCO, death certificate only. a Proportions among patients with available information.
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Overall
Calendar period of diagnosis
1.0 1.0 0.9 1.1 1.0 1.0
AAPC
0.9 1.0 1.4 1.0 0.8 2.1 Annotations/abbreviations: RS, relative survival (period estimate); SE, standard error; AAPC, average annual percentage change. a Difference in percentage points between last and first calendar period. b Using weights from the International Cancer Survival Standards [22].
SE RS
84.1 82.9 87.8 88.4 88.3 74.7 0.9 1.0 1.6 1.1 0.9 2.1 1.0 1.1 1.8 1.3 1.0 2.2 77.1 76.3 78.8 79.1 79.0 73.4 1.1 1.2 2.0 1.4 1.2 2.5 73.2 72.5 75.6 74.5 74.8 69.7 1.2 1.3 2.1 1.5 1.2 2.7 71.4 71.0 75.2 71.7 72.7 68.4 1.2 1.4 2.1 1.7 1.3 2.8 69.4 69.3 72.7 68.3 69.8 68.9 1.3 1.6 2.3 1.8 1.4 3.2 65.5 64.5 70.8 65.2 67.1 61.6 1.3 1.7 2.4 1.7 1.4 3.6 63.8 61.4 66.5 65.9 66.0 55.7 Crude Age-standardizedb 15–49 years 50–69 years 15–69 years 70 years
SE
4. Discussion
79.6 78.7 83.5 81.5 82.0 74.3
SE
2000/1–2004
RS SE
1996/7–2000
RS SE
1992/3–1996
RS SE
1988/9–1992
RS SE
1984/5–1988
RS RS
SE
1980/1–1984 1976/7–1980
RS
2004/5–2008
20.3 21.4 21.2 22.5 22.2 19.0
Differencea Calendar period Age
Table 2 Five-year relative survival of female breast cancer patients (ICD-10: C50) from Saarland by age for successive calendar periods between 1976 and 2008.
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younger patients (differences in increase of survival were 6 and 9% points respectively for localized and locally/regionally spread BRC; AAPC: 0.2 and 1.2%; p-values 0.312 and 0.080). The differences in 5year relative survival between elderly patients and younger ones thus increased to 2 and 14% points in the most recent calendar period. Among patients with metastasized BRC, a substantial increase in survival was observed only for patients below the age of 50 years. Their survival increased by 14%26% in 2004–2008 (AAPC 6.9%; pvalue 0.058). For patients older than 50 years no improvement was seen (relative survival was 25% and 15% respectively in the most recent calendar period; p-values 0.547 and 0.986). Age-standardized 5-year relative survival of patients for whom stage information was incomplete was 84% in 2004–2008, with an increase of 6% points since 1992 (AAPC 0.3%; p-value 0.081). Among these patients, a substantial improvement in survival was only observed for patients below the age of 50 years (increase by 18% units to 97%; AAPC 2.0%; p-value 0.013).
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001
p-Value
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In this population based study from Germany, age-standardized overall 5-year relative survival of BRC patients has steadily increased since 1976 (increase of 21% points to 83% in 2004– 2008). Prognosis was most favourable for localized BRC (overall increase of 6% points since 1992–1998%). Most overall improvement was observed for locally or regionally spread BRC (increase of 15% units to 80%). No improvement was observed for metastasized BRC (survival was 22% in 2004–2008). For women aged 70 years or older both most recent 5-year relative survival and its increase over time were inferior compared to younger patients. Compared to other European countries, Saarland was ranking middle in terms of overall BRC survival and its improvement between 1990 and 2004 (overall range of 5-year relative survival across 11 European countries in 2000–2004: 70–87% vs. 80% in Saarland) [6,28]. In a recent comparison of BRC survival between the US population covered by SEER registries and Saarland, higher 5year relative survival was found for the US during 2000–2002 (crude survival in the US was 99, 83 and 28% respectively for patients with localized, locally/regionally spread and distant BRC) [7]. The increase of BRC survival seen during the past decades has been primarily attributed to introduction of mammography screening and advances in adjuvant treatment [3,4]. During the study period, only opportunistic screening was available (organised screening started in Saarland at the end of 2006). Besides its effect on stage distribution and survival, mammography screening should also affect incidence and mortality. Widespread adoption of mammography screening correlates with an increase of incidence of in situ tumours [29–31]. The ASR of in situ tumours increased by 180% points since end of the 1990s and a major rise was observed for the target group for screening (women aged 50–69 years). The overall proportion of in situ neoplasms among all BRC increased from 3% to 6% (data not shown in tables). Our data further demonstrated a continuous increase of the proportion of T1 tumours from 33% to 46% (among cancers with available information on tumour size) since the 1990s. This shift towards smaller tumours could be interpreted as visible effect from improved BRC early detection (resulting from not only screening activities, but also improved diagnostic processes and raised BRC awareness in the population). The observed incidence trends of invasive BRC most probably reflect an interaction of trends in ‘traditional’ risk factors and effects of opportunistic mammography screening [2]. Most recently, the incidence rates have levelled off or even dropped, possibly a result from changes in prescription of hormone replacement therapy [32–34].
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Table 3 Five-year relative survival of female breast cancer patients (ICD-10: C50) from Saarland by age and stage for successive calendar periods between 1992 and 2008. Stage
Age
Differencea
Calendar period 1992/3–1996
1996/7–2000
2000/1–2004
2004/5–2008
RS
SE
RS
SE
RS
SE
RS
AAPC
p-Value
SE
Crude Age-standardizedb Stage-mix adjustedc
73.2 72.5 74.3
1.1 1.2 1.1
77.1 76.3 77.5
1.0 1.1 1.0
79.6 78.7 78.9
0.9 1.0 1.0
84.1 82.9 83.3
0.9 1.0 0.9
11.0 10.3 9.0
1.1 1.1 0.9
<0.001 <0.001 <0.001
Localized
Crude Age-standardizedb 15–49 years 50–69 years 15–69 years 70 years T1 tumours age-standardizedb T2–3 tumours age-standardizedb
91.0 91.8 87.3 91.8 90.3 93.7 97.5 88.7
1.5 2.1 2.5 1.8 1.5 4.6 3.3 3.3
93.3 94.4 91.9 91.8 91.8 98.7 98.7 94.1
1.2 1.7 1.9 1.5 1.2 3.6 2.4 2.9
95.7 96.7 93.1 95.2 94.6 99.3 99.2 93.6
1.0 1.4 1.6 1.2 0.9 2.9 2.2 2.2
97.7 98.2 95.5 99.3 98.2 95.8 103.5 92.3
0.9 1.3 1.4 0.9 0.7 3.0 1.6 2.3
6.7 6.4 8.1 7.4 7.9 2.1 6.0 3.6
0.6 0.6 0.7 0.7 0.7 0.2 0.5 0.3
0.002 <0.001 0.012 0.001 <0.001 0.312 – 0.008
Local/regional spread
Crude Age-standardizedb 15–49 years 50–69 years 15–69 years 70 years
65.4 64.7 70.7 65.4 67.0 61.8
1.9 2.1 3.4 2.5 2.0 4.1
70.7 70.1 71.8 72.2 72.0 67.8
1.7 1.9 3.1 2.2 1.8 3.7
76.2 75.0 80.1 77.7 78.4 70.2
1.5 1.8 2.7 1.9 1.6 3.7
81.7 79.8 82.4 86.9 85.6 71.7
1.5 1.7 2.7 1.7 1.4 3.6
16.3 15.1 11.7 21.6 18.7 9.9
1.9 1.8 1.4 2.4 2.1 1.2
<0.001 <0.001 0.006 <0.001 <0.001 0.080
Distant metastasis
Crude Age-standardizedb 15–49 years 50–69 years 15–69 years 70 years
20.4 20.6 11.5 25.0 21.9 17.6
3.1 3.0 5.8 4.4 3.7 6.1
21.8 21.7 17.8 24.4 23.7 19.4
3.0 2.9 8.9 4.3 3.9 4.7
18.4 18.2 23.1 20.9 21.5 13.5
2.6 2.5 7.2 3.8 3.4 3.8
20.8 21.6 25.8 25.3 25.3 14.6
2.9 2.8 9.3 4.4 4.0 4.0
0.4 1.0 14.3 0.3 3.4 2.9
0.3 0.1 6.9 0.3 0.9 2.2
0.372 0.366 0.058 0.574 0.180 0.986
Unknown extent of disease
Crude Age-standardizedb 15–49 years 50–69 years 15–69 years 70 years
78.2 78.2 78.5 83.7 82.3 73.7
2.5 2.4 4.7 3.2 2.6 4.5
81.9 82.7 78.0 92.8 88.0 76.3
2.7 2.5 5.2 2.8 2.6 4.8
75.0 75.8 92.2 79.8 82.8 69.9
3.5 3.1 5.1 4.7 3.8 5.1
82.8 83.9 96.8 87.8 90.4 74.8
2.6 2.2 2.1 2.7 2.1 4.5
4.6 5.6 18.3 4.1 8.1 1.1
0.2 0.3 2.0 0.0 0.6 0.1
0.227 0.081 0.013 0.673 0.090 0.599
Annotations/abbreviations: RS, relative survival (period estimate); SE, standard error; AAPC, average annual percentage change. a Difference of relative survival in percentage points between last and first calendar period. b Using weights from the International Cancer Survival Standards (ICSS) [22]. c Weights derived from all cancer patients diagnosed 1988–2007.
B. Holleczek et al. / Cancer Epidemiology 35 (2011) 399–406
Overall
B. Holleczek et al. / Cancer Epidemiology 35 (2011) 399–406
Due to lack of detailed information on the method of first detection, the effect of screening on BRC survival could not be assessed directly from the data. However, the steady and similar increase of 5-year relative survival observed across all strata of age and stage, the similarity of the increase in crude, age-standardized and stage-mix adjusted survival and improvements found for localized T1 and T2–3 tumours do suggest substantial effects of improved treatment on BRC survival. Major advances in BRC treatment during the study period included propagation of breast conserving surgery followed by radiotherapy as effective local treatment for early stage BRC, sentinel node dissection, new agents for chemotherapy and antiestrogen treatment, introduction of targeted biologic agents (e.g. trastruzumab) and combination of these agents according to the patient’s risk of recurrence. Treatments have also become available for a broader range of patients who before had fewer treatment options. Due to lack of therapy data in routine population-based cancer registration, the impact of specific treatments on increases in survival could not be observed directly. The gap and the less pronounced increase in survival among elderly patients [28,35,36] may be explained by co-morbidity and differences in the delivery of cancer care (e.g. delay in seeking medical care and impact of co-morbidity on selection of cancer treatments [11], lower likelihood of receiving adjuvant radiotherapy and systemic chemotherapy compared to younger patients, even when diagnosed with less advanced tumours [10,37,38]). It is striking that overall 5-year relative survival of patients with metastasized BRC has not improved since the 1990s. Interim changes in the treatment of metastasized BRC (mainly systemic treatment options) which have become more and more costly [39,40] are not reflected on a population level. Only patients younger than 50 years have benefited from a substantial improvement of prognosis. Here, reasons might be differences in tumour characteristics as well as provision of palliative treatment. This population based study has a number of strengths and limitations. The strengths include use of incidence data with a high level of completeness and validity of case ascertainment, cancer diagnosis and follow-up which were available for a period of more than 30 years. The completeness of registration of the registry is estimated above 95% [41]. Almost all tumours were microscopically verified. The proportion of DCO cases was rather small (overall 3%) due to trace-back activities to obtain clinical information for death certificate notified cases. Linkage of all patients considered to be survivors at the end of 2008 with administrative population registries ensured complete mortality follow-up. Limitations are mainly related to the limited availability of clinical data. Stage information was incomplete for more than 40% of the patients prior to 1987. We restricted stage stratified analyses to the time after 1992, as stage information was available for at least 77% of the patients diagnosed since 1988. The somewhat increased proportion of missing values in the most recent calendar period was probably due to delay in reporting from clinical sources. Data on the usage of opportunistic mammography screening over time were not available for individual patients or on a population level. Although rather crude, the staging scheme used allowed firstly to analyze the prognosis of three rather distinct groups of BRC patients with regard to treatment options and secondly best possible use of available information on stage. We additionally categorized localized cancers as either T1 or T2–3 (for calendar years right after 1992 not all localized cancers could be categorized this way as for some only a summary stage was available) and provided trends of agestandardized 5-year relative survival for patients with these cancers to account for stage shift. Survival of each of these patient groups improved over time possibly resulting from better treatment, but improved early detection and screening and stage shifts even within those categories could still have made some contribution to the
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observed trends. The fact that relative survival exceeded 100% for T1 cancer patients in the most recent period, which indicates lower mortality for this group of patients than in women from the general population also points to potential overrepresentation of more health conscious women with increased awareness and utilization of breast cancer early detection in this group. Along with increased registration of stage information, its accuracy might have improved as well due to more sensitive diagnostic methods. In the interpretation of stage specific survival trends, the possibility of stage migration, i.e. a shift of classification towards more advanced stages as a result of more sensitive diagnostic procedures has to be kept in mind [42]. Due to the restricted collection of clinical information, the analyses could not include further determinants of prognosis beyond age and stage such as the method of first detection or differences in the provision of cancer care, socio-economic status or co-morbidity. Despite its limitations, the study disclosed patterns of 5-year relative survival of BRC patients which allow to judge progress that has been reached so far. Although improved early detection in general and increased use of mammography screening in particular have certainly contributed to the increase of survival, the observed trends suggest advances in BRC treatment as an important cause for the gain in prognosis. Our findings have a number of important implications. In contrast to localized and locally or regionally spread BRC, patients with metastasized BRC aged 50 years or older did not benefit from improved survival despite interim advances in treatment options. For these patients, the health care systems are faced with an increasing discrepancy between rapidly increasing expenditures on late stage BRC treatment and its impact on survival on the population level. A further shift towards earlier stages with more effective treatment options and further reduction in mortality will hopefully be reached with implementation and widespread use of effective screening. Widening age gradients in relative BRC survival indicate discrepancies in the provision of cancer care among elderly patients who did not benefit from advances in BRC treatment to the same extent as younger ones. Clinicians, researchers and politics need to address these issues, i.e. continue implementation of effective early detection programs and combat inequalities in delivery of BRC care – an issue which will become even more salient with ongoing demographic changes. Conflicts of interest None declared. Acknowledgements This work was supported in part by the German Cancer Aid (grants 70-3166-Br 5, 108257 and 108761). The German Cancer Aid had no role in the design, the data collection, the analysis, the interpretation of the results, the writing of the manuscript, or in the decision to submit the manuscript. References [1] Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010;46(4):765–81. [2] Botha JL, Bray F, Sankila R, Parkin DM. Breast cancer incidence and mortality trends in 16 European countries. Eur J Cancer 2003;39(12):1718–29. [3] Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005;353(17):1784–92. [4] Elmore JG, Armstrong K, Lehman CD, Fletcher SW. Screening for breast cancer. JAMA 2005;293(10):1245–56. [5] Sant M, Allemani C, Berrino F, Coleman MP, Aareleid T, Chaplain G, et al. Breast carcinoma survival in Europe and the United States. Cancer 2004;100(4):715–22.
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