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Age-specific breast, uterine and ovarian cancer mortality trends in Spain: Changes from 1980 to 2006
Cancer Epidemiology 33 (2009) 169–175
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Age-specific breast, uterine and ovarian cancer mortality trends in Spain: Changes from 1980 to 2006 Anna Cabanes a,b,*, Enrique Vidal a,b, Beatriz Pe´rez-Go´mez a,b, Nuria Aragone´s a,b, Gonzalo Lo´pez-Abente a,b, Marina Polla´n a,b a b
A´rea de Epidemiologı´a Ambiental y Ca´ncer, Centro Nacional de Epidemiologı´a (CNE), Instituto de Salud Carlos III (ISCIII), Monforte de Lemos 5, 28029 Madrid, Spain CIBER in Epidemiology and Public Health (CIBERESP), Spain
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 25 August 2009
Introduction: Cancers of the breast, uterus and ovary are responsible for 30% of the cancer deaths in Spanish women. In recent decades, Spain has experienced important socioeconomic transformations, which may have affected mortality trends. We present the current situation of mortality in Spain due to cancers of the breast, uterus and ovary, as well as trends over 1980–2006. Methods: Data on population and deaths due to cancers of the breast, uterus and ovary were obtained from records of the National Statistics Institute. Overall and age-specific changes in mortality of these tumors were studied using change-point Poisson regression models. Results: Breast cancer was responsible for more than 140,000 deaths of females in 1980–2006. Trend analysis of breast cancer mortality of women of all ages showed that rates increased 2.9% annually until 1992 (95% confidence interval (CI) = 2.5, 3.3). After 1992, mortality declined steadily at a rate of 2.1% per year (95% CI = 2.4, 1.8). The number of deaths due to cancers of the uterus was 49,287 between the years 1980 and 2006. Uterine cancer mortality registered a steady decrease of 1.9% every year since 1980 (95% CI = 2.1, 1.8). Ovarian cancer caused 36,157 deaths during the same period, with rates in women older than 50 years more than ten-fold those of younger women. Trend analysis showed a sharp increase of mortality up to 1998 (4.4% annually; 95% CI = 3.9, 4.8) followed by a stabilization. Conclusion: The downturn observed in mortality for these tumors mainly reflects improved survival as a result of earlier diagnosis and better cancer treatments. Cancer management is moving in the right direction in Spain. ß 2009 Elsevier Ltd. All rights reserved.
Keywords: Cancer Mortality Breast cancer Ovarian cancer Uterine cancer Poisson regression model Trends
1. Introduction Cancers of the breast, uterus and ovary are responsible for 30% of cancer deaths in Spanish women. In 2006, breast cancer was the leading cause of cancer mortality among women, producing 5939 deaths. That same year, cancer of the uterus and ovary ranked 6th and 7th, with 1931 and 1908 deaths, respectively [1]. Yet, mortality of these three tumors is relatively low compared to other European countries [2]. Since the 1990s, age-adjusted mortality rates for cancers of the breast, ovary and uterus have declined in most of the developed world, particularly in the young and middle-age groups (35–64 years) [2–8]. In Spain, a downturn in breast cancer mortality has
* Corresponding author at: A´rea de Epidemiologı´a Ambiental y Ca´ncer, Centro Nacional de Epidemiologı´a (CNE), Instituto de Salud Carlos III (ISCIII), Monforte de Lemos 5, 28029 Madrid, Spain. Tel.: +34 918 222 644. E-mail addresses: [email protected] (A. Cabanes), [email protected] (E. Vidal), [email protected] (B. Pe´rez-Go´mez), [email protected] (N. Aragone´s), [email protected] (G. Lo´pez-Abente), [email protected] (M. Polla´n). 1877-7821/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2009.08.010
been shown since 1992 in women of all ages [9–11] except the age group 65–74 [11]. Also, ovarian cancer rates have stabilized or have started to decline since mid 1990s [6,12]. In contrast, uterine cancer mortality rates – including cervix, corpus uteri and uterus unspecified – have displayed a steady decline since 1975 [12,13]. Changes in mortality result from variations in cancer incidence and its determinants. However, mortality is also influenced by case-fatality, which is determined in turn by early diagnosis [14,15] and the availability of better cancer treatments and cancer care [8,16]. Thus, cancer mortality is a complex indicator resulting in large international variations. With breast cancer, for example, mortality rates in Europe in 1995 ranged from 14.5 deaths/100,000 women in Greece to 27 deaths/100,000 women in Denmark (age-adjusted to the world population) [2]. In contrast, in the year 2004, breast cancer mortality figures in Europe varied between 12 deaths/100,000 women in Spain and 19.3 deaths/100,000 women in Hungary [2]. Furthermore, in the UK and Switzerland, breast cancer mortality decreased about 30% between 1990 and 2002, whereas in most Southern, Northern and Western European countries the decline was between 15% and 25%, and in Eastern Europe breast cancer
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mortality only decreased moderately or remained stable during the same period [17]. Similar variability exists with ovarian and uterine cancer mortality in Europe [2,4,8,18]. In recent decades, Spain has experienced extraordinary economic growth and social transformation. These socioeconomic changes have brought improved treatments and advances in screening and early diagnosis; life expectancy has increased and behavioral factors including reduced physical activity, delayed and reduced childbearing, reduced breast-feeding or use of oralcontraceptives and hormone-replacement therapy (HRT) have become more prevalent in Spanish females [19]. In developed countries, macro-economic variables are closely linked to cancer survival [20] whereas the reproductive and lifestyle changes mentioned above are clearly associated with a higher incidence of breast and uterine cancers – and to a lesser extent to ovarian cancer [21] – and cancer mortality. Incidence, mortality, risk factors and treatment guidelines differ for pre- and postmenopausal breast cancer [22]. Uterine and ovarian cancers show different incidence and mortality rates in pre- and postmenopausal women as well [8]. However, an important factor that significantly impacts cancer mortality rates in populations is the early diagnosis of cancer cases through screening programs [23,18]. In Spain, the implementation of these interventions has been different for breast, uterine and ovarian cancers. All Spanish Autonomous regions implemented breast cancer screening programs during the 1990s and, though they mainly targeted women in the age range of 50–64 years, some included the group of 45–49 years. More recently most Spanish programs have extended the target population to include women aged 65–69 years [24]. In contrast, there are no population-based screening programs for uterine or ovarian cancer, and rates of opportunistic screening – particularly for cervical cancer – greatly vary between age groups and regions [25,26]. Given the impact of the changing prevalence of reproductive and lifestyle risk factors [19] on breast, uterine and ovarian cancers; the heterogeneous adoption of interventions responsible for some reduction in cancer mortality across countries or regions (such as screening programs) [24,27]; and the existing disparities in cancer care between populations or subgroups of the same population (i.e. old women vs young women) [28–30], we deemed this study of particular interest and relevance. We present here the most current situation of cancer mortality in Spain due to cancers of the breast, uterus and ovary, as well as mortality trends over the period 1980–2006 using Poisson regression models to identify those years where a significant change in the linear slope of the temporal trend may have occurred. As cancer screening programs may have had a different impact on age-specific mortality rates and because mortality rates are different before and after menopause, trends are analyzed separately for women of different age groups. 2. Methods Data on population and deaths between 1980 and 2006 from the different types of cancer according to age group were obtained from records of the National Statistics Institute. Age-group specific rates, as well as standardized and truncated rates at different ages were calculated using the direct method with the European population as standard. We used estimations from official census of population figures of July 1 of each year [31]. To account for possible differences in age-specific mortality resulting from the impact of breast cancer screening programs, we analyzed breast cancer mortality trends for all ages and for the following age groups: women aged 25–44 years, 45–64 years and 65 years and older. However, as there are no established
population-based screening programs for uterine and ovarian cancers, we studied mortality trends in women of all ages, in women younger than 50 years (mostly premenopausal), in women aged 50–65 and – given the evidence of undertreatment of older cancer female patients compared to younger ones across Europe and North America – [28] we also included trends in the age group of 65 years and above. Though certification of uterine cancers has improved, there is a substantial proportion of tumors of the cervix and corpus uterus that are under- and ill-certified [32]. The percentage of misclassified tumors has changed over time and thus trend analysis of cervical cancer and endometrial cancer separately is meaningless. For this reason, we performed the analysis pooling together the cases coded as corpus uterus, cervix and uterus non-specified in a single category named uterus. Changes in mortality rates over the study period were evaluated using Poisson regression models, with number of deaths as outcome, person-years as offset and age group as categorized covariate. The number of deaths occurring at a certain age in a specific year were presumed to be independent, and the effects of age and year of death on the log rate scale were assumed to be additive. Briefly, to detect and estimate changes in mortality rates we used a predetermined parametric function of the year of death – the function f(p) – consisting of two intersecting linear trends with a smooth transition at an unknown change-point t that included an intercept term as well, qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi f ð pÞ ¼ b0 þ b1 ð p t Þ þ b2 ð p t Þ2 þ g 2 where b0 is the intercept, b1 b2 and b1 + b2 represent the period slopes below and above the change-point t, and g is a transition parameter that controls the sharpness of the transition between the two linear trends at the change-point t. This change-point model was fitted using a grid search over t and g, and the asymptotic significance level of the test for the existence of a change-point was corrected for the search made over t and g by applying improved Bonferroni methods [33]. The model provided: (a) the corrected p-value of the test for the change-point; (b) the estimate and 95% CI for the location of the change-point; and (c) the estimates and 96%CIs for the annual percentage changes in mortality rates below and above the estimated change-point. Further details on inference and testing procedures are provided elsewhere [33]. Due to the limited number of cancer cases in women younger than 25 years, these age groups were excluded from the change-point analysis for all cancers except ovary. All analyses and graphs were carried out with R using the packages ‘‘mvtnorm’’ and ‘‘gplots’’ [34]. 3. Results Table 1 shows number of deaths and age-adjusted mortality rates of breast, uterine and ovarian cancer for each age group. Rates are summarized in 5-year period, except for the last 2 years. In general, breast and uterine cancer rates are currently lower than mortality rates from the 1980–1984 period in all age groups, except in women older than 65 years with breast cancer. Most current mortality rates of ovarian cancer in young women remain stable since 1980, in contrast to the current rates in older women that have almost doubled. 3.1. Breast cancer Fig. 1 depicts overall age-adjusted breast cancer mortality rates by single year for Spanish women older than 25 years, as well as age-specific mortality rates for women between 25 and 44 years, women between 45 and 64 years, and women over 65 years of age.
(5.8–6.3) (1.0–1.2) (12.1–13.4) (26.4–28.3) 4,939 652 1,867 2,420 (3.6–3.8 (1.0–1.1) (8.8–9.8) (10.9–12.0) 3,592 618 1,477 1,497 Ovary, all ages Ovary, <50 years Ovary, 50–64 years Ovary, 65 years
3.7 1.0 9.3 11.4
4.6 1.1 11.0 16.5
(4.5–4.7) (1.1–1.2) (10.5–11.5) (15.8–17.2)
8,051 835 2,229 4,987 (5.4–5.7) (1.2–1.3) (12.5–13.6) (20.3–21.7) 5.5 1.2 13.1 21.0 6,464 773 2,206 3,485
6.2 1.3 13.4 26.4
(6.1–6.4) (1.2–1.3) (12.9–14.0) (15.6–27.1)
3,804 367 1,466 3,782 (6.2–6.6) (1.1–1.2) (12.8–13.9) (28.1 -29.6) 6.4 1.2 13.4 28.8 9,307 858 2,302 6,146
6.1 1.1 12.8 27.4
(5.5–6.0) (8.6–9.3) (2.2–2.7) (9.7–10.9) (26.8–28.7) 5.7 9.0 2.4 10.3 27.7 (5.7–6.0) (9–9.4) (2.5–2.8) (9.9–10.9) (27.3–28.8) 5.9 9.2 2.7 10.4 28.1 8,943 8939 981 1,790 6,168 9,146 9,132 934 2,729 5,469 (9.0–9.4) (14.0–14.6) (3.4–3.9) (18.5–19.9) (39.1–41.3) 9,437 9,419 1,034 3,064 5,321 Uterus, all ages Uterus, >25 years Uterus, 25–49 years Uterus, 50–64 years Uterus, 65 years
9.2 14.3 3.7 19.2 40.2
8.1 12.6 3.3 16.1 36.6
(7.9–8.3) (12.4–12.9) (3.1–3.5) (15.5–16.7) (35.7–37.6)
8,961 8,958 993 1,919 6,046 (7.1–7.4) (11.1–11.6) (2.9–3.3) (13.4–14.5) (32.4–34.2) 7.3 11.4 3.1 13.9 33.3 9,012 9,006 960 2,366 5,680
6.5 10.2 3.0 11.6 30.9
(6.4–6.7) (10 -10.4) (2.8–3.2) (11.1–12.1) (30.1–31.7)
3,788 3,786 399 1,176 3,962
11,642 11,635 876 3,546 7,213
18.6 (18.2–19.0) 29 0 (28.4–29.6) 6.3 (5.9–6.8) 33.8 32.7–34.9) 75.2 (73.9–77.6)
Cases
(19.9–20.4) (31.1–31.99) (6.5–7.1) (36–37.5) (81.2–83.7) 20.2 31.5 6.8 36.7 82.5 29,012 29,003 2,148 8,767 18,088 (22.2–22.9) (34.9–35.8) (8.2–8.9) (42 -43.7) (85.2–87.9) 22.6 35.3 8.6 42.8 86.5 28,929 28,915 2,382 9,712 16,821 (24.2–24.8) (37.8–38.7) (9.7–10.5) (47.7–49.5) (84.9–87.7) 24.5 38.2 10.1 48.6 86.3 28,211 28,199 2,578 10,919 14,702 (22.5–23.1) (35.1–36.1) (9.7–10.5) (44.6–46.4) (76.4–79.3) 22.8 35.6 10.1 45.5 77.8 24,145 24,123 2,432 10,152 11,539 (19.5–20.1) (30.5–31.4) (8.7–9.4) (9.2–40.9) (54.5–67.3) 19.8 30.9 9.1 40.1 65.9 19,370 19,348 2,014 8,697 8,637 Breast, all ages Breast, >25 years Breast, 25–44 years Breast, 45–64 years Breast, 65 years
2005–2006 2000–2004
Rates (95% CI) Cases
1995–1999
Rates (95% CI) Cases
1990–1994
Rates (95% CI) 1985–1989
Cases Rates (95% CI) Cases
1980–1984 Tumor
Table 1 Age-adjusted mortality rates of breast, uterine, cervical and ovarian cancer (per European standard 100,000 population) by 5-year period.
Rates (95% CI)
Cases
Rates (95% CI)
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Throughout the study period, female breast cancer was the deadliest tumor in women in Spain, responsible for more than 140,000 deaths and rates ranging from 24.5 to 18.6 deaths/100,000 women (Table 1). Breast cancer mortality increased 2.9% per year (95% CI = 2.5, 3.3) until 1992 (Table 2). After 1992, mortality started to decline steadily at a rate of 2.1% per year (95% CI = 2.4, 1.8) (Table 2). The analysis per age group showed a downturn in mortality around 1991–1993 in all groups but the decline was more pronounced in younger women, particularly in those aged 25–44 years (Annual Percentage Change (APC)25–44 = 4.0% and 95% CI = 4.4 to 3.5; APC45–64 = 3.1% and 95% CI = 3.4 to 2.9), while in the oldest group the decrease was substantially lower (APC65 = 1.3% and 95% CI = 1.7 to 0.9) (Table 2). 3.2. Uterine cancer The number of deaths due to all types of cancers of the uterus was of 49,287 during the 1980–2006 period and the mortality rate ranged from 9.2 to 5.7 deaths/100,000 women (Table 1). Fig. 2 depicts age-adjusted mortality rates for uterine cancer over time for all women (aged 25 and older), and for the different age groups. Mortality due to uterine tumors registered a discreet but steady decrease in Spain since 1980 of 1.9% average each year (95% CI = 2.1, 1.8) (Table 2). In women younger than 50 years, the model showed a statistically significant decrease in mortality of 1.6% annually (95% CI = 2.0, 1.2), but did not detect a changepoint. The Poisson transition model also showed a decline in mortality in women between 50 and 64 years of 3.2% per year (95% CI = 3.6, 2.9) up to the year 2005, at which time the model detected a statistically significant change-point very close to the end of the series. In the oldest age group, rates decreased steadily since 1980 at a rate of 1.6% annually (95% CI = 1.8, 1.4). 3.3. Ovarian cancer Fig. 3 shows age-adjusted mortality trends of ovarian cancer for the period 1980–2006. Ovarian cancer caused 36,157 deaths between the years 1980–2006, with rates in women older than 50 years more than ten-fold those of younger females (Table 1). Trend analysis showed a sharp increase of mortality up to 1998 (4.3% annually; 95% CI = 3.9, 4.8) (Table 2). After that year ovarian mortality rates stabilized. There were also clear differences between younger and older women. In females under 50 years, rates augmented 1.6% per year (95% CI = 0.7, 2.5) until 1995, and after started to drop at a rate of 1.4% per year (95% CI = 2.4, 0.3). In women aged 50–64 years, rates significantly increased 4.4% annually (95% CI = 3.7, 5.1) up to 1998, and became stable thereafter. In women 65 and older, mortality rates increased 5.8% annually (95% CI = 5.2, 6.3) up to the year 2000, and decreased 2.0% per year (95% CI = 3.3, 0.8) after. 4. Discussion Our results show that the increase of mortality observed for most of the cancers affecting the feminine reproductive organs eventually reversed. Mortality rates for tumors of the breast and ovary showed a downturn in the early and late 1990s that varied by cancer type and age group. Uterine cancer – including cancers of the cervix and corpus uteri – was the only category in which mortality rates steadily decreased since the beginning of the study period. The strength of the study is the use of proper statistical methods to identify trend changes: the transition change-point models, which offer several methodological advantages over the joinpoint regression approach. First, the proposed change-point model
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Fig. 1. Age-adjusted mortality rates of breast cancer (1980–2006): observed rates (dots); estimated trends (solid line); 95% confidence interval (shaded). (A) Women 25 years; (B) women 25–44 years old; women 45–64 years old; and women 65 years and older.
Table 2 Trends of age-adjusted mortality rates of breast, uterine, cervical and ovarian cancers in women aged 25 and older. Tumor type
Change-point
Annual percentage change (95% CI)
p-value
Year (95% CI)
Breast (>25 years) Breast (25–44 years) Breast (45–64 years) Breast (65 years)
<0.05 <0.05 <0.05 <0.05
1992 1991 1993 1993
Uterus (>25 years) Uterus (<50 years) Uterus (50–64 years) Uterus (65 years)
0.65 0.80 <0.05 0.31
Ovary all ages Ovary (<50 years) Ovary (50–64 years) Ovary (65 years)
<0.05 <0.05 <0.05 <0.05
Overall
(1991–1994) (1990–1993) (1992–1994) (1991–1996)
Below change-point 2.9 2.1 2.3 3.2
(2.5, (1.4, (1.9, (2.7,
3.3) 2.8) 2.6) 3.7)
Above change-point 2.1 4.0 3.1 1.3
(2.4, (4.4, (3.4, (1.7,
1.8) 3.5) 2.9) 0.9)
1.9 (2.1, 1.8) 1.6 (2.0, 1.2) 2005 (1993–)
3.2 (3.6,2.9)
4.5 (0.7, 9.9)
1.6 (1.8,–1.4) 1998 1995 1992 2000
(1994–2002) (1991–2001) (1990–1994) (1997–2003)
includes a transition parameter that allows not only for abrupt changes, but also for more gradual transitions between linear trends, which are more plausible in many epidemiologic settings, instead of assuming an overall trend comprising intersecting linear segments with a sharp bend at the change-point [33]. Second, changes in adjusted rates over time are obtained directly by fitting Poisson models with segmented period effect and adjustment factors to the observed counts, rather than by using a segmented regression on the estimated adjusted rates. Though the current implementation of these transition models allows for only a single change-point, sensitivity analyses with joinpoint regression yielded the same number and location of change-points for the overall and age-specific trends. The analysis is further strengthened by using mortality data which is the only comprehensive and homogenous source of information for the country as a whole. The quality of cancer death certificates in Spain has been shown to be comparable to internationally published data [32]. According Percy’s criteria – which depend on detection (sensitivity for a specific site) and confirmation rates (proportion of cancer deaths in which the underlying cause specified in the death certificate is confirmed by hospital diagnosis) – the main leading cancer sites like breast and uterus are well certificated, whereas ovary is under certified.
4.3 1.6 4.4 5.8
(3.9, (0.7, (3.7, (5.2,
4.8) 2.5) 5.1) 6.3)
0.7 1.4 0.4 2.0
(1.5, (2.4, (0.9, (3.3,
0.0) 0.3) 0.1) 0.8)
Regarding cancer of the uterus overall as one category, this location has good accuracy rates, but cervix and corpus uterus are underand ill-certified, respectively [32]. In Spain, breast cancer mortality trends show a clear period effect. The reduction in mortality is detected in all age groups at about the same time, but the largest and earliest decrease occurs in women younger than 45 years. The advances in breast cancer therapy, particularly the introduction of tamoxifen and polychemotherapy treatments as adjuvant therapy after surgery of primary cancers has been, without doubt, a major factor in lowering the mortality in this age group [16,35]. While not formally included in Spain’s screening programs, a general increase in use of mammography among women in this age range might have increased diagnosis and also improved survival. According to the 2006 Spanish National Health Survey, 4% of women aged 25–34 years and 19% aged 35–44 report biennial mammography [26]. In contrast, breast cancer incidence increased in the young cohorts [35], given that they experienced more intensively the striking lifestyle changes occurred in Spanish society in the last decades. A marked decrease of breast cancer mortality is also found in the group aged 45–64 years which, in addition to improved treatments, would also have benefitted from the earlier detection of tumors resulting from their inclusion in screening programs.
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Fig. 2. Age-adjusted mortality rates of cancer of the uterus (1980–2006): observed rates (dots); estimated trends (solid line); 95% confidence interval (shaded). (A) Women 25 years; (B) women 25–49 years old; women 50–64 years old; and women 65 years and older.
Fig. 3. Age-adjusted mortality rates of ovarian cancer (1980–2006): observed rates (dots); estimated trends (solid line); 95% confidence interval (shaded). (A) Women of all ages; (B) women 25–49 years old; women 50–64 years old; and women 65 years and older.
Spain’s population-based screening programs target women in the 50–64 age range (though in some areas the 45–49 age group is also included) and were mostly implemented during the 1990s [36], but screening coverage only exceeded 90% of the population in 2001 [24]. In the 45–64 years group, we observed a decrease in mortality beginning around 1993. The downturn is mostly ascribed to improved treatment, since in 1993 only one screening program had achieved full coverage and randomized prospective trials indicate that there is a delay of 10 years before the effect of screening can be seen in mortality statistics [16]. However, the steady decrease of breast cancer rates observed after 2001 it is probably influenced by mammography screening. There are no current studies analyzing the effect of breast cancer screening in reducing breast cancer incidence in Spain. Finally, the smallest decrease of mortality was found in women of 65 years and older, although this result may not reflect the real death rate of women diagnosed in that age range, but rather an increased survival in the younger age groups that translates into an
older age of death among survivors. Another factor that must be weighed in is the under treatment of older breast cancer patients. Studies have found that increased patient age is associated with decreased guideline concordance for definitive surgery, adjuvant chemotherapy, and adjuvant hormonal therapy, after adjusting for risk factors and tumor characteristics [28,30,37]. Under treatment has shown to increase mortality for breast cancer [28]. Mortality due to cancers of the uterus steadily decreased in Spain during the entire study period, similarly to other countries in Europe [6], possibly as a result of early diagnosis and improved treatments. Mortality data from national death certificates do not make it possible to distinguish between cervical and endometrial cancer deaths. As we explained above, cancers of the corpus uteri and cervix have been under certified in the past because they were misclassified as ‘‘uterus unspecified’’. The proportion of cancers of the uterus not specified as cervical or corpus uteri is different between countries and varies over time within the same
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population. For example, in Spain in 1975 about 80% of deaths from uterine cancer were attributed to ‘‘uterus unspecified’’ [38] whereas more recent data indicates that this figure is currently down to 23%. This progressive decline is a source of artifacts and demands further analysis to estimate the actual trends of cervical cancer and endometrial cancer mortality rates over time [39]. Because most deaths from uterine cancer below the age of 50 years arise from the cervix [38] one could estimate that in this age group total uterine rates and cervical rates will be nearly equivalent. Ecological studies have shown a decrease in cervical cancer mortality in countries with well-organized screening programs [38,40]. Though in Spain there are not population-based screening programs for these tumors, opportunistic screening is extensive. In fact, according to the National Health Survey [26], between 40% and 55% of women younger than 50 years are screened for cervical cancer at least once a year [25]. In women 50–64 years, the model detects an upward change in mortality in 2005 that is also detected with joinpoint analysis and is not seen in other populations. Nonetheless, mortality data was only available up to 2006 and our model was unable to detect an upper confidence interval for the change-point. In the following years, when more mortality data are available we will see if the upward trend is confirmed. In Spain, ovarian cancer was the seventh leading cause of cancer-related death in the year 2006. Our analysis showed increasing mortality rates from 1980 through 1998. A previous study with data up to 1995, found that Spain and Greece were the European countries that recorded the greatest increases in mortality due to this tumor [41], trends that paralleled increasing incidence rates [8]. Mortality rates of ovarian cancer after 1998 stabilized or started to decrease, depending on the age group. Most of the deaths due to cancer of the ovary occurred in women older than 50 years. In fact, from 1980 to the end of the 1990s, mortality rates for women under 50 years remained stable between 1 and 1.3 deaths/100,000 women, whereas mortality rates for women aged 50–64 almost doubled during the same period, and rates for women 65 and above increased 2.5-fold. Between 1992 and 1995, rates stabilized or started to decline in the younger groups (below 65 years), while it was not until the year 2000 that rates started to decrease in the older age group. Improved treatments such as the application of chemotherapeutic agents that are effective for germ-cell cancers, as well as diagnosis of the tumor at earlier, more curable stages have contributed to level mortality rates in all age groups in the past decade [42]. Even though changes in mortality trends are more evident than changes in incidence rates for the same period [8], the younger cohorts also showed less risk of developing ovarian cancer, probably as a result of the spread of use of oral contraceptives across younger generations. Similarly to breast cancer, under treatment of older ovarian cancer patients is a well-documented phenomenon responsible for cancer deaths and may be a primary reason for their having poorer outcomes than younger patients [28]. Elderly patients are less likely to receive standard management for ovarian cancer, compared to younger women, disparity that cannot be explained by differences in tumor characteristics. In summary, mortality due to cancers of the reproductive tract in Spanish women decreased in the last decade, although the magnitude of the changes was different in the age groups. Within the European context, Spain’s mortality rates were low for cancers of the breast, uterus and ovary. Similarly to Spain, in most European countries mortality is at present decreasing, but the decline is variable and not proportional to mortality levels observed in the mid 1990s [2]. Inter-country differences in ageadjusted mortality rates appear to be narrowing in Europe.
The largest decline was detected in breast cancer mortality – the most frequent cancer in women by far – and the decrease in mortality was most noticeable in young and middle age women. The decline in mortality in the older age group was less remarkable because of the increasing survival in younger women and the increasing number of senior cancer patients undertreated. In contrast, mortality due to uterine and ovarian cancer showed much smaller decreases. The downturn observed in mortality for these tumors mainly reflects improved survival as a result of earlier diagnosis and better cancer treatments [43]. Cancer management is moving in the right direction in Spain. However, to continue reducing the burden of cancer in the future in Spanish women, early detection programs must be maintained and expanded in the future to avoid diagnostic delays; as well as provide patients with the best therapeutic strategy, particularly those in the older age groups. Death certification regarding cancers of the uterus must urgently improve so mortality trends of cervical cancer and corpus uteri can be studied separately and future needs can be determined for each particular type of tumor. Conflict of interest None declared. Funding source A.C. position at the ISCIII is funded by the Spanish Ministry of Health to study cancer mortality trends in Spain (DGEG-1304/08TS-16). References ˜ a. An ˜ o 2006. [1] Lopez-Abente G. Mortalidad por cancer y otras causas en Espan Madrid: Centro Nacional de Epidemiologı´a; 24-3-2009. [2] WHO. World Health Organization, mortality database. WHO; 2-6-2009. [3] Hermon C, Beral V. Breast cancer mortality rates are levelling off or beginning to decline in many western countries: analysis of time trends, age-cohort and age-period models of breast cancer mortality in 20 countries. Br J Cancer 1996;73(7):955–60. [4] Jemal A, Thun MJ, Ries LA, Howe HL, Weir HK, Center MM, et al. Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 2008;100(23):1672–94. [5] Levi F, Lucchini F, Negri E, La Vecchia C. Continuing declines in cancer mortality in the European Union. Ann Oncol 2007;18(3):593–5. [6] Karim-Kos HE, de Vries E, Soerjomataram I, Lemmens V, Siesling S, Coebergh JW. Recent trends of cancer in Europe: a combined approach of incidence, survival and mortality for 17 cancer sites since the 1990s. Eur J Cancer 2008;44(10):1345–89. [7] Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24(14):2137–50. [8] Bray F, Loos AH, Tognazzo S, La Vecchia C. Ovarian cancer in Europe: crosssectional trends in incidence and mortality in 28 countries, 1953–2000. Int J Cancer 2005;113(6):977–90. [9] Gispert R, Gervas J, Librero J, Bares M. Criteria to define the list of causes of avoidable mortality: an unavoidable discussion. Gac Sanit 2007;21(2):177–8. [10] Gispert R, Cleries R, Puigdefabregas A, Freitas A, Esteban L, Ribes J. Cancer mortality trends in Catalonia, 1985–2004. Med Clin (Barc) 2008;131(Suppl. 1): 25–31. [11] Cleries R, Ribes J, Esteban L, Martinez JM, Borras JM. Time trends of breast cancer mortality in Spain during the period 1977–2001 and Bayesian approach for projections during 2002–2016. Ann Oncol 2006;17(12):1783–91. [12] Fernandez E, Gonzalez JR, Borras JM, Moreno V, Sanchez V, Peris M. Recent decline in cancer mortality in Catalonia (Spain). A joinpoint regression analysis. Eur J Cancer 2001;37(17):2222–8. [13] Ruiz-Ramos M, Exposito HJ. Cancer mortality trends in Andalusia (Spain) between 1975 and 2003. Med Clin (Barc) 2007;128(12):448–52. [14] Tornberg S, Carstensen J, Hakulinen T, Lenner P, Hatschek T, Lundgren B. Evaluation of the effect on breast cancer mortality of population based mammography screening programmes. J Med Screen 1994;1(3):184–7. [15] Tabar L, Vitak B, Yen MF, Chen HH, Smith RA, Duffy SW. Number needed to screen: lives saved over 20 years of follow-up in mammographic screening. J Med Screen 2004;11(3):126–9. [16] Jatoi I, Miller AB. Why is breast-cancer mortality declining? Lancet Oncol 2003;4(4):251–4.
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Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Age-specific breast, uterine and ovarian cancer mortality trends in Spain: Changes from 1980 to 2006 Anna Cabanes a,b,*, Enrique Vidal a,b, Beatriz Pe´rez-Go´mez a,b, Nuria Aragone´s a,b, Gonzalo Lo´pez-Abente a,b, Marina Polla´n a,b a b
A´rea de Epidemiologı´a Ambiental y Ca´ncer, Centro Nacional de Epidemiologı´a (CNE), Instituto de Salud Carlos III (ISCIII), Monforte de Lemos 5, 28029 Madrid, Spain CIBER in Epidemiology and Public Health (CIBERESP), Spain
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 25 August 2009
Introduction: Cancers of the breast, uterus and ovary are responsible for 30% of the cancer deaths in Spanish women. In recent decades, Spain has experienced important socioeconomic transformations, which may have affected mortality trends. We present the current situation of mortality in Spain due to cancers of the breast, uterus and ovary, as well as trends over 1980–2006. Methods: Data on population and deaths due to cancers of the breast, uterus and ovary were obtained from records of the National Statistics Institute. Overall and age-specific changes in mortality of these tumors were studied using change-point Poisson regression models. Results: Breast cancer was responsible for more than 140,000 deaths of females in 1980–2006. Trend analysis of breast cancer mortality of women of all ages showed that rates increased 2.9% annually until 1992 (95% confidence interval (CI) = 2.5, 3.3). After 1992, mortality declined steadily at a rate of 2.1% per year (95% CI = 2.4, 1.8). The number of deaths due to cancers of the uterus was 49,287 between the years 1980 and 2006. Uterine cancer mortality registered a steady decrease of 1.9% every year since 1980 (95% CI = 2.1, 1.8). Ovarian cancer caused 36,157 deaths during the same period, with rates in women older than 50 years more than ten-fold those of younger women. Trend analysis showed a sharp increase of mortality up to 1998 (4.4% annually; 95% CI = 3.9, 4.8) followed by a stabilization. Conclusion: The downturn observed in mortality for these tumors mainly reflects improved survival as a result of earlier diagnosis and better cancer treatments. Cancer management is moving in the right direction in Spain. ß 2009 Elsevier Ltd. All rights reserved.
Keywords: Cancer Mortality Breast cancer Ovarian cancer Uterine cancer Poisson regression model Trends
1. Introduction Cancers of the breast, uterus and ovary are responsible for 30% of cancer deaths in Spanish women. In 2006, breast cancer was the leading cause of cancer mortality among women, producing 5939 deaths. That same year, cancer of the uterus and ovary ranked 6th and 7th, with 1931 and 1908 deaths, respectively [1]. Yet, mortality of these three tumors is relatively low compared to other European countries [2]. Since the 1990s, age-adjusted mortality rates for cancers of the breast, ovary and uterus have declined in most of the developed world, particularly in the young and middle-age groups (35–64 years) [2–8]. In Spain, a downturn in breast cancer mortality has
* Corresponding author at: A´rea de Epidemiologı´a Ambiental y Ca´ncer, Centro Nacional de Epidemiologı´a (CNE), Instituto de Salud Carlos III (ISCIII), Monforte de Lemos 5, 28029 Madrid, Spain. Tel.: +34 918 222 644. E-mail addresses: [email protected] (A. Cabanes), [email protected] (E. Vidal), [email protected] (B. Pe´rez-Go´mez), [email protected] (N. Aragone´s), [email protected] (G. Lo´pez-Abente), [email protected] (M. Polla´n). 1877-7821/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2009.08.010
been shown since 1992 in women of all ages [9–11] except the age group 65–74 [11]. Also, ovarian cancer rates have stabilized or have started to decline since mid 1990s [6,12]. In contrast, uterine cancer mortality rates – including cervix, corpus uteri and uterus unspecified – have displayed a steady decline since 1975 [12,13]. Changes in mortality result from variations in cancer incidence and its determinants. However, mortality is also influenced by case-fatality, which is determined in turn by early diagnosis [14,15] and the availability of better cancer treatments and cancer care [8,16]. Thus, cancer mortality is a complex indicator resulting in large international variations. With breast cancer, for example, mortality rates in Europe in 1995 ranged from 14.5 deaths/100,000 women in Greece to 27 deaths/100,000 women in Denmark (age-adjusted to the world population) [2]. In contrast, in the year 2004, breast cancer mortality figures in Europe varied between 12 deaths/100,000 women in Spain and 19.3 deaths/100,000 women in Hungary [2]. Furthermore, in the UK and Switzerland, breast cancer mortality decreased about 30% between 1990 and 2002, whereas in most Southern, Northern and Western European countries the decline was between 15% and 25%, and in Eastern Europe breast cancer
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mortality only decreased moderately or remained stable during the same period [17]. Similar variability exists with ovarian and uterine cancer mortality in Europe [2,4,8,18]. In recent decades, Spain has experienced extraordinary economic growth and social transformation. These socioeconomic changes have brought improved treatments and advances in screening and early diagnosis; life expectancy has increased and behavioral factors including reduced physical activity, delayed and reduced childbearing, reduced breast-feeding or use of oralcontraceptives and hormone-replacement therapy (HRT) have become more prevalent in Spanish females [19]. In developed countries, macro-economic variables are closely linked to cancer survival [20] whereas the reproductive and lifestyle changes mentioned above are clearly associated with a higher incidence of breast and uterine cancers – and to a lesser extent to ovarian cancer [21] – and cancer mortality. Incidence, mortality, risk factors and treatment guidelines differ for pre- and postmenopausal breast cancer [22]. Uterine and ovarian cancers show different incidence and mortality rates in pre- and postmenopausal women as well [8]. However, an important factor that significantly impacts cancer mortality rates in populations is the early diagnosis of cancer cases through screening programs [23,18]. In Spain, the implementation of these interventions has been different for breast, uterine and ovarian cancers. All Spanish Autonomous regions implemented breast cancer screening programs during the 1990s and, though they mainly targeted women in the age range of 50–64 years, some included the group of 45–49 years. More recently most Spanish programs have extended the target population to include women aged 65–69 years [24]. In contrast, there are no population-based screening programs for uterine or ovarian cancer, and rates of opportunistic screening – particularly for cervical cancer – greatly vary between age groups and regions [25,26]. Given the impact of the changing prevalence of reproductive and lifestyle risk factors [19] on breast, uterine and ovarian cancers; the heterogeneous adoption of interventions responsible for some reduction in cancer mortality across countries or regions (such as screening programs) [24,27]; and the existing disparities in cancer care between populations or subgroups of the same population (i.e. old women vs young women) [28–30], we deemed this study of particular interest and relevance. We present here the most current situation of cancer mortality in Spain due to cancers of the breast, uterus and ovary, as well as mortality trends over the period 1980–2006 using Poisson regression models to identify those years where a significant change in the linear slope of the temporal trend may have occurred. As cancer screening programs may have had a different impact on age-specific mortality rates and because mortality rates are different before and after menopause, trends are analyzed separately for women of different age groups. 2. Methods Data on population and deaths between 1980 and 2006 from the different types of cancer according to age group were obtained from records of the National Statistics Institute. Age-group specific rates, as well as standardized and truncated rates at different ages were calculated using the direct method with the European population as standard. We used estimations from official census of population figures of July 1 of each year [31]. To account for possible differences in age-specific mortality resulting from the impact of breast cancer screening programs, we analyzed breast cancer mortality trends for all ages and for the following age groups: women aged 25–44 years, 45–64 years and 65 years and older. However, as there are no established
population-based screening programs for uterine and ovarian cancers, we studied mortality trends in women of all ages, in women younger than 50 years (mostly premenopausal), in women aged 50–65 and – given the evidence of undertreatment of older cancer female patients compared to younger ones across Europe and North America – [28] we also included trends in the age group of 65 years and above. Though certification of uterine cancers has improved, there is a substantial proportion of tumors of the cervix and corpus uterus that are under- and ill-certified [32]. The percentage of misclassified tumors has changed over time and thus trend analysis of cervical cancer and endometrial cancer separately is meaningless. For this reason, we performed the analysis pooling together the cases coded as corpus uterus, cervix and uterus non-specified in a single category named uterus. Changes in mortality rates over the study period were evaluated using Poisson regression models, with number of deaths as outcome, person-years as offset and age group as categorized covariate. The number of deaths occurring at a certain age in a specific year were presumed to be independent, and the effects of age and year of death on the log rate scale were assumed to be additive. Briefly, to detect and estimate changes in mortality rates we used a predetermined parametric function of the year of death – the function f(p) – consisting of two intersecting linear trends with a smooth transition at an unknown change-point t that included an intercept term as well, qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi f ð pÞ ¼ b0 þ b1 ð p t Þ þ b2 ð p t Þ2 þ g 2 where b0 is the intercept, b1 b2 and b1 + b2 represent the period slopes below and above the change-point t, and g is a transition parameter that controls the sharpness of the transition between the two linear trends at the change-point t. This change-point model was fitted using a grid search over t and g, and the asymptotic significance level of the test for the existence of a change-point was corrected for the search made over t and g by applying improved Bonferroni methods [33]. The model provided: (a) the corrected p-value of the test for the change-point; (b) the estimate and 95% CI for the location of the change-point; and (c) the estimates and 96%CIs for the annual percentage changes in mortality rates below and above the estimated change-point. Further details on inference and testing procedures are provided elsewhere [33]. Due to the limited number of cancer cases in women younger than 25 years, these age groups were excluded from the change-point analysis for all cancers except ovary. All analyses and graphs were carried out with R using the packages ‘‘mvtnorm’’ and ‘‘gplots’’ [34]. 3. Results Table 1 shows number of deaths and age-adjusted mortality rates of breast, uterine and ovarian cancer for each age group. Rates are summarized in 5-year period, except for the last 2 years. In general, breast and uterine cancer rates are currently lower than mortality rates from the 1980–1984 period in all age groups, except in women older than 65 years with breast cancer. Most current mortality rates of ovarian cancer in young women remain stable since 1980, in contrast to the current rates in older women that have almost doubled. 3.1. Breast cancer Fig. 1 depicts overall age-adjusted breast cancer mortality rates by single year for Spanish women older than 25 years, as well as age-specific mortality rates for women between 25 and 44 years, women between 45 and 64 years, and women over 65 years of age.
(5.8–6.3) (1.0–1.2) (12.1–13.4) (26.4–28.3) 4,939 652 1,867 2,420 (3.6–3.8 (1.0–1.1) (8.8–9.8) (10.9–12.0) 3,592 618 1,477 1,497 Ovary, all ages Ovary, <50 years Ovary, 50–64 years Ovary, 65 years
3.7 1.0 9.3 11.4
4.6 1.1 11.0 16.5
(4.5–4.7) (1.1–1.2) (10.5–11.5) (15.8–17.2)
8,051 835 2,229 4,987 (5.4–5.7) (1.2–1.3) (12.5–13.6) (20.3–21.7) 5.5 1.2 13.1 21.0 6,464 773 2,206 3,485
6.2 1.3 13.4 26.4
(6.1–6.4) (1.2–1.3) (12.9–14.0) (15.6–27.1)
3,804 367 1,466 3,782 (6.2–6.6) (1.1–1.2) (12.8–13.9) (28.1 -29.6) 6.4 1.2 13.4 28.8 9,307 858 2,302 6,146
6.1 1.1 12.8 27.4
(5.5–6.0) (8.6–9.3) (2.2–2.7) (9.7–10.9) (26.8–28.7) 5.7 9.0 2.4 10.3 27.7 (5.7–6.0) (9–9.4) (2.5–2.8) (9.9–10.9) (27.3–28.8) 5.9 9.2 2.7 10.4 28.1 8,943 8939 981 1,790 6,168 9,146 9,132 934 2,729 5,469 (9.0–9.4) (14.0–14.6) (3.4–3.9) (18.5–19.9) (39.1–41.3) 9,437 9,419 1,034 3,064 5,321 Uterus, all ages Uterus, >25 years Uterus, 25–49 years Uterus, 50–64 years Uterus, 65 years
9.2 14.3 3.7 19.2 40.2
8.1 12.6 3.3 16.1 36.6
(7.9–8.3) (12.4–12.9) (3.1–3.5) (15.5–16.7) (35.7–37.6)
8,961 8,958 993 1,919 6,046 (7.1–7.4) (11.1–11.6) (2.9–3.3) (13.4–14.5) (32.4–34.2) 7.3 11.4 3.1 13.9 33.3 9,012 9,006 960 2,366 5,680
6.5 10.2 3.0 11.6 30.9
(6.4–6.7) (10 -10.4) (2.8–3.2) (11.1–12.1) (30.1–31.7)
3,788 3,786 399 1,176 3,962
11,642 11,635 876 3,546 7,213
18.6 (18.2–19.0) 29 0 (28.4–29.6) 6.3 (5.9–6.8) 33.8 32.7–34.9) 75.2 (73.9–77.6)
Cases
(19.9–20.4) (31.1–31.99) (6.5–7.1) (36–37.5) (81.2–83.7) 20.2 31.5 6.8 36.7 82.5 29,012 29,003 2,148 8,767 18,088 (22.2–22.9) (34.9–35.8) (8.2–8.9) (42 -43.7) (85.2–87.9) 22.6 35.3 8.6 42.8 86.5 28,929 28,915 2,382 9,712 16,821 (24.2–24.8) (37.8–38.7) (9.7–10.5) (47.7–49.5) (84.9–87.7) 24.5 38.2 10.1 48.6 86.3 28,211 28,199 2,578 10,919 14,702 (22.5–23.1) (35.1–36.1) (9.7–10.5) (44.6–46.4) (76.4–79.3) 22.8 35.6 10.1 45.5 77.8 24,145 24,123 2,432 10,152 11,539 (19.5–20.1) (30.5–31.4) (8.7–9.4) (9.2–40.9) (54.5–67.3) 19.8 30.9 9.1 40.1 65.9 19,370 19,348 2,014 8,697 8,637 Breast, all ages Breast, >25 years Breast, 25–44 years Breast, 45–64 years Breast, 65 years
2005–2006 2000–2004
Rates (95% CI) Cases
1995–1999
Rates (95% CI) Cases
1990–1994
Rates (95% CI) 1985–1989
Cases Rates (95% CI) Cases
1980–1984 Tumor
Table 1 Age-adjusted mortality rates of breast, uterine, cervical and ovarian cancer (per European standard 100,000 population) by 5-year period.
Rates (95% CI)
Cases
Rates (95% CI)
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Throughout the study period, female breast cancer was the deadliest tumor in women in Spain, responsible for more than 140,000 deaths and rates ranging from 24.5 to 18.6 deaths/100,000 women (Table 1). Breast cancer mortality increased 2.9% per year (95% CI = 2.5, 3.3) until 1992 (Table 2). After 1992, mortality started to decline steadily at a rate of 2.1% per year (95% CI = 2.4, 1.8) (Table 2). The analysis per age group showed a downturn in mortality around 1991–1993 in all groups but the decline was more pronounced in younger women, particularly in those aged 25–44 years (Annual Percentage Change (APC)25–44 = 4.0% and 95% CI = 4.4 to 3.5; APC45–64 = 3.1% and 95% CI = 3.4 to 2.9), while in the oldest group the decrease was substantially lower (APC65 = 1.3% and 95% CI = 1.7 to 0.9) (Table 2). 3.2. Uterine cancer The number of deaths due to all types of cancers of the uterus was of 49,287 during the 1980–2006 period and the mortality rate ranged from 9.2 to 5.7 deaths/100,000 women (Table 1). Fig. 2 depicts age-adjusted mortality rates for uterine cancer over time for all women (aged 25 and older), and for the different age groups. Mortality due to uterine tumors registered a discreet but steady decrease in Spain since 1980 of 1.9% average each year (95% CI = 2.1, 1.8) (Table 2). In women younger than 50 years, the model showed a statistically significant decrease in mortality of 1.6% annually (95% CI = 2.0, 1.2), but did not detect a changepoint. The Poisson transition model also showed a decline in mortality in women between 50 and 64 years of 3.2% per year (95% CI = 3.6, 2.9) up to the year 2005, at which time the model detected a statistically significant change-point very close to the end of the series. In the oldest age group, rates decreased steadily since 1980 at a rate of 1.6% annually (95% CI = 1.8, 1.4). 3.3. Ovarian cancer Fig. 3 shows age-adjusted mortality trends of ovarian cancer for the period 1980–2006. Ovarian cancer caused 36,157 deaths between the years 1980–2006, with rates in women older than 50 years more than ten-fold those of younger females (Table 1). Trend analysis showed a sharp increase of mortality up to 1998 (4.3% annually; 95% CI = 3.9, 4.8) (Table 2). After that year ovarian mortality rates stabilized. There were also clear differences between younger and older women. In females under 50 years, rates augmented 1.6% per year (95% CI = 0.7, 2.5) until 1995, and after started to drop at a rate of 1.4% per year (95% CI = 2.4, 0.3). In women aged 50–64 years, rates significantly increased 4.4% annually (95% CI = 3.7, 5.1) up to 1998, and became stable thereafter. In women 65 and older, mortality rates increased 5.8% annually (95% CI = 5.2, 6.3) up to the year 2000, and decreased 2.0% per year (95% CI = 3.3, 0.8) after. 4. Discussion Our results show that the increase of mortality observed for most of the cancers affecting the feminine reproductive organs eventually reversed. Mortality rates for tumors of the breast and ovary showed a downturn in the early and late 1990s that varied by cancer type and age group. Uterine cancer – including cancers of the cervix and corpus uteri – was the only category in which mortality rates steadily decreased since the beginning of the study period. The strength of the study is the use of proper statistical methods to identify trend changes: the transition change-point models, which offer several methodological advantages over the joinpoint regression approach. First, the proposed change-point model
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Fig. 1. Age-adjusted mortality rates of breast cancer (1980–2006): observed rates (dots); estimated trends (solid line); 95% confidence interval (shaded). (A) Women 25 years; (B) women 25–44 years old; women 45–64 years old; and women 65 years and older.
Table 2 Trends of age-adjusted mortality rates of breast, uterine, cervical and ovarian cancers in women aged 25 and older. Tumor type
Change-point
Annual percentage change (95% CI)
p-value
Year (95% CI)
Breast (>25 years) Breast (25–44 years) Breast (45–64 years) Breast (65 years)
<0.05 <0.05 <0.05 <0.05
1992 1991 1993 1993
Uterus (>25 years) Uterus (<50 years) Uterus (50–64 years) Uterus (65 years)
0.65 0.80 <0.05 0.31
Ovary all ages Ovary (<50 years) Ovary (50–64 years) Ovary (65 years)
<0.05 <0.05 <0.05 <0.05
Overall
(1991–1994) (1990–1993) (1992–1994) (1991–1996)
Below change-point 2.9 2.1 2.3 3.2
(2.5, (1.4, (1.9, (2.7,
3.3) 2.8) 2.6) 3.7)
Above change-point 2.1 4.0 3.1 1.3
(2.4, (4.4, (3.4, (1.7,
1.8) 3.5) 2.9) 0.9)
1.9 (2.1, 1.8) 1.6 (2.0, 1.2) 2005 (1993–)
3.2 (3.6,2.9)
4.5 (0.7, 9.9)
1.6 (1.8,–1.4) 1998 1995 1992 2000
(1994–2002) (1991–2001) (1990–1994) (1997–2003)
includes a transition parameter that allows not only for abrupt changes, but also for more gradual transitions between linear trends, which are more plausible in many epidemiologic settings, instead of assuming an overall trend comprising intersecting linear segments with a sharp bend at the change-point [33]. Second, changes in adjusted rates over time are obtained directly by fitting Poisson models with segmented period effect and adjustment factors to the observed counts, rather than by using a segmented regression on the estimated adjusted rates. Though the current implementation of these transition models allows for only a single change-point, sensitivity analyses with joinpoint regression yielded the same number and location of change-points for the overall and age-specific trends. The analysis is further strengthened by using mortality data which is the only comprehensive and homogenous source of information for the country as a whole. The quality of cancer death certificates in Spain has been shown to be comparable to internationally published data [32]. According Percy’s criteria – which depend on detection (sensitivity for a specific site) and confirmation rates (proportion of cancer deaths in which the underlying cause specified in the death certificate is confirmed by hospital diagnosis) – the main leading cancer sites like breast and uterus are well certificated, whereas ovary is under certified.
4.3 1.6 4.4 5.8
(3.9, (0.7, (3.7, (5.2,
4.8) 2.5) 5.1) 6.3)
0.7 1.4 0.4 2.0
(1.5, (2.4, (0.9, (3.3,
0.0) 0.3) 0.1) 0.8)
Regarding cancer of the uterus overall as one category, this location has good accuracy rates, but cervix and corpus uterus are underand ill-certified, respectively [32]. In Spain, breast cancer mortality trends show a clear period effect. The reduction in mortality is detected in all age groups at about the same time, but the largest and earliest decrease occurs in women younger than 45 years. The advances in breast cancer therapy, particularly the introduction of tamoxifen and polychemotherapy treatments as adjuvant therapy after surgery of primary cancers has been, without doubt, a major factor in lowering the mortality in this age group [16,35]. While not formally included in Spain’s screening programs, a general increase in use of mammography among women in this age range might have increased diagnosis and also improved survival. According to the 2006 Spanish National Health Survey, 4% of women aged 25–34 years and 19% aged 35–44 report biennial mammography [26]. In contrast, breast cancer incidence increased in the young cohorts [35], given that they experienced more intensively the striking lifestyle changes occurred in Spanish society in the last decades. A marked decrease of breast cancer mortality is also found in the group aged 45–64 years which, in addition to improved treatments, would also have benefitted from the earlier detection of tumors resulting from their inclusion in screening programs.
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Fig. 2. Age-adjusted mortality rates of cancer of the uterus (1980–2006): observed rates (dots); estimated trends (solid line); 95% confidence interval (shaded). (A) Women 25 years; (B) women 25–49 years old; women 50–64 years old; and women 65 years and older.
Fig. 3. Age-adjusted mortality rates of ovarian cancer (1980–2006): observed rates (dots); estimated trends (solid line); 95% confidence interval (shaded). (A) Women of all ages; (B) women 25–49 years old; women 50–64 years old; and women 65 years and older.
Spain’s population-based screening programs target women in the 50–64 age range (though in some areas the 45–49 age group is also included) and were mostly implemented during the 1990s [36], but screening coverage only exceeded 90% of the population in 2001 [24]. In the 45–64 years group, we observed a decrease in mortality beginning around 1993. The downturn is mostly ascribed to improved treatment, since in 1993 only one screening program had achieved full coverage and randomized prospective trials indicate that there is a delay of 10 years before the effect of screening can be seen in mortality statistics [16]. However, the steady decrease of breast cancer rates observed after 2001 it is probably influenced by mammography screening. There are no current studies analyzing the effect of breast cancer screening in reducing breast cancer incidence in Spain. Finally, the smallest decrease of mortality was found in women of 65 years and older, although this result may not reflect the real death rate of women diagnosed in that age range, but rather an increased survival in the younger age groups that translates into an
older age of death among survivors. Another factor that must be weighed in is the under treatment of older breast cancer patients. Studies have found that increased patient age is associated with decreased guideline concordance for definitive surgery, adjuvant chemotherapy, and adjuvant hormonal therapy, after adjusting for risk factors and tumor characteristics [28,30,37]. Under treatment has shown to increase mortality for breast cancer [28]. Mortality due to cancers of the uterus steadily decreased in Spain during the entire study period, similarly to other countries in Europe [6], possibly as a result of early diagnosis and improved treatments. Mortality data from national death certificates do not make it possible to distinguish between cervical and endometrial cancer deaths. As we explained above, cancers of the corpus uteri and cervix have been under certified in the past because they were misclassified as ‘‘uterus unspecified’’. The proportion of cancers of the uterus not specified as cervical or corpus uteri is different between countries and varies over time within the same
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population. For example, in Spain in 1975 about 80% of deaths from uterine cancer were attributed to ‘‘uterus unspecified’’ [38] whereas more recent data indicates that this figure is currently down to 23%. This progressive decline is a source of artifacts and demands further analysis to estimate the actual trends of cervical cancer and endometrial cancer mortality rates over time [39]. Because most deaths from uterine cancer below the age of 50 years arise from the cervix [38] one could estimate that in this age group total uterine rates and cervical rates will be nearly equivalent. Ecological studies have shown a decrease in cervical cancer mortality in countries with well-organized screening programs [38,40]. Though in Spain there are not population-based screening programs for these tumors, opportunistic screening is extensive. In fact, according to the National Health Survey [26], between 40% and 55% of women younger than 50 years are screened for cervical cancer at least once a year [25]. In women 50–64 years, the model detects an upward change in mortality in 2005 that is also detected with joinpoint analysis and is not seen in other populations. Nonetheless, mortality data was only available up to 2006 and our model was unable to detect an upper confidence interval for the change-point. In the following years, when more mortality data are available we will see if the upward trend is confirmed. In Spain, ovarian cancer was the seventh leading cause of cancer-related death in the year 2006. Our analysis showed increasing mortality rates from 1980 through 1998. A previous study with data up to 1995, found that Spain and Greece were the European countries that recorded the greatest increases in mortality due to this tumor [41], trends that paralleled increasing incidence rates [8]. Mortality rates of ovarian cancer after 1998 stabilized or started to decrease, depending on the age group. Most of the deaths due to cancer of the ovary occurred in women older than 50 years. In fact, from 1980 to the end of the 1990s, mortality rates for women under 50 years remained stable between 1 and 1.3 deaths/100,000 women, whereas mortality rates for women aged 50–64 almost doubled during the same period, and rates for women 65 and above increased 2.5-fold. Between 1992 and 1995, rates stabilized or started to decline in the younger groups (below 65 years), while it was not until the year 2000 that rates started to decrease in the older age group. Improved treatments such as the application of chemotherapeutic agents that are effective for germ-cell cancers, as well as diagnosis of the tumor at earlier, more curable stages have contributed to level mortality rates in all age groups in the past decade [42]. Even though changes in mortality trends are more evident than changes in incidence rates for the same period [8], the younger cohorts also showed less risk of developing ovarian cancer, probably as a result of the spread of use of oral contraceptives across younger generations. Similarly to breast cancer, under treatment of older ovarian cancer patients is a well-documented phenomenon responsible for cancer deaths and may be a primary reason for their having poorer outcomes than younger patients [28]. Elderly patients are less likely to receive standard management for ovarian cancer, compared to younger women, disparity that cannot be explained by differences in tumor characteristics. In summary, mortality due to cancers of the reproductive tract in Spanish women decreased in the last decade, although the magnitude of the changes was different in the age groups. Within the European context, Spain’s mortality rates were low for cancers of the breast, uterus and ovary. Similarly to Spain, in most European countries mortality is at present decreasing, but the decline is variable and not proportional to mortality levels observed in the mid 1990s [2]. Inter-country differences in ageadjusted mortality rates appear to be narrowing in Europe.
The largest decline was detected in breast cancer mortality – the most frequent cancer in women by far – and the decrease in mortality was most noticeable in young and middle age women. The decline in mortality in the older age group was less remarkable because of the increasing survival in younger women and the increasing number of senior cancer patients undertreated. In contrast, mortality due to uterine and ovarian cancer showed much smaller decreases. The downturn observed in mortality for these tumors mainly reflects improved survival as a result of earlier diagnosis and better cancer treatments [43]. Cancer management is moving in the right direction in Spain. However, to continue reducing the burden of cancer in the future in Spanish women, early detection programs must be maintained and expanded in the future to avoid diagnostic delays; as well as provide patients with the best therapeutic strategy, particularly those in the older age groups. Death certification regarding cancers of the uterus must urgently improve so mortality trends of cervical cancer and corpus uteri can be studied separately and future needs can be determined for each particular type of tumor. Conflict of interest None declared. Funding source A.C. position at the ISCIII is funded by the Spanish Ministry of Health to study cancer mortality trends in Spain (DGEG-1304/08TS-16). References ˜ a. An ˜ o 2006. [1] Lopez-Abente G. Mortalidad por cancer y otras causas en Espan Madrid: Centro Nacional de Epidemiologı´a; 24-3-2009. [2] WHO. World Health Organization, mortality database. WHO; 2-6-2009. [3] Hermon C, Beral V. Breast cancer mortality rates are levelling off or beginning to decline in many western countries: analysis of time trends, age-cohort and age-period models of breast cancer mortality in 20 countries. Br J Cancer 1996;73(7):955–60. [4] Jemal A, Thun MJ, Ries LA, Howe HL, Weir HK, Center MM, et al. Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 2008;100(23):1672–94. [5] Levi F, Lucchini F, Negri E, La Vecchia C. Continuing declines in cancer mortality in the European Union. Ann Oncol 2007;18(3):593–5. [6] Karim-Kos HE, de Vries E, Soerjomataram I, Lemmens V, Siesling S, Coebergh JW. Recent trends of cancer in Europe: a combined approach of incidence, survival and mortality for 17 cancer sites since the 1990s. Eur J Cancer 2008;44(10):1345–89. [7] Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24(14):2137–50. [8] Bray F, Loos AH, Tognazzo S, La Vecchia C. Ovarian cancer in Europe: crosssectional trends in incidence and mortality in 28 countries, 1953–2000. Int J Cancer 2005;113(6):977–90. [9] Gispert R, Gervas J, Librero J, Bares M. Criteria to define the list of causes of avoidable mortality: an unavoidable discussion. Gac Sanit 2007;21(2):177–8. [10] Gispert R, Cleries R, Puigdefabregas A, Freitas A, Esteban L, Ribes J. Cancer mortality trends in Catalonia, 1985–2004. Med Clin (Barc) 2008;131(Suppl. 1): 25–31. [11] Cleries R, Ribes J, Esteban L, Martinez JM, Borras JM. Time trends of breast cancer mortality in Spain during the period 1977–2001 and Bayesian approach for projections during 2002–2016. Ann Oncol 2006;17(12):1783–91. [12] Fernandez E, Gonzalez JR, Borras JM, Moreno V, Sanchez V, Peris M. Recent decline in cancer mortality in Catalonia (Spain). A joinpoint regression analysis. Eur J Cancer 2001;37(17):2222–8. [13] Ruiz-Ramos M, Exposito HJ. Cancer mortality trends in Andalusia (Spain) between 1975 and 2003. Med Clin (Barc) 2007;128(12):448–52. [14] Tornberg S, Carstensen J, Hakulinen T, Lenner P, Hatschek T, Lundgren B. Evaluation of the effect on breast cancer mortality of population based mammography screening programmes. J Med Screen 1994;1(3):184–7. [15] Tabar L, Vitak B, Yen MF, Chen HH, Smith RA, Duffy SW. Number needed to screen: lives saved over 20 years of follow-up in mammographic screening. J Med Screen 2004;11(3):126–9. [16] Jatoi I, Miller AB. Why is breast-cancer mortality declining? Lancet Oncol 2003;4(4):251–4.
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