Background
Breast cancer (BC) is the leading tumour in terms of incidence and the most common cause of cancer death among women in Europe and in Lithuania [
1]. Prostate cancer (PC) is the most common cancer diagnosis in men in most high-income countries and in Lithuania; it is the second most common cause of cancer death [
1]. BC and PC mortality trends were declining in recent years in many countries, reductions were associated mainly with the combined effects of earlier detection and improved awareness and treatment [
2‐
4]. Effective organized population-based BC screening programmes, implemented in many Northern and Western European countries in the late 1980s, have been related to the reduced BC mortality; whereas the role of extensive opportunistic prostate-specific antigen (PSA)-based testing for PC remains uncertain [
1,
2,
4‐
9]. In Central and Eastern Europe, modest and late decreases or the continued increase in BC and PC mortality was observed; unfavourable trends remain largely unexplained and are only partly attributable to less accessible or delayed modern effective treatment [
1‐
3,
5,
9‐
11]. Similar epidemiological features have been shown between BC and PC, implying common causal pathways, including hormonal, metabolic, genetic, dietary and other factors [
6,
7,
12].
The BC incidence rates in Lithuania are lower, but the mortality rates are higher compared to most Northern and Western European countries [
1,
9]. The national population-based BC prevention programme in Lithuania was started in October, 2005, fully implemented in 2006, targeting women aged 50–69 years at two-year intervals [
13]. However, the programme is lacking all the necessary elements of organized population-based screening, including written invitation with prefixed appointment for all eligible women, screening registry and appropriate systematic quality assurance, whereas the examination coverage is low (45% in 2014) [
14].
In Western and Northern European countries, although PC incidence trends increased, mortality rates have been declining since the 1990s [
6,
7,
15]. In Central and Eastern Europe declines in mortality trends started later and were less pronounced [
1,
3,
10,
16]. It has been shown that repeated PC screening using PSA testing reduces PC mortality risk by 20% [
17]. However, population PSA testing is considered controversial due to potential overdiagnosis and overtreatment of clinically insignificant PC [
17‐
19]. There are substantial differences in recommendations by national and international professional associations, European Union and the European Code Against Cancer [
19‐
24]. In Lithuania, PSA test was introduced into clinical practice in 2000, and a nationwide PC screening programme was started in 2006, targeting all men aged 50–75 years and 45–49 years with family history of PC, annually. Biennial PC screening from 2009 and target age 50–69 years from 2017 were introduced. Similar to other screening programmes in Lithuania, screening registry, systematic written invitation or appropriate screening quality assurance are lacking [
25,
26]. Although Lithuania is the only country in the world with an implemented PSA-based systematic PC screening [
24], the age-standardized PC mortality rate (ASMR) was 3rd highest and 4th highest in Europe in 2015–2018 and in 2020, respectively [
3,
9].
Despite the high burden of both tumours in Lithuania, no evaluation of age, period and cohort effects on mortality trends has been performed. The aim of this study was to assess and interpret time trends in BC and PC mortality in Lithuania with particular focus on independent effects of age, time period and birth-cohort in order to better understand the possible impact of screening practices.
Methods
We extracted official data for deaths of BC and PC in Lithuania for the period 1986–2020 from the World Health Organisation (WHO) mortality database [
27]. The 2020 was the last available year for Lithuania in the WHO database. Population counts for each calendar year by sex and 5-year age categories were obtained from the official Statistics Lithuania portal [
28].
Joinpoint regression was used to analyse trends in age-standardised mortality rates (ASMR) (world standard population) per 100,000 for BC and PC for the years 1986–2020. We depicted annual ASMRs for each tumour. The time points called ‘joinpoints’ were identified when a change in the linear slope of the temporal trend occurred [
29]. A maximum number of three Joinpoints was allowed. The estimated annual percent change (APC) was computed for each identified linear segment. The age-specific mortality rates across the 5-year time periods were calculated as the number of new patients per 100,000 person-years, using 5-year age groups (BC 25–29 to 85+ years; PC 45–49 to 85+ years).
With the aim of a more detailed analysis, the age, period and cohort effects were calculated using an age-period-cohort analysis Web tool (
http://analysistools.nci.nih.gov/apc/) [
30]. For this purpose, data were grouped by 5-year age and period intervals, excluding those aged < 25 years for BC analysis and < 45 years for PC analysis due to small number of deaths in these groups. Using the Web tool, we obtained: longitudinal age-specific rates (i.e. fitted age-specific rates in reference cohort adjusted for period deviations), period rate ratios (RRs) and cohort RRs. We used 2006–2010 period (which corresponds to the introduction of screening programmes) as our reference period and the 1946 birth cohort (which is central cohort for BC) as our reference cohort. We also obtained the Net Drift, i.e. model-based estimates of an average APC in the ASMRs over the entire 35-year period; and Local drifts, i.e. age-specific APCs over time. We used the Wald Chi-Square test to determine statistical parameters in the age, period and cohort model. The Web tool is described in detail elsewhere [
30]. All tests of statistical significance were two-sided, a
P value of < 0.05 was considered statistically significant.
Discussion
The study showed that BC age-standardized mortality rates in Lithuania increased by 1.6% annually during the period 1986–1996, then declined by 1.2% per year during 1996–2020. The age-period-cohort analysis suggests that temporal trends in BC mortality could be attributed predominantly to birth cohort effects, implicating contribution of the changes in the prevalence of BC risk factors across generations. The declining period effect in BC mortality trends suggests the beneficial effect of increased mammography testing, as well as general improvements in early detection and new treatments. In PC mortality, a pronounced 3.0% annual increase from 1986 to 2007, followed by a moderate 1.7% decline, was observed. There were differences among age groups, with more favourable trends observed in middle-aged (45–64 years) men. The predominance of period effect over birth cohort effect in PC mortality was observed suggesting the role of increased diagnostic activity using PSA testing and new treatments. An implementation of the screening programme may have contributed to favourable recent trends, particularly in men aged below 65 years.
The age-period-cohort analysis of mortality trends showed that the most prominent effect in BC was the cohort effect. The bell-shaped cohort effect pattern was similar to previous results from white populations, that were related to the combined effects of changes in reproductive factors, overweight and obesity, hormone replacement therapy and screening mammography [
7,
31,
32]. It is likely that postponement of the first birth and having fewer children had an impact on increasing BC mortality risk in older cohorts in Lithuania. A steep decline in cohorts born since 1946 could not be explained by changes in BC risk factors. Similar unexplained declines were reported among European women [
2,
32]. The analysis showed a change point in the cohort effect in youngest generations, born from 1976 onward, when the BC mortality risk increased. Risk factors during adolescence or early adulthood, e.g. increased prevalence of overweight or obesity, lower levels of physical activity, increased alcohol intake, contraceptive use, further changes in childbearing habits could have played a role. The prevalence of obesity among < 25 years old women in Lithuania increased from 1% in 2005 to 8% in 2019 [
28]; the intake of strong alcohol ≥1 times per week increased from 4% in 1994 to 10% in 2015; the intake of beer - from 10 to 21%, respectively [
33,
34]. In addition, contraceptive use among women aged 15–49 years increased from 51% in 1995 to 69% in 2009 [
35].
In comparison to most European countries, where decreases since mid-1980s by at least 2% annually have been reported; in Lithuania BC mortality rates peaked later and annual reductions were smaller [
2,
5‐
7,
36,
37]. The period effect in BC mortality trends decreased gradually since 1991–1995 in Lithuania, no period-specific effect of screening programme was detected. Notably, the BC mortality in Lithuania started to decline prior to the introduction of the screening programme, suggesting that beneficial effects could possibly be attributed to increased mammography testing, general improvements in early detection and subsequent new treatments of earlier diagnosed cases [
2,
36]. The mammography was increasingly used since the beginning of 1990s, including newly installed mammography units and pilot screening programmes that possibly contributed to the sharp rise in BC incidence rates from 29.0 per 100,000 in 1990 to 41.5 per 100,000 in 2002 [
38,
39], followed by a subsequent decline in BC mortality rates due to early diagnosis. In 2004, i.e. before the screening implementation, 17% of women reported having had mammography [
40]. After the introduction of national screening programme, the mammography testing increased; however, the screening examination coverage remained comparatively low, 45% vs. 72–84% in Scandinavian countries or United Kingdom [
14,
33]. Our study showed declines in BC mortality also in women 25–49 years of age, i.e. younger than the target age groups. This result is in agreement with previous studies and possibly reflects an increased population awareness of BC and mammography testing, also improved diagnostics and treatment of BC that impacted younger women [
5,
6].
Relatively slow decline in BC mortality rates may partly be explained by the lack of timely and appropriate treatment that is required after early detection. About one-third of the decline in BC mortality in Western Europe and North America is assumed to be due to screening and better diagnosis, whereas about two-thirds – due to innovative treatment methods [
2]. In order to substantially decrease BC mortality in Lithuania, further improvements in health-care system efficiency and access to effective treatment are essential, including efficient treatment regimens, multidisciplinary approach, adequate cancer services and facilities as well as access to these services [
31,
37].
A pronounced increase in PC mortality was observed from 1986 to 2007 in Lithuania. The age-period-cohort analysis showed the predominant period effect in PC mortality trend, steeply increasing until 2006–2010. This finding is consistent with an increased awareness among the population and professionals and active case searching practices including intensive opportunistic PSA testing. PSA testing became widely available since 2000 in Lithuania and possibly played important role in rising PC mortality [
9,
11]. Our result is in agreement with Center et al. [
41], showing that the PC incidence rates in Lithuania increased from mid-1980s, with a rapid rise by 22.4% per year between 2000 and 2006, corresponding to the introduction of opportunistic PSA testing [
11]. Moreover, the use of advanced diagnostic imaging and radical treatments may have contributed to the increasing detection of indolent tumours with no or weak life threatening potential and rising PC mortality rates due to misattribution of the cause of death [
32,
42]. An increase in mortality rates in 80–84 and 85+ year old men suggest that diagnostic procedures were actively performed also in this age group, although the benefit was unlikely [
11]. The present study observed decline in risk of death due to PC since 2006–2010, particularly among men below 65 years of age. Similar result was apparent in a recent study, which observed a decrease in PC mortality in Lithuania in 2015–2018 versus 2005–2009 for men all ages and in the age group 35–64 years [
3]. This is consistent with the introduction of opportunistic PSA testing in 2000 and suggests beneficial effects of earlier diagnosis and effective early treatment in these age groups. Previous studies have shown the time lag of 7–9 years between the increasing PSA testing and subsequent reductions in mortality due to beneficial treatment of earlier diagnosed cases [
6,
7]. More conservative use of PSA testing (less screening outside the target age groups, longer screening interval) may have also contributed to the reduction in misattributed cause of death and decreasing mortality rates [
11,
42,
43]. Despite the implemented organized national screening programme, the favourable tendency in PC mortality in Lithuania was weak compared to European men, with the death rates remaining among the highest in Europe [
3,
6,
7,
10,
32]. Furthermore, we observed the positive annual net drift of 0.96% and age-specific local drifts, showing that the mortality rates were higher in 2016–2020 compared to baseline 1986–1990. This result may possibly be explained by ineffective screening programme as well as differences in availability and access to important treatments, including surgery, hormonal and radiation therapy, compared to the more affluent countries [
10,
18].
The cohort effect curvature for PC mortality showed similar pattern with BC pattern. The risk factors for PC remain mostly unidentified, however common factors like “westernization” (increasing obesity, dietary fat consumption and reduced physical activity) could probably explain similarity in cohort effects in BC and PC mortality in older generations. The interpretation of changes in 1936 to 1966 birth cohorts is complicated due to increased diagnostic activity and improved PC treatment.
Our results suggest that opportunistic PSA-based screening programme may have somewhat contributed to the downward PC mortality trend in Lithuania, but the effect was modest. The role of PSA testing in PC mortality reduction and balance between benefits and risks remains equivocal due to overdiagnosis and overtreatment [
8,
41,
44,
45]. Instead of the PSA-only diagnostic strategy, new early PC detection algorithms and technologies have been suggested in order to differentiate life-threatening PC from clinically insignificant PC, using urine, serum or tissue biomarkers, risk calculators, multivariable prediction models and imaging by MRI [
22‐
24].
The strength of our study is the comprehensive quantification and comparison of BC and PC mortality trends using the high-quality cancer mortality data from the WHO mortality database. The study has several limitations. First, interpretation of results is complicated because declining mortality rates in Lithuania could reflect either the impact of the early diagnosis using widespread testing or the improved treatment, as they occurred at a similar time period. Second, sharp changes for the youngest cohorts may be less stable and should be interpreted with caution because of few age-specific rates and small number of cancer cases; however, recent death rates in the young may carry important information for future trends.
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