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An Age-Period-Cohort Analysis of Gastric Cancer Mortality from 1950 to 2007 in Europe
An Age-Period-Cohort Analysis of Gastric Cancer Mortality from 1950 to 2007 in Europe MATTEO MALVEZZI, PHD, MARTINA BONIFAZI, MD, PAOLA BERTUCCIO, SCD, FABIO LEVI, MD, CARLO LA VECCHIA, MD, ADRIANO DECARLI, SCD, AND EVA NEGRI, SCD
PURPOSE: To analyze the components of the favorable trends in gastric cancer in Europe. METHODS: From official certified deaths from gastric cancer and population estimates for 42 countries of the European geographical region, during the period 1950 to 2007, age-standardized death rates (World Standard Population) were computed, and an age-period-cohort analysis was performed. RESULTS: Central and Northern countries with lower rates in the 2005 to 2007 period, such as France (5.28 and 1.93/100,000, men and women respectively) and Sweden (4.49 and 2.21/100,000), had descending period and cohort effects that decreased steeply from the earliest cohorts until those born in the 1940s, to then stabilize. Former nonmarket economy countries had mortality rates greater than 20/100,000 men and 10/100,000 women, and displayed a later start in the cohort effect fall, which continued in the younger cohorts. Mortality remained high in some countries of Southern and Eastern Europe. CONCLUSIONS: The decrease in gastric cancer mortality was observed in both cohort and period effects but was larger in the cohorts, suggesting that the downward trends are likely to persist in countries with higher rates. In a few Western countries with very low rates an asymptote appears to have been reached for cohorts born after the 1940s, particularly in women. Ann Epidemiol 2010;20:898–905. Ó 2010 Elsevier Inc. All rights reserved. KEY WORDS:
Age Period Cohort Analysis, Europe, Gastric Cancer, Mortality.
INTRODUCTION In Europe, gastric cancer was the leading cause of cancer death up to the middle of the 20th century, although a steady decrease in rates has been observed in Northern and Western European countries for several decades (1). The decrease in stomach cancer rates was less marked in Russia and in other countries of Central and Eastern Europe, as well as some countries of Southern Europe, where gastric From Istituto di Ricerche Farmacologiche ‘‘Mario Negri,’’ Via Giuseppe La Masa 19, 20156 Milano, Italia (M.M., M.B., P.B., C.L.V., E.N.); Dipartimento di Medicina del Lavoro ‘‘Clinica del Lavoro Luigi Devoto,’’ Sezione di Statistica Medica e Biometria ‘‘Giulio A. Maccacaro,’’ Universita degli Studi di Milano, Via Vanzetti 4, 20133 Milano, Italia (M.M., P.B., C.L.V., A.D.); Struttura Complessa di Statistica Medica, Biometria e Bioinformatica. Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italia (M.M., A.D.); Istituto di Clinica Medica, Universita Politecnica delle Marche, Via Tronto 10/A, 60100 Ancona, Italy (M.B.); and Unite d’epidemiologie du cancer et Registres vaudois et neuch^atelois des tumeurs, Institut de medecine sociale et preventive, Centre hospitalier universitaire vaudois et Faculte de biologie et medecine, Falaises 1, 1011 Lausanne, Switzerland (F.L.). Address correspondence to: Eva Negri, ScD, Istituto di Ricerche Farmacologiche ‘‘Mario Negri,’’ Via Giuseppe La Masa 19, 20156 Milano, Italia. Tel.: 0039 02 39014525; Fax: 0039 02 33200231. E-mail: eva.negri@ marionegri.it. This work was conducted with the contribution of the Swiss Cancer League and the Italian Association for Cancer Research (AIRC). Paola Bertuccio and Matteo Malvezzi were supported by a fellowship from the Italian Foundation for Cancer Research (FIRC). Received April 29, 2010; accepted August 26, 2010. Ó 2010 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
cancer remains a major public health issue. Consequently, gastric cancer still ranks as the fourth-leading cause of cancer death in Europe (2), and as the second worldwide, after lung cancer (3). A recent global overview of gastric cancer mortality in Europe and other areas of the world showed an annual percent change in gastric cancer mortality rates of approximately 3% and 4% for the major European countries. These decreases were also observed in countries with very low rates, such as Sweden and Switzerland, and were evident in middle aged and young adults too, indicating that downward trends are likely to persist in the future (4). In the present report, we updated gastric cancer mortality data to 2007 or the most recent available calendar year for 42 countries of the European region and for the European Union (EU) as a whole. To disentangle the effects of age, birth cohort, and period of death on gastric cancer mortality, an Age-Period-Cohort (APC) model was applied. The use of this model may shed light on likely determinants of the trends, in terms of changes in risk factor exposure, rather than diagnosis and management of the disease (5–7). MATERIALS AND METHODS Official death certifications from gastric cancer for 42 countries of the European Region (according to the World Health Organization [WHO] definition), of which 26 were 1047-2797/$ - see front matter doi:10.1016/j.annepidem.2010.08.013
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Selected Abbreviations and Acronyms EU Z European Union APC Z Age Period Cohort WHO Z World Health Organization ICD Z International Classification of Disease CI Z confidence interval UK Z United Kingdom HP Z Helicobacter pylori
EU countries (Cyprus was excluded because of insufficient data), the other 16 being Albania, Armenia, Azerbaijan, Belarus, Croatia, Georgia, Kazakhstan, Kyrgyzstan, Iceland, Macedonia, Moldova, Norway, Russia, Switzerland, Ukraine and Uzbekistan, plus the EU as a whole (27 member states as defined in January 2007), during the period 1950 to 2007 were derived, whenever available, from the WHO database (8). The WHO Statistical Information System (i.e., WHOSIS) mortality database estimated that data completeness for the countries studied was close to 100%, with the exceptions of Albania, Armenia, Azerbaijan (60%70%) and Georgia, Kazakhstan, Kyrgyzstan, and Uzbekistan (80%90%) (9). Mortality was coded according to the Seventh Revision of the International Classification of Diseases (ICD-7) from the 1950s to the end of the 1960s, the Eighth Revision (ICD-8) was used throughout the 1970s, whereas the Ninth (ICD-9) was used up to the mid 1990s (with the exception of Switzerland and Denmark, which skipped this revision and moved to the Tenth in 1995 and 1994, respectively). The Tenth Revision of the International statistical Classification of Diseases and Health Related Problems (ICD-10) was adopted between the late 1990s and early 2000s by most countries (10), with the exceptions of Albania and Greece. Encoding for stomach cancer mortality was straightforward, and its transition between revisions did not present particular issues; it was coded as 151 for ICDs 7, 8, and 9 and C16 in ICD-10. Estimates of the resident populations for the corresponding calendar periods, on the basis of official censuses, were extracted from the same WHO database. From the matrices of certified deaths and resident population, we computed age-specific rates for each 5-year age group (from 0, 1–4 to 85þ years). We computed age-standardized mortality rates per 100,000 men and women by using the direct method on the basis of the all-ages world standard and world standard truncated (35–64 years) populations and the corresponding percent change in rates during the period 1950 to 2007 (11). From these same matrices, we calculated age-specific mortality rates per 100,000 inhabitants for 5-year age groups (from 3034 to 8084 years), for the 12 calendar periods considered (from 19501954 to 20052007) where data were available. No interpolations were made for missing
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data as detailed in Appendix 1, in Figure 1 in parenthesis data available for the last period is specified. Cohorts were defined according to their central year of birth. Thus, the earliest possible cohort (the 1870 one) relates to individuals aged 80 to 84 who died in the quinquennium 1950 to 1954; they could have been born in any of the 10 years from 1865 to 1874. From the matrices of age-specific death rates for each 5-year calendar period and age group, the effects of age, cohort of birth, and period of death were evaluated through a log-linear Poisson model by the use of a penalized likelihood model (5, 6). In simplified terms, the estimates presented are derived from the model including the three factors (age, period, and cohort) that minimize the sum of the Euclidean distances between the three possible twofactor models (age-period; age-cohort; cohort-period). The age values are interpretable in terms of mean age-specific death rates in the period considered, whereas cohort and period of death values were expressed in relative terms and averaged to unity. This modelling technique does not allow for the calculation of confidence intervals in a conventional manner. Hence, a parametric bootstrap simulation technique was used (12). Simulated data for each 5-year age-specific number of deaths in all time periods were obtained by extracting randomly from a Poisson distribution characterized by the observed number of deaths for that period and age group. The resulting datasets were fed through the model and for every parameter, values for the 2.5th and 97.5th percentiles from the resulting estimate sets were used as an approximation for a 95% confidence interval (CI). For this paper 1000 simulations per model were used.
RESULTS Figure 1 shows the overall age-standardized mortality rates from gastric cancer per 100,000 men or women for each European country from which data were available and for Europe as a whole from 2005 to 2007. There was a 7- to 10-fold difference in gastric cancer mortality rates across Europe. The greatest rates were in Belarus, the Russian Federation (greater than 25/100,000 men and 10/100,000 women at all-ages), and other former Soviet Union countries. The lowest ones were in Nordic and Western European countries such as France, the United Kingdom (UK), Switzerland, and Belgium, with rates between 4 and 5/100,000 men and between 2 and 2.5/100,000 women at all-ages. Italy and Portugal had mortality rates of 9.5 and 17.3/100,000 in men and 4.5 and 7.9 in women, respectively. Eastern countries belonging to the EU showed even greater mortality rates, with Latvia and Lithuania peaking at around 20/ 100,000 in men and nearly 8/100,000 in women. Estonia
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FIGURE 1. Overall age standardized (world population) death certification rates from gastric cancer per 100,000 inhabitants, in the European Union (highlighted) and selected European countries, for the period 2005 to 2007 (unless otherwise specified in parentheses).
had the greatest all-ages female gastric cancer mortality rate in the EU with 8.8/100,000. Romania, Albania, and Bulgaria also had high rates. The pattern was similar in the truncated (35–64 years) rates (data not shown). For the EU taken as a whole, the overall and truncated age-standardized mortality rates were, respectively, 8.0 and 9.6/100,000 for men; for women they were 3.6 and 4.3/ 100,000. Figure 2, in the upper row, gives age-specific rate trends in mortality for gastric cancer from 3034 to 8084 years plotted against the period of death on a logarithmic scale and stratified by both quinquennium of age (horizontal lines, labels on the right) and cohort of birth (diagonal grey lines, labels on the left and bottom), in the EU for men and women. These show steady downward trends for all the age groups in both sexes from the earliest calendar years. These trends, however, show some tendency towards attenuation over the more recent calendar years in the young, and consequently the more recent cohorts of birth. The lower row of the figure shows the APC analysis plots with CI for the same EU data. In these analyses the age values increased in both sexes to reach 220/100.000 in men and 130 in women in the 80- to 84-year age group.
For both sexes the peak value in the cohort effect was reached for the cohorts with central year of birth in 1875. A substantial decrease in risk was observed for each subsequent cohort, although the slope tended to flatten for generations born after the 1920s, particularly in women. The period effect reached a peak in the 1960 to 1964 quinquennium and steadily declined thereafter. Figures 3 and 4 show the estimates of the effects of age, period, and cohort of birth with approximate 95% CIs for men and women, respectively. Countries with smaller populations, and consequently, lower absolute numbers of certified deaths displayed greater variability in their estimates, this being particularly evident for Albania, Estonia, and Slovakia. The age curves reflect the geographic difference observed in the age standardized mortality rates. In Northern and Western European countries such as France, Sweden, and the UK, the age values were lower in both sexes compared with those found in Southern and Eastern countries such as Italy, Portugal, and Hungary. The Western and Northern European countries with the more favorable rates had strong period and cohort effects, that decreased steeply from the earliest cohorts until those born in the 1940s. For more recent cohorts, however, the descending trend slowed
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FIGURE 2. EU male and female age-specific mortality rate trends, from 30–34 to 80–84 years, plotted, in the upper row, on a logarithmic scale, against period of death and stratified by both quinquennium of age (horizontal black lines with labels to the right) and cohort of birth (diagonal gray lines with labels to the left and bottom). The lower row of the figure shows the APC analysis plots: age (30–34 to 80–84 years), period (quinquennia 1950–54 to 2005–07), and cohort (central years of birth 1870 to 1975) effect estimates. Age estimates are expressed as age-specific mortality rates per 100 000 inhabitants; cohort and period estimates are expressed as multiplicative effects relative to the age estimates. Effect estimates are in black, approximate 95% confidence interval limits in grey.
down and eventually, in some countries, reached a plateau. In men, this was particularly evident in France and the UK for birth cohorts born after the 1940s. In women, this phenomenon was apparent in more countries, such as Denmark, Finland, the Netherlands, Sweden, and Switzerland. Hints of this behavior were also seen, to a lesser degree, in Southern and Central European countries like Austria and Italy. Former nonmarket economy Central and Eastern European countries (13) displayed a later start in the cohort effect decrease, but showed persistent decreases up to the most recent cohorts born in the 1970s. Some stabilization in the younger cohorts was restricted to
selected countries, such as the Czech Republic and Slovenia, particularly in women. DISCUSSION Before discussing the results of the APC analysis, a few general considerations on the model are useful. Firstly, random variation differs in relation to age, period, and cohort estimates. These are minor when related to period of death values because they are based on relatively similar numbers over subsequent calendar periods; for age values, problems usually concern the younger age groups, where
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FIGURE 3. Age (30–34 to 80–84 years), period (quinquennia 1950–1954 to 2005–2007), and cohort (central years of birth 1870 to 1975) effect estimates. Age estimates are expressed as age-specific mortality rates per 100,000 men for selected countries of the European geographical area, cohort, and period estimates are expressed as multiplicative effects relative to the age estimates. Effect estimates are in black, approximate 95% confidence interval limits in gray.
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FIGURE 4. Age (30–34 to 80–84 years), period (quinquennia 1950–1954 to 2005–2007), and cohort (central years of birth 1870 to 1975) effect estimates. Age estimates are expressed as age-specific mortality rates per 100,000 women for selected countries of the European geographical area, cohort, and period estimates are expressed as multiplicative effects relative to the age estimates. Effect estimates are in black, approximate 95% confidence interval limits in gray.
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absolute numbers of gastric cancer deaths are lower. For cohort effects, these issues are greater at both ends of the curve because the earlier and more recent cohorts are based on very few observations; again, the more recent cohorts are based on smaller numbers of deaths, given that they refer to the youngest age groups. Consequently, changes in trends in recent cohorts should be examined with caution, even though they provide important information towards future trends (7, 14). Another limit of the model is that it has difficulties discerning whether the major underlying trend is a cohort or a period one when both their estimated effects share the same direction, as in the case of the downward trends recorded in the analysis of gastric cancer mortality. Furthermore, this model also has a systematic tendency to favor cohort effects as they have greater weight with their larger number of parameters (6, 15, 16). These limitations of the model may also partly explain the downturn in effects found in the older age groups of some countries, together with undercertification in the elderly. The reasons for this marked and widespread decrease in gastric cancer mortality are complex. Most certainly, they reflect the effects of Helicobacter pylori (HP) infection control, the major known risk factor (17, 18). The role of HP infection on stomach cancer through the promotion of precancerous lesions, such as atrophic gastritis and dysplasia, is well established, and prevalence of HP infection is correlated with gastric cancer rates in Europe (19, 20). HP prevalence has substantially decreased in developed countries during recent decades, paralleling the decrease in gastric cancer incidence (21); better hygiene, less crowding, richer nutrition, and the use of antibiotics have all been suggested as potential reasons for the fall in HP prevalence (22). Since in most cases the infection is acquired in childhood, this would be essentially reflected in a cohort effect on gastric cancer mortality. However, not all populations with high rates of HP infection, such as Africa and south Asia, have an increased incidence of gastric cancer, and only a proportion of all infected hosts develop gastric cancer during their lifetime. Therefore, additional factors appear to influence the outcome of infection and the development of gastric cancer, and these include bacterial virulence, host genetics, age of acquisition of infection, and environmental factors (23). Furthermore, the decrease in stomach cancer rates is, at least in part, the result of improvements in diet, and in particular, to the availability of a richer, more varied and affluent diet (17, 18, 24) and to the introduction of refrigeration, which increased the consumption of fruit and vegetables and decreased the use of salt for food storage and conservation (25). In North America and in most Nordic European countries, electric refrigeration became widely available between the 1930s and 1950s. In Italy refrigeration
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was still uncommon in the 1950s but had become almost universal one decade later. In Japan, the use of electric refrigeration increased rapidly in households between 1960 and 1970, approximately when gastric cancer rates started to decrease (26). In Russia and other Central and Eastern European countries, refrigeration was available later, and this may in part explain the later onset of declines in gastric cancer and the present high rates (27). Further availability of foods and variety of diet were limited in those countries before the 1990s (28), and gastric cancer rates were inversely related to markers of vegetable and fruit intake and directly to carbohydrate intake (29). Current Russian rates are comparable with those of several Western European countries 40 to 50 years ago (17, 30). There is also a positive correlation between consumption of salt and salted foods and stomach cancer risk (31). The authors of analytic epidemiological studies have generally found an approximately 2-fold risk of gastric cancer for frequent consumption of salt and salted food (4, 31–33). Salt was widely used as a method of food preservation in the past, and its use has decreased with the adoption of refrigeration, food additives, and other modern methods of food preservation. Ecological data on salt intake and gastric cancer incidence or mortality in various populations are, however, limited and inconsistent. In Japan, time trend analyses showed a parallel decline in per capita consumption of salted fish and vegetables and gastric cancer mortality, but little correlation with total salt intake (26). Another important cause of gastric cancer is tobacco smoking, with a positive relationship with duration of smoking and number of cigarettes smoked, as well as risk reduction with increasing duration of quitting (23). Given that smokers have a 50% to 60% increased risk of stomach cancer compared with nonsmokers, the proportion of gastric cancer cases attributable to cigarette smoking is estimated to approximately 10% (34) and may be larger in men in several Central European populations. Therefore, the recent decrease in smoking prevalence in men in most European countries may account for part of the fall in gastric cancer rates (35–37). The dietary and lifestyle changes have occurred over different calendar periods and age groups of various individuals, and are likely to have an impact not only on gastric cancer initiation but also on promotion. Consequently, their impact on gastric cancer mortality will be reflected both in an age and a cohort effect, leading to the mixed pattern observed in most countries. There have also been advancements in management (diagnosis and treatment) of gastric cancer during the last few decades, including earlier detection through gastroscopy, and advancements mostly in surgical but also in medical treatment of the disease (38). Any such advancement in diagnosis and treatment would essentially have an
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impact on the period effect. Its quantification on a population level in various countries remains open to discussion, but is unlikely to have been the key determinant of the fall in rates in most European countries. In conclusion, the main findings from the present analysis confirm the presence of a persisting and steady decrease of gastric cancer mortality in all the major European countries for both sexes, although there are areas in Southern and Eastern Europe in which the mortality rates still remain high. Estimates from the APC models show that such a decrease was mainly on a cohort of birth basis, which indicates that the downward trends are likely to continue in the near future, with the exception of a few Northern and Western European countries with very low rates, where an asymptote appears to have been reached for cohorts born since the 1940s. The authors thank Ivana Garimoldi for editorial assistance.
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PURPOSE: To analyze the components of the favorable trends in gastric cancer in Europe. METHODS: From official certified deaths from gastric cancer and population estimates for 42 countries of the European geographical region, during the period 1950 to 2007, age-standardized death rates (World Standard Population) were computed, and an age-period-cohort analysis was performed. RESULTS: Central and Northern countries with lower rates in the 2005 to 2007 period, such as France (5.28 and 1.93/100,000, men and women respectively) and Sweden (4.49 and 2.21/100,000), had descending period and cohort effects that decreased steeply from the earliest cohorts until those born in the 1940s, to then stabilize. Former nonmarket economy countries had mortality rates greater than 20/100,000 men and 10/100,000 women, and displayed a later start in the cohort effect fall, which continued in the younger cohorts. Mortality remained high in some countries of Southern and Eastern Europe. CONCLUSIONS: The decrease in gastric cancer mortality was observed in both cohort and period effects but was larger in the cohorts, suggesting that the downward trends are likely to persist in countries with higher rates. In a few Western countries with very low rates an asymptote appears to have been reached for cohorts born after the 1940s, particularly in women. Ann Epidemiol 2010;20:898–905. Ó 2010 Elsevier Inc. All rights reserved. KEY WORDS:
Age Period Cohort Analysis, Europe, Gastric Cancer, Mortality.
INTRODUCTION In Europe, gastric cancer was the leading cause of cancer death up to the middle of the 20th century, although a steady decrease in rates has been observed in Northern and Western European countries for several decades (1). The decrease in stomach cancer rates was less marked in Russia and in other countries of Central and Eastern Europe, as well as some countries of Southern Europe, where gastric From Istituto di Ricerche Farmacologiche ‘‘Mario Negri,’’ Via Giuseppe La Masa 19, 20156 Milano, Italia (M.M., M.B., P.B., C.L.V., E.N.); Dipartimento di Medicina del Lavoro ‘‘Clinica del Lavoro Luigi Devoto,’’ Sezione di Statistica Medica e Biometria ‘‘Giulio A. Maccacaro,’’ Universita degli Studi di Milano, Via Vanzetti 4, 20133 Milano, Italia (M.M., P.B., C.L.V., A.D.); Struttura Complessa di Statistica Medica, Biometria e Bioinformatica. Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italia (M.M., A.D.); Istituto di Clinica Medica, Universita Politecnica delle Marche, Via Tronto 10/A, 60100 Ancona, Italy (M.B.); and Unite d’epidemiologie du cancer et Registres vaudois et neuch^atelois des tumeurs, Institut de medecine sociale et preventive, Centre hospitalier universitaire vaudois et Faculte de biologie et medecine, Falaises 1, 1011 Lausanne, Switzerland (F.L.). Address correspondence to: Eva Negri, ScD, Istituto di Ricerche Farmacologiche ‘‘Mario Negri,’’ Via Giuseppe La Masa 19, 20156 Milano, Italia. Tel.: 0039 02 39014525; Fax: 0039 02 33200231. E-mail: eva.negri@ marionegri.it. This work was conducted with the contribution of the Swiss Cancer League and the Italian Association for Cancer Research (AIRC). Paola Bertuccio and Matteo Malvezzi were supported by a fellowship from the Italian Foundation for Cancer Research (FIRC). Received April 29, 2010; accepted August 26, 2010. Ó 2010 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
cancer remains a major public health issue. Consequently, gastric cancer still ranks as the fourth-leading cause of cancer death in Europe (2), and as the second worldwide, after lung cancer (3). A recent global overview of gastric cancer mortality in Europe and other areas of the world showed an annual percent change in gastric cancer mortality rates of approximately 3% and 4% for the major European countries. These decreases were also observed in countries with very low rates, such as Sweden and Switzerland, and were evident in middle aged and young adults too, indicating that downward trends are likely to persist in the future (4). In the present report, we updated gastric cancer mortality data to 2007 or the most recent available calendar year for 42 countries of the European region and for the European Union (EU) as a whole. To disentangle the effects of age, birth cohort, and period of death on gastric cancer mortality, an Age-Period-Cohort (APC) model was applied. The use of this model may shed light on likely determinants of the trends, in terms of changes in risk factor exposure, rather than diagnosis and management of the disease (5–7). MATERIALS AND METHODS Official death certifications from gastric cancer for 42 countries of the European Region (according to the World Health Organization [WHO] definition), of which 26 were 1047-2797/$ - see front matter doi:10.1016/j.annepidem.2010.08.013
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Selected Abbreviations and Acronyms EU Z European Union APC Z Age Period Cohort WHO Z World Health Organization ICD Z International Classification of Disease CI Z confidence interval UK Z United Kingdom HP Z Helicobacter pylori
EU countries (Cyprus was excluded because of insufficient data), the other 16 being Albania, Armenia, Azerbaijan, Belarus, Croatia, Georgia, Kazakhstan, Kyrgyzstan, Iceland, Macedonia, Moldova, Norway, Russia, Switzerland, Ukraine and Uzbekistan, plus the EU as a whole (27 member states as defined in January 2007), during the period 1950 to 2007 were derived, whenever available, from the WHO database (8). The WHO Statistical Information System (i.e., WHOSIS) mortality database estimated that data completeness for the countries studied was close to 100%, with the exceptions of Albania, Armenia, Azerbaijan (60%70%) and Georgia, Kazakhstan, Kyrgyzstan, and Uzbekistan (80%90%) (9). Mortality was coded according to the Seventh Revision of the International Classification of Diseases (ICD-7) from the 1950s to the end of the 1960s, the Eighth Revision (ICD-8) was used throughout the 1970s, whereas the Ninth (ICD-9) was used up to the mid 1990s (with the exception of Switzerland and Denmark, which skipped this revision and moved to the Tenth in 1995 and 1994, respectively). The Tenth Revision of the International statistical Classification of Diseases and Health Related Problems (ICD-10) was adopted between the late 1990s and early 2000s by most countries (10), with the exceptions of Albania and Greece. Encoding for stomach cancer mortality was straightforward, and its transition between revisions did not present particular issues; it was coded as 151 for ICDs 7, 8, and 9 and C16 in ICD-10. Estimates of the resident populations for the corresponding calendar periods, on the basis of official censuses, were extracted from the same WHO database. From the matrices of certified deaths and resident population, we computed age-specific rates for each 5-year age group (from 0, 1–4 to 85þ years). We computed age-standardized mortality rates per 100,000 men and women by using the direct method on the basis of the all-ages world standard and world standard truncated (35–64 years) populations and the corresponding percent change in rates during the period 1950 to 2007 (11). From these same matrices, we calculated age-specific mortality rates per 100,000 inhabitants for 5-year age groups (from 3034 to 8084 years), for the 12 calendar periods considered (from 19501954 to 20052007) where data were available. No interpolations were made for missing
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data as detailed in Appendix 1, in Figure 1 in parenthesis data available for the last period is specified. Cohorts were defined according to their central year of birth. Thus, the earliest possible cohort (the 1870 one) relates to individuals aged 80 to 84 who died in the quinquennium 1950 to 1954; they could have been born in any of the 10 years from 1865 to 1874. From the matrices of age-specific death rates for each 5-year calendar period and age group, the effects of age, cohort of birth, and period of death were evaluated through a log-linear Poisson model by the use of a penalized likelihood model (5, 6). In simplified terms, the estimates presented are derived from the model including the three factors (age, period, and cohort) that minimize the sum of the Euclidean distances between the three possible twofactor models (age-period; age-cohort; cohort-period). The age values are interpretable in terms of mean age-specific death rates in the period considered, whereas cohort and period of death values were expressed in relative terms and averaged to unity. This modelling technique does not allow for the calculation of confidence intervals in a conventional manner. Hence, a parametric bootstrap simulation technique was used (12). Simulated data for each 5-year age-specific number of deaths in all time periods were obtained by extracting randomly from a Poisson distribution characterized by the observed number of deaths for that period and age group. The resulting datasets were fed through the model and for every parameter, values for the 2.5th and 97.5th percentiles from the resulting estimate sets were used as an approximation for a 95% confidence interval (CI). For this paper 1000 simulations per model were used.
RESULTS Figure 1 shows the overall age-standardized mortality rates from gastric cancer per 100,000 men or women for each European country from which data were available and for Europe as a whole from 2005 to 2007. There was a 7- to 10-fold difference in gastric cancer mortality rates across Europe. The greatest rates were in Belarus, the Russian Federation (greater than 25/100,000 men and 10/100,000 women at all-ages), and other former Soviet Union countries. The lowest ones were in Nordic and Western European countries such as France, the United Kingdom (UK), Switzerland, and Belgium, with rates between 4 and 5/100,000 men and between 2 and 2.5/100,000 women at all-ages. Italy and Portugal had mortality rates of 9.5 and 17.3/100,000 in men and 4.5 and 7.9 in women, respectively. Eastern countries belonging to the EU showed even greater mortality rates, with Latvia and Lithuania peaking at around 20/ 100,000 in men and nearly 8/100,000 in women. Estonia
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FIGURE 1. Overall age standardized (world population) death certification rates from gastric cancer per 100,000 inhabitants, in the European Union (highlighted) and selected European countries, for the period 2005 to 2007 (unless otherwise specified in parentheses).
had the greatest all-ages female gastric cancer mortality rate in the EU with 8.8/100,000. Romania, Albania, and Bulgaria also had high rates. The pattern was similar in the truncated (35–64 years) rates (data not shown). For the EU taken as a whole, the overall and truncated age-standardized mortality rates were, respectively, 8.0 and 9.6/100,000 for men; for women they were 3.6 and 4.3/ 100,000. Figure 2, in the upper row, gives age-specific rate trends in mortality for gastric cancer from 3034 to 8084 years plotted against the period of death on a logarithmic scale and stratified by both quinquennium of age (horizontal lines, labels on the right) and cohort of birth (diagonal grey lines, labels on the left and bottom), in the EU for men and women. These show steady downward trends for all the age groups in both sexes from the earliest calendar years. These trends, however, show some tendency towards attenuation over the more recent calendar years in the young, and consequently the more recent cohorts of birth. The lower row of the figure shows the APC analysis plots with CI for the same EU data. In these analyses the age values increased in both sexes to reach 220/100.000 in men and 130 in women in the 80- to 84-year age group.
For both sexes the peak value in the cohort effect was reached for the cohorts with central year of birth in 1875. A substantial decrease in risk was observed for each subsequent cohort, although the slope tended to flatten for generations born after the 1920s, particularly in women. The period effect reached a peak in the 1960 to 1964 quinquennium and steadily declined thereafter. Figures 3 and 4 show the estimates of the effects of age, period, and cohort of birth with approximate 95% CIs for men and women, respectively. Countries with smaller populations, and consequently, lower absolute numbers of certified deaths displayed greater variability in their estimates, this being particularly evident for Albania, Estonia, and Slovakia. The age curves reflect the geographic difference observed in the age standardized mortality rates. In Northern and Western European countries such as France, Sweden, and the UK, the age values were lower in both sexes compared with those found in Southern and Eastern countries such as Italy, Portugal, and Hungary. The Western and Northern European countries with the more favorable rates had strong period and cohort effects, that decreased steeply from the earliest cohorts until those born in the 1940s. For more recent cohorts, however, the descending trend slowed
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FIGURE 2. EU male and female age-specific mortality rate trends, from 30–34 to 80–84 years, plotted, in the upper row, on a logarithmic scale, against period of death and stratified by both quinquennium of age (horizontal black lines with labels to the right) and cohort of birth (diagonal gray lines with labels to the left and bottom). The lower row of the figure shows the APC analysis plots: age (30–34 to 80–84 years), period (quinquennia 1950–54 to 2005–07), and cohort (central years of birth 1870 to 1975) effect estimates. Age estimates are expressed as age-specific mortality rates per 100 000 inhabitants; cohort and period estimates are expressed as multiplicative effects relative to the age estimates. Effect estimates are in black, approximate 95% confidence interval limits in grey.
down and eventually, in some countries, reached a plateau. In men, this was particularly evident in France and the UK for birth cohorts born after the 1940s. In women, this phenomenon was apparent in more countries, such as Denmark, Finland, the Netherlands, Sweden, and Switzerland. Hints of this behavior were also seen, to a lesser degree, in Southern and Central European countries like Austria and Italy. Former nonmarket economy Central and Eastern European countries (13) displayed a later start in the cohort effect decrease, but showed persistent decreases up to the most recent cohorts born in the 1970s. Some stabilization in the younger cohorts was restricted to
selected countries, such as the Czech Republic and Slovenia, particularly in women. DISCUSSION Before discussing the results of the APC analysis, a few general considerations on the model are useful. Firstly, random variation differs in relation to age, period, and cohort estimates. These are minor when related to period of death values because they are based on relatively similar numbers over subsequent calendar periods; for age values, problems usually concern the younger age groups, where
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FIGURE 3. Age (30–34 to 80–84 years), period (quinquennia 1950–1954 to 2005–2007), and cohort (central years of birth 1870 to 1975) effect estimates. Age estimates are expressed as age-specific mortality rates per 100,000 men for selected countries of the European geographical area, cohort, and period estimates are expressed as multiplicative effects relative to the age estimates. Effect estimates are in black, approximate 95% confidence interval limits in gray.
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FIGURE 4. Age (30–34 to 80–84 years), period (quinquennia 1950–1954 to 2005–2007), and cohort (central years of birth 1870 to 1975) effect estimates. Age estimates are expressed as age-specific mortality rates per 100,000 women for selected countries of the European geographical area, cohort, and period estimates are expressed as multiplicative effects relative to the age estimates. Effect estimates are in black, approximate 95% confidence interval limits in gray.
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absolute numbers of gastric cancer deaths are lower. For cohort effects, these issues are greater at both ends of the curve because the earlier and more recent cohorts are based on very few observations; again, the more recent cohorts are based on smaller numbers of deaths, given that they refer to the youngest age groups. Consequently, changes in trends in recent cohorts should be examined with caution, even though they provide important information towards future trends (7, 14). Another limit of the model is that it has difficulties discerning whether the major underlying trend is a cohort or a period one when both their estimated effects share the same direction, as in the case of the downward trends recorded in the analysis of gastric cancer mortality. Furthermore, this model also has a systematic tendency to favor cohort effects as they have greater weight with their larger number of parameters (6, 15, 16). These limitations of the model may also partly explain the downturn in effects found in the older age groups of some countries, together with undercertification in the elderly. The reasons for this marked and widespread decrease in gastric cancer mortality are complex. Most certainly, they reflect the effects of Helicobacter pylori (HP) infection control, the major known risk factor (17, 18). The role of HP infection on stomach cancer through the promotion of precancerous lesions, such as atrophic gastritis and dysplasia, is well established, and prevalence of HP infection is correlated with gastric cancer rates in Europe (19, 20). HP prevalence has substantially decreased in developed countries during recent decades, paralleling the decrease in gastric cancer incidence (21); better hygiene, less crowding, richer nutrition, and the use of antibiotics have all been suggested as potential reasons for the fall in HP prevalence (22). Since in most cases the infection is acquired in childhood, this would be essentially reflected in a cohort effect on gastric cancer mortality. However, not all populations with high rates of HP infection, such as Africa and south Asia, have an increased incidence of gastric cancer, and only a proportion of all infected hosts develop gastric cancer during their lifetime. Therefore, additional factors appear to influence the outcome of infection and the development of gastric cancer, and these include bacterial virulence, host genetics, age of acquisition of infection, and environmental factors (23). Furthermore, the decrease in stomach cancer rates is, at least in part, the result of improvements in diet, and in particular, to the availability of a richer, more varied and affluent diet (17, 18, 24) and to the introduction of refrigeration, which increased the consumption of fruit and vegetables and decreased the use of salt for food storage and conservation (25). In North America and in most Nordic European countries, electric refrigeration became widely available between the 1930s and 1950s. In Italy refrigeration
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was still uncommon in the 1950s but had become almost universal one decade later. In Japan, the use of electric refrigeration increased rapidly in households between 1960 and 1970, approximately when gastric cancer rates started to decrease (26). In Russia and other Central and Eastern European countries, refrigeration was available later, and this may in part explain the later onset of declines in gastric cancer and the present high rates (27). Further availability of foods and variety of diet were limited in those countries before the 1990s (28), and gastric cancer rates were inversely related to markers of vegetable and fruit intake and directly to carbohydrate intake (29). Current Russian rates are comparable with those of several Western European countries 40 to 50 years ago (17, 30). There is also a positive correlation between consumption of salt and salted foods and stomach cancer risk (31). The authors of analytic epidemiological studies have generally found an approximately 2-fold risk of gastric cancer for frequent consumption of salt and salted food (4, 31–33). Salt was widely used as a method of food preservation in the past, and its use has decreased with the adoption of refrigeration, food additives, and other modern methods of food preservation. Ecological data on salt intake and gastric cancer incidence or mortality in various populations are, however, limited and inconsistent. In Japan, time trend analyses showed a parallel decline in per capita consumption of salted fish and vegetables and gastric cancer mortality, but little correlation with total salt intake (26). Another important cause of gastric cancer is tobacco smoking, with a positive relationship with duration of smoking and number of cigarettes smoked, as well as risk reduction with increasing duration of quitting (23). Given that smokers have a 50% to 60% increased risk of stomach cancer compared with nonsmokers, the proportion of gastric cancer cases attributable to cigarette smoking is estimated to approximately 10% (34) and may be larger in men in several Central European populations. Therefore, the recent decrease in smoking prevalence in men in most European countries may account for part of the fall in gastric cancer rates (35–37). The dietary and lifestyle changes have occurred over different calendar periods and age groups of various individuals, and are likely to have an impact not only on gastric cancer initiation but also on promotion. Consequently, their impact on gastric cancer mortality will be reflected both in an age and a cohort effect, leading to the mixed pattern observed in most countries. There have also been advancements in management (diagnosis and treatment) of gastric cancer during the last few decades, including earlier detection through gastroscopy, and advancements mostly in surgical but also in medical treatment of the disease (38). Any such advancement in diagnosis and treatment would essentially have an
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impact on the period effect. Its quantification on a population level in various countries remains open to discussion, but is unlikely to have been the key determinant of the fall in rates in most European countries. In conclusion, the main findings from the present analysis confirm the presence of a persisting and steady decrease of gastric cancer mortality in all the major European countries for both sexes, although there are areas in Southern and Eastern Europe in which the mortality rates still remain high. Estimates from the APC models show that such a decrease was mainly on a cohort of birth basis, which indicates that the downward trends are likely to continue in the near future, with the exception of a few Northern and Western European countries with very low rates, where an asymptote appears to have been reached for cohorts born since the 1940s. The authors thank Ivana Garimoldi for editorial assistance.
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