GYNECOLOGICONCOLOGY46, 208215 (1992)
Descriptive Epidemiology of Ovarian Cancer in Europe CARLO LA VECCHIA,*‘~ FABIO LEVI,*$~’
FRANCA
LUCCHINI,*
EVA NEGRI,~ AND SILVIA FRANCESCHIQ
‘Znstitut universitaire de medecine sociale et preventive, Bugnon 17, 1005 Lausanne, Switzerland; tlstituto di Ricerche Farmacologiche “Mario Negri,” Via Eritrea 62, 20157 Milano, Italy; SRegistre vaudois des tumeurs, Znstitut universitaire de mkdecine sociale et preventive, CHLTVFalaises 1, 1011 Lausanne, Switzerland; and $Servizio di Epidemiologia, Centro di Riferimento Oncologico, Via Pedemontana Occ, 33081 Aviano (PN), Ztaly
ReceivedNovember 13, 1991 Trends in ovarian cancer mortality over the period 1955-1989 were analyzed for 25 European countries (excluding the Soviet Union and a few small counties) on the basis of the official death certification data from the World Health Organization database. The overall variation in age-standardized ovarian cancer mortality at all ages declined appreciably, from over 17-fold during the period 19551959 (i.e., between 10.5/100,000 in Denmark and 0.6/100,000 in Spain, world standard) to 3.4-fold (i.e., between 9.9/100,000 in Denmark and 2.9/100,000 in Spain) in the late 1980s.When a comparison was made between the late 1950sand the 198Os,ovarian cancer mortality increased in most European countries, except Denmark, Sweden, and Switzerland, where certified mortality was already elevated in the late 195Os,although also in these countries the peak rate around or over lO/lOO,OOO was reached during the 1960s. However, when the changes over the last decade were considered, ovarian cancer mortality trends were downward in all Nordic countries, Germany, Switzerland, Austria, and Czechoslovakia. Mortality was rising somewhat, though to a smaller extent, in Ireland, Britain, and Southern Europe. Trends were more favorable in middle-aged women (35 to 64 years), and, to an even greater extent, in young women (aged 20 to 44), among whom substantial declines, particularly over the last decade, were observed in most European countries, approaching 50% in Britain and Scandinavia. These trends are discussed in terms of changes in risk factor exposure (i.e., trends in average parity and oral contraceptive use), diagnostic and therapeutic improvements, ovariectomy, and changes in case ascertainment and certification. o 1~ AC&& press, IX Ovarian cancer is a disease of affluent societies and is among the five leading sites for incidence and mortality (and the first killer among gynecological malignancies) in most industrialized countries [l]. Also within developed countries, however, there is an appreciable variation in ovarian cancer incidence and mortality, the highest risk areas being in North America, Scandinavian countries, ’ To whom reprint requests should be addressed. 208 OOW8258B2 $4.00 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
TABLE 1 List of Countries and Calendar Years for Which Data for Ovarian Cancer Were Missing Across the Period 1955-1989 Country Austria
Belgium Bulgaria Czechoslovakia Denmark Finland France Germany, GDR Germany, FRG Greece Hungary Iceland Ireland Italy Netherlands Norway Poland Portugal Spain Sweden Yugoslavia
Years 55-68 80-83, 85, 87-89 55-65, 80-88 79, 81, 84-86, 89 89 87-89 89 55-75, 77-82 55-67 55-65, 89 55-69 55-70, 81-82 89 89 89 89 55-60, 69, 72-89 55-83 87-89 88-89 55-59, 79-89
and the United Kingdom in Europe, while lower rates were generally observed in southern and eastern Europe
P-51
The picture is less clear in relation to trends in ovarian cancer rates, since a general impression of increasing rates is probably still influenced by earlier rises rather than by more recent trends [6]. There is also scope for detailed analysis of patterns and trends in ovarian cancer rates in separate age groups, which may reflect different histological distribution of ovarian neoplasms in younger and older women, and the changing impact of various risk
OVARIAN
CANCER MORTALITY
209
IN EUROPE
TABLE 2
Trends in Mortality from Ovarian Cancer in Selected European Countries Percentage change Age-standardized” death certification rate 100,000 women Average population (x 1000, last census, circa 1980)
Country Austria Belgium Bulgaria Czechoslovakia Denmark Finland France Germany, GDR Germany, FRG Greece Hungary Iceland Ireland Italy Netherlands Norway Poland Portugal Spain Sweden Switzerland UK, England, and Wales UK, Northern Ireland UK, Scotland Yugoslavia
3,954.9 5,034.6 4446.5 7J33.5 2,591.3 2,470.8 27,456.6 8J89.6 32J41.6 4,887.0 5,516.5 110.5 1,692.4 29,124.l 7,123.0 2,061.3 l&269.7 5,158.2 19,061.o 4J90.3 3,252.8 25,323.5 779.4 2,676.3 11,315.2
Highest/lowest
1955-1959
1965-1969
1975-1979
198.5-1989
4.3 3.0 7.7 7.9 0.6 8.8 7.8 8.1 5.8 7.3 -
9.3 6.2 3.5 7.1 11.8 6.4 4.1 7.5 1.1 5.8 3.4 8.6 8.6 4.1 0.9 9.6 8.5 8.6 5.9 8.1 3.5
9.0 7.1 7.8 10.9 7.2 5.2 9.0 8.0 2.1 6.9 9.1 7.5 3.9 9.0 8.5 2.0 9.6 8.6 8.9 6.4 8.3 3.8
8.0 7.2 3.5 6.3 9.9 6.0 5.9 6.5 7.7 3.0 7.0 8.3 8.1 4.9 7.9 8.3 3.0 2.9 7.9 7.0 8.5 7.5 8.0 -
17.5
13.1
5.5
3.4
5.3 6.0 10.5 5.3 3.2 -
1985-1989 vs. 1955-1959
+36 +5 -6 +13 +84
-
+88 +63 +3 +5 + 383 -10 -10 +5 +29 +10 -
Last decade -11 +1 -19 -9 -17 +13 -28 -4 +43 +1 -9 +8 +26 -12 -2 +45 -18 -19 -4 +17 -4 -
’ Based on the world standard population.
factors and hence diverging cohort effects, besides a variable influence of diagnostic and certification accuracy. With these considerations in mind, we decided to examine the pattern of trends in ovarian cancer mortality in various European countries over the last few decades. MATERIALS AND METHODS Official death certification numbers for 25 European countries (excluding the former Soviet Union and a few countries like Andorra and Liechtenstein) were derived from the World Health Organization (WHO) database [7]. During the calendar period considered (1955-1989) four different Revisions of the International Classification of Diseases (ICD) were used [8-111. Classification of ovarian cancer deaths was thus recoded, for all calendar periods and countries, according to the Ninth Revision of the International Classification of Diseases (ICD-9), i.e., the ICD code 175 for the Sixth and Seventh Revisions was pooled together with the code 183 for the Eighth and
Ninth Revisions. There is little reason to suspect that coding and classification changes have materially affected ovarian cancer rates, and no systematic change in rates was observed across subsequent ICD Revisions. Estimates of the resident population, generally based on official censuses, were obtained from the same WHO databank. Population estimates are acceptably accurate for various European countries. From the matrices of certified deaths and resident populations, age-specific rates for each 5-year age group and calendar period were computed. Age-standardized rates, at all ages and truncated 35-64 and 20-44 years, were based on the world standard population [12]. Truncated rates from 35 to 64 years were generally adopted to reduce problems of death certification reliability at more advanced ages; trends in young adults may give useful information on future trends. In a few countries, data were missing for part of one or more calendar periods (Table 1). When a single year was missing within a quinquennium, numerators and de-
210
LA VECCHIA TABLE
ET AL. 3
Trends in Mortality from Ovarian Cancer at Ages 35-64 in Selected European Countries Percentage change
Age-standardized” death certification rate 100,000 women aged 35-64 Country
1955-1959
-
1965-1969
1975-1979
1985-1989
17.4 13.6 15.9 20.9 13.7 10.0 18.8 15.5 5.0 13.2 17.1 15.5 8.0 17.6 17.3 4.3 18.4 15.8 18.4 12.8 17.0 8.2
13.8 12.6 7.9 13.3 18.9 10.6 10.4 12.2 13.2 6.2 12.6 14.8 15.9 9.1 13.1 15.9 5.8 5.9 14.8 11.5 16.5 14.5 14.7 -
4.9
3.3
Austria Belgium Bulgaria Czechoslovakia Denmark Finland France Germany, GDR Germany, FRG Greece Hungary Iceland Ireland Italy Netherlands Norway Poland Portugal Spain Sweden Switzerland UK, England, and Wales UK, Northern Ireland UK, Scotland Yugoslavia
10.0 6.0 15.9 17.4 1.2 18.7 15.5 17.7 11.7 15.8 -
18.6 12.4 7.9 14.5 23.1 12.4 8.3 15.4 2.6 12.2 7.2 16.5 17.9 9.0 2.1 18.8 15.9 18.0 13.2 17.1 6.5
Highest/lowest
18.3
11.0
11.7 13.1 22.0 10.5 6.9 -
-
1985-1989 1955ysl959
-
+8
+2 -14 +1 +51
-
+59 +52 -18 -9
-
+ 392 -21 -26 -7 +24 -7 -
Last decade -21 -7 -16 -10 -23 -4 -35 -15 +24 -5 -13 +3 +14 -26 -8 -
+37 -20 -27 -10 +13 -14 -
* Based on the world standard population.
nominators were interpolated linearly for the previous and subsequent calendar year. No extrapolation was made for missing data at the beginning or the end of the calendar period considered, or when data on one or more quinquennia were not available. RESULTS
Table 2 gives the trends in overall age-standardized death certification rates from ovarian cancer in various European countries over the period 1955-1989. The last 5 years of each decade (i.e., 1955-1959,1965-1969) were shown since data were scanty for early 1950sand to reduce the figures given in the table. Rates in the missing calendar quinquennia were consistent with those presented. The overall variation diminished appreciably, from over 17-fold during the period 1955-1959 (i.e., between 10.5/100,000 in Denmark and 0.6/100,000 in Spain) to 3.4-fold (i.e., between 9.9/100,000 in Denmark and
2.9/100,000 in Spain) in the late 1980s. When comparison was made between the last and the first calendar period, ovarian cancer mortality increased in most European countries, except Denmark, Sweden, and Switzerland, where certified mortality was already elevated in the late 1950s(although also in these countries the peak rate, over or around 10/100,000, was reached during the 1960s). Moreover, when the changes over the last decade-i.e., between the late 1970s and the late 1980s-were considered, ovarian cancer rates were decreased in all Nordic countries, Germany, Switzerland, Austria, and Czechoslovakia. Mortality was still somewhat rising, though to a smaller extent than in the previous decades, in Ireland, Britain, France, Spain, Italy, and Greece. When truncated, ages 35-64, ovarian mortality rates were considered (Table 3), earlier upward trends were more moderate and restricted to Ireland, France, Belgium, Italy, and Spain. Again, there was a systematic tendency toward flattening of differences over more re-
OVARIAN
CANCER MORTALITY
211
IN EUROPE
TABLE 4 Trends in Mortality from Ovarian Cancer at Ages 20-44 in Selected European Countries Percentage change
Age-standardized“ death certification rate 100,000 women aged 20-44 country Austria Belgium Bulgaria Czechoslovakia Denmark Finland France Germany, GDR Germany, FRG Greece Hungary Iceland Ireland Italy Netherlands Norway Poland Portugal Spain Sweden Switzerland UK, England, and Wales UK, Northern Ireland UK, Scotland Yugoslavia Highest/lowest
19.5-1959
196551969
1975-1979
1985-1989
-
2.16 2.17 1.56 2.21 3.18 2.03 1.50
1.39 1.16 1.46 1.63 1.86 1.17 1.22 1.47 1.36 1.08 1.87 0.92 1.54 1.39 1.56 1.58 1.22 0.94 1.33 1.12 1.83 1.91 1.45 2.1
2.08 1.27 2.82 2.98 -
2.72 0.68 2.15 1.44 2.69 2.43 1.89
0.38 2.69 1.88 2.93 2.48 2.78 -
0.50 2.65 2.08 2.77 2.17 2.73 1.19
2.42 1.93 2.48 2.47 1.71 1.54 2.97 2.03 0.94 1.98 1.14 2.16 1.47 2.15 1.79 0.90 2.26 1.73 2.52 1.17 2.65 1.30
7.8
6.4
3.3
2.08 2.13 2.83 2.15 1.31
-
1985-1989 vs. 1955-1959 -44 -
-23 -34 -46 -7
-26 +9 -45 -47
-
+ 147 -51 -40 -38 -23 -48 -
Last decade -43 -40 -34 -25 -32 -21 -51 -33 +15 -6 -19 -29 -5 -27 - 12 -
+4 -41 -35 -27 -63 -45 -
s Based on the world standard population.
cent calendar periods, from over l&fold in the late 1950s to 3.3-fold in 1985-1989. Over the last decade, the trends for ovarian cancer rates in middle age were increasing only in southern Europe, while substantial declines were observed in northern and central European countries, reaching 35% in Eastern Germany and over 20% in Austria, Finland, the Netherlands, Sweden, and Switzerland. The pattern was even more favorable when only young adults (ages 20 to 44) were considered (Table 4). Substantial declines, particularly over the last decade, were observed in most European countries, approaching 30% in Britain and Nordic countries. Some upward trend was present only in southern Europe, which, however, tended to flatten off over recent calendar periods. Again, the ratio between the highest and the lowest mortality rate declined from almost eightfold in 1955-1959 to about twofold in 1985-1989. Trends in age-standardized and age-specific ovarian cancer mortality are further presented in Fig. 1 for a few selected countries. A first group included France, Italy,
and, particularly, Spain, and showed overall increases in ovarian cancer rates. In contrast, trends in ovarian cancer mortality were stable or favorable, though to a variable degree and particularly over the last decade, in countries like the Federal Republic of Germany, Sweden, Switzerland, and England and Wales. Accurate inspection of age-specific rates in subsequent groups, moreover, shows that upward trends persisted longer at older ages in most countries, while recent trends tended to be favorable at younger ages in most European populations. Finally, Fig. 2 shows a graph of the histogram of ovarian cancer mortality over the most recent calendar quinquennium at all ages and in the two truncated age groups, 35-64 and 20-44. DISCUSSION
This overview of ovarian cancer trends in various European countries showed appreciable heterogeneity across different age groups and countries. The major observa-
212
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OVARIAN
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213
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tions were a generalized trend towards a leveling of between-country differences in ovarian cancer mortality, since the stable+or declining-trends in northern Europe were counterbalanced by upward trends in southern European countries, where rates were initially lower. Further, some persisting rise in elderly women was not reproduced in middle age and in the young, where recent trends were almost uniformly favorable. This pattern of trends probably reflects a complex of factors, including changes in risk factor exposure, diagnostic and therapeutic improvement, ovariectomy , and changes in case ascertainment and certification. Risk factors for ovarian cancer are only partly recognized [l], but can explain at least part of the pattern of trends. It is known, in fact, that nulliparity, low parity, and, possibly, late age at first birth are associated with elevated ovarian cancer risk [l]. In the past, average parity in northern European countries was lower than that in southern Europe, whereas now reproductive patterns have tended to become more uniform across various countries, thus being consistent with the later increases in ovarian cancer rates in southern Europe [13]. Oral contraceptives-a well-defined and quantified protective factor for ovarian cancer--spread earlier and to a larger extent in northern Europe [14-161 and are still less frequently used in southern Europe, particularly in Italy and Greece [16,17]. This may well explain some of the
214
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FIG. 2. Variation of age-standardized (world standard) ovarian cancer mortality in various European countries and age groups, 19851989.
favorable trends, particularly in more recent cohorts. For instance, in the mid 1970s the estimated percentage of women ages 15 to 44 buying oral contraceptives from pharmacies was already over 40% in the Netherlands and between 20 and 30% in Britain, France, Germany, and Sweden, but less than 5% in Italy, Spain, and Greece. In the late 1980s the frequencies did not change appreciably or systematically in northern or central Europe and, although rising to about 12% in Spain, 10% in Italy, and 5% in Greece, remained substantially lower in southern European countries [ 181. In addition to reproductive or hormonal factors, diet is likely to be of some relevance to the etiology of ovarian cancer, although its role is still poorly quantified [1,13,19]. Diet may well explain part of the international variation of the disease, and also some of the narrowing of ranges across Europe, since dietary patterns have also tended to become more uniform in various countries over most recent decades [13]. Finally, it is possible that recent improvements in therapy have had some favorable impact on ovarian cancer mortality, particularly for nonepithelial neoplasms which are more common at younger ages [20-231. Indeed, although improvements in overall survival rates from ovarian cancer have been limited (5-year relative survival rates from the Surveillance, Epidemiology, and End Results (SEER) Program changed from 36.4% in casesdiagnosed in 1974-1976 to 38.8% in those diagnosed in 1981-1987 [24]), there is evidence that the survival rates among the youngest age groups have improved appreciably [22]. There are, therefore, various reasons to indicate that the patterns of ovarian cancer trends observed over the past four decades in various European countries are, at least in part, real. However, some of these trends are almost certainly due to differential changes in ovariectomy rates, and hence of the population at risk. Another
appreciable proportion of certified trends-though difficult to quantify-is probably artifactual, and due to different patterns of change in accuracy and reliability of death notification, since diagnosis and ascertainment of cancer of the ovary are often complex and may have improved to a different extent in various countries and age groups [25]. If these changes in death certification accuracy account for at least part of the increases of death rates in the elderly, the real trends in ovarian cancer mortality are probably more favorable than indicated by simple inspection of overall age-standardized rates, and the favorable trends observed in younger women may well involve older ages in the future [26,27]. Still, since ovarian cancer incidence and mortality are comparatively low in young women, on a population level the impact of these trends is relatively limited. Further, the different histologic distribution of ovarian cancer at various ages, the presence of complex cohort effects, and, most of all, the uncertainties in the etiology of ovarian cancer hamper simple extrapolation of trends now observed in the young at older ages [20], thus underlining the importance of continuing surveillance of future ovarian cancer trends. ACKNOWLEDGMENTS This study has been made possible by a core grant from the Swiss (Aargau and St-Gall) League against cancer. Support was also received from the Italian Association for Cancer Research and the Italian League against cancer. This study was conducted within the framework of the CNR (Italian National Research Council) Applied Projects “Clinical Application of Oncological Research” and of the “Europe Against Cancer” Program of the Commission of the “Risk Factors for Disease,” and European Communities.
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OVARIAN
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Descriptive Epidemiology of Ovarian Cancer in Europe CARLO LA VECCHIA,*‘~ FABIO LEVI,*$~’
FRANCA
LUCCHINI,*
EVA NEGRI,~ AND SILVIA FRANCESCHIQ
‘Znstitut universitaire de medecine sociale et preventive, Bugnon 17, 1005 Lausanne, Switzerland; tlstituto di Ricerche Farmacologiche “Mario Negri,” Via Eritrea 62, 20157 Milano, Italy; SRegistre vaudois des tumeurs, Znstitut universitaire de mkdecine sociale et preventive, CHLTVFalaises 1, 1011 Lausanne, Switzerland; and $Servizio di Epidemiologia, Centro di Riferimento Oncologico, Via Pedemontana Occ, 33081 Aviano (PN), Ztaly
ReceivedNovember 13, 1991 Trends in ovarian cancer mortality over the period 1955-1989 were analyzed for 25 European countries (excluding the Soviet Union and a few small counties) on the basis of the official death certification data from the World Health Organization database. The overall variation in age-standardized ovarian cancer mortality at all ages declined appreciably, from over 17-fold during the period 19551959 (i.e., between 10.5/100,000 in Denmark and 0.6/100,000 in Spain, world standard) to 3.4-fold (i.e., between 9.9/100,000 in Denmark and 2.9/100,000 in Spain) in the late 1980s.When a comparison was made between the late 1950sand the 198Os,ovarian cancer mortality increased in most European countries, except Denmark, Sweden, and Switzerland, where certified mortality was already elevated in the late 195Os,although also in these countries the peak rate around or over lO/lOO,OOO was reached during the 1960s. However, when the changes over the last decade were considered, ovarian cancer mortality trends were downward in all Nordic countries, Germany, Switzerland, Austria, and Czechoslovakia. Mortality was rising somewhat, though to a smaller extent, in Ireland, Britain, and Southern Europe. Trends were more favorable in middle-aged women (35 to 64 years), and, to an even greater extent, in young women (aged 20 to 44), among whom substantial declines, particularly over the last decade, were observed in most European countries, approaching 50% in Britain and Scandinavia. These trends are discussed in terms of changes in risk factor exposure (i.e., trends in average parity and oral contraceptive use), diagnostic and therapeutic improvements, ovariectomy, and changes in case ascertainment and certification. o 1~ AC&& press, IX Ovarian cancer is a disease of affluent societies and is among the five leading sites for incidence and mortality (and the first killer among gynecological malignancies) in most industrialized countries [l]. Also within developed countries, however, there is an appreciable variation in ovarian cancer incidence and mortality, the highest risk areas being in North America, Scandinavian countries, ’ To whom reprint requests should be addressed. 208 OOW8258B2 $4.00 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
TABLE 1 List of Countries and Calendar Years for Which Data for Ovarian Cancer Were Missing Across the Period 1955-1989 Country Austria
Belgium Bulgaria Czechoslovakia Denmark Finland France Germany, GDR Germany, FRG Greece Hungary Iceland Ireland Italy Netherlands Norway Poland Portugal Spain Sweden Yugoslavia
Years 55-68 80-83, 85, 87-89 55-65, 80-88 79, 81, 84-86, 89 89 87-89 89 55-75, 77-82 55-67 55-65, 89 55-69 55-70, 81-82 89 89 89 89 55-60, 69, 72-89 55-83 87-89 88-89 55-59, 79-89
and the United Kingdom in Europe, while lower rates were generally observed in southern and eastern Europe
P-51
The picture is less clear in relation to trends in ovarian cancer rates, since a general impression of increasing rates is probably still influenced by earlier rises rather than by more recent trends [6]. There is also scope for detailed analysis of patterns and trends in ovarian cancer rates in separate age groups, which may reflect different histological distribution of ovarian neoplasms in younger and older women, and the changing impact of various risk
OVARIAN
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209
IN EUROPE
TABLE 2
Trends in Mortality from Ovarian Cancer in Selected European Countries Percentage change Age-standardized” death certification rate 100,000 women Average population (x 1000, last census, circa 1980)
Country Austria Belgium Bulgaria Czechoslovakia Denmark Finland France Germany, GDR Germany, FRG Greece Hungary Iceland Ireland Italy Netherlands Norway Poland Portugal Spain Sweden Switzerland UK, England, and Wales UK, Northern Ireland UK, Scotland Yugoslavia
3,954.9 5,034.6 4446.5 7J33.5 2,591.3 2,470.8 27,456.6 8J89.6 32J41.6 4,887.0 5,516.5 110.5 1,692.4 29,124.l 7,123.0 2,061.3 l&269.7 5,158.2 19,061.o 4J90.3 3,252.8 25,323.5 779.4 2,676.3 11,315.2
Highest/lowest
1955-1959
1965-1969
1975-1979
198.5-1989
4.3 3.0 7.7 7.9 0.6 8.8 7.8 8.1 5.8 7.3 -
9.3 6.2 3.5 7.1 11.8 6.4 4.1 7.5 1.1 5.8 3.4 8.6 8.6 4.1 0.9 9.6 8.5 8.6 5.9 8.1 3.5
9.0 7.1 7.8 10.9 7.2 5.2 9.0 8.0 2.1 6.9 9.1 7.5 3.9 9.0 8.5 2.0 9.6 8.6 8.9 6.4 8.3 3.8
8.0 7.2 3.5 6.3 9.9 6.0 5.9 6.5 7.7 3.0 7.0 8.3 8.1 4.9 7.9 8.3 3.0 2.9 7.9 7.0 8.5 7.5 8.0 -
17.5
13.1
5.5
3.4
5.3 6.0 10.5 5.3 3.2 -
1985-1989 vs. 1955-1959
+36 +5 -6 +13 +84
-
+88 +63 +3 +5 + 383 -10 -10 +5 +29 +10 -
Last decade -11 +1 -19 -9 -17 +13 -28 -4 +43 +1 -9 +8 +26 -12 -2 +45 -18 -19 -4 +17 -4 -
’ Based on the world standard population.
factors and hence diverging cohort effects, besides a variable influence of diagnostic and certification accuracy. With these considerations in mind, we decided to examine the pattern of trends in ovarian cancer mortality in various European countries over the last few decades. MATERIALS AND METHODS Official death certification numbers for 25 European countries (excluding the former Soviet Union and a few countries like Andorra and Liechtenstein) were derived from the World Health Organization (WHO) database [7]. During the calendar period considered (1955-1989) four different Revisions of the International Classification of Diseases (ICD) were used [8-111. Classification of ovarian cancer deaths was thus recoded, for all calendar periods and countries, according to the Ninth Revision of the International Classification of Diseases (ICD-9), i.e., the ICD code 175 for the Sixth and Seventh Revisions was pooled together with the code 183 for the Eighth and
Ninth Revisions. There is little reason to suspect that coding and classification changes have materially affected ovarian cancer rates, and no systematic change in rates was observed across subsequent ICD Revisions. Estimates of the resident population, generally based on official censuses, were obtained from the same WHO databank. Population estimates are acceptably accurate for various European countries. From the matrices of certified deaths and resident populations, age-specific rates for each 5-year age group and calendar period were computed. Age-standardized rates, at all ages and truncated 35-64 and 20-44 years, were based on the world standard population [12]. Truncated rates from 35 to 64 years were generally adopted to reduce problems of death certification reliability at more advanced ages; trends in young adults may give useful information on future trends. In a few countries, data were missing for part of one or more calendar periods (Table 1). When a single year was missing within a quinquennium, numerators and de-
210
LA VECCHIA TABLE
ET AL. 3
Trends in Mortality from Ovarian Cancer at Ages 35-64 in Selected European Countries Percentage change
Age-standardized” death certification rate 100,000 women aged 35-64 Country
1955-1959
-
1965-1969
1975-1979
1985-1989
17.4 13.6 15.9 20.9 13.7 10.0 18.8 15.5 5.0 13.2 17.1 15.5 8.0 17.6 17.3 4.3 18.4 15.8 18.4 12.8 17.0 8.2
13.8 12.6 7.9 13.3 18.9 10.6 10.4 12.2 13.2 6.2 12.6 14.8 15.9 9.1 13.1 15.9 5.8 5.9 14.8 11.5 16.5 14.5 14.7 -
4.9
3.3
Austria Belgium Bulgaria Czechoslovakia Denmark Finland France Germany, GDR Germany, FRG Greece Hungary Iceland Ireland Italy Netherlands Norway Poland Portugal Spain Sweden Switzerland UK, England, and Wales UK, Northern Ireland UK, Scotland Yugoslavia
10.0 6.0 15.9 17.4 1.2 18.7 15.5 17.7 11.7 15.8 -
18.6 12.4 7.9 14.5 23.1 12.4 8.3 15.4 2.6 12.2 7.2 16.5 17.9 9.0 2.1 18.8 15.9 18.0 13.2 17.1 6.5
Highest/lowest
18.3
11.0
11.7 13.1 22.0 10.5 6.9 -
-
1985-1989 1955ysl959
-
+8
+2 -14 +1 +51
-
+59 +52 -18 -9
-
+ 392 -21 -26 -7 +24 -7 -
Last decade -21 -7 -16 -10 -23 -4 -35 -15 +24 -5 -13 +3 +14 -26 -8 -
+37 -20 -27 -10 +13 -14 -
* Based on the world standard population.
nominators were interpolated linearly for the previous and subsequent calendar year. No extrapolation was made for missing data at the beginning or the end of the calendar period considered, or when data on one or more quinquennia were not available. RESULTS
Table 2 gives the trends in overall age-standardized death certification rates from ovarian cancer in various European countries over the period 1955-1989. The last 5 years of each decade (i.e., 1955-1959,1965-1969) were shown since data were scanty for early 1950sand to reduce the figures given in the table. Rates in the missing calendar quinquennia were consistent with those presented. The overall variation diminished appreciably, from over 17-fold during the period 1955-1959 (i.e., between 10.5/100,000 in Denmark and 0.6/100,000 in Spain) to 3.4-fold (i.e., between 9.9/100,000 in Denmark and
2.9/100,000 in Spain) in the late 1980s. When comparison was made between the last and the first calendar period, ovarian cancer mortality increased in most European countries, except Denmark, Sweden, and Switzerland, where certified mortality was already elevated in the late 1950s(although also in these countries the peak rate, over or around 10/100,000, was reached during the 1960s). Moreover, when the changes over the last decade-i.e., between the late 1970s and the late 1980s-were considered, ovarian cancer rates were decreased in all Nordic countries, Germany, Switzerland, Austria, and Czechoslovakia. Mortality was still somewhat rising, though to a smaller extent than in the previous decades, in Ireland, Britain, France, Spain, Italy, and Greece. When truncated, ages 35-64, ovarian mortality rates were considered (Table 3), earlier upward trends were more moderate and restricted to Ireland, France, Belgium, Italy, and Spain. Again, there was a systematic tendency toward flattening of differences over more re-
OVARIAN
CANCER MORTALITY
211
IN EUROPE
TABLE 4 Trends in Mortality from Ovarian Cancer at Ages 20-44 in Selected European Countries Percentage change
Age-standardized“ death certification rate 100,000 women aged 20-44 country Austria Belgium Bulgaria Czechoslovakia Denmark Finland France Germany, GDR Germany, FRG Greece Hungary Iceland Ireland Italy Netherlands Norway Poland Portugal Spain Sweden Switzerland UK, England, and Wales UK, Northern Ireland UK, Scotland Yugoslavia Highest/lowest
19.5-1959
196551969
1975-1979
1985-1989
-
2.16 2.17 1.56 2.21 3.18 2.03 1.50
1.39 1.16 1.46 1.63 1.86 1.17 1.22 1.47 1.36 1.08 1.87 0.92 1.54 1.39 1.56 1.58 1.22 0.94 1.33 1.12 1.83 1.91 1.45 2.1
2.08 1.27 2.82 2.98 -
2.72 0.68 2.15 1.44 2.69 2.43 1.89
0.38 2.69 1.88 2.93 2.48 2.78 -
0.50 2.65 2.08 2.77 2.17 2.73 1.19
2.42 1.93 2.48 2.47 1.71 1.54 2.97 2.03 0.94 1.98 1.14 2.16 1.47 2.15 1.79 0.90 2.26 1.73 2.52 1.17 2.65 1.30
7.8
6.4
3.3
2.08 2.13 2.83 2.15 1.31
-
1985-1989 vs. 1955-1959 -44 -
-23 -34 -46 -7
-26 +9 -45 -47
-
+ 147 -51 -40 -38 -23 -48 -
Last decade -43 -40 -34 -25 -32 -21 -51 -33 +15 -6 -19 -29 -5 -27 - 12 -
+4 -41 -35 -27 -63 -45 -
s Based on the world standard population.
cent calendar periods, from over l&fold in the late 1950s to 3.3-fold in 1985-1989. Over the last decade, the trends for ovarian cancer rates in middle age were increasing only in southern Europe, while substantial declines were observed in northern and central European countries, reaching 35% in Eastern Germany and over 20% in Austria, Finland, the Netherlands, Sweden, and Switzerland. The pattern was even more favorable when only young adults (ages 20 to 44) were considered (Table 4). Substantial declines, particularly over the last decade, were observed in most European countries, approaching 30% in Britain and Nordic countries. Some upward trend was present only in southern Europe, which, however, tended to flatten off over recent calendar periods. Again, the ratio between the highest and the lowest mortality rate declined from almost eightfold in 1955-1959 to about twofold in 1985-1989. Trends in age-standardized and age-specific ovarian cancer mortality are further presented in Fig. 1 for a few selected countries. A first group included France, Italy,
and, particularly, Spain, and showed overall increases in ovarian cancer rates. In contrast, trends in ovarian cancer mortality were stable or favorable, though to a variable degree and particularly over the last decade, in countries like the Federal Republic of Germany, Sweden, Switzerland, and England and Wales. Accurate inspection of age-specific rates in subsequent groups, moreover, shows that upward trends persisted longer at older ages in most countries, while recent trends tended to be favorable at younger ages in most European populations. Finally, Fig. 2 shows a graph of the histogram of ovarian cancer mortality over the most recent calendar quinquennium at all ages and in the two truncated age groups, 35-64 and 20-44. DISCUSSION
This overview of ovarian cancer trends in various European countries showed appreciable heterogeneity across different age groups and countries. The major observa-
212
LA VECCHIA ET AL. a
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FIG. 1. Trends in age-standardized (world standard) and age-specific death rates from ovarian cancer in selected European countries, 1955 1989.
OVARIAN
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MORTALITY
213
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tions were a generalized trend towards a leveling of between-country differences in ovarian cancer mortality, since the stable+or declining-trends in northern Europe were counterbalanced by upward trends in southern European countries, where rates were initially lower. Further, some persisting rise in elderly women was not reproduced in middle age and in the young, where recent trends were almost uniformly favorable. This pattern of trends probably reflects a complex of factors, including changes in risk factor exposure, diagnostic and therapeutic improvement, ovariectomy , and changes in case ascertainment and certification. Risk factors for ovarian cancer are only partly recognized [l], but can explain at least part of the pattern of trends. It is known, in fact, that nulliparity, low parity, and, possibly, late age at first birth are associated with elevated ovarian cancer risk [l]. In the past, average parity in northern European countries was lower than that in southern Europe, whereas now reproductive patterns have tended to become more uniform across various countries, thus being consistent with the later increases in ovarian cancer rates in southern Europe [13]. Oral contraceptives-a well-defined and quantified protective factor for ovarian cancer--spread earlier and to a larger extent in northern Europe [14-161 and are still less frequently used in southern Europe, particularly in Italy and Greece [16,17]. This may well explain some of the
214
LA VECCHIA ALL
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FIG. 2. Variation of age-standardized (world standard) ovarian cancer mortality in various European countries and age groups, 19851989.
favorable trends, particularly in more recent cohorts. For instance, in the mid 1970s the estimated percentage of women ages 15 to 44 buying oral contraceptives from pharmacies was already over 40% in the Netherlands and between 20 and 30% in Britain, France, Germany, and Sweden, but less than 5% in Italy, Spain, and Greece. In the late 1980s the frequencies did not change appreciably or systematically in northern or central Europe and, although rising to about 12% in Spain, 10% in Italy, and 5% in Greece, remained substantially lower in southern European countries [ 181. In addition to reproductive or hormonal factors, diet is likely to be of some relevance to the etiology of ovarian cancer, although its role is still poorly quantified [1,13,19]. Diet may well explain part of the international variation of the disease, and also some of the narrowing of ranges across Europe, since dietary patterns have also tended to become more uniform in various countries over most recent decades [13]. Finally, it is possible that recent improvements in therapy have had some favorable impact on ovarian cancer mortality, particularly for nonepithelial neoplasms which are more common at younger ages [20-231. Indeed, although improvements in overall survival rates from ovarian cancer have been limited (5-year relative survival rates from the Surveillance, Epidemiology, and End Results (SEER) Program changed from 36.4% in casesdiagnosed in 1974-1976 to 38.8% in those diagnosed in 1981-1987 [24]), there is evidence that the survival rates among the youngest age groups have improved appreciably [22]. There are, therefore, various reasons to indicate that the patterns of ovarian cancer trends observed over the past four decades in various European countries are, at least in part, real. However, some of these trends are almost certainly due to differential changes in ovariectomy rates, and hence of the population at risk. Another
appreciable proportion of certified trends-though difficult to quantify-is probably artifactual, and due to different patterns of change in accuracy and reliability of death notification, since diagnosis and ascertainment of cancer of the ovary are often complex and may have improved to a different extent in various countries and age groups [25]. If these changes in death certification accuracy account for at least part of the increases of death rates in the elderly, the real trends in ovarian cancer mortality are probably more favorable than indicated by simple inspection of overall age-standardized rates, and the favorable trends observed in younger women may well involve older ages in the future [26,27]. Still, since ovarian cancer incidence and mortality are comparatively low in young women, on a population level the impact of these trends is relatively limited. Further, the different histologic distribution of ovarian cancer at various ages, the presence of complex cohort effects, and, most of all, the uncertainties in the etiology of ovarian cancer hamper simple extrapolation of trends now observed in the young at older ages [20], thus underlining the importance of continuing surveillance of future ovarian cancer trends. ACKNOWLEDGMENTS This study has been made possible by a core grant from the Swiss (Aargau and St-Gall) League against cancer. Support was also received from the Italian Association for Cancer Research and the Italian League against cancer. This study was conducted within the framework of the CNR (Italian National Research Council) Applied Projects “Clinical Application of Oncological Research” and of the “Europe Against Cancer” Program of the Commission of the “Risk Factors for Disease,” and European Communities.
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OVARIAN
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