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Ovarian cancer incidence (1989–1991) and mortality (1954–1993) in the Netherlands
Ovarian Cancer Incidence (1989-1991) and Mortality (1954-1993) in the Netherlands NORBERT P. KOPER, MSc, LAMBERTUS A. L. M. KIEMENEY, PhD, LEON F. A. G. MASSUGER, MD, PhD, CHRIS M. G. THOMAS, PhD, CHARLES P. T. SCHIJF, MD, A N D ANDRE L. M. VERBEEK, MD, PhD Objective: To examine ovarian cancer incidence and mortality in the Netherlands, and to relate trends in mortality to changes in parity and use of oral contraceptives. Methods: Age-standardized and age-specific incidence and mortality rates are presented using incidence data from the Netherlands Cancer Registry, 1989-1991, and mortality data from the Netherlands Central Bureau of Statistics, 19541993. Results: In the period 1989-1991, age-standardized incidence of ovarian cancer was 14.9 per 105 woman-years. The majority (89%) of these tumors had an epithelial origin. Two-thirds of all newly diagnosed ovarian cancers already showed extension to the pelvis or beyond at diagnosis. From the period 1954-1958 to 1969-1973, age-standardized mortality rates increased from 10.6 to 13.1 per 10s woman-years. Thereafter, a decline was noted to 11.4 per 105 woman-years in the period 1989-1993. Age-specific mortality rates showed a pattern of rising mortality in the elderly, whereas mortality in the younger age categories was declining. The number of live births has declined gradually, and oral contraceptive use has increased. Conclusion: Incidence of ovarian cancer is high in the Netherlands, but comparable to other countries in northwestern Europe and North America. Mortality rates are rising in the elderly and declining in the young. Further research is needed concerning the effects of oral contraceptives, fertility drugs, and hormone replacement therapy on the incidence and mortality of ovarian cancer. (Obstet Gynecol 1996;88:387-93)
Ovarian cancer is one of the most frequent malignancies in w o m e n and shows a wide geographic variation in incidence. Highest risks are observed a m o n g the more affluent populations in northwestern Europe and North From the Department of Obstetrics and Gynecology and the Laboratory of Endocrinology and Reproduction, University Hospital Nijmey,en, Nijmegen; the Department of Epidemiology, University of Nijmegen, Nijmegen; and the Comprehensive Cancer Center IKO, N!jmegen, the Netherlands.
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America, with a 1-2% cumulative risk of being diagnosed with ovarian cancer before the age of 75.1'2 The majority of the ovarian cancers remain unnoticed until disease has spread beyond the ovary. Survival rates have increased since the introduction of more aggressive treatment modalities in the late 1970s (extensive surgery followed by platinum-based chemotherapy regimens), but are still extremely poor. Reported stagespecific 5-year survival rates range from approximately 80% for localized disease to less than 10% in case of distant metastases. 2 7 At present, ovarian cancer remains the most lethal gynecologic malignancy in the western world. 7 Extensive research has been done in the etiology of ovarian cancer, but so far the pathogenesis is only partially understood, s The key findings in this field are the identification of genetic factors related to ovarian cancer and the important role of the hormonal system in the etiologic pathway. ~'a-~3 Fathalla (Incessant ovulation: A factor in ovarian neoplasia [letter]. Lancet 1971; ii:163) suggested that the disruption of the ovarian epithelium at ovulation may represent the key step leading to malignant transformation. Consequently, fewer ovulations during a w o m a n ' s lifetime might lead to a lower risk of ovarian malignancy. The protective effect of increased parity, breast feeding, and use of oral contraceptives (OC) found in several studies is consistent with this hypothesis of "incessant ovulation. "s 13 Oral contraceptives were introduced in the 1960s and gained widespread use thereafter. Consequently, the potential protective effect of OCs could result in a decline in the occurrence of ovarian cancer. Evidence of such a decreasing trend in incidence and / or mortality is a l r e a d y f o u n d in several countries a r o u n d the world. 1'2"14-23However, large geographic variations exist, and the major decrease is still to come because most women who used OCs are only now reaching high-risk
0029-7844/96/$15.00
PIl S0029-7844(96)00198-6
387
Incidence rate ( p e r 1 0 0 , 0 0 0 w o m a n - y e a r s ) 60--
50--
40
Figure 1. Age-specificovarian cancer incidence in the Netherlands, 1989-1991. Cum. = cumulative.
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ages for developing ovarian cancer. 24 The aim of this study was to investigate the incidence and mortality of ovarian cancer in the Netherlands. Because national incidence data were available only recently, the emphasis will be on the analysis of mortality data.
Materials and Methods Numbers of newly diagnosed ovarian cancers for the period 1989-1991 were derived from the Netherlands Cancer RegistryY For ovarian cancer, we used International Classification of Diseases (ICD) for Oncology code 183.0. 2(' Data regarding morphology and lateralization were derived directly from the registry records. The Netherlands Cancer Registry records International Federation of Gynecology and Obstetrics (FIGO) stage from 1992 onward. Therefore, the FIGO stage of all diagnosed cases had to be assigned retrospectively by using the clinical and pathologic tumor node metastasis classification. 27 Data regarding the number of women with ovarian cancer as the underlying cause of death as well as the age- and calendar year-specific numbers of Dutch females were abstracted from publications of the Netherlands Central Bureau of Statistics for the years 19541993. 2s'2'~During this period, death from ovarian cancer was coded as 175.3-175.5 according to the ICD-6 (19541957), 175.0 according to ICD-7 (1958-1968), and thereafter as 183.0 according to ICD-8 and ICD-9. Age-specific incidence rates are presented for the
388 Koper et al
Ovarian Cancer m the Netlwrla,ds
years 1989-1991 combined. All rates are expressed in 105 woman-years. In addition to the crude incidence rate, the age-standardized incidence rate using the European Standard Population 3° and the cumulative risk of ovarian cancer before the age of 75 are presented. Age-specific mortality rates are presented by 5-year calendar periods (1954-1958 to 1989-1993). Agestandardized rates (all ages) are presented for the same periods.
Results Since the start of the Netherlands Cancer Registry in 1989, 3622 new cases of ovarian cancer have been registered in the Netherlands in the period 1989-1991. Age-specific incidence rates gradually increased to 57.3 per 105 woman-years for the 75-79 age category (Figure 1). The age-standardized incidence rate is 14.9 per 105 woman-years. Of all ovarian cancers diagnosed in the period 1989-1991, 89% had an epithelial origin (adeno, endometrioid, and clear cell carcinomas), with the majority being serous and mucinous cystic adenocarcinomas (Table 1). Germ cell tumors were especially frequent at younger ages; 66% (43 of 65) occurred at ages under 40. Moreover, 30% (30 of 99) of all ovarian cancers of known morphology that occurred before the age of 30 were of germ cell origin. In two of every three cases of ovarian cancer diagnosed in this period, the tumor showed extension to the pelvis (FIGO stage II) or beyond (FIGO stage III or IV). In 239 cases (6.6%), the
Obstetrics & Gynecology
Table 1. Distribution of Morphology, Stage, and Lateralization of Ovarian Cancer in the Netherlands, 1989-1991
Morphology Serous cystic adenocarcinoma Mucinous cystic adenocarcinoma Other adenocarcinoma Endometrioid carcinoma Clear cell carcinoma Sex cord stromal tumor Germ cell tumor Other specified morphology Unspecified morphology Tumors not microscopically verified FIGO stage Tumor limited to one or both ovaries I* Ia Ib Ic Pelvic extension II* Ila lib IIc Microscopically confirmed peritoneal metastasis outside the pelvis and/or regional lymph node metastasis III* IIIa IIIb IIIc Distant metastasis t IV Unknown* Lateralization Bilateral Left Right Unknown* Total
Cases (n)
(%)
1090 498 1193 305 139 50 65 136 71 75
(30.1%) (13.7%) (32.9%) (8.4%) (3.8%) (1.4%) (1.8%) (3.8%) (2.0%) (2.1%)
Discussion 86 75 55 328
(2.4%) (13.1%) (1.5%) (9.1%)
9 51 150 124
(0.3%) (1.4%) (4.1%) (3.4%)
334 174 362 630
(9.2%) (4.8%) (10.0%) (17.4%)
605 239
(16.7%) (6.6%)
1177 893 999 553
(32.5%) (24.6%) (27.6%) (15.3%)
3622
(100.0%)
FIGO - International Federation of Gynecology and Obstetrics. * Not enough information available to allot cases to subcategories. * Liver metastasis must be of parenchymal tissue to allot a case to FIGO stage IV. Pleural effusion must have positive cytology for FIGO stage IV.
n e c e s s a r y r e q u i r e m e n t s for F I G O staging w e r e not met. A l m o s t o n e - t h i r d of all p a t i e n t s (1177 cases) h a d bilateral disease. The right-to-left ratio w a s 1.12, i n d i c a t i n g that r i g h t - s i d e d t u m o r s o c c u r r e d slightly m o r e often. In 15.3% of all cases, no lateralization w a s specified. In 1954, o v a r i a n cancer w a s the u n d e r l y i n g cause of d e a t h of 443 D u t c h w o m e n . This n u m b e r has s t e a d i l y increased, r e a c h i n g 1029 in 1993. H o w e v e r , after adjustm e n t for p o p u l a t i o n g r o w t h and a g i n g of the D u t c h female p o p u l a t i o n , a g e - s t a n d a r d i z e d m o r t a l i t y rates are fairly stable. A g e - s t a n d a r d i z e d o v a r i a n cancer m o r t a l i t y
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i n c r e a s e d g r a d u a l l y until 1969-1973, b u t w e f o u n d a decline to 11.4 p e r 105 w o m a n - y e a r s in 1989-1993 thereafter (Table 2). W h e n age-specific m o r t a l i t y rates are c o n s i d e r e d , a m o r e d i v e r s e p a t t e r n in m o r t a l i t y rates can be o b s e r v e d (Table 2, F i g u r e 2). W h e r e a s the y o u n g e r age g r o u p s s h o w e d relatively stable or e v e n slightly d e c l i n i n g m o r t a l i t y rates after the p e r i o d 1 9 6 9 1973, the o l d e r age g r o u p s s h o w e d an i n c r e a s i n g t r e n d in mortality. This is illustrated in Figure 2 (for clarity, age-specific m o r t a l i t y rates are p r e s e n t e d b y 10-year age groups).
The a g e - s t a n d a r d i z e d incidence of o v a r i a n cancer in the N e t h e r l a n d s is in the s a m e o r d e r of m a g n i t u d e as d e s c r i b e d for S w e d e n , D e n m a r k , G e r m a n y , a n d Canada. 14'16"18"19 The d i s t r i b u t i o n of m o r p h o l o g y , F I G O stage, a n d lateralization of all o v a r i a n cancer cases in the N e t h e r l a n d s is also c o m p a r a b l e to those r e p o r t e d in other studies. 21"31 The slightly h i g h e r occurrence of o v a r i a n cancer in the right o v a r y is p r o b a b l y d u e to chance b e c a u s e it w a s n o t f o u n d in a m u c h larger s t u d y of u n i l a t e r a l o v a r i a n cancers in the U n i t e d States. 3a Age-specific rates are climbing w i t h age. Several s t u d i e s h a v e d e s c r i b e d a p a t t e r n of d e c l i n i n g incidence rates over time in y o u n g e r ages, w h e r e a s an increase in incidence is d e s c r i b e d in o l d e r ages. 18-21"23 Because the N e t h e r l a n d s Cancer Registry h a s b e e n o p e r a t i o n a l o n l y since 1989, it w a s not possible to investigate the t r e n d in incidence rates in o u r data. Instead, w e i n v e s t i g a t e d w h e t h e r such a trend c o u l d be o b s e r v e d in m o r t a l i t y d a t a available for the N e t h e r l a n d s over a m u c h l o n g e r period. O v a r i a n cancer m o r t a l i t y in the N e t h e r l a n d s w a s relatively stable. H o w e v e r , age-specific m o r t a l i t y rates are rising in the o l d e r a g e - g r o u p s a n d are declining in the y o u n g . Several other studies, d e a l i n g w i t h d a t a from other countries, d e s c r i b e d a similar p a t t e r n in age-specific m o r t a l i t y o v e r time, 1'2"15-17'19~3 a n d m a n y factors h a v e been p u t f o r w a r d to e x p l a i n the o b s e r v e d changes. E w e r t z a n d Kjaer 1~" s u g g e s t e d that changes in p a r i t y b e t w e e n different birth cohorts of w o m e n could e x p l a i n s o m e of the o b s e r v e d variation in D a n i s h o v a r i a n cancer m o r t a l i t y rates. Recently, Dos Santos Silva a n d S w e r d l o w 23 c o n f i r m e d this h y p o t h e s i s in their s t u d y of t r e n d s in incidence a n d m o r t a l i t y f r o m breast, ovarian, a n d e n d o m e t r i a l cancers in E n g l a n d a n d Wales. In their s t u d y , the m a r k e d decrease in family size w a s p a r a l leled b y an increase in the risk of o v a r i a n cancer for successive birth cohorts b o r n before 1920. In the N e t h e r l a n d s a similar p a t t e r n has b e e n o b s e r v e d . 32-34 The n u m b e r of live births in the N e t h e r l a n d s h a s g r a d u a l l y
Koper et at
Ovarian Cancer in the Netherlands
389
Table 2. Age-Specific and Age-Standardized (European Population) Ovarian Cancer Mortality Rates (per 105 Woman-Years) in the Netherlands, 1954-1993 Period of mortality 1954 1958
1959-1963
1964-1968
1969 1973
1974-1978
1979-1983
1984 1988
1989-1993
5.6 10.8 19.2 26.9
4.1 8.9 15.7 24.9 33.7 44.8 55.0 60.7 65,6 68.4 11.4
Age (y) 40-44 45-49
50 54 55-59 60- 64 65-69 70-74 75-79 80-84 -->85 Age-standardized rate 0 85
K6 14.3 19.4 27.6 29.9 3l .4 38.1 40.0 38.2 38.9
7.6 13.9 20.5 26.4 33.8 36.8 41.3 37.5 41.2 35.2
8.0 14.5 21.2 26.1 34.5 4(].1 43.7 50.5 51.4 52.9
8.8 16.7 25.0 30.0 35.1 44.1 51.3 57.4 54.4 47.6
7.4 15.9 22.3 31.6 36.7 40.4 51.0 61.7 56.9 55.9
39.(] 46.9 62.1 56.0 55.6
5.1 9.4 17.1 23.1 34.9 44.7 50.5 63.2 67.9 66.2
10.6
I1.0
11.8
13.1
12.8
11.5
11.5
decreased since the b e g i n n i n g of this century (Figure 3). There was a t e m p o r a r y increase just after World War II, b u t the n u m b e r of live births has decreased further and stabilized in recent years. Therefore, the increase in o v a r i a n cancer mortality in the oldest age g r o u p s (born a r o u n d the t u r n of the century) m a y in part be attributed to their declining parity. This decrease in the n u m b e r of live births is a c c o m p a n i e d by an increase in the n u m b e r of n u l l i p a r o u s w o m e n in the period 19451970. 35 It is n o t clear h o w this lower parity a n d higher n u m b e r of n u l l i p a r o u s w o m e n in the Dutch p o p u l a t i o n will affect the o v a r i a n cancer risk of y o u n g e r birth cohorts. Moreover, one should be aware of the so-called
Mortality
34.9
"ecologic fallacy," which implies that caution should be exercised w h e n inferences are m a d e from observed trends in p o p u l a t i o n statistics because the a p p a r e n t relationship m a y not hold on an i n d i v i d u a l level. Dos Santos Silva a n d Swerdlow 23 also f o u n d an inverse relationship b e t w e e n the n u m b e r of w o m e n u s i n g OCs a n d the risk of ovarian cancer. This relationship had already been observed earlier by VillardMackintosh et al. 2° In the Netherlands, OCs were marketed at the e n d of 1961 a n d gained w i d e s p r e a d use (Figure 4). Apart from a slight decline in the n u m b e r of w o m e n u s i n g OCs in the period 1977-1980 due to negative reports on the increased risk of cardiovascular
rate ( p e r 1 0 0 , 0 0 0 w o m a n - y e a r s )
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Figure 2. Age-specificovarian cancer mortality in the Netherlands, 1954 1993.
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390 Koper et al
Ovarian Cancer in the Netherlands
Obstetrics & Gynecology
Number
of live births
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Figure 3. Number of live births per 1000 women aged 15-44 years in the Netherlands, 1900-1993.
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been a trend to y o u n g e r starting ages a n d p r o l o n g e d use at older ages. 34'3(' These d e v e l o p m e n t s m a y have contributed to the stabilization a n d the onset of the decrease in o v a r i a n cancer mortality in the y o u n g e r age groups in the Netherlands. If this is true, then the decreasing trend m i g h t c o n t i n u e w h e n more birth co-
disease a m o n g w o m e n u s i n g OCs in that period, the percentage of w o m e n age 10-54 u s i n g OCs increased to 32% in 1993. The dip in 1991 was caused b y a lack of i n f o r m a t i o n o n the q u a n t i t y of parallel i m p o r t e d OCs in that year a n d thus can be considered a registration a n o m a l y due to u n d e r r e p o r t i n g . There appears to have
Use of oral contraceptives (%) 35
Figure 4. Percentage of women aged 10-54 years using oral contraceptives in the Netherlands, 19671993. (Source: Institute for Medical Statistics, the Netherlands.)
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h o r t s w i t h a h i s t o r y of OC use reach h i g h - r i s k ages for d e v e l o p i n g o v a r i a n cancer. H o w e v e r , the use of thirdg e n e r a t i o n OCs m a y decrease the p r o t e c t i v e effects of OCs b e c a u s e o v a r i a n activity r e m a i n s p o s s i b l e w i t h these pills. A p a r t from the m o r e w i d e s p r e a d use of OCs as a potential e x p l a n a t i o n of the decline in o v a r i a n cancer m o r t a l i t y rates in the y o u n g e r age g r o u p s , A y i o m a m i t i s et a119 s u g g e s t e d that earlier d i a g n o s e s a n d earlier a n d better t r e a t m e n t in the y o u n g c o u l d e x p l a i n the obs e r v e d change. F u r t h e r m o r e , t h e y s u g g e s t e d that o l d e r w o m e n are treated less a g g r e s s i v e l y ap_d/or r e s p o n d less effectively to t h e r a p y c o m p a r e d w i t h y o u n g e r w o m e n , as s u g g e s t e d earlier b y Yancik et al. 37 This difference in t r e a t m e n t over age w a s affirmed b y Ries, 3~ w h o i n v e s t i g a t e d t r e a t m e n t i n f o r m a t i o n of m o r e t h a n 20,000 w o m e n d i a g n o s e d d u r i n g 1973-1987 in the U n i t e d States. This c o u l d a p p l y to the s i t u a t i o n in the N e t h e r l a n d s , b e c a u s e w e h a v e no i n d i c a t i o n that systematic differences exist w i t h other countries in therap e u t i c decisions or p a t i e n t r e s p o n s e to treatment. Also, a m o r e accurate d e a t h certification a n d registration is s u g g e s t e d as an e x p l a n a t i o n for the increase in m o r t a l ity in o l d e r age g r o u p s . 19 I n d e e d , since 1954, techniques in p a t h o l o g y h a v e e m e r g e d , b u t it is u n c e r t a i n w h e t h e r this e x p l a n a t i o n h o l d s for the increase visible in recent y e a r s as well. The influence of c h a n g e s in o o p h o r e c t o m y rates in the N e t h e r l a n d s s h o u l d also be c o n s i d e r e d in this regard. Data o b t a i n e d from the a n n u a l r e p o r t s of the N a t i o n a l Medical Register in the N e t h e r l a n d s s h o w that o o p h o r e c t o m y rates i n c r e a s e d s t e a d i l y to 130 p e r 105 w o m a n - y e a r s in the early 1980s b u t d e c l i n e d to less then 85 p e r 105 w o m a n - y e a r s in 1990. The influence of these c h a n g e s in o o p h o r e c t o m y rates on age-specific o v a r i a n cancer m o r t a l i t y is difficult to estimate in m o r e detail b e c a u s e w e h a v e no i n f o r m a t i o n a b o u t the age d i s t r i b u t i o n of t h e s e p a t i e n t s . N e v e r t h e l e s s , t h e s e c h a n g e s s e e m difficult to reconcile with the onset of the d e c r e a s e in o v a r i a n cancer m o r t a l i t y in the y o u n g e r age groups. The increase in the o l d e r age g r o u p s m i g h t h a v e c o n t r i b u t e d in p a r t to the c h a n g e s in o o p h o r e c t o m y rates. But similar analysis r e g a r d i n g the influence of c h a n g i n g h y s t e r e c t o m y rates on cervical cancer m o r t a l ity in the N e t h e r l a n d s h a v e s h o w n that this c o n t r i b u t i o n is e s t i m a t e d to be a b o u t 6% of the o b s e r v e d change. 39 A n o t h e r s u g g e s t e d r e a s o n for the increase in o v a r i a n cancer m o r t a l i t y in the e l d e r l y is the increased use of e s t r o g e n r e p l a c e m e n t t h e r a p y in peri- a n d p o s t m e n o p a u s a l w o m e n . 4° I n d e e d the use of e s t r o g e n s b y e l d e r l y w o m e n to p r e v e n t o s t e o p o r o s i s a n d other climacteric a n d m e n o p a u s a l c o m p l a i n t s is increasing. A n d alt h o u g h the n o r m a l d o s e of e s t r o g e n has d e c r e a s e d since the 1970s a n d the c o m p o s i t i o n of the m e d i c a t i o n u s e d
392 Koper et al
Ovarian Cancer in the Netherlands
c h a n g e d w i t h the inclusion of p r o g e s t e r o n e , this m a y h a v e influenced o v a r i a n cancer mortality. O n the other hand, estrogen replacement during menopause lowers the b l o o d g o n a d o t r o p i n levels, w h i c h m i g h t d e c r e a s e the risk of o v a r i a n cancer, a c c o r d i n g to the g o n a d o t r o p i n h y p o t h e s i s p u t f o r w a r d b y Stadel. 4J Therefore, definitive conclusions a b o u t the effect on o v a r i a n cancer risk of h o r m o n e r e p l a c e m e n t t h e r a p y cannot be d r a w n . W h i t t e m o r e et al 9-11 s u g g e s t e d o v a r i a n s t i m u l a t i o n for in vitro fertilization c o u l d increase the risk of o v a r i a n cancer. Recently, Venn et a142 r e p o r t e d an increase in o v a r i a n cancer risk after o v a r i a n s t i m u l a t i o n for in vitro fertilization in a cohort of 10,358 A u s t r a l i a n w o m e n . A l t h o u g h the n u n l b e r of cases in this large s t u d y w a s v e r y small (n -- 6), w h i c h limits the conclusions that can be d r a w n , this finding s u p p o r t s the h y p o t h e s i s of W h i t t e m o r e et al. H o w e v e r , it is d o u b t f u l w h e t h e r IVF has a large i m p a c t on p o p u l a t i o n incidence a n d m o r t a l i t y e v e n if the h y p o t h e s i s is true. F u r t h e r research into this m a t t e r is indicated.
References 1. Coleman MP, Estev6 J, Damiecki P, Arslan A, Renard H, eds. Trends in cancer incidence and mortality. IARC publication no. 21. Lyon, France: IARC Scientific Publications 1993. 2. Ries LAG, Hartge P, Trimble E. Ovary. In: Miller BA, Ries LAG, Hankey BF, Kosary CL, Harras A, Devesa SS, et al, eds. SEER cancer statistics review 1973-1990. NIH publication no. 93-2789. Bethesda, Maryland: National Cancer Institute, 1993. 3. Balvert-Locht HR, Coebergh JWW, Hop WCJ, Br61mann HAM, Crommelin MA, van Wijck DJAM, et al. hnproved prognosis of ovarian cancer in the Netherlands during the period 1975-1985: A registry-based study. Gynecol Oncol 1991;42:3-8. 4. Neijt JP, ten Bokkel Huinink WW, van der Burg MEL, van Oosterom AT, Willemse PHB, Vermorken JB, et al. Long-term survival in ovarian cancer: Mature data from the Netherlands Joint Study Group for Ovarian Cancer. Eur J Cancer 1991;27:1367-72. 5. Chang J, Bridgewater J, Gore M, Fisher C, Schofield J, A'Hern R, et al. Non-surgical aspects of ovarian cancer. Lancet 1994;343:335-41, 6. Averette HE, Janicek MF, Menck HR. The national cancer data base report on ovarian cancer. Cancer 1995;76:1096-103. 7. Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. 1995;45:8-30. 8. Shoham Z. Epidemiology, etiology, and fertility drugs in ovarian epithelial carcinoma: Where are we today? Ferti] Steril 1994;62: 433- 48. 9. Whittemore AS, Harris R, Itnyre J, Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: Collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 1992;136:1184203. 10. Harris R, Whittemore AS, Itnyre J, Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: Collaborative analysis of 12 US case-control studies. III. Epithelial tumors of low malignant potential in white women. Am J Epidemiol 1992; 136:1204-11. 11. Whittemore AS, Harris R, Itnyre J, Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: Collabora-
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26. 27.
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tive analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer. Am J Epidemiol 1992;136:1212-20. Risch HA, Marrett LD, Howe GR. Parity, contraception, infertility, and the risk of epithelial ovarian cancer. A m J Epidemiol 1994;140: 585-97. Piver MS, Baker TR, Piedmonte M, Sandecki AM. Epidemiology and etiology of ovarian cancer. Semin Oncol 1991;18:177-85. Adami H, Bergstr6m R, Persson I, Spar6n P. The incidence of ovarian cancer in Sweden, 1960-1984. Am J Epidemiol 1990;132: 446 -52. Devesa SS, Blot WJ, Stone BJ, Miller BA, Tarone RE, Fraumeni JF. Recent cancer trends in the United States. J Natl Cancer Inst 1995;87:175-82. Ewertz M, Kjaer SK. Ovarian cancer incidence and mortality in Denmark, 1943-1982. Int J Cancer 1988;42:690-6. Negri E, La Vecchia C, Decarli A, Boyle P. Projections to the end of the century of mortality from major cancer sites in Italy. Tumori 1990;76:420-8. Brenner H, Ziegler H. Monitoring and projecting cancer incidence in Saarland, Germany, based on age-cohort analyses. J Epidemiol Community Health 1992;46:15-20. Ayiomamitis A. The epidemiology of malignant neoplasms of the ovary, fallopian tube, and broad ligament in Canada: 1950-1984. Obstet Gynecol 1989;73:1017-21. Villard-Mackintosh L, Vessey MP, Jones L. The effects of oral contraceptives and parity on ovarian cancer trends in women under 55 years of age. Br J Obstet Gynaecol 1989;96:783-8. Yancik R. Ovarian cancer: Age contrasts in incidence, histology, disease stage at diagnosis, and mortality. Cancer 1993;71:517-23. Riggs JE. Rising ovarian cancer mortality in the elderly: A manifestation of differential survival. Gynecol Oncol 1995;58:64-7. Dos Santos Silva I, Swerdlow AJ. Recent trends in incidence of and mortality from breast, ovarian and endometrial cancers in England and Wales and their relation to changing fertility and oral contraceptive use. Br J Cancer 1995;72:485-92. Stanford JL Oral contraceptives and neoplasia of the ovary. Contraception 1991;43:543-56. Visser O, Coebergh JWW, Schouten LJ, eds. Incidence of cancer in the Netherlands 1991: Third report of the Netherlands Cancer Registry. Utrecht: Netherlands Cancer Registry, 1994. World Health Organization (WHO). International classification of diseases for oncology. 1st ed. Geneva, Switzerland: WHO, 1976. Hermanek P, Sobin LH, eds. TNM classification of malignant tumours. UICC international union against cancer. 4th fully revised ed. Berlin: Springer-Verlag, 1987. Central Bureau of Statistics. Mortality by cause of death, 1950 1977. The Hague: Staatsuitgeverij, 1980. Central Bureau of Statistics. Mortality by cause of death, age and sex in the year 1978, 1979 . . . . . 1993 Series A1. The Hague: Staatsuitgeverij, 1979, 1980 . . . . . 1994. Smith P. Comparison between registries: Age-standardized rates.
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31. 32. 33. 34. 35. 36. 37.
38. 39.
40.
41. 42.
In: Muir CS, Waterhouse J, Mack T, Powell J, Whelan S, eds. Cancer incidence in five continents. Vol. V. IARC publication no. 88:709 15. Lyon, France: IARC Scientific Publications 1987. Hartge P, Devesa S. Ovarian cancer, ovulation and side of origin. Br J Cancer 1995;71:642-3. Central Bureau of Statistics. C o m p e n d i u m health statistics of the Netherlands 1979. The Hague: Staatsuitgeverij, 1980. Central Bureau of Statistics. Vademecum of health statistics of the Netherlands 1993. The Hague: SDU/Publishers, 1993. Central Bureau of Statistics. Vademecum of health statistics of the Netherlands 1995. The Hague: SDU/Publishers, 1995. Central Bureau of Statistics. Statistical yearbook 1994. The Hague: SDU / Publishers, 1994. Verweij GCG. Pill consumption is still increasing (in Dutch). Month bull health stat 1989;7:14-9. Yancik R, Ries LG, Yates JW. Ovarian cancer in the elderly: An analysis of surveillance, epidemiology, and end results program data. Am J Obstet Gynecol 1986;154:639-47. Ries LAG. Ovarian cancer: Survival and treatment differences by age. Cancer 1993;71:524-9. Bosman JM, Lako CJ, Sturmans F, Willenrs JHBM. The increase of the number of hysterectomies in the Netherlands: The influence on incidence and mortality rates of cervival carcinoma (in Dutch). Ned Tijdschr Geneeskd 1983;127:900-5. Rodriguez C, Calle EE, Coates RJ, Miracle-McMahill HL, Thun MJ, Heath CW. Estrogen replacement therapy and fetal ovarian cancer. Am J Epidemiol 1995;141:828-35. Stadel BV. The etiology and prevention of ovarian cancer. Am J Obstet Gynecol 1975;123:772-4. Venn A, Watson L, Lumley J, Giles G, King C, Healy D. Breast and ovarian cancer incidence after infertility and in vitro fertilisation. Lancet 1995;346:995-1000.
A d d r e s s r e p r i n t r e q u e s t s to:
Norbert P. Koper, MSc Department of Obstetrics and Gynecology University Hospital Nijmegen P.O. Box 9101 6500 HB Nijmegen The Netherlands
Received January 22, 1996. Received in revisedform April 24, 1996. Accepted April 30, 1996. Copyright © 1996 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
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393
Ovarian cancer is one of the most frequent malignancies in w o m e n and shows a wide geographic variation in incidence. Highest risks are observed a m o n g the more affluent populations in northwestern Europe and North From the Department of Obstetrics and Gynecology and the Laboratory of Endocrinology and Reproduction, University Hospital Nijmey,en, Nijmegen; the Department of Epidemiology, University of Nijmegen, Nijmegen; and the Comprehensive Cancer Center IKO, N!jmegen, the Netherlands.
VOL. 88, NO, 3, SEPTEMBER 1996
America, with a 1-2% cumulative risk of being diagnosed with ovarian cancer before the age of 75.1'2 The majority of the ovarian cancers remain unnoticed until disease has spread beyond the ovary. Survival rates have increased since the introduction of more aggressive treatment modalities in the late 1970s (extensive surgery followed by platinum-based chemotherapy regimens), but are still extremely poor. Reported stagespecific 5-year survival rates range from approximately 80% for localized disease to less than 10% in case of distant metastases. 2 7 At present, ovarian cancer remains the most lethal gynecologic malignancy in the western world. 7 Extensive research has been done in the etiology of ovarian cancer, but so far the pathogenesis is only partially understood, s The key findings in this field are the identification of genetic factors related to ovarian cancer and the important role of the hormonal system in the etiologic pathway. ~'a-~3 Fathalla (Incessant ovulation: A factor in ovarian neoplasia [letter]. Lancet 1971; ii:163) suggested that the disruption of the ovarian epithelium at ovulation may represent the key step leading to malignant transformation. Consequently, fewer ovulations during a w o m a n ' s lifetime might lead to a lower risk of ovarian malignancy. The protective effect of increased parity, breast feeding, and use of oral contraceptives (OC) found in several studies is consistent with this hypothesis of "incessant ovulation. "s 13 Oral contraceptives were introduced in the 1960s and gained widespread use thereafter. Consequently, the potential protective effect of OCs could result in a decline in the occurrence of ovarian cancer. Evidence of such a decreasing trend in incidence and / or mortality is a l r e a d y f o u n d in several countries a r o u n d the world. 1'2"14-23However, large geographic variations exist, and the major decrease is still to come because most women who used OCs are only now reaching high-risk
0029-7844/96/$15.00
PIl S0029-7844(96)00198-6
387
Incidence rate ( p e r 1 0 0 , 0 0 0 w o m a n - y e a r s ) 60--
50--
40
Figure 1. Age-specificovarian cancer incidence in the Netherlands, 1989-1991. Cum. = cumulative.
30--
20
10 - -
0 O-
5-
1 O-
15-
20-
25-
30-
35-
40-
45-
50-
55-
60-
65-
70-
75-
80-
85 +
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ages for developing ovarian cancer. 24 The aim of this study was to investigate the incidence and mortality of ovarian cancer in the Netherlands. Because national incidence data were available only recently, the emphasis will be on the analysis of mortality data.
Materials and Methods Numbers of newly diagnosed ovarian cancers for the period 1989-1991 were derived from the Netherlands Cancer RegistryY For ovarian cancer, we used International Classification of Diseases (ICD) for Oncology code 183.0. 2(' Data regarding morphology and lateralization were derived directly from the registry records. The Netherlands Cancer Registry records International Federation of Gynecology and Obstetrics (FIGO) stage from 1992 onward. Therefore, the FIGO stage of all diagnosed cases had to be assigned retrospectively by using the clinical and pathologic tumor node metastasis classification. 27 Data regarding the number of women with ovarian cancer as the underlying cause of death as well as the age- and calendar year-specific numbers of Dutch females were abstracted from publications of the Netherlands Central Bureau of Statistics for the years 19541993. 2s'2'~During this period, death from ovarian cancer was coded as 175.3-175.5 according to the ICD-6 (19541957), 175.0 according to ICD-7 (1958-1968), and thereafter as 183.0 according to ICD-8 and ICD-9. Age-specific incidence rates are presented for the
388 Koper et al
Ovarian Cancer m the Netlwrla,ds
years 1989-1991 combined. All rates are expressed in 105 woman-years. In addition to the crude incidence rate, the age-standardized incidence rate using the European Standard Population 3° and the cumulative risk of ovarian cancer before the age of 75 are presented. Age-specific mortality rates are presented by 5-year calendar periods (1954-1958 to 1989-1993). Agestandardized rates (all ages) are presented for the same periods.
Results Since the start of the Netherlands Cancer Registry in 1989, 3622 new cases of ovarian cancer have been registered in the Netherlands in the period 1989-1991. Age-specific incidence rates gradually increased to 57.3 per 105 woman-years for the 75-79 age category (Figure 1). The age-standardized incidence rate is 14.9 per 105 woman-years. Of all ovarian cancers diagnosed in the period 1989-1991, 89% had an epithelial origin (adeno, endometrioid, and clear cell carcinomas), with the majority being serous and mucinous cystic adenocarcinomas (Table 1). Germ cell tumors were especially frequent at younger ages; 66% (43 of 65) occurred at ages under 40. Moreover, 30% (30 of 99) of all ovarian cancers of known morphology that occurred before the age of 30 were of germ cell origin. In two of every three cases of ovarian cancer diagnosed in this period, the tumor showed extension to the pelvis (FIGO stage II) or beyond (FIGO stage III or IV). In 239 cases (6.6%), the
Obstetrics & Gynecology
Table 1. Distribution of Morphology, Stage, and Lateralization of Ovarian Cancer in the Netherlands, 1989-1991
Morphology Serous cystic adenocarcinoma Mucinous cystic adenocarcinoma Other adenocarcinoma Endometrioid carcinoma Clear cell carcinoma Sex cord stromal tumor Germ cell tumor Other specified morphology Unspecified morphology Tumors not microscopically verified FIGO stage Tumor limited to one or both ovaries I* Ia Ib Ic Pelvic extension II* Ila lib IIc Microscopically confirmed peritoneal metastasis outside the pelvis and/or regional lymph node metastasis III* IIIa IIIb IIIc Distant metastasis t IV Unknown* Lateralization Bilateral Left Right Unknown* Total
Cases (n)
(%)
1090 498 1193 305 139 50 65 136 71 75
(30.1%) (13.7%) (32.9%) (8.4%) (3.8%) (1.4%) (1.8%) (3.8%) (2.0%) (2.1%)
Discussion 86 75 55 328
(2.4%) (13.1%) (1.5%) (9.1%)
9 51 150 124
(0.3%) (1.4%) (4.1%) (3.4%)
334 174 362 630
(9.2%) (4.8%) (10.0%) (17.4%)
605 239
(16.7%) (6.6%)
1177 893 999 553
(32.5%) (24.6%) (27.6%) (15.3%)
3622
(100.0%)
FIGO - International Federation of Gynecology and Obstetrics. * Not enough information available to allot cases to subcategories. * Liver metastasis must be of parenchymal tissue to allot a case to FIGO stage IV. Pleural effusion must have positive cytology for FIGO stage IV.
n e c e s s a r y r e q u i r e m e n t s for F I G O staging w e r e not met. A l m o s t o n e - t h i r d of all p a t i e n t s (1177 cases) h a d bilateral disease. The right-to-left ratio w a s 1.12, i n d i c a t i n g that r i g h t - s i d e d t u m o r s o c c u r r e d slightly m o r e often. In 15.3% of all cases, no lateralization w a s specified. In 1954, o v a r i a n cancer w a s the u n d e r l y i n g cause of d e a t h of 443 D u t c h w o m e n . This n u m b e r has s t e a d i l y increased, r e a c h i n g 1029 in 1993. H o w e v e r , after adjustm e n t for p o p u l a t i o n g r o w t h and a g i n g of the D u t c h female p o p u l a t i o n , a g e - s t a n d a r d i z e d m o r t a l i t y rates are fairly stable. A g e - s t a n d a r d i z e d o v a r i a n cancer m o r t a l i t y
VOL. 88, NO. 3, SEPTEMBER 1996
i n c r e a s e d g r a d u a l l y until 1969-1973, b u t w e f o u n d a decline to 11.4 p e r 105 w o m a n - y e a r s in 1989-1993 thereafter (Table 2). W h e n age-specific m o r t a l i t y rates are c o n s i d e r e d , a m o r e d i v e r s e p a t t e r n in m o r t a l i t y rates can be o b s e r v e d (Table 2, F i g u r e 2). W h e r e a s the y o u n g e r age g r o u p s s h o w e d relatively stable or e v e n slightly d e c l i n i n g m o r t a l i t y rates after the p e r i o d 1 9 6 9 1973, the o l d e r age g r o u p s s h o w e d an i n c r e a s i n g t r e n d in mortality. This is illustrated in Figure 2 (for clarity, age-specific m o r t a l i t y rates are p r e s e n t e d b y 10-year age groups).
The a g e - s t a n d a r d i z e d incidence of o v a r i a n cancer in the N e t h e r l a n d s is in the s a m e o r d e r of m a g n i t u d e as d e s c r i b e d for S w e d e n , D e n m a r k , G e r m a n y , a n d Canada. 14'16"18"19 The d i s t r i b u t i o n of m o r p h o l o g y , F I G O stage, a n d lateralization of all o v a r i a n cancer cases in the N e t h e r l a n d s is also c o m p a r a b l e to those r e p o r t e d in other studies. 21"31 The slightly h i g h e r occurrence of o v a r i a n cancer in the right o v a r y is p r o b a b l y d u e to chance b e c a u s e it w a s n o t f o u n d in a m u c h larger s t u d y of u n i l a t e r a l o v a r i a n cancers in the U n i t e d States. 3a Age-specific rates are climbing w i t h age. Several s t u d i e s h a v e d e s c r i b e d a p a t t e r n of d e c l i n i n g incidence rates over time in y o u n g e r ages, w h e r e a s an increase in incidence is d e s c r i b e d in o l d e r ages. 18-21"23 Because the N e t h e r l a n d s Cancer Registry h a s b e e n o p e r a t i o n a l o n l y since 1989, it w a s not possible to investigate the t r e n d in incidence rates in o u r data. Instead, w e i n v e s t i g a t e d w h e t h e r such a trend c o u l d be o b s e r v e d in m o r t a l i t y d a t a available for the N e t h e r l a n d s over a m u c h l o n g e r period. O v a r i a n cancer m o r t a l i t y in the N e t h e r l a n d s w a s relatively stable. H o w e v e r , age-specific m o r t a l i t y rates are rising in the o l d e r a g e - g r o u p s a n d are declining in the y o u n g . Several other studies, d e a l i n g w i t h d a t a from other countries, d e s c r i b e d a similar p a t t e r n in age-specific m o r t a l i t y o v e r time, 1'2"15-17'19~3 a n d m a n y factors h a v e been p u t f o r w a r d to e x p l a i n the o b s e r v e d changes. E w e r t z a n d Kjaer 1~" s u g g e s t e d that changes in p a r i t y b e t w e e n different birth cohorts of w o m e n could e x p l a i n s o m e of the o b s e r v e d variation in D a n i s h o v a r i a n cancer m o r t a l i t y rates. Recently, Dos Santos Silva a n d S w e r d l o w 23 c o n f i r m e d this h y p o t h e s i s in their s t u d y of t r e n d s in incidence a n d m o r t a l i t y f r o m breast, ovarian, a n d e n d o m e t r i a l cancers in E n g l a n d a n d Wales. In their s t u d y , the m a r k e d decrease in family size w a s p a r a l leled b y an increase in the risk of o v a r i a n cancer for successive birth cohorts b o r n before 1920. In the N e t h e r l a n d s a similar p a t t e r n has b e e n o b s e r v e d . 32-34 The n u m b e r of live births in the N e t h e r l a n d s h a s g r a d u a l l y
Koper et at
Ovarian Cancer in the Netherlands
389
Table 2. Age-Specific and Age-Standardized (European Population) Ovarian Cancer Mortality Rates (per 105 Woman-Years) in the Netherlands, 1954-1993 Period of mortality 1954 1958
1959-1963
1964-1968
1969 1973
1974-1978
1979-1983
1984 1988
1989-1993
5.6 10.8 19.2 26.9
4.1 8.9 15.7 24.9 33.7 44.8 55.0 60.7 65,6 68.4 11.4
Age (y) 40-44 45-49
50 54 55-59 60- 64 65-69 70-74 75-79 80-84 -->85 Age-standardized rate 0 85
K6 14.3 19.4 27.6 29.9 3l .4 38.1 40.0 38.2 38.9
7.6 13.9 20.5 26.4 33.8 36.8 41.3 37.5 41.2 35.2
8.0 14.5 21.2 26.1 34.5 4(].1 43.7 50.5 51.4 52.9
8.8 16.7 25.0 30.0 35.1 44.1 51.3 57.4 54.4 47.6
7.4 15.9 22.3 31.6 36.7 40.4 51.0 61.7 56.9 55.9
39.(] 46.9 62.1 56.0 55.6
5.1 9.4 17.1 23.1 34.9 44.7 50.5 63.2 67.9 66.2
10.6
I1.0
11.8
13.1
12.8
11.5
11.5
decreased since the b e g i n n i n g of this century (Figure 3). There was a t e m p o r a r y increase just after World War II, b u t the n u m b e r of live births has decreased further and stabilized in recent years. Therefore, the increase in o v a r i a n cancer mortality in the oldest age g r o u p s (born a r o u n d the t u r n of the century) m a y in part be attributed to their declining parity. This decrease in the n u m b e r of live births is a c c o m p a n i e d by an increase in the n u m b e r of n u l l i p a r o u s w o m e n in the period 19451970. 35 It is n o t clear h o w this lower parity a n d higher n u m b e r of n u l l i p a r o u s w o m e n in the Dutch p o p u l a t i o n will affect the o v a r i a n cancer risk of y o u n g e r birth cohorts. Moreover, one should be aware of the so-called
Mortality
34.9
"ecologic fallacy," which implies that caution should be exercised w h e n inferences are m a d e from observed trends in p o p u l a t i o n statistics because the a p p a r e n t relationship m a y not hold on an i n d i v i d u a l level. Dos Santos Silva a n d Swerdlow 23 also f o u n d an inverse relationship b e t w e e n the n u m b e r of w o m e n u s i n g OCs a n d the risk of ovarian cancer. This relationship had already been observed earlier by VillardMackintosh et al. 2° In the Netherlands, OCs were marketed at the e n d of 1961 a n d gained w i d e s p r e a d use (Figure 4). Apart from a slight decline in the n u m b e r of w o m e n u s i n g OCs in the period 1977-1980 due to negative reports on the increased risk of cardiovascular
rate ( p e r 1 0 0 , 0 0 0 w o m a n - y e a r s )
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->80
60
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Figure 2. Age-specificovarian cancer mortality in the Netherlands, 1954 1993.
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i 1959-1963
d 1964-1968
r
I
1969-1979
1974-1978
1979-1983
1984-1988
1989-1993
Period
390 Koper et al
Ovarian Cancer in the Netherlands
Obstetrics & Gynecology
Number
of live births
(per
1,000
women)
160 --
140
120
100
Figure 3. Number of live births per 1000 women aged 15-44 years in the Netherlands, 1900-1993.
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been a trend to y o u n g e r starting ages a n d p r o l o n g e d use at older ages. 34'3(' These d e v e l o p m e n t s m a y have contributed to the stabilization a n d the onset of the decrease in o v a r i a n cancer mortality in the y o u n g e r age groups in the Netherlands. If this is true, then the decreasing trend m i g h t c o n t i n u e w h e n more birth co-
disease a m o n g w o m e n u s i n g OCs in that period, the percentage of w o m e n age 10-54 u s i n g OCs increased to 32% in 1993. The dip in 1991 was caused b y a lack of i n f o r m a t i o n o n the q u a n t i t y of parallel i m p o r t e d OCs in that year a n d thus can be considered a registration a n o m a l y due to u n d e r r e p o r t i n g . There appears to have
Use of oral contraceptives (%) 35
Figure 4. Percentage of women aged 10-54 years using oral contraceptives in the Netherlands, 19671993. (Source: Institute for Medical Statistics, the Netherlands.)
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h o r t s w i t h a h i s t o r y of OC use reach h i g h - r i s k ages for d e v e l o p i n g o v a r i a n cancer. H o w e v e r , the use of thirdg e n e r a t i o n OCs m a y decrease the p r o t e c t i v e effects of OCs b e c a u s e o v a r i a n activity r e m a i n s p o s s i b l e w i t h these pills. A p a r t from the m o r e w i d e s p r e a d use of OCs as a potential e x p l a n a t i o n of the decline in o v a r i a n cancer m o r t a l i t y rates in the y o u n g e r age g r o u p s , A y i o m a m i t i s et a119 s u g g e s t e d that earlier d i a g n o s e s a n d earlier a n d better t r e a t m e n t in the y o u n g c o u l d e x p l a i n the obs e r v e d change. F u r t h e r m o r e , t h e y s u g g e s t e d that o l d e r w o m e n are treated less a g g r e s s i v e l y ap_d/or r e s p o n d less effectively to t h e r a p y c o m p a r e d w i t h y o u n g e r w o m e n , as s u g g e s t e d earlier b y Yancik et al. 37 This difference in t r e a t m e n t over age w a s affirmed b y Ries, 3~ w h o i n v e s t i g a t e d t r e a t m e n t i n f o r m a t i o n of m o r e t h a n 20,000 w o m e n d i a g n o s e d d u r i n g 1973-1987 in the U n i t e d States. This c o u l d a p p l y to the s i t u a t i o n in the N e t h e r l a n d s , b e c a u s e w e h a v e no i n d i c a t i o n that systematic differences exist w i t h other countries in therap e u t i c decisions or p a t i e n t r e s p o n s e to treatment. Also, a m o r e accurate d e a t h certification a n d registration is s u g g e s t e d as an e x p l a n a t i o n for the increase in m o r t a l ity in o l d e r age g r o u p s . 19 I n d e e d , since 1954, techniques in p a t h o l o g y h a v e e m e r g e d , b u t it is u n c e r t a i n w h e t h e r this e x p l a n a t i o n h o l d s for the increase visible in recent y e a r s as well. The influence of c h a n g e s in o o p h o r e c t o m y rates in the N e t h e r l a n d s s h o u l d also be c o n s i d e r e d in this regard. Data o b t a i n e d from the a n n u a l r e p o r t s of the N a t i o n a l Medical Register in the N e t h e r l a n d s s h o w that o o p h o r e c t o m y rates i n c r e a s e d s t e a d i l y to 130 p e r 105 w o m a n - y e a r s in the early 1980s b u t d e c l i n e d to less then 85 p e r 105 w o m a n - y e a r s in 1990. The influence of these c h a n g e s in o o p h o r e c t o m y rates on age-specific o v a r i a n cancer m o r t a l i t y is difficult to estimate in m o r e detail b e c a u s e w e h a v e no i n f o r m a t i o n a b o u t the age d i s t r i b u t i o n of t h e s e p a t i e n t s . N e v e r t h e l e s s , t h e s e c h a n g e s s e e m difficult to reconcile with the onset of the d e c r e a s e in o v a r i a n cancer m o r t a l i t y in the y o u n g e r age groups. The increase in the o l d e r age g r o u p s m i g h t h a v e c o n t r i b u t e d in p a r t to the c h a n g e s in o o p h o r e c t o m y rates. But similar analysis r e g a r d i n g the influence of c h a n g i n g h y s t e r e c t o m y rates on cervical cancer m o r t a l ity in the N e t h e r l a n d s h a v e s h o w n that this c o n t r i b u t i o n is e s t i m a t e d to be a b o u t 6% of the o b s e r v e d change. 39 A n o t h e r s u g g e s t e d r e a s o n for the increase in o v a r i a n cancer m o r t a l i t y in the e l d e r l y is the increased use of e s t r o g e n r e p l a c e m e n t t h e r a p y in peri- a n d p o s t m e n o p a u s a l w o m e n . 4° I n d e e d the use of e s t r o g e n s b y e l d e r l y w o m e n to p r e v e n t o s t e o p o r o s i s a n d other climacteric a n d m e n o p a u s a l c o m p l a i n t s is increasing. A n d alt h o u g h the n o r m a l d o s e of e s t r o g e n has d e c r e a s e d since the 1970s a n d the c o m p o s i t i o n of the m e d i c a t i o n u s e d
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c h a n g e d w i t h the inclusion of p r o g e s t e r o n e , this m a y h a v e influenced o v a r i a n cancer mortality. O n the other hand, estrogen replacement during menopause lowers the b l o o d g o n a d o t r o p i n levels, w h i c h m i g h t d e c r e a s e the risk of o v a r i a n cancer, a c c o r d i n g to the g o n a d o t r o p i n h y p o t h e s i s p u t f o r w a r d b y Stadel. 4J Therefore, definitive conclusions a b o u t the effect on o v a r i a n cancer risk of h o r m o n e r e p l a c e m e n t t h e r a p y cannot be d r a w n . W h i t t e m o r e et al 9-11 s u g g e s t e d o v a r i a n s t i m u l a t i o n for in vitro fertilization c o u l d increase the risk of o v a r i a n cancer. Recently, Venn et a142 r e p o r t e d an increase in o v a r i a n cancer risk after o v a r i a n s t i m u l a t i o n for in vitro fertilization in a cohort of 10,358 A u s t r a l i a n w o m e n . A l t h o u g h the n u n l b e r of cases in this large s t u d y w a s v e r y small (n -- 6), w h i c h limits the conclusions that can be d r a w n , this finding s u p p o r t s the h y p o t h e s i s of W h i t t e m o r e et al. H o w e v e r , it is d o u b t f u l w h e t h e r IVF has a large i m p a c t on p o p u l a t i o n incidence a n d m o r t a l i t y e v e n if the h y p o t h e s i s is true. F u r t h e r research into this m a t t e r is indicated.
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A d d r e s s r e p r i n t r e q u e s t s to:
Norbert P. Koper, MSc Department of Obstetrics and Gynecology University Hospital Nijmegen P.O. Box 9101 6500 HB Nijmegen The Netherlands
Received January 22, 1996. Received in revisedform April 24, 1996. Accepted April 30, 1996. Copyright © 1996 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
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