Thames Cancer Registry, King's College London and Cancer and Public Health Unit, London School of Hygiene & Tropical Medicine, London, UK
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Abstract |
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Key words: age-period-cohort models/incidence trends/prostate cancer/testicular cancer
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Introduction |
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Materials and methods |
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Subsequently, the age-specific trends were summarized using ageperiodcohort (APC) analysis (Clayton and Schifflers, 1987a,b
). The APC analysis fits regression models to the data and describes the incidence rate as a function of age, calendar period and birth cohort. Each parameter estimate is interpretable as the natural logarithm of a relative risk (RR) and it is estimated along with its 95% confidence limits. For the analysis of testicular cancer the data were tabulated in nine 5-year age groups (from around 17 years to around 57 years), 11 5-year periods (from around 1945 to around 1995), and 19 `synthetic' cohorts, derived by subtraction of the age mid-point from the period-mid-point (producing cohorts from around 1888 to around 1978). In the analysis of prostate cancer the nine age groups were from around 47 to around 87, and the cohorts were from around 1858 to around 1948.
Due to the linear dependence of age, period and cohort, all parameters in the full APC model cannot be estimated simultaneously. The final model from which parameters were estimated were parameterized to include an intercept term, eight age parameters (setting the value to RR = 1.0 in the middle age group), a drift parameter, nine period parameters (setting the value to RR = 1.0 in 1950 and in 1990), and 17 cohort parameters (setting the value to RR = 1.0 in the second and in the penultimate cohort). The drift parameter describes the linear trend in incidence that cannot be attributed to either period effects or cohort effects; it can be expressed as a percentage change in incidence per year. The period and cohort parameters are used to evaluate the role of period effects and cohort effects. The parameters are mutually adjusted and adjusted for age. Inclusion of a drift parameter in the full model means that the period and cohort parameters are `undrifted', i.e. the null-expectation is that they form a straight horizontal line when plotted. Due to the linear dependence of age, period and cohort, in order to fit the model, two period parameters and two cohort parameters are forced to take the baseline value of RR = 1.0. Therefore, the pattern of each set of parameters cannot be evaluated by the position of the resulting graph in the plane (because the choice of the two parameters to take the baseline value of RR = 1.0 is arbitrary), but only by the change in parameter values from one period to the next or from one cohort to the next.
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Results |
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Prostate cancer
Figure 6 shows the age-specific incidence rates of prostate cancer around 1995. The incidence was very low up to the age of 50 but increased rapidly thereafter to a level of around 600 per 100 000 around the age of 82.
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Discussion |
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The great majority of testicular cancer, particularly before the age of 60 years, are germ cell tumours. The origin of these cancers is likely to be the population of primordial germ cells, and testicular cancers express markers that are similar to fetal germ cells (Jørgensen et al., 1995). Both of the main clinical types of testicular germ cell cancer, seminoma and non-seminoma, are preceded by carcinoma in situ (Skakkebæk et al., 1987
). It has been shown that the prevalence of carcinoma in situ in a population corresponds quite accurately to the lifetime occurrence of testicular cancer in that population (Giwercman et al., 1989
, 1991
; Dieckman and Loy, 1998). Carcinoma in situ has not been observed to regress spontaneously, but men with untreated carcinoma in situ have been observed to develop testicular cancer with a high frequency (Skakkebæk et al., 1981
).
The implication of these observations is that testicular cancer is initiated in fetal life before the normal differentiation of the primordial germ cells into spermatogonia, which coincides with the differentiation of the male sexual phenotype. A role of hormones, particularly maternal endogenous oestrogens (Henderson et al., 1979) and environmental exposure to substances with oestrogen-like action (Sharpe and Skakkebæk, 1993
) has been postulated. More recently, the interest has been expanded to include also substances with anti-androgenic potential, as discussed in other articles in this issue. This line of causation of testicular cancer remains hypothetical, but it may potentially account for the established association between testicular cancer and cryptorchidism and the possible association with hypospadias, both of which may represent imperfect differentiation of the male sexual phenotype.
The increase in age-standardized incidence of testicular cancer in Denmark is consistent with similar changes in a number of other populations of European origin (Coleman et al., 1993), with the possible exception of Switzerland where the age-adjusted incidence rate is high and seems to have been stable in the last 23 decades (Levi et al., 1990
).
The cohort pattern of testicular cancer incidence strongly suggests a role of exposures in everyday life that act through exposure of the developing male embryo, and which may change quite rapidly. The wartime effect in Denmark, Norway and Sweden (Wanderås et al., 1995; Bergström et al., 1996
) is suggestive of a role of dietary habits, particularly the dietary habits of pregnant women. This idea remains to be explored in a large, well-designed epidemiological study.
Perhaps an even more important observation is the possible attenuation of the increase in testicular cancer incidence in men born after around 1960. If this is a real phenomenon (which will be clear after a few more years of data), the implication is that the great part of the recent increase in incidence has been due a rapid increase in incidence in successive birth cohorts born in the period from 1945 to 1960. A stabilization in the incidence of testicular cancer in young men has also been reported from the SEER programme in the USA (Pharris-Ciurej et al., 1999). Recent data on trends in the youngest age groups in other populations would be very interesting.
The observation of a period effect in the trend of testicular cancer (Figure 5) was unexpected. If the causation of testicular cancer is prenatal and irreversible then there should be no period effect, only cohort effects. The magnitude of the decline in incidence due to the period effect is around 20% in 19901995. In part the decline may have to do with the screening for contralateral carcinoma in situ in testicular cancer patients, which has been introduced since the 1980s (Østerlind et al., 1991
) and possibly to some degree with informal screening of infertile men. However, since only around 5% of testicular cancer patients develop a second testicular cancer, these changes are not strong enough to account for the apparent reduction in period parameters in the most recent decade.
The evidence for an involvement of hormones or hormone-like exposures in testicular cancer is still at best circumstantial. The descriptive epidemiological features of testicular cancer, particularly the strong geographical variation and the strong variation with birth cohort, would seem to suggest the role of a single or a few strong risk factors. Large casecontrol studies in several populations, based on interviews with the men and their mothers, have not been successful in identifying such strong risk factors. The problem may be due to lack of variation in the relevant factors within the studied populations, or to difficulties with exposure characterization if, for example, the process of testicular carcinogenesis is dependent on a very narrow time-window of susceptibility, or on a particular combination of exposures, either simultaneously or sequentially.
Prostate cancer
There is a definite role of androgens in the progression of prostate cancer, which may be treated (but not cured) by surgical castration or administration of anti-androgens.
The geographical variation in incidence varies considerably. Among populations of European origin the incidence in the USA is about twice as high as in Europe, but the mortality rates are about the same (Oliver et al., 2000). A marked increase in incidence in the USA peaked in 1992 and was attributable to the widespread testing for the serum marker prostate specific antigen (PSA) leading to increasing detection of localized disease (Hankey et al., 1999
; Schwartz et al., 1999
).
The registered incidence of prostate cancer is dependent on the level of diagnostic activity and screening in the population. In Denmark, the cumulative incidence of prostate cancer up to the age of 75 years is ~3.5%. Yet prostatic intra-epithelial neoplasia (PIN) has been found in 50% of American Caucasian men in their 70s (Sakr et al., 1995) and the prevalence of invasive latent carcinoma is ~30% in autopsied men in their 70s (Breslow et al., 1977
). Pathological investigation of specimens from transurethral resections for presumed benign prostatic hyperplasia (BPH) leads to a diagnosis of prostate cancer in about 10% of the cases (Sheldon et al., 1980
; Rohr, 1987
).
The frequency of surgical treatment for BPH has decreased in Denmark with the introduction of medical treatment for this condition. The annual number of operations was around 6500 per year in the 1980s and decreased to about half that number in the 1990s (J.Nordling, personal communication). The expected reduction in the number of prostate cancer cases could therefore be around 325 per year which is more than enough to account for the observed decrease.
The cohort effect in the earliest birth cohorts (Figures 8 and 9) is most likely to be due to incomplete diagnosis and registration of prostate cancer in the oldest age groups in the period up to around 1960.
The epidemiological pattern of prostate cancer incidence seems totally dominated by artefactual changes in the processes of diagnosis and registration. The incidence of this cancer has undoubtedly increased over time but the data do not permit inferences to be drawn about corresponding changes in the causal factors.
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Acknowledgements |
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Notes |
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References |
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Submitted on August 15, 2000; accepted on February 6, 2001.