Cancer Causesand Control,3, 481
- 492
Time trend and age-period-cohort effects on incidence of esophageal cancer in Connecticut, 1935-89
T o n g z h a n g Z h e n g , S u s a n T a y l o r M a y n e , T h e o d o r e R. H o l f o r d , P e t e r Boyle, W e n l i a n g Liu, Y a t i n g C h e n , M a r t y M a d o r a n d John Flannery
(Received 2June 1992;accepted 16June 1992) The purpose of this study was to examine the incidence pattern of esophageal cancer in Connecticut (USA) during the past decades, and to identify components of birth cohort, period, and age as determinants of the observed time trends by regression modelling. This study is based on all of the esophageal cancer cases reported to the Connecticut Tumor Registry between 1935 and 1989. A total of 6,310 incident cases were included. Results indicate that among males, the overall age-adjusted incidence rate of esophageal cancer increased after 1935 and peaked between 1955 and 1959. Since then, incidence rates have been relatively stable. Among females, the overall esophageal cancer rate has not changed markedly since 1935. Analysis by histologic type indicates that the incidence rate of squamous cell carcinoma has been declining in this population; adenocarcinoma, however, showed a continuous increase. A fivefold increase among males and a threefold increase among females were observed for adenocarcinoma of the esophagus between 1970 and 1989. If cancers of the esophagus and gastric cardia are considered together, the incidence rate of adenocarcinoma exceeds that of squamous cell carcinoma among males during 1985-89. The observed increasing trend for adenocarcinoma of the esophagus is mainly from cancers arising in the lower third of the esophagus and primarily among Whites, especially White males. The results from regression modeling indicate that both period and birth cohort may have contributed to the observed increasing trend, and adenocarcinoma of the esophagus is likely to increase continuously in this population in the coming years.
Key words:Age-period-cohort, epidemiology, esophageal cancer, tumor registry, USA. Introduction Recent population-based cancer-registry data from the United States1~and the United Kingdom3indicate that incidence rates of adenocarcinoma of the esophagus and gastric cardia have been increasing. Populationbased cancer-registry data from Switzerland4,5indicate that a significant increase in the incidence rate of adenocarcinoma of the esophagus is restricted to males; among females, adenocarcinoma of the esophagus is
basically stable. In contrast to the US/UK data, there is no observed increasing or decreasing trend for adenocarcinoma of the gastric cardia for the past decade in the Swiss population.4,5 Several clinic-based studies 6-8 indicate an increase in adenocarcinoma of the esophagus and gastric cardia. Exposure to new environmental carcinogens and changes in the criteria for the histopathologic diagnosis of esophageal cancer have been
Drs Zheng, Mayne, and Holford, Mr Liu, Ms Chen, and Mr Mador are from the Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA. Dr Boyle is in the Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. Mr Flannery is in the Connecticut Tumor Registry, Hartford, CT, USA. Address correspondence to Dr Zheng, Cancer Prevention Research Unit for Connecticut, Yale University School of Medicine, 26 High Street, New Haven, CT 06510, USA. This study was supported by N I H grant # CA-42101. © 1992 Rapid Communications of Oxford Ltd
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T. Zheng et al suggested to be responsible for the observed increasing trend for adenocarcinoma of the esophagus and gastric cardia. Connecticut is both the oldest population-based cancer registry in the world that has data on all types of cancer since 1935 and the largest population-based registry in the US. This data set provides a unique opportunity to examine the long-term trend for the disease. The major purposes of the current study were: (i) to examine the incidence pattern of esophageal cancer in Connecticut during the past decades; (ii) to separate components of birth cohort, time period, and age as determinants of the observed time trends by fitting a regression model; and (iii) to use this information to project the future trend of esophageal cancer in Connecticut.
Materials and methods Connecticut Tumor Registry As has been described elsewhere,9,~°the Connecticut Tumor Registry has been an important source of cancer incidence data for both descriptive and analytic epidemiologic studies within the US. The Registry has collected data continuously on all types of cancer since 1935. By 1965, reporting by hospitals was considered nearly complete?,~°Less than two percent of the cases registered were identified through death certificate only, since 1968. Several systems of classification and coding for the primary site and histology have been used by the Connecticut Tumor Registry during the decades of cancer registration. All records in earlier codes, however, were recoded in 1977 according to the International Classification of Disease for Oncology (ICD-O). According to the ICD-O first edition, .1 esophageal cancer is coded as 150.0 to 150.9.
Methods of analysis This study is based on all the esophageal cancer cases reported to the Connecticut Tumor Registry over the period 1935-89. The data were prepared and provided by the Connecticut Tumor Registry as computer files. On the basis of this data set, crude and age-adjusted incidence rates of esophageal cancer were calculated for each sex and for Whites and Blacks, and by anatomic sites and histologic types. When anatomic sites were considered, esophageal cancers were divided into cancers of the upper third (ICD-O codes 150.0 and 150.3); middle third (150.1,150.4); lower third (150.2, 150.5), and multiple origin or not otherwise specified (150.8, 150.9). When histologic types were considered, esophageal cancers were classified as squamous cell carcinoma (ICD-O codes 8050-8082); adenocarci482
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noma (8140-8573); other specified malignant neoplasms (8580-9680), and neoplasms not otherwise specified (8000-8045). Since it may be difficult to determine the origin of cancers at the gastroesophageal junction, classifying more cases to esophagus rather than to gastric cardia may affect, and limit the interpretation of the observed time trend for esophageal cancer. Consequently, we also examined the time trend for cancers of the esophagus and gastric cardia together, with cardia cancers defined as ICD-O code 151.0. In this study, age-adjusted incidence rates were calculated by the direct method standardized to the 1970 US population. To calculate age-specific incidence rates, cases were grouped into 10-year age intervals up to age 80 with two exceptions: age 0 to 29 was considered as one group, and age 80 and over as another. The data are presented by calendar year and cohort year of birth. In order to analyze the time trends in esophageal cancer incidence in more detail, an ageperiod-cohort model was fitted to the rates as described elsewhere.12-~ Not only does this type of analysis consider the effect of age, but it also allows consideration of the effects of year of diagnosis (period), as well as generational or year of birth effects (cohort). Both age and period were divided into fiveyear intervals. If i ( = 1,2 .... /) is the index representing age group, and j ( = 1, 2,...J) represents period, then a particular birth cohort can be identified by k - - j i + I. The model fitted to these data was a log-linear model for the effects of age, period, and cohort for the rate
log k iik= ~ + 0~i+ ~ri + %, where % "trj,and ~/~represent the effects of age, period, and cohort, respectively. It was assumed that the number of cases followed a Poisson distribution with mean kiik~jk, where Tiik represents person-years experience, and maximum likelihood estimates were obtained using the regression package, GLIM. ~ It is well known that a model that simultaneously considers all three time factors suffers from the nonidentifiability problem due to the linear dependence among the indices i, j, and k. ~' One approach to the problem is to limit discussion to estimable functions of the parameters, i.e., relationships that are not affected by nonidentifiability. This can be accomplished by partitioning the effects into two components, which might be illustrated using the effect of age. Let the ith age effect be expressed as ~, = 13~*[ i - (I + 1)/2] + % where [3~represents the overall slope or trend for age, and % is the departure of the individual age effects from the overall trend; the departure also is referred to as curvature. A similar partition can be used for each of the time factors, and it has been shown that all the cur-
Age-period-cohort and esophageal cancer vature components are estimable, i.e., they can be uniquely determined. The slopes, on the other hand, cannot be uniquely determined, but they each may be biased by the same unidentifiable constant, O, that can be expressed as
13, = 13.' + 0
10
8 o o
1?5= 1 3 / - 0 13c= 13c'+ 0 where ~a"' ~p't and 13ct are the true slopes. While the individual slopes are indeterminant, certain combinations can be determined; for instance, the sum of the period and cohort slope ([3c+ f~p) is estimable because the Os cancel when taking the sum, 42.14 giving rise to a parameter similar to what Clayton and Schifflers16,17call the drift. This quantity is useful for deciding whether trends are increasing over time.
6
o" 0 ~. ~ rr
4
019 3 5-39 ' 45~49 , 55~59 ' 65~69 ' 75~79 '1985-89 Year
Figure 1. Age-adjusted incidence rates of esophagealcancer
Results
for Connecticut, 1935-89, (VI)Male; (O) female.
Time trends A total of 6,310 newly diagnosed cases of esophageal cancer were reported to the Connecticut Tumor Registry between 1935 and 1989. Of these, 4,888 (77 percent) were diagnosed in males and 1,422 (23 percent) in females. Figure 1 presents the age-adjusted incidence rates of esophageal cancer for both males and females. Among males, the age-adjusted incidence rates increased rapidly after 1935, and peaked during the time period between 1955 and 1959. Since 1960, the incidence rate has been relatively stable. Among females, there is no obvious increasing or decreasing trend for the age-adjusted incidence rate of esophageal cancers during the past decades. Tables 1 and 2 present the age-specific incidence rates of esophageal cancer by calendar year and age
group for males and females, respectively. As can be seen from the tables, there is no clear time trend for the incidence rates from any age group among either males or females. Birth cohort examination indicates that for males (Figure 2), earlier birth cohorts have comparable incidence rates to more recent birth cohorts. Among the older age groups, recent birth cohorts actually have lower incidence rates than the earlier birth cohorts. The incidence rates for females show a similar birth-cohort pattern to that observed for males (Figure not shown). Figures 3 and 4 present the time trends of the ageadjusted incidence rates of esophageal cancer by histologic type for males and females between 1955 and 1989. This time period was selected for these analyses
Table 1. Average age-specific and age-adjusted incidence rates (per 100,000) of esophageal cancer for C o n n e c t i c u t b y time period, males only Year group
Age group < 30
30-39
40-49
50-59
60-69
70-79
80 +
Ageadjusted incidence
HC'
rate 1935-39 1940-44 1945-49 1950-54 1955-59 1960-64 1965-69 1970-74 1975-79 1980-84 1985-89
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0
0.3 0.6 0.1 0.4 0.1 0.2 0.4 0.4 0.3 0.4 0.5
2.4 2.1 2.2 3.1 3.8 3.9 3.7 3.3 4.4 4.2 4.9
14.5 13.8 18.2 16.4 14.5 15.3 13.4 16.3 14.3 15.4 16.0
30.7 27.4 36.9 38.5 43.8 34.8 35.5 26.3 29.5 29.3 34.8
33.9 48.7 55.0 57.1 57.4 45.7 45.2 38.7 45.6 42.7 39.7
37.4 21.9 50.6 65.9 54.5 39.0 42.2 41.5 44.6 41.8 34.8
6.5 6.5 8.5 8.9 9.0 7.6 7.5 6.7 7.2 7.1 7.4
31 45 54 64 74 76 83 86 89 93 95
HC = percentage of newly diagnosed cases of esophageal cancer with histologic confirmation. Cancer Causes and Control. Vol 3. 1992
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T. Zheng et al Table 2. Average age-specificand age-adjusted incidence rates (per 100,000) of esophageal cancer for Connecticut by time period, femalesonly Year group
Age group < 30
30-39
40-49
50-59
60-69
70-79
Ageadjusted incidence
80 +
HC'
rate 1935-39 1940-44 1945-49 1950-54 1955-59 1960-64 1965-69 1970-74 1975-79 1980-84 1985-89 '
HC
=
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0,0 0,0 0,0 0.0
0.2 0.1 0.0 0.0 0.1 0.2 0.1 0.0 0.1 0.0 0.1
0.5 0.6 0.9 0.6 0.8 0.4 1.0 1.5 1,9 1.3 0.7
3.3 3.8 1.6 2.2 2.3 3.1 4.7 4,6 4.9 5.2 3.6
5.7 6.0 7.2 4.6 3.2 5.7 6.0 5.0 8.8 7.4 8.8
10.5 15.9 9.2 11.2 8.0 6.6 9.8 6.0 13.4 12.5 12.1
21.1 11.5 12.9 18.1 10.7 15.1 13.8 11.3 11.5 15.3 15.5
1.7 1.9 1.5 1.5 1.2 1.4 1.8 1,5 2,2 2.1 2.0
19 42 44 61 66 82 78 82 91 92 92
percentage of newly diagnosed cases of esophageal cancer with histologic confirmation.
100
6
5-
10 ¸
0 0 0
0
o o 0
4'
0
O
,r-
n"
¢II n-
.1
i
1860
1880
i
i
i
1900
1920
1940
i
1960
Median year of birth
i
1955-59 60-64
i
•
i
65-69
70-74
75-79
•
i
80-84 1 9 8 5 - 8 9
Year
Figure 2. Incidence rates of esophagealcancer in Connecticut males, presented by age and median year of birth. Age group: (D) 80-84; (O) 75-79; (n) 70-74; (O) 65-69; (m) 60-64; ([~) 55-59; (&) 50-54; (A) 45-49; (I) 40-44.
Figure 3. Age-adjusted incidencerates of esophagealcancer by histologic types for Connecticut males, 1955-89. ([71) Squamous cell carcinoma; (O) adenocarcinoma;(n) multiple origin or not otherwise specified;(O) other histologic types.
since more than 70 percent of the cases were histologically confirmed after 1955. For males the age-adjusted incidence rate for squamous cell carcinoma decreased from 5.8/100,000 in 1955-59 to 4.4/100,000 in 1985-89. The incidence rate for adenocarcinoma, however, began to increase around 1970 among males and has increased steadily from 0.6/100,000 in 1970-74 to 2.5/ 100,000 in 1985-89. Among females, the age-adjusted incidence rate for squamous cell carcinoma showed an increasing trend between 1955 and 1979, followed by a decreasing trend during the past 10 years. The ageadjusted incidence rate for adenocarcinoma in females
also began to increase around 1970, from 0.1/100,000 in 1970-74 to 0.3/100,000 in 1985-89. The incidence rates for esophageal cancers of other histologic types were very low and did not show obvious time trends. Table 3 presents the age-adjusted incidence rates of esophageal cancer by anatomic sites for males and females. For cancer of the upper third of the esophagus, the incidence rate has been stable during the past decades for both males and females. For cancer of the middle third of the esophagus, the incidence rate showed a slight decline during the past 20 years in both males and females. In contrast, however, cancer of the
484
Cancer Causes and Control. Vol 3. 1992
Age-period-cohort and esophageal cancer 2.0
6
5 1.5
i
N
4
1.0
,,.-
3
2
0.5
° n-
1
0.0
~ , 1955-59 60-64
,
,
,
65-69
70-74
75-79
0
,
T
80-84 1985-89
,
1955-59 60-64
65-69
Figure 4. Age-adjusted incidence rates of esophageal cancer by histologic types for Connecticut females, 1955-89. (I-q) Squamous cell carcinoma; (0) adenocarcinoma; (I) multiple origin or not otherwise specified; (©) other histologic types.
Middle third
80 84 1985-89
Figure 5. Age-adjusted incidence rates for cancer of the esophagus and gastric cardia by histologic types for Connecticut males, 1955-89. ([]) Squamous cell carcinoma; (O) adenocarcinoma; (I) multiple origin or not otherwise specified; (O) other histologic types. 2.0
Table 3. Age-adjusted incidence rates of esophageal cancer per 100,000 for Connecticut by anatomic sites and time period Upper third
,
75 79
Year
Year
Year group
70 74
Lower third
NOS"
1.3 1.4 1.3 2.0 2.0 2.6 2.8
5.4 3.8 2.7 1.5 1.6 1.3 2.1
0.2 0.3 0.4 0.5 0.4 0.5 0.6
0.7 0.7 0.6 0.4 0.5 0.6 0.5
1.5" (D
Males 1955-59 1960-64 1965-69 1970-74 1975-79 1980-84 1985-89
0.9 0.8 0.9 1.0 1.0 1.0 0.8
1.3 1.5 2.6 2.2 2.6 2.2 1.8
1955-59 1960-64 1965-69 1970-74 1975-79 1980-84 1985-89
0.1 0.1 0.1 0.2 0.4 0.3 0.3
0.2 0.3 0.6 0.5 0.9 0.7 0.6
1.0" I:E 0.5,
Females
" T u m o r s with multiple origin or not otherwise specified ( I C D - O
codes 150.8 and 150.9).
lower third of the esophagus showed a continuous increasing trend during the past decades, from 1.3/ 100,000 in 1955-59 to 2.8/100,000 in 1985-89 among males, and from 0.2/100,000 to 0.6/100,000 among females. As previously mentioned, tumors originating from the gastroesophageal junction are difficult to locate
O.O
I
I
l
955-59 60-64
65~69
70~74
75~79
80~84 1985-89
Year
Figure 6. Age-adjusted incidence rates for cancer of the esophagus and gastric cardia by histologic types for Connecticut females, 1955-89. ([][])Squamous cell carcinoma; (O) adenocarcinoma; (n) multiple origin or not otherwise specified; (C)) other histologic types.
precisely, therefore, the observed increasing trend for adenocarcinoma of the lower third of the esophagus potentially could reflect a change in classification from cardia tumors to esophageal tumors. This could result from the more widespread use of endoscopy, which is able to locate tumors more precisely. To examine this possibility, combined analyses of trends in the inciCancer Causes and Control. Vol 3. 1992
485
T. Zheng et al Table 4. The time trend for the age-adjusted incidence rates (per 100,000) of esophageal cancer by race, histologic type, and gender for Connecticut, 1970-89
100 '
Year O O C,
10'
Squamous cell carcinoma Black
White
RR"
1970-74 1975-79 1980-84 1985-89
19.5 22.1 23.0 22.6
4.3 4.4 4.2 3.6
4.5 5.0 5.5 6.3
1970-74
3.6 5.5 5.1 5.1
0.9 1.5 1.5 1.3
4.0 3.7 3.4 3.9
Adenocarcinoma B l a c k White
RR"
Male
O O T--
0.0 1.4 0.3 0.8
0.6 0.9 1.5 2.7
0.0 1.6 0.2 0.3
0.1 0.2 0.3 0.4
0.0 1.5 0.0 0.0
Female
.1 1840
I
I
I
I
/
1860
1880
1900
1920
1940
1975-79 1980-84 1985-89 1960
0.0 0.3 0.0 0.0
• RR = relativerisk in Blacksrelativeto Whites.
Median Year of Birth Figure 7. Incidence rates for adenocarcinoma of the esopha-
gus and gastric cardia in Connecticut males, presented by age and median year of birth. ([]) 80 +; (O) 70 -; (m) 60 -; (O) 50 -; (m) 40 - . 10
O O O Q O
_/-
n"
.01 1860
I
l
I
l
1880
1900
1920
1940
1960
Median Year of Birth
Figure 8. Incidence rates for adenocarcinoma of the esophagus and gastric cardia in Connecticut females, presented by age and median year of birth. ([71)80 +; (O) 70-79; (m) 60-69; (O) 50-59; (m) 40-49.
dence of cancer of the gastric cardia and lower third of the esophagus were conducted. Results indicate that cancer of the gastric cardia and lower third of the esophagus has been increasing during the past decades for both males and females, and adenocarcinoma (the major type of cancer for these anatomic sites) accounts for the observed increasing trend for both males and females (data not shown). 486
Cancer Causes and Control. Vol 3. 1992
Figure 5 and Figure 6 show the results when cancer of the gastric cardia and the entire esophagus are considered together. As shown in these Figures, adenocarcinoma of the esophagus and gastric cardia has been increasing while squamous cell carcinoma has been decreasing among both males and females. In males, the age-adjusted incidence rate of adenocarcinoma of the esophagus and gastric cardia has exceeded the rate for squamous cell carcinoma between 1985 and 1989. Cohort examination shows that recent birth cohorts have much higher incidence rates of adenocarcinoma of the esophagus and gastric cardia than earlier birth cohorts for all the ages examined and for both males and females; moreover, there is no indication of a leveling-off in the incidence rate (Figures 7 and 8). Table 4 presents the time trends for the age-adjusted incidence rates of esophageal cancer (excluding gastric cardia) by race and by histologic type. The time period between 1970 and 1989 was selected for this analysis since racial information is of uncertain validity prior to 1970. Squamous cell carcinoma showed a slightly decreasing trend for White males and females for the last study period, but no obvious secular trend was observed from Blacks. For adenocarcinoma, it appears that the observed increasing trend is only evident in Whites. White males and White females experienced a fourfold increase in the age-adjusted incidence rates of adenocarcinoma of the esophagus. For each sex, incidence rates of squamous cell carcinoma were consistently higher in Blacks than Whites during the study period. For adenocarcinoma, however, Whites have a much higher incidence rate than Blacks.
Age-period-cohort modeling An age-period-cohort model was fitted to the data describing the overall trends for squamous cell carci-
Age-period-cohort and esophageal cancer 4 3
Males
2 1 0 -1 -2 -3
~0 ' 70
'
Age
1~S6'1~75'
1~88'1~05'1~.5'
Period
Cohort
Period
Cohort
Females 2 I 0 -I -2 -3
Age
Figure9. Age, period and cohort effects on incidence of adenocarcinoma of the esophagus and cardia, under different assumptions for period slope.
noma and adenocarcinoma of the esophagus (ages 45-84 and years 1955-89). The statistical significance of each factor was assessed using the likelihood ratio test. Because of the nonidentifiability problem, these tests only address the issue of curvature, i.e., departure from linear trend, and do not consider the possibility of a substantial trend that is essentially linear. Hence, the primary focus on the direction of the trends considers estimates of drift. The age-period-cohort model gave a good fit to the data for adenocarcinoma cases of the esophagus and cardia. Figure 9 shows plots of the estimated effects for age, period, and cohort using several plausible assump-
tions for the period slope, i.e., each line corresponds to a particular value of the unidentified constant, O. Several sets of slopes are presented to emphasize the fact that a unique set is not available because of the nonidentifiability problem as discussed earlier and elsewhere. 12The dotted line is based on an assumption of no overall period slope. Under this assumption, birth cohort slopes showed a continuous increasing trend for recent birth cohorts for both males and females. In fact, no matter what kind of assumption regarding period effect, the increasing birth cohort trend from adenocarcinoma of the esophagus persists, which is true for both males and females. The net drift for adenocarcinoma of the esophagus based on periods since 1975 and cohorts since 1900 is 0.536/5-years for males (95 percent confidence interval [CI] = 0.4310.642), and 0.474/5-years for females (CI = 0.2580.691). This translates into a net increase of 11.3 percent for males, and 10.0 percent for females. Figure 10 gives plots of the estimated effects for squamous cell carcinoma of the esophagus for males and females. Squamous cell carcinoma of the esophagus showed a quite different birth-cohort pattern from adenocarcinoma of the esophagus. As can be seen from Figure 10, if period slope is represented by the dotted line, that is, if there is no overall period slope, no clear cohort trend from males was observed for recent birth cohorts. For females, a decline in trend was obvious for cohorts born after 1910. If the period slope is in fact larger than zero (a likely assumption as discussed later), birth cohort slopes for squamous cell carcinoma of the esophagus showed a continuous decreasing trend for both males and females in recent birth cohorts. As expected, the drift for males tends to be negative, ~+ + 13p = - 0.0298 (CI = - 0.0585- - 0.0012). For females, the drift was 0.138/5-years (CI=0.0610.2155), suggesting an average increase of 2.8 percent per year. The downward bend in the curvature seen for female cohort-effects suggests that most of the overall increase is among cohorts born prior to 1920, and the drift is much smaller if one only considers the more recent cohorts.
Discussion The results from this descriptive epidemiologic study show that even though the overall incidence rate of esophageal cancer has been relatively stable in Connecticut during the past six decades, squamous cell carcinoma, the major cell type, has been decreasing slightly among Whites and is relatively stable among Blacks. Adenocarcinoma, however, showed a continuous increase among Whites during the past two decades. The increased incidence rate of adenocarcinoma is Cancer Causes and Control. Vol 3. 1992
487
T. Zheng et al conceived several possible explanations which merit discussion (see below).
2
Males
,
f
(
\ .,,'.;,..
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\
.,
~X%
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.,/
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11l'80' 1900' Ilt20' 19~40
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:.:
-I
1ff55' 19'75'
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F'x
..X x ~
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:
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t
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-4
45 ' 65 '
19'5S'1~7'5'
1~80'1~0'1~0'1~40
Age
Period
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Figure 10. Age, period and cohert effects on incidence of squamous cell carcinoma of the esophagus and cardia, under different assumptions for period slope.
mainly for tumors arising in the lower third of the esophagus, and is evident primarily among White males. This observation is consistent with several previous studies.1~,6,7 Does the observed increasing trend from adenocarcinoma of the esophagus reflect a true change in the disease occurrence due to a change in one or more determinants of the disease, an artifact from other changes such as the recognition of the disease, or both ? Our results indicate both period (year of diagnosis) and cohort (year of birth) effects may be contributing to the observed increasing trend for adenocarcinoma of the esophagus. With regard to a period effect, we have 488
Cancer Causes and Control. Vol 3. 1992
(i) A shift in classificationof tumors arising in the gastroesophagealjunction. It is true that, at one time, adenocarcinomas in the lower third of the esophagus with gastroesophageal junction involvement were more likely to be classified as being of gastric origin, 6,18.19whereas today they are more likely to be classified as arising from the esophagusY ,2° Also, the increasing use of endoscopic methods for the diagnosis of esophageal and cardia cancers may have improved diagnosis with respect to the specific anatomic subsites/,3 However, adenocarcinoma of both the esophagus and gastric cardia is increasing in Connecticut as shown in Figures 5 and 6. In fact, adenocarcinoma of the esophagus and gastric cardia together have exceeded squamous cell carcinoma among males during the past 10 years. This implies that a shift in classification cannot explain the observed increasing incidence of adenocarcinoma of the esophagus. (ii) More precise discrimination of adenocarcinomas from other histologic subtypes. Hesketh et al6 suggested that better diagnostic techniques now allow for more precise discrimination of adenocarcinomas from other histologic subtypes. Our data, however, do not support this argument. As can be seen from Figures 3 and 4, the increase in incidence rate from adenocarcinoma is not paralleled by a corresponding decreasing pattern from squamous cell carcinoma. For cancers of other histologic types (cancers other than squamous cell carcinoma and adenocarcinoma), the incidence rates are very low and remain unchanged during the study period as shown in Figures 3 and 4. In fact, if cancers of the esophagus and cardia are considered together, the incidence rate of cancers of histologic types other than squamous and adenocarcinomas has increased as shown in Figures 5 and 6. (iii) A decreasing trend from esophageal cancer of unspecified histology. It has been suggested that this could explain, in part, the observed increasing trend for adenocarcinoma of the esophagus. 1,5 Esophageal cancer of unspecified histology has decreased materially during the past decades, from 3/100,000 in 1955-59 to 0.5/100,000 in 1985-89 among males, and from 0.5/100,000 in 1955-59 to 0.2/100,000 in 1985-89 among females. Among males, the increase for adenocarcinoma is paralleled by a decrease for esophageal cancer of unspecified histology between 1965 and 1980, as can be seen from Figure 3. However, the decrease
Age-period-cohort and esophageal cancer in cancer of unspecified histology cannot account totally for the observed increasing trend for adenocarcinoma. As can be seen from Figures 3 and 4, esophageal cancer of unspecified histology experienced a dramatic decrease between 1955 and 1969, from about 3/100,000 to 1.5/100,000 among males, whereas adenocarcinoma of the esophagus remained stable. However, when cancer of unspecified histology was relatively stable, especially during the last 10 years, adenocarcinoma experienced the largest increase. These rates are mirrored in females. Thus, a decrease in esophageal cancer of unspecified histology is unlikely to explain the increase in adenocarcinoma of the esophagus. (iv) An improved ascertainment of cases in Connecticut. More complete case ascertainment would affect the overall incidence rate of esophageal cancer, rather than adenocarcinoma alone. Considering that the overall incidence of esophageal cancer has been relatively stable and squamous cell carcinoma of the esophagus is decreasing slightly, then more complete ascertainment of cases is a very unlikely explanation for the observed increasing trend for adenocarcinoma of the esophagus. The suggested cohort effect by age-period analysis indicates risk factors for this type of cancer have been increasing in our environment. What are these factors ? Very few epidemiologic studies have investigated the etiology of esophageal cancer by histology; most of the studies treated esophageal cancers as a single entity. Potential risk factors include: (i) Barrett's esophagus. Barrett's esophagus, also called Barrett's mucosa or Barrett's esophageal mucosa, refers to a metaplastic change in which the normal squamous epithelium above the physiologic lower esophageal sphincter is replaced with a complex mixture of columnar epithelial types. Barrett's esophagus is considered as a complication of protracted gastroesophageal reflux, including the reflux of acidic gastric or bile-containing small bowel contents into the distal esophagus. 21,22 Barrett's esophagus carries a significantly high risk of malignant transformation to adenocarcinoma. It is considered as the common neoplastic pathway for development of adenocarcinoma of the lower esophagus and gastric cardia. One study found evidence of Barrett's metaplasia in the background of 86 percent of their cases of esophageal adenocarcinoma. 23 Another clinical-based case series showed that all clear-cut
adenocarcinoma arising within the lower esophagus was associated with Barrett's mucosa? Studies also show that adenocarcinoma associated with Barrett's esophagus is more common in Whites than Blacks24~s and much more common in men than in womenfl~a6 The question now is not whether Barrett's esophagus increases the risk of adenocarcinoma of the esophagus; rather, the question is whether Barrett's esophagus is responsible for the observed increase in adenocarcinoma of the esophagus. There are no population-based data regarding disease rates or time trends for Barrett's esophagus. If Barrett's esophagus is responsible for the increasing trend of adenocarcinoma of the esophagus, then Barrett's esophagus must be increasing in the population, or the risk factors for Barrett's esophagus have been increasing in our environment, since factors increasing the risk of Barrett's esophagus also would be expected to increase the risk of adenocarcinoma of the esophagus. The major risk factors for Barrett's esophagus are persistent reflux, the presence of hiatal hernia, acidity of the gastric contents and ulceration of the squamous epithelium.8ala2,2zIt is estimated that about two to 11 percent of the patients with reflux esophagitis will develop Barrett's metaplasia. 21 Factors which have been associated with gastroesophageal reflux include consumption of acidic foods (such as citric juices, oranges, tomatoes); and consumption of foods that decrease lower esophageal sphincter pressure (such as alcohol, chocolate, and fats); and consumption of large meals. 28~9 Gastric surgery, duodenal ulcer, and use of medications such as 0t-adrenergic antagonists, 13-adrenergic agonists, and progestational agents have also been linked to the risk of gastroesophageal reflux? °
(ii) Tobacco. Tobacco smoking usually is considered as the most fully established risk factor for esophageal cancer in Western countries. 3143Together with alcohol drinking, it is estimated that at least 80 percent of the esophageal cancer in males from the US, France, Japan, and certain Latin American countries could be attributed to these two risk factors ?4 There are also some studies indicating that adenocarcinoma of the esophagus and/or cardia might be associated with the use of cigarettes, z;4," However, the incidence rate of esophageal cancer shows a very different pattern from other smokingrelated cancers, such as cancers of the lung and bladder. Unlike these cancers for which the incidence rates have been increasing during the past Cancer Causes and Control. Vol 3. 1992
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decades, the overall rate of esophageal cancer has not changed significantly in the US 35or in several European countries 4,36 during the past decades. Squamous cell carcinoma of the esophagus, which is usually considered to be associated with smoking, has been decreasing in Connecticut and in other populations 4 and among Whites for a long time. z; The increase in adenocarcinoma of the esophagus, as our results suggested, started in the 1970s. Adenocarcinoma of the esophagus is a cancer with White male predominance as suggested by this study and other studies, L,2but a recent report from NC137 indicates that Black males have a higher rate of current smokers than White males: the proportion of current US adult smokers is 32.9percent for Black males, 27.0percent for White males, 23.2 percent for Black females and 23.3 percent for White females. One author has attributed this obviously unclear relationship between smoking and esophageal cancer to the possible balance in the population between the detrimental effects of smoking and the beneficial effects from other lifestyle factors, 38but the author did not offer any potential beneficial change which can only overcome the detrimental effects of smoking on the risk of esophageal cancer. Considering the epidemiologic features of esophageal cancer worldwide, our impression is that while smoking is a risk factor for esophageal cancer, smoking is unlikely to be major risk factor for adenocarcinoma of the esophagus and does not explain several observed epidemiologic features of adenocarcinoma of the esophagus: a disease with White male predominance, ~,2,~ mainly affecting those in the professional classes, ~ and showing recent increasing trends while other smokingrelated diseases are beginning to level off27,39-43 (iii) Alcohol. Alcohol drinking, together with smoking, is considered a dominant risk-factor for esophageal cancer in developed countries. 44 One study suggested that the attributable risk for alcohol drinking alone is much higher than that for tobacco smoking alone. 45 Smoking and alcohol drinking also show a very strong synergy in producing esophageal cancer. 32,~4A recent European study 36 showed that in countries with high and increasing levels of alcohol consumption (Denmark, Hungary, Federal Republic of Germany, and Czechoslovakia), successive birth cohorts born after about 1910 experience increasing mortality from esophageal cancer in all age-groups. However, how much the observed increasing trend of adenocarcinoma of the esophagus is 490
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explained by alcohol drinking is unclear. A recent study from Italy46did not show an association between alcohol use, tobacco smoking, and the risk of the adenocarcinoma arising in Barrett's esophagus. However, a recent study from the US 7 reported that alcohol drinking and smoking increased the risk of adenocarcinoma of the proximal esophagus in men. (iv) Diet and nutrients. Early studies from China, Iran, and South Africa indicate that overall dietary or nutritional deficiencies, consumption of foods with N-nitrosocompound contamination, or consumption of moldy foods, especially foods contaminated by Fusariurn and Geotrichurn candidum species, play an important role in the genesis of esophageal cancer. 33,34A recent study from China suggests that low levels of fluid intake and possibly genetic effects might be major risk factors for the disease. ~7 In Western countries, nutritional deficiencies are unlikely to be major risk factors for the disease. However, several recent studies from France, Italy, and the US indicate that higher dietary retinol is associated with an increased risk of esophageal cancer. 48Tuyns et a149in France found that the relative risk (RR) for the highest level of dietary retinol is 3.1, with a statistically significant test for trend. A case-control study from Italy 5° reported an RR of 2.3 for the highest retinol index, and again the test for trend was highly significant. A US study from South Carolina 5~ found an enhancing effect of dietary retinol (odds ratio [OR] = 1.9), and another US study from New York 52reported an OR of 3.04 for dietary retinol. An experimental study has also shown that vitamin A appeared to have a promoting role in carcinogenesis in the esophagus23 However, at present, there are no data relating dietary retinol or other nutrients to specific histologic types of esophageal cancer. In conclusion, this study confirms the findings from other recent studies indicating a rapid increase in the incidence rate of adenocarcinoma of the esophagus among Whites, especially among White males during the past two decades. Our results indicate that both period and cohort effects may have contributed to the observed increasing trend. However, the factor or factors responsible for this observed increasing trend of adenocarcinoma of the esophagus are unknown. Considering the contrasting epidemiologic features of squamous cell carcinoma (a disease with Black predominance, 1,2mainly affecting those in relatively lower socioeconomic groups, ~3 showing a recent decreasing
Age-period-cohort and esophageal cancer trend, and arising mainly from the upper and middle third of the esophagus) and adenocarcinoma of the esophagus (a disease with White male predominance, mainly affecting those in relatively higher socioeconomic groups, showing recent increasing trends, and arising mainly from the lower third of the esophagus), future analytic studies should examine the etiologic factors of esophageal cancer by histologic types and anatomic subsites.
References 1. Blot WJ, Devesa SS, Kneller RW, Fraumeni JF, Jr. Rising incidence of adenocarcinoma of the esophagus and gastric cardia.JAMA 1991; 265: 1287-9. 2. Yang PC, Davis S. Incidence of cancer of the esophagus in the US by histologic type. Cancer 1988; 61: 612-7. 3. PowellJ, McConkey CC. Increasing incidence of adenocarcinoma of the gastric cardia and adjacent sites. BrJ Cancer 1990; 62: 440-3. 4. Levi F, La Vecchia C, Te VC. Descriptive epidemiology of adenocarcinomas of the cardia and distal stomach in the Swiss Canton of Vaud. Tumori 1990; 76: 167-71. 5. Levi F, La Vecchia C. Adenocarcinoma of the esophagus in Switzerland. JAMA 1991; 22: 2960. 6. Hesketh PJ, Clapp RW, Doos WG, Splecher SJ. The increasing frequency of adenocarcinoma of the esophagus. Cancer 1989; 64: 526-30. 7. Wang HH, Antonioli DA, Goldman H. Comparative features of esophageal and gastric adenocarcinomas: recent changes in type and frequency. Human Pathol 1986; 17: 482-7. 8. Kalish RJ, Clancy PE, Orringer MB, Appelman HD. Clinical, epidemiologic, and morphologic comparison between adenocarcinomas arising in Barrett's esophageal mucosa and in the gastric cardia. Gastroenterology 1984; 86: 461-7. 9. Zheng T, Mayne ST, Flannery J. The time trends of multiple myeloma in Connecticut, 1935-1987. IntJ Cancer 1992; 50:163-4. 10. Zheng T, Mayne ST, Holford TR, Boyle P, Flannery J. Epidemiology of non-Hodgkin's lymphoma in Connecticut, 1935-1988. Cancer (in press). 11. World Health Organization. ICD-O, International Classification of Diseasesfor Oncology, 1st edn. Geneva: WHO, 1976. 12. Holford TR, Zheng T, Mayne ST, McKay LA. Time trends of non-Hodgkin's lymphoma: are they real? What do they mean? Cancer Res (in press). 13. Holford TR. The estimation of age, period and cohort effects for vital rates. Biometrics 1983; 39:311-24. 14. Holford TR. Understanding the effects of age, period, and cohort on incidence and mortality rates. Ann Rev Public Health 1991; 12: 425-57. 15. GLIM Working Party. In: The GLIM System, Release 3.77. Oxford: Numerical Algorithms Group, Ltd, 1987. 16. Clayton D, SchifflersE. Models for temporal variation in cancer rates. I. Age-period and age-cohort models. Stats In Med 1987; 6: 449-67. 17. Clayton D, SchifflersE. Models for temporal variation in cancer rates. II. Age-period and age-cohort models. Stats In Med 1987; 6: 469-81.
18. Bosch A, Frias Z, Caldwell WL. Adenocarcinoma of the esophagus. Cancer 1979; 43: 1557-61. 19. Webb JN, Busuttil A. Adenocarcinoma of the esophagus and esophagogastric junction. BrJ Surg 1978; 65: 475-9. 20. Levine MS, Caroline D, Thompson JJ, et al. Adenocarcinoma of the esophagus: relationship to Barrett mucosa. Radiology 1984; 150: 305-9. 21. Enterline H, Thompson J. Pathology of the Esophagus. Barrett's Metaplasia and Adenocarcinoma. New York: Springer-Verlag Inc., 1984: 109-27. 22. Rubio CA, Aberg B. Barrett's mucosa in conjunction with squamous carcinoma of the esophagus. Cancer 1991; 68: 583-6. 23. Haggitt RC, Tryzelaar J, Ellis FH, Jr, Colcher H. Adenocarcinoma complicating columnar epithelium-lined (Barrett's) esophagus. AmJ Clin Patho11978; 70: 1-5. 24. Skinner DB, Walther BC, Riddell RH, et aL Barrett's esophagus: comparison of benign and malignant cases. Ann Surg 1983; 198: 554-65. 25. Smith RL, Boimott JK, Hamilton SR, Rogers EL. The spectrum of carcinoma arising in Barrett's esophagus. Am J Surg Patho11984; 8: 563-73. 26. Thompson JJ, Zinsser KR, Enterline HT. Barrett's metaplasia and adenocarcinoma of the esophagus and gastroesophageal junction. Hum Patho11983; 14: 42-61. 27. MacDonald WC, MacDonald JB. Adenocarcinoma of the esophagus and/or gastric cardia. Cancer 1987; 60: 1094-8. 28. Bennett JR. Medical therapy for gastro-oesophageal reflux. In: Hennessy TPJ, Cuschieri A, Bennett JR, eds. Reflux Oesophagitis. London: Butterworth, 1989: 123-41. 29. Jamieson GG, Duranceau A. Gastroesophageal Reflux. Philadelphia, PA: WB Saunders, 1988. 30. DayJP, Richter JE. Medical and surgical conditions predisposing to gastroesophageal reflux disease. Gastroenterol Clin N Am 1990; 19: 587-697. 31. Wynder EL, Mabuchi K. Etiological and environmental factors.JAMA 1973; 226: 1546-8. 32. International Agency for Research on Cancer. Tobacco Smoking. Lyon, France: IARC 1986; IARC Monogr Eval Carginog Risk Chem Humans, Vol. 38. 33. Day NE, Munoz N. Esophagus. In: Schottenfeld D, Fraumeni JF, eds. Cancer Epidemiology and Prevention. Philadelphia, PA: WB Saunders, 1982: 596-623. 34. Day NE, Munoz N, Ghadirian P. Epidemiology of esophageal cancer: a review. In: Correa P, Haenszel W, eds. Epidemiology of Cancer of the Digestive Tract. The Hague: Nijhoff, 1982: 21-5. 35. Devesa SS, Silverman DT, Young JL, Jr, et al. Cancer incidence and mortality trends among whites in the United States: 1947-84.JNCI 1987; 79: 701-70. 36. MollerH, Boyle P, Maisonneuve P, et al. Changingmortality from esophageal cancer in males in Denmark and other European countries in relation to changing levels of alcohol consumption. Cancer Causes Control 1990; 1: 181-8. 37. Mahaney FX, Jr. Lung cancer rates in white males levelling off.JNC11992; 84: 83-4. 38. Ernster VL. Women, smoking, cigarette advertising and cancer. In: Stellman SD, eds. Women and Cancer. New York: The Haworth Press, Inc., 1987: 217-35. 39. Devesa SS, Shaw GL, Blot WJ. Changing patterns of lung cancer incidence by histological type. Cancer Epidemiol Cancer Causes and Control. Vol 3. 1992
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T. Zheng et al Biomark Prevent 1991; 1: 29-34. 40. Devesa SS, Blot WJ, Fraumeni JF Jr. Declining lung cancer among young men and women in the United States: a cohort analysis.JNCI 1989; 81: 1568-71. 41. Auerbach O, Garfinkel L. The changing pattern of lung carcinoma. Cancer 1991; 68: 1973-7. 42. Tuyns AJ. Incidence trends of laryngeal cancer in relation to national alcohol and tobacco consumption. In: Magnus K, eds. Trends in Cancer Incidence: Causes and Practical Implications. Washington, DC: Hemisphere, 1982; 199-214. 43. Roush GC, Holford TR, Schymura MJ, et al. Larynx. In: Cancer Risk and lncidence Trends: The Connecticut Perspective. Washington, DC: Hemisphere, 1987: 173-86. 44. International Agency for Research on Cancer. Alcohol Drinking. Lyon, France: IARC5 1988, IARC Monog Eval Carcinog Risk Chem Humans, Vol. 44. 45. Pottern LM, Morris LE, Blot WJ, et aL Esophageal cancer among Black men in Washington DC. I. Alcohol, tobacco, and other risk factors.JNCI 1981; 67: 777-83. 46. Levi F, Ollyo JB, La Vecchia C, Boyle P, et al. The consumption of tobacco, alcohol and the risk of adenocarcinoma in Barrett's oesophagus. Int J Cancer 1990; 45:
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852-4. 47. Li JY, Ershow AG, Chen ZJ, et al. A case-control study of cancer of the esophagus and gastric cardia in Linxian. IntJ Cancer 1989; 43: 755-61. 48. Mayne ST, Graham S, Zheng T. Dietary retinol: prevention or promotion of carcinogenesis in humans? Cancer Causes Control 1991; 2: 443-50. 49. Tuyns AJ, Riboli E, Doornbos G, Pequignot G. Diet and esophageal cancer in Calvados (France). Nutr Cancer 1987; 9: 81-92. 50. Decarli A, Liati P, Negri E, Franceschi S, La Vecchia C. Vitamin A and other dietary factors in the etiology of esophageal cancer. Nutr Cancer 1987; 10: 29-37. 51. Brown LM, Blot WJ, Schuman SH, etal. Environmental factors and high risk of esophageal cancer among men in Coastal South Carolina.JNCl 1988; 80: 1620-5. 52. Graham S, Marshall J, Haughey B, et al. Nutritional epidemiology of cancer of the esophagus. Am J Epidemiol 1990; 131: 454-67. 53. VanRensberg SJ, Krukger EF, Louw MEJ, duPlessis Jp. Vitamin A status and esophageal cancer risk: epidemiologic and experimental evidence for a positive association. Nutr Rep Int 1981; 24:1123-31.
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Time trend and age-period-cohort effects on incidence of esophageal cancer in Connecticut, 1935-89
T o n g z h a n g Z h e n g , S u s a n T a y l o r M a y n e , T h e o d o r e R. H o l f o r d , P e t e r Boyle, W e n l i a n g Liu, Y a t i n g C h e n , M a r t y M a d o r a n d John Flannery
(Received 2June 1992;accepted 16June 1992) The purpose of this study was to examine the incidence pattern of esophageal cancer in Connecticut (USA) during the past decades, and to identify components of birth cohort, period, and age as determinants of the observed time trends by regression modelling. This study is based on all of the esophageal cancer cases reported to the Connecticut Tumor Registry between 1935 and 1989. A total of 6,310 incident cases were included. Results indicate that among males, the overall age-adjusted incidence rate of esophageal cancer increased after 1935 and peaked between 1955 and 1959. Since then, incidence rates have been relatively stable. Among females, the overall esophageal cancer rate has not changed markedly since 1935. Analysis by histologic type indicates that the incidence rate of squamous cell carcinoma has been declining in this population; adenocarcinoma, however, showed a continuous increase. A fivefold increase among males and a threefold increase among females were observed for adenocarcinoma of the esophagus between 1970 and 1989. If cancers of the esophagus and gastric cardia are considered together, the incidence rate of adenocarcinoma exceeds that of squamous cell carcinoma among males during 1985-89. The observed increasing trend for adenocarcinoma of the esophagus is mainly from cancers arising in the lower third of the esophagus and primarily among Whites, especially White males. The results from regression modeling indicate that both period and birth cohort may have contributed to the observed increasing trend, and adenocarcinoma of the esophagus is likely to increase continuously in this population in the coming years.
Key words:Age-period-cohort, epidemiology, esophageal cancer, tumor registry, USA. Introduction Recent population-based cancer-registry data from the United States1~and the United Kingdom3indicate that incidence rates of adenocarcinoma of the esophagus and gastric cardia have been increasing. Populationbased cancer-registry data from Switzerland4,5indicate that a significant increase in the incidence rate of adenocarcinoma of the esophagus is restricted to males; among females, adenocarcinoma of the esophagus is
basically stable. In contrast to the US/UK data, there is no observed increasing or decreasing trend for adenocarcinoma of the gastric cardia for the past decade in the Swiss population.4,5 Several clinic-based studies 6-8 indicate an increase in adenocarcinoma of the esophagus and gastric cardia. Exposure to new environmental carcinogens and changes in the criteria for the histopathologic diagnosis of esophageal cancer have been
Drs Zheng, Mayne, and Holford, Mr Liu, Ms Chen, and Mr Mador are from the Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA. Dr Boyle is in the Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. Mr Flannery is in the Connecticut Tumor Registry, Hartford, CT, USA. Address correspondence to Dr Zheng, Cancer Prevention Research Unit for Connecticut, Yale University School of Medicine, 26 High Street, New Haven, CT 06510, USA. This study was supported by N I H grant # CA-42101. © 1992 Rapid Communications of Oxford Ltd
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T. Zheng et al suggested to be responsible for the observed increasing trend for adenocarcinoma of the esophagus and gastric cardia. Connecticut is both the oldest population-based cancer registry in the world that has data on all types of cancer since 1935 and the largest population-based registry in the US. This data set provides a unique opportunity to examine the long-term trend for the disease. The major purposes of the current study were: (i) to examine the incidence pattern of esophageal cancer in Connecticut during the past decades; (ii) to separate components of birth cohort, time period, and age as determinants of the observed time trends by fitting a regression model; and (iii) to use this information to project the future trend of esophageal cancer in Connecticut.
Materials and methods Connecticut Tumor Registry As has been described elsewhere,9,~°the Connecticut Tumor Registry has been an important source of cancer incidence data for both descriptive and analytic epidemiologic studies within the US. The Registry has collected data continuously on all types of cancer since 1935. By 1965, reporting by hospitals was considered nearly complete?,~°Less than two percent of the cases registered were identified through death certificate only, since 1968. Several systems of classification and coding for the primary site and histology have been used by the Connecticut Tumor Registry during the decades of cancer registration. All records in earlier codes, however, were recoded in 1977 according to the International Classification of Disease for Oncology (ICD-O). According to the ICD-O first edition, .1 esophageal cancer is coded as 150.0 to 150.9.
Methods of analysis This study is based on all the esophageal cancer cases reported to the Connecticut Tumor Registry over the period 1935-89. The data were prepared and provided by the Connecticut Tumor Registry as computer files. On the basis of this data set, crude and age-adjusted incidence rates of esophageal cancer were calculated for each sex and for Whites and Blacks, and by anatomic sites and histologic types. When anatomic sites were considered, esophageal cancers were divided into cancers of the upper third (ICD-O codes 150.0 and 150.3); middle third (150.1,150.4); lower third (150.2, 150.5), and multiple origin or not otherwise specified (150.8, 150.9). When histologic types were considered, esophageal cancers were classified as squamous cell carcinoma (ICD-O codes 8050-8082); adenocarci482
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noma (8140-8573); other specified malignant neoplasms (8580-9680), and neoplasms not otherwise specified (8000-8045). Since it may be difficult to determine the origin of cancers at the gastroesophageal junction, classifying more cases to esophagus rather than to gastric cardia may affect, and limit the interpretation of the observed time trend for esophageal cancer. Consequently, we also examined the time trend for cancers of the esophagus and gastric cardia together, with cardia cancers defined as ICD-O code 151.0. In this study, age-adjusted incidence rates were calculated by the direct method standardized to the 1970 US population. To calculate age-specific incidence rates, cases were grouped into 10-year age intervals up to age 80 with two exceptions: age 0 to 29 was considered as one group, and age 80 and over as another. The data are presented by calendar year and cohort year of birth. In order to analyze the time trends in esophageal cancer incidence in more detail, an ageperiod-cohort model was fitted to the rates as described elsewhere.12-~ Not only does this type of analysis consider the effect of age, but it also allows consideration of the effects of year of diagnosis (period), as well as generational or year of birth effects (cohort). Both age and period were divided into fiveyear intervals. If i ( = 1,2 .... /) is the index representing age group, and j ( = 1, 2,...J) represents period, then a particular birth cohort can be identified by k - - j i + I. The model fitted to these data was a log-linear model for the effects of age, period, and cohort for the rate
log k iik= ~ + 0~i+ ~ri + %, where % "trj,and ~/~represent the effects of age, period, and cohort, respectively. It was assumed that the number of cases followed a Poisson distribution with mean kiik~jk, where Tiik represents person-years experience, and maximum likelihood estimates were obtained using the regression package, GLIM. ~ It is well known that a model that simultaneously considers all three time factors suffers from the nonidentifiability problem due to the linear dependence among the indices i, j, and k. ~' One approach to the problem is to limit discussion to estimable functions of the parameters, i.e., relationships that are not affected by nonidentifiability. This can be accomplished by partitioning the effects into two components, which might be illustrated using the effect of age. Let the ith age effect be expressed as ~, = 13~*[ i - (I + 1)/2] + % where [3~represents the overall slope or trend for age, and % is the departure of the individual age effects from the overall trend; the departure also is referred to as curvature. A similar partition can be used for each of the time factors, and it has been shown that all the cur-
Age-period-cohort and esophageal cancer vature components are estimable, i.e., they can be uniquely determined. The slopes, on the other hand, cannot be uniquely determined, but they each may be biased by the same unidentifiable constant, O, that can be expressed as
13, = 13.' + 0
10
8 o o
1?5= 1 3 / - 0 13c= 13c'+ 0 where ~a"' ~p't and 13ct are the true slopes. While the individual slopes are indeterminant, certain combinations can be determined; for instance, the sum of the period and cohort slope ([3c+ f~p) is estimable because the Os cancel when taking the sum, 42.14 giving rise to a parameter similar to what Clayton and Schifflers16,17call the drift. This quantity is useful for deciding whether trends are increasing over time.
6
o" 0 ~. ~ rr
4
019 3 5-39 ' 45~49 , 55~59 ' 65~69 ' 75~79 '1985-89 Year
Figure 1. Age-adjusted incidence rates of esophagealcancer
Results
for Connecticut, 1935-89, (VI)Male; (O) female.
Time trends A total of 6,310 newly diagnosed cases of esophageal cancer were reported to the Connecticut Tumor Registry between 1935 and 1989. Of these, 4,888 (77 percent) were diagnosed in males and 1,422 (23 percent) in females. Figure 1 presents the age-adjusted incidence rates of esophageal cancer for both males and females. Among males, the age-adjusted incidence rates increased rapidly after 1935, and peaked during the time period between 1955 and 1959. Since 1960, the incidence rate has been relatively stable. Among females, there is no obvious increasing or decreasing trend for the age-adjusted incidence rate of esophageal cancers during the past decades. Tables 1 and 2 present the age-specific incidence rates of esophageal cancer by calendar year and age
group for males and females, respectively. As can be seen from the tables, there is no clear time trend for the incidence rates from any age group among either males or females. Birth cohort examination indicates that for males (Figure 2), earlier birth cohorts have comparable incidence rates to more recent birth cohorts. Among the older age groups, recent birth cohorts actually have lower incidence rates than the earlier birth cohorts. The incidence rates for females show a similar birth-cohort pattern to that observed for males (Figure not shown). Figures 3 and 4 present the time trends of the ageadjusted incidence rates of esophageal cancer by histologic type for males and females between 1955 and 1989. This time period was selected for these analyses
Table 1. Average age-specific and age-adjusted incidence rates (per 100,000) of esophageal cancer for C o n n e c t i c u t b y time period, males only Year group
Age group < 30
30-39
40-49
50-59
60-69
70-79
80 +
Ageadjusted incidence
HC'
rate 1935-39 1940-44 1945-49 1950-54 1955-59 1960-64 1965-69 1970-74 1975-79 1980-84 1985-89
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0
0.3 0.6 0.1 0.4 0.1 0.2 0.4 0.4 0.3 0.4 0.5
2.4 2.1 2.2 3.1 3.8 3.9 3.7 3.3 4.4 4.2 4.9
14.5 13.8 18.2 16.4 14.5 15.3 13.4 16.3 14.3 15.4 16.0
30.7 27.4 36.9 38.5 43.8 34.8 35.5 26.3 29.5 29.3 34.8
33.9 48.7 55.0 57.1 57.4 45.7 45.2 38.7 45.6 42.7 39.7
37.4 21.9 50.6 65.9 54.5 39.0 42.2 41.5 44.6 41.8 34.8
6.5 6.5 8.5 8.9 9.0 7.6 7.5 6.7 7.2 7.1 7.4
31 45 54 64 74 76 83 86 89 93 95
HC = percentage of newly diagnosed cases of esophageal cancer with histologic confirmation. Cancer Causes and Control. Vol 3. 1992
483
T. Zheng et al Table 2. Average age-specificand age-adjusted incidence rates (per 100,000) of esophageal cancer for Connecticut by time period, femalesonly Year group
Age group < 30
30-39
40-49
50-59
60-69
70-79
Ageadjusted incidence
80 +
HC'
rate 1935-39 1940-44 1945-49 1950-54 1955-59 1960-64 1965-69 1970-74 1975-79 1980-84 1985-89 '
HC
=
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0,0 0,0 0,0 0.0
0.2 0.1 0.0 0.0 0.1 0.2 0.1 0.0 0.1 0.0 0.1
0.5 0.6 0.9 0.6 0.8 0.4 1.0 1.5 1,9 1.3 0.7
3.3 3.8 1.6 2.2 2.3 3.1 4.7 4,6 4.9 5.2 3.6
5.7 6.0 7.2 4.6 3.2 5.7 6.0 5.0 8.8 7.4 8.8
10.5 15.9 9.2 11.2 8.0 6.6 9.8 6.0 13.4 12.5 12.1
21.1 11.5 12.9 18.1 10.7 15.1 13.8 11.3 11.5 15.3 15.5
1.7 1.9 1.5 1.5 1.2 1.4 1.8 1,5 2,2 2.1 2.0
19 42 44 61 66 82 78 82 91 92 92
percentage of newly diagnosed cases of esophageal cancer with histologic confirmation.
100
6
5-
10 ¸
0 0 0
0
o o 0
4'
0
O
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i
1860
1880
i
i
i
1900
1920
1940
i
1960
Median year of birth
i
1955-59 60-64
i
•
i
65-69
70-74
75-79
•
i
80-84 1 9 8 5 - 8 9
Year
Figure 2. Incidence rates of esophagealcancer in Connecticut males, presented by age and median year of birth. Age group: (D) 80-84; (O) 75-79; (n) 70-74; (O) 65-69; (m) 60-64; ([~) 55-59; (&) 50-54; (A) 45-49; (I) 40-44.
Figure 3. Age-adjusted incidencerates of esophagealcancer by histologic types for Connecticut males, 1955-89. ([71) Squamous cell carcinoma; (O) adenocarcinoma;(n) multiple origin or not otherwise specified;(O) other histologic types.
since more than 70 percent of the cases were histologically confirmed after 1955. For males the age-adjusted incidence rate for squamous cell carcinoma decreased from 5.8/100,000 in 1955-59 to 4.4/100,000 in 1985-89. The incidence rate for adenocarcinoma, however, began to increase around 1970 among males and has increased steadily from 0.6/100,000 in 1970-74 to 2.5/ 100,000 in 1985-89. Among females, the age-adjusted incidence rate for squamous cell carcinoma showed an increasing trend between 1955 and 1979, followed by a decreasing trend during the past 10 years. The ageadjusted incidence rate for adenocarcinoma in females
also began to increase around 1970, from 0.1/100,000 in 1970-74 to 0.3/100,000 in 1985-89. The incidence rates for esophageal cancers of other histologic types were very low and did not show obvious time trends. Table 3 presents the age-adjusted incidence rates of esophageal cancer by anatomic sites for males and females. For cancer of the upper third of the esophagus, the incidence rate has been stable during the past decades for both males and females. For cancer of the middle third of the esophagus, the incidence rate showed a slight decline during the past 20 years in both males and females. In contrast, however, cancer of the
484
Cancer Causes and Control. Vol 3. 1992
Age-period-cohort and esophageal cancer 2.0
6
5 1.5
i
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1
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,
,
,
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0
,
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80-84 1985-89
,
1955-59 60-64
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Figure 4. Age-adjusted incidence rates of esophageal cancer by histologic types for Connecticut females, 1955-89. (I-q) Squamous cell carcinoma; (0) adenocarcinoma; (I) multiple origin or not otherwise specified; (©) other histologic types.
Middle third
80 84 1985-89
Figure 5. Age-adjusted incidence rates for cancer of the esophagus and gastric cardia by histologic types for Connecticut males, 1955-89. ([]) Squamous cell carcinoma; (O) adenocarcinoma; (I) multiple origin or not otherwise specified; (O) other histologic types. 2.0
Table 3. Age-adjusted incidence rates of esophageal cancer per 100,000 for Connecticut by anatomic sites and time period Upper third
,
75 79
Year
Year
Year group
70 74
Lower third
NOS"
1.3 1.4 1.3 2.0 2.0 2.6 2.8
5.4 3.8 2.7 1.5 1.6 1.3 2.1
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0.7 0.7 0.6 0.4 0.5 0.6 0.5
1.5" (D
Males 1955-59 1960-64 1965-69 1970-74 1975-79 1980-84 1985-89
0.9 0.8 0.9 1.0 1.0 1.0 0.8
1.3 1.5 2.6 2.2 2.6 2.2 1.8
1955-59 1960-64 1965-69 1970-74 1975-79 1980-84 1985-89
0.1 0.1 0.1 0.2 0.4 0.3 0.3
0.2 0.3 0.6 0.5 0.9 0.7 0.6
1.0" I:E 0.5,
Females
" T u m o r s with multiple origin or not otherwise specified ( I C D - O
codes 150.8 and 150.9).
lower third of the esophagus showed a continuous increasing trend during the past decades, from 1.3/ 100,000 in 1955-59 to 2.8/100,000 in 1985-89 among males, and from 0.2/100,000 to 0.6/100,000 among females. As previously mentioned, tumors originating from the gastroesophageal junction are difficult to locate
O.O
I
I
l
955-59 60-64
65~69
70~74
75~79
80~84 1985-89
Year
Figure 6. Age-adjusted incidence rates for cancer of the esophagus and gastric cardia by histologic types for Connecticut females, 1955-89. ([][])Squamous cell carcinoma; (O) adenocarcinoma; (n) multiple origin or not otherwise specified; (C)) other histologic types.
precisely, therefore, the observed increasing trend for adenocarcinoma of the lower third of the esophagus potentially could reflect a change in classification from cardia tumors to esophageal tumors. This could result from the more widespread use of endoscopy, which is able to locate tumors more precisely. To examine this possibility, combined analyses of trends in the inciCancer Causes and Control. Vol 3. 1992
485
T. Zheng et al Table 4. The time trend for the age-adjusted incidence rates (per 100,000) of esophageal cancer by race, histologic type, and gender for Connecticut, 1970-89
100 '
Year O O C,
10'
Squamous cell carcinoma Black
White
RR"
1970-74 1975-79 1980-84 1985-89
19.5 22.1 23.0 22.6
4.3 4.4 4.2 3.6
4.5 5.0 5.5 6.3
1970-74
3.6 5.5 5.1 5.1
0.9 1.5 1.5 1.3
4.0 3.7 3.4 3.9
Adenocarcinoma B l a c k White
RR"
Male
O O T--
0.0 1.4 0.3 0.8
0.6 0.9 1.5 2.7
0.0 1.6 0.2 0.3
0.1 0.2 0.3 0.4
0.0 1.5 0.0 0.0
Female
.1 1840
I
I
I
I
/
1860
1880
1900
1920
1940
1975-79 1980-84 1985-89 1960
0.0 0.3 0.0 0.0
• RR = relativerisk in Blacksrelativeto Whites.
Median Year of Birth Figure 7. Incidence rates for adenocarcinoma of the esopha-
gus and gastric cardia in Connecticut males, presented by age and median year of birth. ([]) 80 +; (O) 70 -; (m) 60 -; (O) 50 -; (m) 40 - . 10
O O O Q O
_/-
n"
.01 1860
I
l
I
l
1880
1900
1920
1940
1960
Median Year of Birth
Figure 8. Incidence rates for adenocarcinoma of the esophagus and gastric cardia in Connecticut females, presented by age and median year of birth. ([71)80 +; (O) 70-79; (m) 60-69; (O) 50-59; (m) 40-49.
dence of cancer of the gastric cardia and lower third of the esophagus were conducted. Results indicate that cancer of the gastric cardia and lower third of the esophagus has been increasing during the past decades for both males and females, and adenocarcinoma (the major type of cancer for these anatomic sites) accounts for the observed increasing trend for both males and females (data not shown). 486
Cancer Causes and Control. Vol 3. 1992
Figure 5 and Figure 6 show the results when cancer of the gastric cardia and the entire esophagus are considered together. As shown in these Figures, adenocarcinoma of the esophagus and gastric cardia has been increasing while squamous cell carcinoma has been decreasing among both males and females. In males, the age-adjusted incidence rate of adenocarcinoma of the esophagus and gastric cardia has exceeded the rate for squamous cell carcinoma between 1985 and 1989. Cohort examination shows that recent birth cohorts have much higher incidence rates of adenocarcinoma of the esophagus and gastric cardia than earlier birth cohorts for all the ages examined and for both males and females; moreover, there is no indication of a leveling-off in the incidence rate (Figures 7 and 8). Table 4 presents the time trends for the age-adjusted incidence rates of esophageal cancer (excluding gastric cardia) by race and by histologic type. The time period between 1970 and 1989 was selected for this analysis since racial information is of uncertain validity prior to 1970. Squamous cell carcinoma showed a slightly decreasing trend for White males and females for the last study period, but no obvious secular trend was observed from Blacks. For adenocarcinoma, it appears that the observed increasing trend is only evident in Whites. White males and White females experienced a fourfold increase in the age-adjusted incidence rates of adenocarcinoma of the esophagus. For each sex, incidence rates of squamous cell carcinoma were consistently higher in Blacks than Whites during the study period. For adenocarcinoma, however, Whites have a much higher incidence rate than Blacks.
Age-period-cohort modeling An age-period-cohort model was fitted to the data describing the overall trends for squamous cell carci-
Age-period-cohort and esophageal cancer 4 3
Males
2 1 0 -1 -2 -3
~0 ' 70
'
Age
1~S6'1~75'
1~88'1~05'1~.5'
Period
Cohort
Period
Cohort
Females 2 I 0 -I -2 -3
Age
Figure9. Age, period and cohort effects on incidence of adenocarcinoma of the esophagus and cardia, under different assumptions for period slope.
noma and adenocarcinoma of the esophagus (ages 45-84 and years 1955-89). The statistical significance of each factor was assessed using the likelihood ratio test. Because of the nonidentifiability problem, these tests only address the issue of curvature, i.e., departure from linear trend, and do not consider the possibility of a substantial trend that is essentially linear. Hence, the primary focus on the direction of the trends considers estimates of drift. The age-period-cohort model gave a good fit to the data for adenocarcinoma cases of the esophagus and cardia. Figure 9 shows plots of the estimated effects for age, period, and cohort using several plausible assump-
tions for the period slope, i.e., each line corresponds to a particular value of the unidentified constant, O. Several sets of slopes are presented to emphasize the fact that a unique set is not available because of the nonidentifiability problem as discussed earlier and elsewhere. 12The dotted line is based on an assumption of no overall period slope. Under this assumption, birth cohort slopes showed a continuous increasing trend for recent birth cohorts for both males and females. In fact, no matter what kind of assumption regarding period effect, the increasing birth cohort trend from adenocarcinoma of the esophagus persists, which is true for both males and females. The net drift for adenocarcinoma of the esophagus based on periods since 1975 and cohorts since 1900 is 0.536/5-years for males (95 percent confidence interval [CI] = 0.4310.642), and 0.474/5-years for females (CI = 0.2580.691). This translates into a net increase of 11.3 percent for males, and 10.0 percent for females. Figure 10 gives plots of the estimated effects for squamous cell carcinoma of the esophagus for males and females. Squamous cell carcinoma of the esophagus showed a quite different birth-cohort pattern from adenocarcinoma of the esophagus. As can be seen from Figure 10, if period slope is represented by the dotted line, that is, if there is no overall period slope, no clear cohort trend from males was observed for recent birth cohorts. For females, a decline in trend was obvious for cohorts born after 1910. If the period slope is in fact larger than zero (a likely assumption as discussed later), birth cohort slopes for squamous cell carcinoma of the esophagus showed a continuous decreasing trend for both males and females in recent birth cohorts. As expected, the drift for males tends to be negative, ~+ + 13p = - 0.0298 (CI = - 0.0585- - 0.0012). For females, the drift was 0.138/5-years (CI=0.0610.2155), suggesting an average increase of 2.8 percent per year. The downward bend in the curvature seen for female cohort-effects suggests that most of the overall increase is among cohorts born prior to 1920, and the drift is much smaller if one only considers the more recent cohorts.
Discussion The results from this descriptive epidemiologic study show that even though the overall incidence rate of esophageal cancer has been relatively stable in Connecticut during the past six decades, squamous cell carcinoma, the major cell type, has been decreasing slightly among Whites and is relatively stable among Blacks. Adenocarcinoma, however, showed a continuous increase among Whites during the past two decades. The increased incidence rate of adenocarcinoma is Cancer Causes and Control. Vol 3. 1992
487
T. Zheng et al conceived several possible explanations which merit discussion (see below).
2
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:
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Figure 10. Age, period and cohert effects on incidence of squamous cell carcinoma of the esophagus and cardia, under different assumptions for period slope.
mainly for tumors arising in the lower third of the esophagus, and is evident primarily among White males. This observation is consistent with several previous studies.1~,6,7 Does the observed increasing trend from adenocarcinoma of the esophagus reflect a true change in the disease occurrence due to a change in one or more determinants of the disease, an artifact from other changes such as the recognition of the disease, or both ? Our results indicate both period (year of diagnosis) and cohort (year of birth) effects may be contributing to the observed increasing trend for adenocarcinoma of the esophagus. With regard to a period effect, we have 488
Cancer Causes and Control. Vol 3. 1992
(i) A shift in classificationof tumors arising in the gastroesophagealjunction. It is true that, at one time, adenocarcinomas in the lower third of the esophagus with gastroesophageal junction involvement were more likely to be classified as being of gastric origin, 6,18.19whereas today they are more likely to be classified as arising from the esophagusY ,2° Also, the increasing use of endoscopic methods for the diagnosis of esophageal and cardia cancers may have improved diagnosis with respect to the specific anatomic subsites/,3 However, adenocarcinoma of both the esophagus and gastric cardia is increasing in Connecticut as shown in Figures 5 and 6. In fact, adenocarcinoma of the esophagus and gastric cardia together have exceeded squamous cell carcinoma among males during the past 10 years. This implies that a shift in classification cannot explain the observed increasing incidence of adenocarcinoma of the esophagus. (ii) More precise discrimination of adenocarcinomas from other histologic subtypes. Hesketh et al6 suggested that better diagnostic techniques now allow for more precise discrimination of adenocarcinomas from other histologic subtypes. Our data, however, do not support this argument. As can be seen from Figures 3 and 4, the increase in incidence rate from adenocarcinoma is not paralleled by a corresponding decreasing pattern from squamous cell carcinoma. For cancers of other histologic types (cancers other than squamous cell carcinoma and adenocarcinoma), the incidence rates are very low and remain unchanged during the study period as shown in Figures 3 and 4. In fact, if cancers of the esophagus and cardia are considered together, the incidence rate of cancers of histologic types other than squamous and adenocarcinomas has increased as shown in Figures 5 and 6. (iii) A decreasing trend from esophageal cancer of unspecified histology. It has been suggested that this could explain, in part, the observed increasing trend for adenocarcinoma of the esophagus. 1,5 Esophageal cancer of unspecified histology has decreased materially during the past decades, from 3/100,000 in 1955-59 to 0.5/100,000 in 1985-89 among males, and from 0.5/100,000 in 1955-59 to 0.2/100,000 in 1985-89 among females. Among males, the increase for adenocarcinoma is paralleled by a decrease for esophageal cancer of unspecified histology between 1965 and 1980, as can be seen from Figure 3. However, the decrease
Age-period-cohort and esophageal cancer in cancer of unspecified histology cannot account totally for the observed increasing trend for adenocarcinoma. As can be seen from Figures 3 and 4, esophageal cancer of unspecified histology experienced a dramatic decrease between 1955 and 1969, from about 3/100,000 to 1.5/100,000 among males, whereas adenocarcinoma of the esophagus remained stable. However, when cancer of unspecified histology was relatively stable, especially during the last 10 years, adenocarcinoma experienced the largest increase. These rates are mirrored in females. Thus, a decrease in esophageal cancer of unspecified histology is unlikely to explain the increase in adenocarcinoma of the esophagus. (iv) An improved ascertainment of cases in Connecticut. More complete case ascertainment would affect the overall incidence rate of esophageal cancer, rather than adenocarcinoma alone. Considering that the overall incidence of esophageal cancer has been relatively stable and squamous cell carcinoma of the esophagus is decreasing slightly, then more complete ascertainment of cases is a very unlikely explanation for the observed increasing trend for adenocarcinoma of the esophagus. The suggested cohort effect by age-period analysis indicates risk factors for this type of cancer have been increasing in our environment. What are these factors ? Very few epidemiologic studies have investigated the etiology of esophageal cancer by histology; most of the studies treated esophageal cancers as a single entity. Potential risk factors include: (i) Barrett's esophagus. Barrett's esophagus, also called Barrett's mucosa or Barrett's esophageal mucosa, refers to a metaplastic change in which the normal squamous epithelium above the physiologic lower esophageal sphincter is replaced with a complex mixture of columnar epithelial types. Barrett's esophagus is considered as a complication of protracted gastroesophageal reflux, including the reflux of acidic gastric or bile-containing small bowel contents into the distal esophagus. 21,22 Barrett's esophagus carries a significantly high risk of malignant transformation to adenocarcinoma. It is considered as the common neoplastic pathway for development of adenocarcinoma of the lower esophagus and gastric cardia. One study found evidence of Barrett's metaplasia in the background of 86 percent of their cases of esophageal adenocarcinoma. 23 Another clinical-based case series showed that all clear-cut
adenocarcinoma arising within the lower esophagus was associated with Barrett's mucosa? Studies also show that adenocarcinoma associated with Barrett's esophagus is more common in Whites than Blacks24~s and much more common in men than in womenfl~a6 The question now is not whether Barrett's esophagus increases the risk of adenocarcinoma of the esophagus; rather, the question is whether Barrett's esophagus is responsible for the observed increase in adenocarcinoma of the esophagus. There are no population-based data regarding disease rates or time trends for Barrett's esophagus. If Barrett's esophagus is responsible for the increasing trend of adenocarcinoma of the esophagus, then Barrett's esophagus must be increasing in the population, or the risk factors for Barrett's esophagus have been increasing in our environment, since factors increasing the risk of Barrett's esophagus also would be expected to increase the risk of adenocarcinoma of the esophagus. The major risk factors for Barrett's esophagus are persistent reflux, the presence of hiatal hernia, acidity of the gastric contents and ulceration of the squamous epithelium.8ala2,2zIt is estimated that about two to 11 percent of the patients with reflux esophagitis will develop Barrett's metaplasia. 21 Factors which have been associated with gastroesophageal reflux include consumption of acidic foods (such as citric juices, oranges, tomatoes); and consumption of foods that decrease lower esophageal sphincter pressure (such as alcohol, chocolate, and fats); and consumption of large meals. 28~9 Gastric surgery, duodenal ulcer, and use of medications such as 0t-adrenergic antagonists, 13-adrenergic agonists, and progestational agents have also been linked to the risk of gastroesophageal reflux? °
(ii) Tobacco. Tobacco smoking usually is considered as the most fully established risk factor for esophageal cancer in Western countries. 3143Together with alcohol drinking, it is estimated that at least 80 percent of the esophageal cancer in males from the US, France, Japan, and certain Latin American countries could be attributed to these two risk factors ?4 There are also some studies indicating that adenocarcinoma of the esophagus and/or cardia might be associated with the use of cigarettes, z;4," However, the incidence rate of esophageal cancer shows a very different pattern from other smokingrelated cancers, such as cancers of the lung and bladder. Unlike these cancers for which the incidence rates have been increasing during the past Cancer Causes and Control. Vol 3. 1992
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T. Zheng et al
decades, the overall rate of esophageal cancer has not changed significantly in the US 35or in several European countries 4,36 during the past decades. Squamous cell carcinoma of the esophagus, which is usually considered to be associated with smoking, has been decreasing in Connecticut and in other populations 4 and among Whites for a long time. z; The increase in adenocarcinoma of the esophagus, as our results suggested, started in the 1970s. Adenocarcinoma of the esophagus is a cancer with White male predominance as suggested by this study and other studies, L,2but a recent report from NC137 indicates that Black males have a higher rate of current smokers than White males: the proportion of current US adult smokers is 32.9percent for Black males, 27.0percent for White males, 23.2 percent for Black females and 23.3 percent for White females. One author has attributed this obviously unclear relationship between smoking and esophageal cancer to the possible balance in the population between the detrimental effects of smoking and the beneficial effects from other lifestyle factors, 38but the author did not offer any potential beneficial change which can only overcome the detrimental effects of smoking on the risk of esophageal cancer. Considering the epidemiologic features of esophageal cancer worldwide, our impression is that while smoking is a risk factor for esophageal cancer, smoking is unlikely to be major risk factor for adenocarcinoma of the esophagus and does not explain several observed epidemiologic features of adenocarcinoma of the esophagus: a disease with White male predominance, ~,2,~ mainly affecting those in the professional classes, ~ and showing recent increasing trends while other smokingrelated diseases are beginning to level off27,39-43 (iii) Alcohol. Alcohol drinking, together with smoking, is considered a dominant risk-factor for esophageal cancer in developed countries. 44 One study suggested that the attributable risk for alcohol drinking alone is much higher than that for tobacco smoking alone. 45 Smoking and alcohol drinking also show a very strong synergy in producing esophageal cancer. 32,~4A recent European study 36 showed that in countries with high and increasing levels of alcohol consumption (Denmark, Hungary, Federal Republic of Germany, and Czechoslovakia), successive birth cohorts born after about 1910 experience increasing mortality from esophageal cancer in all age-groups. However, how much the observed increasing trend of adenocarcinoma of the esophagus is 490
Cancer Causes and Control. Vol 3. 1992
explained by alcohol drinking is unclear. A recent study from Italy46did not show an association between alcohol use, tobacco smoking, and the risk of the adenocarcinoma arising in Barrett's esophagus. However, a recent study from the US 7 reported that alcohol drinking and smoking increased the risk of adenocarcinoma of the proximal esophagus in men. (iv) Diet and nutrients. Early studies from China, Iran, and South Africa indicate that overall dietary or nutritional deficiencies, consumption of foods with N-nitrosocompound contamination, or consumption of moldy foods, especially foods contaminated by Fusariurn and Geotrichurn candidum species, play an important role in the genesis of esophageal cancer. 33,34A recent study from China suggests that low levels of fluid intake and possibly genetic effects might be major risk factors for the disease. ~7 In Western countries, nutritional deficiencies are unlikely to be major risk factors for the disease. However, several recent studies from France, Italy, and the US indicate that higher dietary retinol is associated with an increased risk of esophageal cancer. 48Tuyns et a149in France found that the relative risk (RR) for the highest level of dietary retinol is 3.1, with a statistically significant test for trend. A case-control study from Italy 5° reported an RR of 2.3 for the highest retinol index, and again the test for trend was highly significant. A US study from South Carolina 5~ found an enhancing effect of dietary retinol (odds ratio [OR] = 1.9), and another US study from New York 52reported an OR of 3.04 for dietary retinol. An experimental study has also shown that vitamin A appeared to have a promoting role in carcinogenesis in the esophagus23 However, at present, there are no data relating dietary retinol or other nutrients to specific histologic types of esophageal cancer. In conclusion, this study confirms the findings from other recent studies indicating a rapid increase in the incidence rate of adenocarcinoma of the esophagus among Whites, especially among White males during the past two decades. Our results indicate that both period and cohort effects may have contributed to the observed increasing trend. However, the factor or factors responsible for this observed increasing trend of adenocarcinoma of the esophagus are unknown. Considering the contrasting epidemiologic features of squamous cell carcinoma (a disease with Black predominance, 1,2mainly affecting those in relatively lower socioeconomic groups, ~3 showing a recent decreasing
Age-period-cohort and esophageal cancer trend, and arising mainly from the upper and middle third of the esophagus) and adenocarcinoma of the esophagus (a disease with White male predominance, mainly affecting those in relatively higher socioeconomic groups, showing recent increasing trends, and arising mainly from the lower third of the esophagus), future analytic studies should examine the etiologic factors of esophageal cancer by histologic types and anatomic subsites.
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