Int. J . Cancer: 46, 965-971 (1990) 0 1990 Wiley-Liss, Inc.
Publication of the International Union Against Cancer Publication de I‘Union lnternationale Contre le Cancer
BILIARY-TRACT CANCER IN CHILE Ivan SEW’, Alfonso CALVO*,Mauricio MATURANA’ and Allan SHARP? ‘School of Public Health, Faculty of Medicine, University of Chile, Santiago; 2Emergency and Surgical Departments, Sdtero del R fo Hospital, Santiago; 3Department of Surgery, San Felipe Hospital, San Felipe, Chile. This epidemiological study in Chile shows a marked increase in biliary-tract cancer based on mortality data, from an age-adjustedrate (I 970 world population) of 5. I per 100,000 in I970 to 12.0 per IO0,OOO in 1988. There is an increased risk of this cancer in all age groups but especially in young adults (I 2-44 years). The female ratio of 3: I persists. The increase in biliary-tract cancer in 1 9 7 U 9 8 5 was particularly important for young women but occurred in all female age groups whereas in men i t was mostly in the elderly (65 years and more) and less in the middle-aged (45-64 years); no changes were observed in young men. Regionaldifferenceshave begun to be appreciated. One of the factors which may account for this impressive and unexpected increase is the remarkable decrease in cholecystectomyrates. Less than 20% of the 154% increase in biliary-tract cancer mortality in the period 197& I985 could be attributed to population aging. Improvements in diagnostic methods did not appear to be an important contributing factor. Other factors that could affect this increase in the incidence to epidemic levels include: an increase in the prevalence of cholelithiasis, an increase in the number of typhoid carriers and possible environmental carcinogens.
Cancer of the gall-bladder and of the extrahepatic biliary tract has a long-registered high incidence in Chile (Puffer and Griffith, 1967) that is greater than that in most of the developed countries (Fraumeni, 1975), but has manifested a marked and steady increase in all regions of the country during the last 2 decades, reaching a crude mortality rate of 9.9 per 100,000 in 1988 (Serra et al., 1990). The age-adjusted rate in the Chilean population was 3.7 in 1970 and 13.3 in 1988, which is probably one of the highest in the world (Serra et al., 1990). The causes of the observed increase are still not well understood, but several hypothesis have been postulated, such as relative decrease in number of cholecystectomies, increase in the prevalence of gall-stones, deterioration of sanitary conditions, longer life span of the population, and possible increase of carcinogens in the environment (Serra et al., 1986). This increase contrasts with mortality for all types of cancer of which the crude rate in Chile has become stabilised since the late 1960’s, at around 100 per 100,000 population (Medina and Csendes, 1983). No major advances in early diagnosis or therapy of gallbladder cancer have occurred during this century, so a short survival is the common outcome. This high fatality rate makes mortality statistics particularly suitable for examination of the incidence trends of this cancer (Diehl, 1980). The aim is to present an extensive and analytical view of the epidemiological changes in gall-bladder and extrahepatic biliary-tract cancer observed in Chile in the period 1970 to 1988, which are comparable to the crude figures of biliary-tract cancer mortality and cholecystectomy rates published for Sweden in the late 1960’s and 1970’s (Ahlberg et a / . , 1984; Philipp et al., 1987). The epidemiological situation in Chile is comparable to that described in other countries with high incidence of gall-bladder cancer such as Mexico, with adjusted mortality rate for females of 8.5 per 100,000 (Puffer and Griffith, 1967) or Bolivia. with an age-adjusted rate to world population for females of 14.9 per 100,000 (Rios-Dalenz et al., 1983).
statistics based on reliable medical death certificates published annually by the National Health Service (Chile, 1970-1975), Ministry of Health (Chile, 1976-1983), and National Institute of Statistics (Chile, 1982-1987) have been used to produce the rates. Certification by a physician, which provides the sole basis for the 3 sources, has increased from 97.7%, 96.9% and 94.5% in 1970 through 99.3%, 99.1%, and 99.7% in 1985 for deaths from cancer of the liver, biliary tract and pancreas respectively (Chile, 1970-1975; 1976-1981 and 1983; 19821987). Histological verification is accepted as relatively high but national figures are not available. It was 97.6% between 1970 and 1988 in our hospital which is attended by 6% of the country’s population. All of the population of Chile derive from the censuses performed every 10 years since 1835, and for this report the population data derive from the last 1970 and 1982 censuses published by the National Institute of Statistics, corrected by 6.2% and 1.5% respectively, for censal omission (Chile, 1987). Chile has a stable population, predominantly urban (81%) and a national registration system which is computerized and provides an additional control of the population counts. The quality of mortality data in Chile, seldom presented, is considered quite acceptable (Armijo, 1979). An international analysis of underregistration of mortality and of some indices on cause of death declaration considered that the information in 1978 was very good for Chile and 4 other Latin American countries (Chackiel, 1987). The proportion of total deaths registered as ill-defined (Codes 780 to 789, ICD-9) fluctuated between 5.4% and 11.O% during the period 1970-1985 (Chile, 1970-1985). Tumors as a cause of death certified by a doctor amounted to 93.2% in 1983: personal physician in 50.5%, pathologist in 5.1%, and another physician in 37.6% (Castillo and Mardones, 1986). Incidence has been assumed from mortality given the extremely high fatality rate and short survival of biliary tract cancer. Special studies have been requested from the Informatic Department in the Ministry of Health to obtain mortality statistics at the provincial level, and not, as has been routinely the case since 1976, at a regional or health service level. Several decisions have been taken in comparing age, sex, and regional differences; for example, 5-year intervals have been used to simplify and clarify trends. In order to compare rates by calendar time, sex and region, a direct standardization procedure was utilised and the rates were standardized to the Chilean population of 1970 and the world population of 1970. Population aging between 1970 and 1985, as presented in Table I, has been weighted by 2 methods: (1) comparison with the world population (Parkin, 1985); and (2) measurement of changes occurring in the age group of 65 years and over in Chile. The proportion of people 65 years and over in 1970 was 5.1% and taken as a base. The proportions in 1975 (5.4%), 1980 (5.6%) and 1985 (5.8%) have provided differentials of 0.3, 0.5 and 0.7 respectively. These differentials have been subtracted from the crude mortality rate for biliary-tract cancer
MATERIAL AND METHODS
Because of the lack of cancer registries, the official mortality
Received: February 6 , 1990, and in revised form June 20, 1990.
966
SERRA ET AL.
in 1975, 1980 and 1985 (5.3,6.9and 9.4per 100,000 respectively), giving the presented age-adjusted rates for the 65 years and over population. A special study to establish mortality rates for biliary-tract cancer by provinces which were 24 in the early 1970’s(with Talca and Cauquenes as one) has been carried out, choosing 1985 as the present situation. As a consequence of the changes observed, the provinces have been grouped into areas of similar relative risk, labelled as “major”, “intermediate”, and “minor”. The 3 ranges were established in a conventional way and based on the relative risk in every province as compared to the national mean of the same year. Crude rates and not ageadjusted rates have been used because no important changes in the age structure of the provincial populations had occurred. The old distribution of 24 provinces (Talca and Made merged) has been considered to compare the whole period for the advantage of an adequate size and to eliminate certain biases that could appear by using the present distribution of 51 provinces or 13 regions. Since the data concern the whole population, and not a sample, the present epidemiological changes are true and statistical calculations of significance are unnecessary. RESULTS
The crude mortality rate for biliary-tract cancer (Code 156) has increased from 3.7per 100,000in 1970 to 9.9in 1988.The upward trend has been constant throughout the period 19701988,but it becomes more evident from 1979 onwards, particularly for women. Age-adjusted rates (1970world population) show the same trends at a slightly higher level, from 5.1 per 100,000to 12.0 per 100,000(Fig. 1). The mortality rate for gastric cancer, the most prevalent cancer in Chile for both sexes until 1984,has been decreasing constantly over the period 1970-1988. Since 1985 the most common type of cancer as a cause of death among Chilean women is that of the biliary tract, preceding cancer of the stomach, cervix and breast. The other important location of
cancer for both sexes combined is the lung, which at present occupies the second place in mortality. In contrast, pancreatic cancer shows only a moderately increasing trend (Fig. 2). Sex
The preponderance of biliary-tract cancer mortality occurs in women, with a sex ratio of 3:1. Age-adjusted rates (1970Chilean population) show that the increase was equal for both sexes during the periods 197C-1975 and 1975-1980, but that the frequency rose more sharply for women after 1980 (Fig. 3). Age
The risk of cancer has increased in all age groups but proportionally more in young adults (15-44 years). The mortality rate for this group has risen from 0.3 in 1970 to 1.0 per 100,000in 1985, whereas for adults in the next age group (45-64 years) it has gone from 12.3 to 24.1,and in elderly people (65years and over) from 37.4to 94.6per 100,000.The mortality for these 3 age groups was, considering both sexes combined, 3.3,2.0and 2.5 times higher than in 1970 (data not shown). The age structure shows that in 1985, of all deaths from cancer of the biliary tract, 6% occurred in young adults, 36% in middle-aged adults, and 58% in elderly people (65years and over). Sex and age
By using both variables together it can be appreciated that the increase is rather different for men than for women. Mortality has risen markedly in young women, going from 0.4 in 1970 to 1.6per 100,000in 1985,a 4-fold increase as compared to mere duplication of the figures in middle-aged women, 18.7 to 36.7,almost the same proportional increase that has occurred in elderly women in whom the rates were 51.9 and 115.5 per 100,000,respectively. In men, the increase took place mainly in people 65 years and over with mortality rising from 18.7 to 65.7per 100,OOO, whereas in middle-aged men Ad’usted raic per 105,
N-O of deaths
N?of deaths
900 OooI
.
Women Men
Rate per 1W.aoO : Women o--o Men
M
Year S
AGE -ADJUSTED
10 1970 WORLD POPULATION
(
I I R C . 1985
FIGURE1 - Mortality for biliary tract cancer by sex. Chile 1970-1988.
967
BILlARY -TRACT CANCER IN CHILE Adjuitrd Rate pcr 100.000
Adjusted Rate pcr 100.000
~
8 4GE-4DJUSlLD
TO l l S ClULfAN r o N L 4 T l O N
FIGURE 2 - Mortality for selected cancers, both sexes combined. Chile 1969-1988. Adjusted rate per 100.000
Adjusted rate (. per 100.000 20
r20
19 3
0 Men Women Both Sexes
15
15
11.6
10
10
5
1970 AGE
- ADJUSTED
1975
1980
1988
Year
TO 1970 CHILEAN POPULATION
FIGURE3 - Mortality for biliary tract cancer by sex. Chile 1970-1988.
only a mild increase from 5.2 to 9.9 and no changes at all in young adult men were observed (Fig. 4). Site The prevalent site of biliary-tract cancer in Chile is the gall-
bladder. Its preponderance, as compared to common bile duct and ampulla of Vater, apparently increased during the period 197CL1985. In our health care area (6% of the national population), 418 cases of biliary-tract cancer were treated surgically and verified in the period 1970-1988; these comprised 374
968
SERRA ET AL. Crude Rate per lo5 betwren 117 / 174
RR between 13 / 1 9
Intermdiate Risk
between 7 6 / 11 0
R R between 09 / 12
Minor Rtsk
between 63 / 6 4
RR between 0 5 / 0 7
0
15-41 years
Relative Risk
Major Risk
65 years and mom
15-Slyoars 120
DO 80
MEN 20
15 1.0 05
15- 11 y r a r s
45 - 5 1 y n r a
65years and mare
FIGURE4 - Mortality for biliary tract cancer by age and sex. Chile 1970-1985. Crude rates per 100,000.
cancers of the gall-bladder (89.5%), 31 cancers of the choledochus (7.4%) and 13 cancers of the ampulla of Vater (3.1%). Regional diyerences Cancer of the gall-bladder and extra-hepatic biliary tract have traditionally not been considered to present regional differences in Chile (Morales, 1974; Csendes er al., 1977). A special study to establish mortality rates for this type of cancer by provinces indicates that incipient but clear regional changes began to appear between 1970 and 1985. All the Chilean provinces show increases in crude mortality rates of biliary-tract cancer, but all the Southern provinces, with the exceptions of Chilot and Aystn, have progressively reached peak positions. The mortality rate for Valdivia, which has consistently presented the highest risk, was 17.4 per 100,000 in 1985, with a relative risk of 1.9, as compared with the national mean of 9.4. At present the maximal differences in mortality risk between the provinces are 1:4 (Fig. 5). Ageadjustment (1970 Chilean population) does not produce substantial changes in the trends described. Aging of population By using age-adjustment (based on the Chilean population structure of 1970, and taking into account what has happened with the 65 years and over age group) one reaches the conclusion that only 12.3% of the observed 154% increase in crude mortality rates between 1970 and 1985 (or 135% increase in age-adjusted rates) may be attributed to population aging. Based on the world population, however, the result is somewhat higher, reaching an estimate of 16.0% (Table I). Based on the logical association between gall-bladder cancer and cholecystectomy rates (Serra era!., 1986), a special study in the south-east health care area in Santiago, which covers a population of around 900,000 (97% urban, and served by one general hospital of 700 beds) shows that the crude cholecystectomy rate has decreased for this population from 1.6 per 1,000 inhabitants in 1970 to 0.9 in 1985, according to official figures. While there is a lack of national data on biliary surgery, a decrease in cholecystectomies in this important health care area contrasts with the increase in biliary-tract cancer in Chile (Fig. 6). If hospital admissions for cholecystitis and cho-
CH,LE
N! of Deaths Crude Rate per lo5 '
:
FIGURE 5 - Biliary tract cancer mortality, both sexes combined. Chile by provinces, 1985. TABLE I - POPULATION AGING AND BILIARY TRACT CANCER MORTALITY CHILE 1970-1985
Biliary tract cancer modity-rates per 100,033
1975
1980
1985
Increase
1970-1985
Value
Crude rates 3.7 5.3 6.9 9.4 154.1% 100.0 Age-adjustedrates 3.7 5.0 6.4 8.7 135.1% 87.7 (65 years and more) Age-adjusted rates 5.1' 7.1' 8.8' 11.6' 129.4% 84.0 (World population i97m 'Standard error
0.3
0.3
0.3
0.4
lelithiasis were to be established as biliary interventions there is, at the national level, a clear decline in age-adjusted cholecystectomy rates to 1970 Chilean population from 4.8 per 1,000 in 1970 to 3.5 per 1,OOO in 1985 for both sexes combined. DISCUSSION
The substantial increase in mortality from gall-bladder and extrahepatic biliary-tract cancer in Chile is evident to clinicians, pathologists and epidemiologists. At present the epidemiological increase is largely accepted, but the special Chilean situation has to deal not only with a very high incidence, but also with a relatively sharp growth in a short period of time, deserving therefore more critical analysis. At first, this con-
BILIARY-TRACT CANCER IN CHILE
Yeor
1970 1971 1972
e.5
1973
1.9
5.2 5.3
5.2 6.2
5.8 1.3
b.8 1.5
I
197L 1975 1976 1977 1978 1979 1980 1981 1982 1983 1986 1985
FIGURE6 - Biliary tract cancer mortality and cholecystectomy rates. Both sexes combined. Chile 197Cb1985 and South-east Health Area 1970-1985. (Chile: 9,367,633 inhabitants in 1970 and 12,074,477 in 1985. South-east Health Area: 335,828 inhabitants in 1970 and 798,811 in 1985.)
siderable increase in biliary tract cancer was misinterpreted. Explanations such as possible false diagnosis (Smok and Cervilla, 1986), mistakes in tabulation (Medina and Csendes, 1983), or the increased life span of the population had been formulated for this unexpected increase, but all these explanations have been refuted (Serra et al., 1987). The remarkable increase in biliary tract cancer mortality observed in Chile since the 1970's is probably due to several factors, one of which is population aging. It is well known that morbidity and mortality rates due to cancer are higher in the older age groups, and since population aging has taken place in Chile over the period in question, it seems convenient to determine its influence. Several statistical methods have been employed to determine how much of the change in cancer mortality over a period is due to a real change in age-specific risks and how much is due to changes in age composition of the population, such as decomposition analysis (WHO, 1985), age-adjustments, accumulated incidence rates or truncated rates. The purpose here is not to delve into this problem but only to estimate the influence that this factor may have on the increase in biliary tract cancer in Chile. Two classical techniques have been used: age-adjustment with older people and age-adjustment to world population. Both have provided similar estimates: 12% and 16% respectively. Consequently, our concern is to account for the remaining 8688% of the increase observed in Chile from 1970 to 1985. The increase could also be attributed to changes in the incidence of other types of cancer, such as cancers of the stomach, pancreas, liver or colon, which could erroneously have been assigned to gall-bladder or biliary-tract cancer. All these cancers, however, have also become more frequent, except gastric neoplasia, which has decreased following world trends (Correa, 1986). The increase in all these types of cancer in Chile could be partially explained by the improvement of surgical and pathological diagnoses and a more exact completion of medical death certificates, but the relevance of these factors and also of the reasons mentioned above seems negligible, because the improvements are limited or debatable and do not correspond with regional and local variations observed in the period 1970-1985. Clinical practice and pathological experience point in other directions. Cancer of gall bladder (Code 156.0) accounts for an estimated 90% of biliary tract cancer (Code 156) in Chile (Amat and Amat, 1983). This proportion contrasts with that observed
969
in other countries, where gall-bladder cancer appears to be less widespread. Differences are observed in many countries, but around more balanced proportions, in the incidence rates of the 3 main biliary tract neoplasms: gall-bladder, extrahepatic bile duct and ampulla of Vater (Strom et al., 1986). However, the Chilean situation has to deal with gall-bladder cancer and not with extrahepatic biliary-tract cancer. Age composition has varied to a slight extent in Chile from 1970 through 1985, but the regional changes are not explained by age differences. In an international comparison, the mean age observed for both gall-bladder and extrahepatic biliarytract cancer at diagnosis is around 62 years in Chilean clinical services, higher than in Bolivia (Trujillo et al., 1986), but lower than in developed countries such as Sweden (with high biliary-tract cancer incidence) (BrodCn and Bengtsson, 1980) or the United States (with low biliary-tract cancer incidence) (Whetstone et al., 1986). Three risk factors are largely accepted as risk factors for cancer of the gall bladder (Code 156.0) which are: age, female sex, and gall-stones (Hartet al., 1972). Other suggested risk factors are: association with bacteria such as Salmonella typhi (Welton et al., 1979), biliary surgery (Diehl and Beral, 1981), and environmental carcinogens such as nitrosamine (Kowalesky and Todd, 1971). The roles of occupation, radiation, immunological response (nutritional status), among others, still lack good support. Genetic influence cannot be postulated in Chile because no immigration has occurred in recent times, and emigration has not been selective in a way that would explain the change observed. Cholelithiasis is, of course, a risk factor that could well explain the high incidence of biliary-tract cancer in Chile, but not the high increase in this incidence during the last 2 decades. Apparently there has been some increase in the frequency of gall-stones in the Chilean population during the last 30 years, according to autopsies performed in the same centers (Medina et al., 1983). An unestablished amount of environmental estrogens could have originated from the cattle and poultry industry (Montes et al., 1985), and could thus have influenced cholelithiasis and gall-bladder cancer (Pettiti et al., 1988). Bacterial influence, a challenging risk factor which still has to be fully proved, may also play a role in the situation that exists in Chile. A growing incidence of endemic typhoid and paratyphoid fevers since 1976 has contributed to increase the number of chronic carriers of S. typhi (Ristori et a l . , 1982), a fact that could, perhaps, support the bacterial hypothesis. A decrease in biliary-tract surgery, measured through cholecystectomy rates, has been associated with rising trends in mortality due to cancer of the gall-bladder, and vice versa (Diehl and Beral, 1981). The present study was initiated several years ago on the basis of the reasonings first expounded by other investigators (BrodCn et al., 1978). National information about biliary surgery in Chile is not registered. The existing situation in the south-east health care area in Santiago, as far as biliary tract surgery is concerned, probably represents the general situation because of the relatively large size of this community (0.9 x lo6 people) within the Metropolitan Area (population of 5 x lo6), and its proportion of 20% of all surgeries being biliary tract surgeries, which is very similar to national figures taken from a recent random sample (Csendes et al., 1983). The downward trend in the rates of cholecystectomies seems unquestionable if hospital admissions for cholecystitis and cholelithiasis are accepted as biliary surgery. This trend is related to reductions in the resources assigned to medical care: surgical medical hours in the public sector decreased relatively from 2,272 per day in 1970 to 2,490 in 1981 and surgical beds from 3,855 in 1970 to 3,769 in 1985 (Chile, 1970-1985),
970
SERRA ET AL.
while the population increase during the same period (19701985) was 28.9% (Chile, 1987). Of course, the subpopulation which experienced a decline in cholecystectomy may be partially different from the one which underwent an increase in incidence of biliary-tract cancer. Environmental carcinogens may also be contributing factors to the growing incidence of biliary-tract cancer in Chile. Carcinogenic chemicals in very low concentrations associated with air, food and water pollution are also a problem in Chile, where controls in this respect have slackened (Medina and IrarrBzaVal, 1983). Special studies will have to be undertaken, however, firstly to identify the chemicals and secondly to establish
the link between these chemicals and cancer of the gallbladder. The interaction between risk factors may be not only additive but also multiplicative, as has been experimentally demonstrated for this cancer (Kowalesky and Todd, 1971). ACKNOWLEDGEMENTS
The authors are grateful to Dr. A.K. Diehl (San Antonio, TX) for a careful review of the manuscript and helpful comments. They also thank Miss I. Gonzalez for preparing the Figures, and Mr. C.I.Maturana for computational help.
REFERENCES
AHLBERG,J., BERGSTRAND, L. and SABLIN, S., Changes in gallstone morbidity with decreasing frequencies of cholecystectomies. Acta chir. S c a d . , 39, 201-207 (SUPPI.1984). ALBORES-SAAVEDRA, J. and ALTAMIRANO-DIMAS, M., Algunas consideraciones sobre 9412 autopsias en el Hospital General de MCxico. Gac. mid. Mex., 102, 193-203 (1971). AMAT,J. and AMAT,J.I., Chcer de la vesicula y via biliar extrahepitica. Nuevos conceptos en el tratamiento. Cuad. Chile Cir., 27, 49-55 (1983). ARMIJO, R., The Epidemiology of Cancer in Chile. Nat. Cancer Inst. Monogr., 53, 115-118 (1979). BRODBN,G., AHLBERG, J., BENGTSSON, L. and HELLERS, G., The incidence of carcinoma of the gallbladder and bile ducts in Sweden 19581972. Acta Chir. Scand., 482, 24-25 (suppl.) (1978). BRODBN, G. and BENGTSSON, L., Carcinoma of the gallbladder. Its relation to cholelithiasis and to the concept of prophylactic cholecystectomy. Acta chir. Scand., 500, 15-18 (suppl. 1980). CASTILLO, B. and MARWNES, G., Certificacih mkdica de las defunciones en 10s servicios de salud de Chile. Rev. mid. Chile, 114, 693-700 (1986). CHACKIEL, J., Research on causes of death in Latin America. Popul. Notes, 15, (44),11-30 (1987). CHILE. MINISTERIO DE ECONOMfA. INSTITUTO NACIONAL DE ESTADfSTICAS: Anuarios de Demografia. Instituto Nacional de Estadisticas, Santiago (1982-1987). CHILE. MINISTERIO DE ECONOMfA. INSTITUTO NACIONAL DE ESTADfSTICAS: Proyeccidn de Poblacidn por sex0 y edad-Total del Pals. 19502025. Instituto Nacional de Estadisticas, Santiago (1987). CHILE.MINISTERIO DE SALUD:Anuarios de Defunciones y Causas de Muerte, Servicio Nacional de Salud, Santiago (1976-1981 and 1983). CHILE.MINISTERIO DE SALUD: Anuarios de Atenciones y Recursos. Servicio Nacional de Salud, Santiago (1970-1985). CHILE. MINISTERIO DE SALUD: specially requested computational reports for 1985-1988, Servicio Nacional de Salud, Santiago (1988). CHILE.SERVICIO NACIONAL DE SALUD, Anuarios de Defunciones y Causas de Muerte, Servicio Nacional de Salud, Santiago (197G1975). CORREA, P., Etiology of gastric cancer. In: M. Khogali, Y.T. Oman, A. Gjorgov and A.S. Ismail (eds.), Cancer prevention in developing countries, pp. 183-191, Pergamon, London (1986). CSENDES, A., MEDINA,E. and BRAGHETTO, I., Algunas caractedsticas epidemiol6gicas de 10s cinceres del esbfago, vesicula y vias b i k e s , pincreas e intestino delgado. Rev. mid. Chile, 105, 804-807 (1977). CSENDES, A., MEDINA,E. and MEDINA, A.M., Caractenstisticas de 10s serviciosde cirugia en Chile y operaciones m6s frecuentesrealizadasen 10s diversos tipos de hospitales. Rev. mid. Chile, 111, 1065-1074 (1983). CUBILLOS. L.. DUARTE.I.. OUAPPE. G.. ALFARO. E. and FERREIRO. 0.. CGcer de vesicula b i l k . ’ E h d i o kitomo-clinico de 100 casos. Rev. Chile. Cir., 39, 201-207 (1987). DIEHL,A.K., Epidemiology of gall bladder cancer: A synthesis of recent data. J. nat. Cancer Insr.. 65, 1209-1214 (1980). DIEHL,A.K. and BERAL,V., Cholecystectomy and changing mortality from gallbladder cancer. Lancet, 2, 187-189 (1981). FRAUMENI, J.F., JR., Cancer of the pancreas and biliary tract: epidemiological considerations. Cancer Res., 35, 3437-3446 (1975). GALLO,G., Litiasis biliar como factor de riesgo del cincer biiar y de la pancreatitis aguda. In: F. Nervi (ed.),Symposium “Litiasis biliar”, p. 63, Sociedad MCdica de Santiago, Santiago (1983). HART,J., SHANI,M. and MODAN,B.. Epidemiological aspects of gall
bladder and biliary tract neoplasm. Amer. J. Publ. Hlth., 62, 36-39 (1972). PARKIN, D.M. (ed.), Cancer occurrence in developing countries, pp. 2122, IARC, Lyon (1985). KITAWAGA, E.M., Components of a difference between two rates. J . Amer. statist. Ass., 50, 1168-1194 (1955). KOWALESKI, K. and TODD,E.F., Carcinoma of the gallbladder in hamsters by insertion of cholesterol pellets and feeding dimethyl nitrosamine. Proc. SOC. exp. Biol. (N.Y.),136, 482486 (197 1). LARSON, G.M., Gastric carcinoma. A 25-year experience. Amer. Surg., 49, 105-109 (1983). MEDINA, E. and CSENDES, A., Caractensticas epidemiol6gicas del cancer en Chile. Rev. mkd. Chile, 111, 69-75 (1983). MEDINA,E. and IRARRAZAVAL, M., Fiebre tifoidea en Chile: consideraciones epidemiolbgicas. Rev. mid. Chile, 111, 60%615 (1983). MEDINA,E., PASCUAL, J.P. and MEDINA,R., Frecuencia de la litiasis biliar en Chile. Rev. mkd. Chile, 111, 668-675 (1983). MONTES,J., TAMAYO, R., GESCHE,E., PINTO, M., CASTRO, R., SCHOEBITz, R., CRISTI,R., ARANDA, X.,SAEZ,L., DOLZ,H. and SILVA,R., Analisis redrico de la situacibn actual nacional en relacidn a la aplicacidn de hormonas en bovinos. Universidad Austral de Chile and Ministerio de Agricultura, Valdivia (1985). MORALES, A,, Algunos aspectos epidemioldgicos de la mortalidad por cancer en Chile. Cuad. mtd. SOC., 15, I s 1 9 (1974). PETTITI, D.B.. SIDNEY, S. and PERLMAN, V.A., Increased risk of cholecystectomy in users of supplemental estrogen. Gastroenterology, 94, 9 195 (1988). PHILIPP,R., BARNARD, C., PYCOCK,C., HUGHES,A,, HEATON,K., S., Cholecystectomy rates. LanRAZAY, G., WATTS,P. and COCHRANE, cet, I, 170-171 (1987). PIEHLER,J.M. and CRICHLOW,R.W., Primary carcinoma of the gallbladder. Surg. Gynec. Obstet., 147, 929-942 (1986). PUFFER,R.R. and GRIFFITH,G.W., Patterns of urban mortality. Pan American Health Organization. Scientific Publication 151, pp. 106-108, PAHO, Washington, D.C. (1967). NOS-DALENZ, J., TAKABAYASHI, A,, HENSON,D.E., STROM,B.L. and SOLOWAY, R.D., The epidemiology of cancer of the extra-hepatic biliary tract in Bolivia. In?. J . Epidemiol., 12, 156-160 (1983).
c., RODR~GUEZ, H.,VICENT,P., FERRECCIO,c . , GARCfA, J., LOBOS,H. and D’OTTONE,K., Persistence of the Salmonella typhiparafyphi carrier state after gallbladder removal. PAHO Bull., 16, 361366 (1982). SEPSTLVEDA, C., Mortalidad y morbilidad por cancer en Chile. Bol. Vigil. Epidemiol., 12, 3-13 (1985). SERRA,I., CALVO,A., MATURANA, M., MEDINA,E. and SHARP,A,, Changing trends of gall-bladder cancer in Chile, a high-risk area. lnt. J. Cancer, 45, 376-377 (1990). SERRA, I., CALVO, A. and SHARP, A,, Epidemiologfadel cancer biliar en Chile. Anilisis preliminar. Cuad. mid. SOC., 27, 63-73 (1986). SERRA, I., CALVO,A., SHARP,A. and GoRI, I., Sobre carcinoma de la veslcula biliar. Carts al editor. Rev. mid. Chile, 115, 706-708 (1987). SMOK,G. and CERVILLA, K., Carcinoma de vesicula biliar. Rev. mid. Chile, 144, 104&1046 (1986). SOUMASTRE, R., AMAT, J., MERIRO,H. and VARGAS, R., Diagn6stico y RISTORI,
BILIARY-TRACT CANCER IN CHILE
tratamiento del cancer de la vesicula y vias biliares. Rev. mid. Valpo., 23, 19-22 (1969). STROM,B.L., HIBBERD,P.L., JOPER,K.A., STOLLEY, P.P. and NELSON, W .L., International variations in epidemiology of the extra-hepatic biliary tract. Cancer Res.. 45, 5165-5168 (1986). TRIVIRO,I., Residuos de pesticidas organoclorados en leche humana, tejido adiposo femenino y leche de vaca. Bol. Insr. Salud publ. Chile, 23, 90-99 (1982). TRUJILLO, c . , OLAECHEA, B., URIA,J.L., VILLAG6MEZ, G.and ANTELO, J ., Comportamiento anatomopatol6gico del cancer de vesicula M a r . Acta gastroenterol. latinoam., 16, 67-74 (1986).
97 1
WELTON,J.C.,MARR,J.S. and FRIEDMAN,J.M., Association between hepatobiliary cancer and typhoid carrier state. Lancet, I, 791-794 (1979). WHETSTONE, M.R., SALTZSTEIN, E.C. and MERCER,L.C., Demographic characteristicsof gallbladder cancer in an area endemic for biliary calculi. Amer. J . Surg., 152, 728-730 (1986). WHO, Cancer increases in developed countries. Weekly epidemiol. Rec., 60, 125-129 (1985). ZAHOR,Z., STERNBY, N.H., KAGAN,A., UEMURA,K., VANECEK, R. and VICHERT,A.M., Frequency of cholelithiasis in Prague and Malmo. An autopsy study. S c a d . J. Gastroenterol., 9, 3-7 (1974).
Publication of the International Union Against Cancer Publication de I‘Union lnternationale Contre le Cancer
BILIARY-TRACT CANCER IN CHILE Ivan SEW’, Alfonso CALVO*,Mauricio MATURANA’ and Allan SHARP? ‘School of Public Health, Faculty of Medicine, University of Chile, Santiago; 2Emergency and Surgical Departments, Sdtero del R fo Hospital, Santiago; 3Department of Surgery, San Felipe Hospital, San Felipe, Chile. This epidemiological study in Chile shows a marked increase in biliary-tract cancer based on mortality data, from an age-adjustedrate (I 970 world population) of 5. I per 100,000 in I970 to 12.0 per IO0,OOO in 1988. There is an increased risk of this cancer in all age groups but especially in young adults (I 2-44 years). The female ratio of 3: I persists. The increase in biliary-tract cancer in 1 9 7 U 9 8 5 was particularly important for young women but occurred in all female age groups whereas in men i t was mostly in the elderly (65 years and more) and less in the middle-aged (45-64 years); no changes were observed in young men. Regionaldifferenceshave begun to be appreciated. One of the factors which may account for this impressive and unexpected increase is the remarkable decrease in cholecystectomyrates. Less than 20% of the 154% increase in biliary-tract cancer mortality in the period 197& I985 could be attributed to population aging. Improvements in diagnostic methods did not appear to be an important contributing factor. Other factors that could affect this increase in the incidence to epidemic levels include: an increase in the prevalence of cholelithiasis, an increase in the number of typhoid carriers and possible environmental carcinogens.
Cancer of the gall-bladder and of the extrahepatic biliary tract has a long-registered high incidence in Chile (Puffer and Griffith, 1967) that is greater than that in most of the developed countries (Fraumeni, 1975), but has manifested a marked and steady increase in all regions of the country during the last 2 decades, reaching a crude mortality rate of 9.9 per 100,000 in 1988 (Serra et al., 1990). The age-adjusted rate in the Chilean population was 3.7 in 1970 and 13.3 in 1988, which is probably one of the highest in the world (Serra et al., 1990). The causes of the observed increase are still not well understood, but several hypothesis have been postulated, such as relative decrease in number of cholecystectomies, increase in the prevalence of gall-stones, deterioration of sanitary conditions, longer life span of the population, and possible increase of carcinogens in the environment (Serra et al., 1986). This increase contrasts with mortality for all types of cancer of which the crude rate in Chile has become stabilised since the late 1960’s, at around 100 per 100,000 population (Medina and Csendes, 1983). No major advances in early diagnosis or therapy of gallbladder cancer have occurred during this century, so a short survival is the common outcome. This high fatality rate makes mortality statistics particularly suitable for examination of the incidence trends of this cancer (Diehl, 1980). The aim is to present an extensive and analytical view of the epidemiological changes in gall-bladder and extrahepatic biliary-tract cancer observed in Chile in the period 1970 to 1988, which are comparable to the crude figures of biliary-tract cancer mortality and cholecystectomy rates published for Sweden in the late 1960’s and 1970’s (Ahlberg et a / . , 1984; Philipp et al., 1987). The epidemiological situation in Chile is comparable to that described in other countries with high incidence of gall-bladder cancer such as Mexico, with adjusted mortality rate for females of 8.5 per 100,000 (Puffer and Griffith, 1967) or Bolivia. with an age-adjusted rate to world population for females of 14.9 per 100,000 (Rios-Dalenz et al., 1983).
statistics based on reliable medical death certificates published annually by the National Health Service (Chile, 1970-1975), Ministry of Health (Chile, 1976-1983), and National Institute of Statistics (Chile, 1982-1987) have been used to produce the rates. Certification by a physician, which provides the sole basis for the 3 sources, has increased from 97.7%, 96.9% and 94.5% in 1970 through 99.3%, 99.1%, and 99.7% in 1985 for deaths from cancer of the liver, biliary tract and pancreas respectively (Chile, 1970-1975; 1976-1981 and 1983; 19821987). Histological verification is accepted as relatively high but national figures are not available. It was 97.6% between 1970 and 1988 in our hospital which is attended by 6% of the country’s population. All of the population of Chile derive from the censuses performed every 10 years since 1835, and for this report the population data derive from the last 1970 and 1982 censuses published by the National Institute of Statistics, corrected by 6.2% and 1.5% respectively, for censal omission (Chile, 1987). Chile has a stable population, predominantly urban (81%) and a national registration system which is computerized and provides an additional control of the population counts. The quality of mortality data in Chile, seldom presented, is considered quite acceptable (Armijo, 1979). An international analysis of underregistration of mortality and of some indices on cause of death declaration considered that the information in 1978 was very good for Chile and 4 other Latin American countries (Chackiel, 1987). The proportion of total deaths registered as ill-defined (Codes 780 to 789, ICD-9) fluctuated between 5.4% and 11.O% during the period 1970-1985 (Chile, 1970-1985). Tumors as a cause of death certified by a doctor amounted to 93.2% in 1983: personal physician in 50.5%, pathologist in 5.1%, and another physician in 37.6% (Castillo and Mardones, 1986). Incidence has been assumed from mortality given the extremely high fatality rate and short survival of biliary tract cancer. Special studies have been requested from the Informatic Department in the Ministry of Health to obtain mortality statistics at the provincial level, and not, as has been routinely the case since 1976, at a regional or health service level. Several decisions have been taken in comparing age, sex, and regional differences; for example, 5-year intervals have been used to simplify and clarify trends. In order to compare rates by calendar time, sex and region, a direct standardization procedure was utilised and the rates were standardized to the Chilean population of 1970 and the world population of 1970. Population aging between 1970 and 1985, as presented in Table I, has been weighted by 2 methods: (1) comparison with the world population (Parkin, 1985); and (2) measurement of changes occurring in the age group of 65 years and over in Chile. The proportion of people 65 years and over in 1970 was 5.1% and taken as a base. The proportions in 1975 (5.4%), 1980 (5.6%) and 1985 (5.8%) have provided differentials of 0.3, 0.5 and 0.7 respectively. These differentials have been subtracted from the crude mortality rate for biliary-tract cancer
MATERIAL AND METHODS
Because of the lack of cancer registries, the official mortality
Received: February 6 , 1990, and in revised form June 20, 1990.
966
SERRA ET AL.
in 1975, 1980 and 1985 (5.3,6.9and 9.4per 100,000 respectively), giving the presented age-adjusted rates for the 65 years and over population. A special study to establish mortality rates for biliary-tract cancer by provinces which were 24 in the early 1970’s(with Talca and Cauquenes as one) has been carried out, choosing 1985 as the present situation. As a consequence of the changes observed, the provinces have been grouped into areas of similar relative risk, labelled as “major”, “intermediate”, and “minor”. The 3 ranges were established in a conventional way and based on the relative risk in every province as compared to the national mean of the same year. Crude rates and not ageadjusted rates have been used because no important changes in the age structure of the provincial populations had occurred. The old distribution of 24 provinces (Talca and Made merged) has been considered to compare the whole period for the advantage of an adequate size and to eliminate certain biases that could appear by using the present distribution of 51 provinces or 13 regions. Since the data concern the whole population, and not a sample, the present epidemiological changes are true and statistical calculations of significance are unnecessary. RESULTS
The crude mortality rate for biliary-tract cancer (Code 156) has increased from 3.7per 100,000in 1970 to 9.9in 1988.The upward trend has been constant throughout the period 19701988,but it becomes more evident from 1979 onwards, particularly for women. Age-adjusted rates (1970world population) show the same trends at a slightly higher level, from 5.1 per 100,000to 12.0 per 100,000(Fig. 1). The mortality rate for gastric cancer, the most prevalent cancer in Chile for both sexes until 1984,has been decreasing constantly over the period 1970-1988. Since 1985 the most common type of cancer as a cause of death among Chilean women is that of the biliary tract, preceding cancer of the stomach, cervix and breast. The other important location of
cancer for both sexes combined is the lung, which at present occupies the second place in mortality. In contrast, pancreatic cancer shows only a moderately increasing trend (Fig. 2). Sex
The preponderance of biliary-tract cancer mortality occurs in women, with a sex ratio of 3:1. Age-adjusted rates (1970Chilean population) show that the increase was equal for both sexes during the periods 197C-1975 and 1975-1980, but that the frequency rose more sharply for women after 1980 (Fig. 3). Age
The risk of cancer has increased in all age groups but proportionally more in young adults (15-44 years). The mortality rate for this group has risen from 0.3 in 1970 to 1.0 per 100,000in 1985, whereas for adults in the next age group (45-64 years) it has gone from 12.3 to 24.1,and in elderly people (65years and over) from 37.4to 94.6per 100,000.The mortality for these 3 age groups was, considering both sexes combined, 3.3,2.0and 2.5 times higher than in 1970 (data not shown). The age structure shows that in 1985, of all deaths from cancer of the biliary tract, 6% occurred in young adults, 36% in middle-aged adults, and 58% in elderly people (65years and over). Sex and age
By using both variables together it can be appreciated that the increase is rather different for men than for women. Mortality has risen markedly in young women, going from 0.4 in 1970 to 1.6per 100,000in 1985,a 4-fold increase as compared to mere duplication of the figures in middle-aged women, 18.7 to 36.7,almost the same proportional increase that has occurred in elderly women in whom the rates were 51.9 and 115.5 per 100,000,respectively. In men, the increase took place mainly in people 65 years and over with mortality rising from 18.7 to 65.7per 100,OOO, whereas in middle-aged men Ad’usted raic per 105,
N-O of deaths
N?of deaths
900 OooI
.
Women Men
Rate per 1W.aoO : Women o--o Men
M
Year S
AGE -ADJUSTED
10 1970 WORLD POPULATION
(
I I R C . 1985
FIGURE1 - Mortality for biliary tract cancer by sex. Chile 1970-1988.
967
BILlARY -TRACT CANCER IN CHILE Adjuitrd Rate pcr 100.000
Adjusted Rate pcr 100.000
~
8 4GE-4DJUSlLD
TO l l S ClULfAN r o N L 4 T l O N
FIGURE 2 - Mortality for selected cancers, both sexes combined. Chile 1969-1988. Adjusted rate per 100.000
Adjusted rate (. per 100.000 20
r20
19 3
0 Men Women Both Sexes
15
15
11.6
10
10
5
1970 AGE
- ADJUSTED
1975
1980
1988
Year
TO 1970 CHILEAN POPULATION
FIGURE3 - Mortality for biliary tract cancer by sex. Chile 1970-1988.
only a mild increase from 5.2 to 9.9 and no changes at all in young adult men were observed (Fig. 4). Site The prevalent site of biliary-tract cancer in Chile is the gall-
bladder. Its preponderance, as compared to common bile duct and ampulla of Vater, apparently increased during the period 197CL1985. In our health care area (6% of the national population), 418 cases of biliary-tract cancer were treated surgically and verified in the period 1970-1988; these comprised 374
968
SERRA ET AL. Crude Rate per lo5 betwren 117 / 174
RR between 13 / 1 9
Intermdiate Risk
between 7 6 / 11 0
R R between 09 / 12
Minor Rtsk
between 63 / 6 4
RR between 0 5 / 0 7
0
15-41 years
Relative Risk
Major Risk
65 years and mom
15-Slyoars 120
DO 80
MEN 20
15 1.0 05
15- 11 y r a r s
45 - 5 1 y n r a
65years and mare
FIGURE4 - Mortality for biliary tract cancer by age and sex. Chile 1970-1985. Crude rates per 100,000.
cancers of the gall-bladder (89.5%), 31 cancers of the choledochus (7.4%) and 13 cancers of the ampulla of Vater (3.1%). Regional diyerences Cancer of the gall-bladder and extra-hepatic biliary tract have traditionally not been considered to present regional differences in Chile (Morales, 1974; Csendes er al., 1977). A special study to establish mortality rates for this type of cancer by provinces indicates that incipient but clear regional changes began to appear between 1970 and 1985. All the Chilean provinces show increases in crude mortality rates of biliary-tract cancer, but all the Southern provinces, with the exceptions of Chilot and Aystn, have progressively reached peak positions. The mortality rate for Valdivia, which has consistently presented the highest risk, was 17.4 per 100,000 in 1985, with a relative risk of 1.9, as compared with the national mean of 9.4. At present the maximal differences in mortality risk between the provinces are 1:4 (Fig. 5). Ageadjustment (1970 Chilean population) does not produce substantial changes in the trends described. Aging of population By using age-adjustment (based on the Chilean population structure of 1970, and taking into account what has happened with the 65 years and over age group) one reaches the conclusion that only 12.3% of the observed 154% increase in crude mortality rates between 1970 and 1985 (or 135% increase in age-adjusted rates) may be attributed to population aging. Based on the world population, however, the result is somewhat higher, reaching an estimate of 16.0% (Table I). Based on the logical association between gall-bladder cancer and cholecystectomy rates (Serra era!., 1986), a special study in the south-east health care area in Santiago, which covers a population of around 900,000 (97% urban, and served by one general hospital of 700 beds) shows that the crude cholecystectomy rate has decreased for this population from 1.6 per 1,000 inhabitants in 1970 to 0.9 in 1985, according to official figures. While there is a lack of national data on biliary surgery, a decrease in cholecystectomies in this important health care area contrasts with the increase in biliary-tract cancer in Chile (Fig. 6). If hospital admissions for cholecystitis and cho-
CH,LE
N! of Deaths Crude Rate per lo5 '
:
FIGURE 5 - Biliary tract cancer mortality, both sexes combined. Chile by provinces, 1985. TABLE I - POPULATION AGING AND BILIARY TRACT CANCER MORTALITY CHILE 1970-1985
Biliary tract cancer modity-rates per 100,033
1975
1980
1985
Increase
1970-1985
Value
Crude rates 3.7 5.3 6.9 9.4 154.1% 100.0 Age-adjustedrates 3.7 5.0 6.4 8.7 135.1% 87.7 (65 years and more) Age-adjusted rates 5.1' 7.1' 8.8' 11.6' 129.4% 84.0 (World population i97m 'Standard error
0.3
0.3
0.3
0.4
lelithiasis were to be established as biliary interventions there is, at the national level, a clear decline in age-adjusted cholecystectomy rates to 1970 Chilean population from 4.8 per 1,000 in 1970 to 3.5 per 1,OOO in 1985 for both sexes combined. DISCUSSION
The substantial increase in mortality from gall-bladder and extrahepatic biliary-tract cancer in Chile is evident to clinicians, pathologists and epidemiologists. At present the epidemiological increase is largely accepted, but the special Chilean situation has to deal not only with a very high incidence, but also with a relatively sharp growth in a short period of time, deserving therefore more critical analysis. At first, this con-
BILIARY-TRACT CANCER IN CHILE
Yeor
1970 1971 1972
e.5
1973
1.9
5.2 5.3
5.2 6.2
5.8 1.3
b.8 1.5
I
197L 1975 1976 1977 1978 1979 1980 1981 1982 1983 1986 1985
FIGURE6 - Biliary tract cancer mortality and cholecystectomy rates. Both sexes combined. Chile 197Cb1985 and South-east Health Area 1970-1985. (Chile: 9,367,633 inhabitants in 1970 and 12,074,477 in 1985. South-east Health Area: 335,828 inhabitants in 1970 and 798,811 in 1985.)
siderable increase in biliary tract cancer was misinterpreted. Explanations such as possible false diagnosis (Smok and Cervilla, 1986), mistakes in tabulation (Medina and Csendes, 1983), or the increased life span of the population had been formulated for this unexpected increase, but all these explanations have been refuted (Serra et al., 1987). The remarkable increase in biliary tract cancer mortality observed in Chile since the 1970's is probably due to several factors, one of which is population aging. It is well known that morbidity and mortality rates due to cancer are higher in the older age groups, and since population aging has taken place in Chile over the period in question, it seems convenient to determine its influence. Several statistical methods have been employed to determine how much of the change in cancer mortality over a period is due to a real change in age-specific risks and how much is due to changes in age composition of the population, such as decomposition analysis (WHO, 1985), age-adjustments, accumulated incidence rates or truncated rates. The purpose here is not to delve into this problem but only to estimate the influence that this factor may have on the increase in biliary tract cancer in Chile. Two classical techniques have been used: age-adjustment with older people and age-adjustment to world population. Both have provided similar estimates: 12% and 16% respectively. Consequently, our concern is to account for the remaining 8688% of the increase observed in Chile from 1970 to 1985. The increase could also be attributed to changes in the incidence of other types of cancer, such as cancers of the stomach, pancreas, liver or colon, which could erroneously have been assigned to gall-bladder or biliary-tract cancer. All these cancers, however, have also become more frequent, except gastric neoplasia, which has decreased following world trends (Correa, 1986). The increase in all these types of cancer in Chile could be partially explained by the improvement of surgical and pathological diagnoses and a more exact completion of medical death certificates, but the relevance of these factors and also of the reasons mentioned above seems negligible, because the improvements are limited or debatable and do not correspond with regional and local variations observed in the period 1970-1985. Clinical practice and pathological experience point in other directions. Cancer of gall bladder (Code 156.0) accounts for an estimated 90% of biliary tract cancer (Code 156) in Chile (Amat and Amat, 1983). This proportion contrasts with that observed
969
in other countries, where gall-bladder cancer appears to be less widespread. Differences are observed in many countries, but around more balanced proportions, in the incidence rates of the 3 main biliary tract neoplasms: gall-bladder, extrahepatic bile duct and ampulla of Vater (Strom et al., 1986). However, the Chilean situation has to deal with gall-bladder cancer and not with extrahepatic biliary-tract cancer. Age composition has varied to a slight extent in Chile from 1970 through 1985, but the regional changes are not explained by age differences. In an international comparison, the mean age observed for both gall-bladder and extrahepatic biliarytract cancer at diagnosis is around 62 years in Chilean clinical services, higher than in Bolivia (Trujillo et al., 1986), but lower than in developed countries such as Sweden (with high biliary-tract cancer incidence) (BrodCn and Bengtsson, 1980) or the United States (with low biliary-tract cancer incidence) (Whetstone et al., 1986). Three risk factors are largely accepted as risk factors for cancer of the gall bladder (Code 156.0) which are: age, female sex, and gall-stones (Hartet al., 1972). Other suggested risk factors are: association with bacteria such as Salmonella typhi (Welton et al., 1979), biliary surgery (Diehl and Beral, 1981), and environmental carcinogens such as nitrosamine (Kowalesky and Todd, 1971). The roles of occupation, radiation, immunological response (nutritional status), among others, still lack good support. Genetic influence cannot be postulated in Chile because no immigration has occurred in recent times, and emigration has not been selective in a way that would explain the change observed. Cholelithiasis is, of course, a risk factor that could well explain the high incidence of biliary-tract cancer in Chile, but not the high increase in this incidence during the last 2 decades. Apparently there has been some increase in the frequency of gall-stones in the Chilean population during the last 30 years, according to autopsies performed in the same centers (Medina et al., 1983). An unestablished amount of environmental estrogens could have originated from the cattle and poultry industry (Montes et al., 1985), and could thus have influenced cholelithiasis and gall-bladder cancer (Pettiti et al., 1988). Bacterial influence, a challenging risk factor which still has to be fully proved, may also play a role in the situation that exists in Chile. A growing incidence of endemic typhoid and paratyphoid fevers since 1976 has contributed to increase the number of chronic carriers of S. typhi (Ristori et a l . , 1982), a fact that could, perhaps, support the bacterial hypothesis. A decrease in biliary-tract surgery, measured through cholecystectomy rates, has been associated with rising trends in mortality due to cancer of the gall-bladder, and vice versa (Diehl and Beral, 1981). The present study was initiated several years ago on the basis of the reasonings first expounded by other investigators (BrodCn et al., 1978). National information about biliary surgery in Chile is not registered. The existing situation in the south-east health care area in Santiago, as far as biliary tract surgery is concerned, probably represents the general situation because of the relatively large size of this community (0.9 x lo6 people) within the Metropolitan Area (population of 5 x lo6), and its proportion of 20% of all surgeries being biliary tract surgeries, which is very similar to national figures taken from a recent random sample (Csendes et al., 1983). The downward trend in the rates of cholecystectomies seems unquestionable if hospital admissions for cholecystitis and cholelithiasis are accepted as biliary surgery. This trend is related to reductions in the resources assigned to medical care: surgical medical hours in the public sector decreased relatively from 2,272 per day in 1970 to 2,490 in 1981 and surgical beds from 3,855 in 1970 to 3,769 in 1985 (Chile, 1970-1985),
970
SERRA ET AL.
while the population increase during the same period (19701985) was 28.9% (Chile, 1987). Of course, the subpopulation which experienced a decline in cholecystectomy may be partially different from the one which underwent an increase in incidence of biliary-tract cancer. Environmental carcinogens may also be contributing factors to the growing incidence of biliary-tract cancer in Chile. Carcinogenic chemicals in very low concentrations associated with air, food and water pollution are also a problem in Chile, where controls in this respect have slackened (Medina and IrarrBzaVal, 1983). Special studies will have to be undertaken, however, firstly to identify the chemicals and secondly to establish
the link between these chemicals and cancer of the gallbladder. The interaction between risk factors may be not only additive but also multiplicative, as has been experimentally demonstrated for this cancer (Kowalesky and Todd, 1971). ACKNOWLEDGEMENTS
The authors are grateful to Dr. A.K. Diehl (San Antonio, TX) for a careful review of the manuscript and helpful comments. They also thank Miss I. Gonzalez for preparing the Figures, and Mr. C.I.Maturana for computational help.
REFERENCES
AHLBERG,J., BERGSTRAND, L. and SABLIN, S., Changes in gallstone morbidity with decreasing frequencies of cholecystectomies. Acta chir. S c a d . , 39, 201-207 (SUPPI.1984). ALBORES-SAAVEDRA, J. and ALTAMIRANO-DIMAS, M., Algunas consideraciones sobre 9412 autopsias en el Hospital General de MCxico. Gac. mid. Mex., 102, 193-203 (1971). AMAT,J. and AMAT,J.I., Chcer de la vesicula y via biliar extrahepitica. Nuevos conceptos en el tratamiento. Cuad. Chile Cir., 27, 49-55 (1983). ARMIJO, R., The Epidemiology of Cancer in Chile. Nat. Cancer Inst. Monogr., 53, 115-118 (1979). BRODBN,G., AHLBERG, J., BENGTSSON, L. and HELLERS, G., The incidence of carcinoma of the gallbladder and bile ducts in Sweden 19581972. Acta Chir. Scand., 482, 24-25 (suppl.) (1978). BRODBN, G. and BENGTSSON, L., Carcinoma of the gallbladder. Its relation to cholelithiasis and to the concept of prophylactic cholecystectomy. Acta chir. Scand., 500, 15-18 (suppl. 1980). CASTILLO, B. and MARWNES, G., Certificacih mkdica de las defunciones en 10s servicios de salud de Chile. Rev. mid. Chile, 114, 693-700 (1986). CHACKIEL, J., Research on causes of death in Latin America. Popul. Notes, 15, (44),11-30 (1987). CHILE. MINISTERIO DE ECONOMfA. INSTITUTO NACIONAL DE ESTADfSTICAS: Anuarios de Demografia. Instituto Nacional de Estadisticas, Santiago (1982-1987). CHILE. MINISTERIO DE ECONOMfA. INSTITUTO NACIONAL DE ESTADfSTICAS: Proyeccidn de Poblacidn por sex0 y edad-Total del Pals. 19502025. Instituto Nacional de Estadisticas, Santiago (1987). CHILE.MINISTERIO DE SALUD:Anuarios de Defunciones y Causas de Muerte, Servicio Nacional de Salud, Santiago (1976-1981 and 1983). CHILE.MINISTERIO DE SALUD: Anuarios de Atenciones y Recursos. Servicio Nacional de Salud, Santiago (1970-1985). CHILE. MINISTERIO DE SALUD: specially requested computational reports for 1985-1988, Servicio Nacional de Salud, Santiago (1988). CHILE.SERVICIO NACIONAL DE SALUD, Anuarios de Defunciones y Causas de Muerte, Servicio Nacional de Salud, Santiago (197G1975). CORREA, P., Etiology of gastric cancer. In: M. Khogali, Y.T. Oman, A. Gjorgov and A.S. Ismail (eds.), Cancer prevention in developing countries, pp. 183-191, Pergamon, London (1986). CSENDES, A., MEDINA,E. and BRAGHETTO, I., Algunas caractedsticas epidemiol6gicas de 10s cinceres del esbfago, vesicula y vias b i k e s , pincreas e intestino delgado. Rev. mid. Chile, 105, 804-807 (1977). CSENDES, A., MEDINA,E. and MEDINA, A.M., Caractenstisticas de 10s serviciosde cirugia en Chile y operaciones m6s frecuentesrealizadasen 10s diversos tipos de hospitales. Rev. mid. Chile, 111, 1065-1074 (1983). CUBILLOS. L.. DUARTE.I.. OUAPPE. G.. ALFARO. E. and FERREIRO. 0.. CGcer de vesicula b i l k . ’ E h d i o kitomo-clinico de 100 casos. Rev. Chile. Cir., 39, 201-207 (1987). DIEHL,A.K., Epidemiology of gall bladder cancer: A synthesis of recent data. J. nat. Cancer Insr.. 65, 1209-1214 (1980). DIEHL,A.K. and BERAL,V., Cholecystectomy and changing mortality from gallbladder cancer. Lancet, 2, 187-189 (1981). FRAUMENI, J.F., JR., Cancer of the pancreas and biliary tract: epidemiological considerations. Cancer Res., 35, 3437-3446 (1975). GALLO,G., Litiasis biliar como factor de riesgo del cincer biiar y de la pancreatitis aguda. In: F. Nervi (ed.),Symposium “Litiasis biliar”, p. 63, Sociedad MCdica de Santiago, Santiago (1983). HART,J., SHANI,M. and MODAN,B.. Epidemiological aspects of gall
bladder and biliary tract neoplasm. Amer. J. Publ. Hlth., 62, 36-39 (1972). PARKIN, D.M. (ed.), Cancer occurrence in developing countries, pp. 2122, IARC, Lyon (1985). KITAWAGA, E.M., Components of a difference between two rates. J . Amer. statist. Ass., 50, 1168-1194 (1955). KOWALESKI, K. and TODD,E.F., Carcinoma of the gallbladder in hamsters by insertion of cholesterol pellets and feeding dimethyl nitrosamine. Proc. SOC. exp. Biol. (N.Y.),136, 482486 (197 1). LARSON, G.M., Gastric carcinoma. A 25-year experience. Amer. Surg., 49, 105-109 (1983). MEDINA, E. and CSENDES, A., Caractensticas epidemiol6gicas del cancer en Chile. Rev. mkd. Chile, 111, 69-75 (1983). MEDINA,E. and IRARRAZAVAL, M., Fiebre tifoidea en Chile: consideraciones epidemiolbgicas. Rev. mid. Chile, 111, 60%615 (1983). MEDINA,E., PASCUAL, J.P. and MEDINA,R., Frecuencia de la litiasis biliar en Chile. Rev. mkd. Chile, 111, 668-675 (1983). MONTES,J., TAMAYO, R., GESCHE,E., PINTO, M., CASTRO, R., SCHOEBITz, R., CRISTI,R., ARANDA, X.,SAEZ,L., DOLZ,H. and SILVA,R., Analisis redrico de la situacibn actual nacional en relacidn a la aplicacidn de hormonas en bovinos. Universidad Austral de Chile and Ministerio de Agricultura, Valdivia (1985). MORALES, A,, Algunos aspectos epidemioldgicos de la mortalidad por cancer en Chile. Cuad. mtd. SOC., 15, I s 1 9 (1974). PETTITI, D.B.. SIDNEY, S. and PERLMAN, V.A., Increased risk of cholecystectomy in users of supplemental estrogen. Gastroenterology, 94, 9 195 (1988). PHILIPP,R., BARNARD, C., PYCOCK,C., HUGHES,A,, HEATON,K., S., Cholecystectomy rates. LanRAZAY, G., WATTS,P. and COCHRANE, cet, I, 170-171 (1987). PIEHLER,J.M. and CRICHLOW,R.W., Primary carcinoma of the gallbladder. Surg. Gynec. Obstet., 147, 929-942 (1986). PUFFER,R.R. and GRIFFITH,G.W., Patterns of urban mortality. Pan American Health Organization. Scientific Publication 151, pp. 106-108, PAHO, Washington, D.C. (1967). NOS-DALENZ, J., TAKABAYASHI, A,, HENSON,D.E., STROM,B.L. and SOLOWAY, R.D., The epidemiology of cancer of the extra-hepatic biliary tract in Bolivia. In?. J . Epidemiol., 12, 156-160 (1983).
c., RODR~GUEZ, H.,VICENT,P., FERRECCIO,c . , GARCfA, J., LOBOS,H. and D’OTTONE,K., Persistence of the Salmonella typhiparafyphi carrier state after gallbladder removal. PAHO Bull., 16, 361366 (1982). SEPSTLVEDA, C., Mortalidad y morbilidad por cancer en Chile. Bol. Vigil. Epidemiol., 12, 3-13 (1985). SERRA,I., CALVO,A., MATURANA, M., MEDINA,E. and SHARP,A,, Changing trends of gall-bladder cancer in Chile, a high-risk area. lnt. J. Cancer, 45, 376-377 (1990). SERRA, I., CALVO, A. and SHARP, A,, Epidemiologfadel cancer biliar en Chile. Anilisis preliminar. Cuad. mid. SOC., 27, 63-73 (1986). SERRA, I., CALVO,A., SHARP,A. and GoRI, I., Sobre carcinoma de la veslcula biliar. Carts al editor. Rev. mid. Chile, 115, 706-708 (1987). SMOK,G. and CERVILLA, K., Carcinoma de vesicula biliar. Rev. mid. Chile, 144, 104&1046 (1986). SOUMASTRE, R., AMAT, J., MERIRO,H. and VARGAS, R., Diagn6stico y RISTORI,
BILIARY-TRACT CANCER IN CHILE
tratamiento del cancer de la vesicula y vias biliares. Rev. mid. Valpo., 23, 19-22 (1969). STROM,B.L., HIBBERD,P.L., JOPER,K.A., STOLLEY, P.P. and NELSON, W .L., International variations in epidemiology of the extra-hepatic biliary tract. Cancer Res.. 45, 5165-5168 (1986). TRIVIRO,I., Residuos de pesticidas organoclorados en leche humana, tejido adiposo femenino y leche de vaca. Bol. Insr. Salud publ. Chile, 23, 90-99 (1982). TRUJILLO, c . , OLAECHEA, B., URIA,J.L., VILLAG6MEZ, G.and ANTELO, J ., Comportamiento anatomopatol6gico del cancer de vesicula M a r . Acta gastroenterol. latinoam., 16, 67-74 (1986).
97 1
WELTON,J.C.,MARR,J.S. and FRIEDMAN,J.M., Association between hepatobiliary cancer and typhoid carrier state. Lancet, I, 791-794 (1979). WHETSTONE, M.R., SALTZSTEIN, E.C. and MERCER,L.C., Demographic characteristicsof gallbladder cancer in an area endemic for biliary calculi. Amer. J . Surg., 152, 728-730 (1986). WHO, Cancer increases in developed countries. Weekly epidemiol. Rec., 60, 125-129 (1985). ZAHOR,Z., STERNBY, N.H., KAGAN,A., UEMURA,K., VANECEK, R. and VICHERT,A.M., Frequency of cholelithiasis in Prague and Malmo. An autopsy study. S c a d . J. Gastroenterol., 9, 3-7 (1974).
