Epidemiologic Aspects of Gallbladder Cancer: a Case-Control Study of the SEARCH Program of the International Agency for Research on Cancer
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Epidemiologic Aspects of Gallbladder Cancer:
a Case–Control Study of the SEARCH Program
of the International Agency for Research on Cancer
W. A. Zatonski, A. B. Lowenfels, P. Boyle, P. Maisonneuve,
H. B. Bueno de Mesquita, P. Ghadirian, M. Jain, K. Przewozniak,
P. Baghurst, C. J. Moerman, A. Simard, G. R. Howe, A. J. McMichael,
C. C. Hsieh, A. M. Walker*
whether or not screening high-risk subjects for gallstones or
Background: There are few previous epidemiologic studies of gallbladder cancer is needed. [J Natl Cancer Inst 1997;89:
gallbladder cancer, a rare but nearly always lethal gastro- 1132-8]
intestinal cancer with a demonstrated greater frequency in
adult women and older subjects of both sexes, and also in the
There are few previous epidemiologic studies of gallbladder
members of populations throughout central and eastern Eu-
cancer, a rare but nearly always lethal gastrointestinal tumor (1).
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rope and certain racial groups such as native American In-
Descriptive studies have demonstrated the greater frequency of
dians. Unfortunately, the prospects for the prevention of this
this disease in older subjects, women, throughout central and
form of cancer are poor. Purpose: Our purpose in conduct- eastern Europe (2) and certain racial groups such as native
ing this study was to investigate possible new risk factors for American Indians (3-5). Other studies have emphasized the im-
gallbladder cancer and to strengthen our understanding of portance of gallstones (6,7) and obesity (8) as risk factors for this
established causal agents that may be involved in this dis- disease, and parity (9), family history (10), history of typhoid
ease. Methods: A large, collaborative, multicenter, case– infection (11,12), and exposure to thorotrast (13) have recently
control study of cancer of the gallbladder was conducted in been suggested as risk factors for gallbladder cancer. However,
five centers located in Australia (Adelaide), Canada (Mon- because of the rarity of this tumor, it has been difficult to con-
treal and Toronto), The Netherlands (Utrecht), and Poland duct a detailed case–control study in a single center that has been
(Opole) from January 1983 through July 1988. Case subjects of a sufficient size and statistical power to detect other poten-
with gallbladder cancer were accrued by the centers from tially important risk factors, such as diet, prior medical history,
hospital pathology records and from reports to regional can- and reproductive factors as the cause of this disease.
cer registries. Cancer diagnosis was confirmed by either bi- We investigated possible new risk factors for this disease, and
opsy, cholecystectomy, or at the time of autopsy. Control to strengthen our understanding of established causal agents, a
subjects were randomly assigned at each center from the relatively large multicenter international case–control study was
population. The pooled analysis included 196 case subjects conducted within the Surveillance of Environmental Aspects
and 1515 control subjects (who did not report previous cho- Related to Cancer in Humans (SEARCH) Program (14) of the
lecystectomy). Ninety-eight percent of the subjects were International Agency for Research on Cancer (IARC) (14).
white. Personal interviews of case subjects, control subjects,
and surrogates (spouse or next of kin) were conducted by
trained personnel. Results: After adjusting for potential con-
founding factors (age, sex, center, type of interview, years of
schooling, alcohol intake, and lifetime cigarette smoking), a *Affiliations of authors: W. A. Zatonski, K. Przewozniak, Department of Can-
cer Control and Epidemiology, Maria Sklodowska-Curie Memorial Cancer Cen-
history of gallbladder symptoms requiring medical attention
ter and Institute of Oncology, Warsaw, Poland; A. B. Lowenfels, Departments of
(e.g., reduced bile secretion from the gallbladder into the Surgery and Community and Preventive Medicine, New York Medical College,
small intestine due to obstructions of the common bile or Valhalla; P. Boyle, P. Maisonneuve, SEARCH Programme, Unit of Analytical
cystic ducts) was the major risk factor associated with this Epidemiology, International Agency for Research on Cancer, Lyon, France, and
form of cancer (odds ratio [OR] = 4.4; 95% confidence in- Division of Epidemiology and Biostatistics, European Institute of Oncology,
Milan, Italy; H. B. Bueno de Mesquita, C. J. Moerman, National Institute of
terval [CI] = 2.6-7.5). This association was present even in
Public Health and Environmental Protection, Department of Epidemiology,
subjects who had their first gallbladder examination because Bilthoven, The Netherlands; P. Ghadirian, A. Simard, Unité de Recherche en
of symptoms present more than 20 years earlier (OR = 6.2; Epidémiologie, Centre de Recherche, Hôtel-Dieu de Montréal, Canada; M. Jain,
95% CI = 2.8-13.4). Other variables associated with gallblad- G. R. Howe, NCIC Epidemiology Unit, Toronto, ON, Canada; P. Baghurst, A. J.
der cancer risk included an elevated body mass index, high McMichael, CSIRO Division of Human Nutrition, Adelaide, Australia; C. C.
Hsieh, A. M. Walker, SEARCH Programme, Unit of Analytical Epidemiology,
total energy intake, high carbohydrate intake (after adjust-
International Agency for Research on Cancer, and Department of Epidemiology,
ment for total energy intake), and chronic diarrhea. All of Harvard School of Public Health, Boston, MA.
these risk factors have been previously associated with gall- Correspondence to: P. Boyle, Ph.D., Division of Epidemiology and Biosta-
stone disease. Conclusions: These findings are consistent tistics, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy.
with a major role of gallstones, or risk factors for gallstones, See ‘‘Notes’’ following ‘‘References.’’
in the cause of gallbladder cancer. Additional information on © Oxford University Press
1132 ARTICLES Journal of the National Cancer Institute, Vol. 89, No. 15, August 6, 1997Materials and Methods Statistical Methods
The odds ratio (OR) was used as the measure of association between specific
A population-based, case–control study was conducted in five centers located
variables and gallbladder cancer. Unconditional logistic regression analysis (16)
in Australia (Adelaide), Canada (Montreal and Toronto), The Netherlands
was performed using the GLIM (Generalized Linear Interactive Modeling) sta-
(Utrecht), and Southwest Poland (Opole) from January 1983 through July 1988.
tistical package (17). Strategy for grouping continuous variables was determined
This study formed part of a larger collaborative study of cancer of the pancreas
a priori. For continuous variables, such as smoking and drinking, the nonexposed
and was conducted within the framework of the SEARCH Program of the IARC
group was used as a reference category, and the remaining variables were di-
(15).
vided into quartiles. For variables lacking a zero category such as body weight,
Case subjects with gallbladder cancer were accrued at the participating cen-
the range was divided into quartiles, with the lowest fourth designated as the
ters by monitoring new cases, as determined from hospital pathology records
reference category. Confounding variables were entered in stepwise fashion, and
and from reports to regional cancer registries. One hundred ninety-six case
the final model was corrected for age, sex, center, response status, smoking,
subjects with gallbladder cancer are included in the present study, representing
education, and alcohol consumption. Variables could either be present, absent, or
about 70% of all case subjects that were diagnosed with gallbladder cancer at the
unknown and missing data were handled using dummy variables. Statistical
participating centers during the study period. A confirmatory tissue diagnosis
significance was assessed using 95% confidence intervals (CIs) or P valuesTable 2. Gastrointestinal variables and gallbladder cancer
No. of case subjects/ Odds ratio
Variable No. of control subjects* (95% confidence interval)†
History of gallbladder problem versus no history‡ 54/113 4.4 (2.6-7.5)§
Years since first gallbladder examination
versus no examination
20 years ago 20/36 6.2 (2.8-13.4)
Surgery for ulcer disease, yes versus none 5/27 3.0 (1.0-9.4)
Other digestive problems
Yes versus no 41/263 1.7 (1.1-2.7)Table 3. Reproductive variables and gallbladder cancer risk
No. of case subjects/ Odds ratio
Variable No. of control subjects* (95% confidence interval)†
Age at menarche, yTable 5. Selected dietary variables as risk factors for gallbladder cancer
Quartile
Dietary items 1 2 3 4 Trend*
Total energy intake†
No. of case subjects/No. of control subjects 46/379 45/381 46/380 57/369 5.77
Odds ratio 1.0 1.0 1.6 2.0 (P 4 .02)
95% confidence interval 0.6-1.6 1.0-2.7 1.1-3.7
Total fat‡
No. of case subjects/No. of control subjects 49/376 48/379 37/388 60/366 3.75
Odds ratio 1.0 0.7 0.4 0.6 (P 4 .05)
95% confidence interval 0.4-1.3 0.2-0.8 0.3-1.2
Total protein‡
No. of case subjects/No. of control subjects 46/380 54/371 40/389 54/369 1.9
Odds ratio 1.0 1.1 0.6 0.6 (P 4 .18)
95% confidence interval 0.7-1.9 0.3-1.2 0.3-1.4
Dietary cholesterol§
No. of case subjects/No. of control subjects 43/384 50/377 44/378 57/369 0.5
Odds ratio 1.0 1.0 1.0 1.0 (P 4 .48)
95% confidence interval 0.6-1.7 0.5-1.8 0.5-2.1
Vitamin B6§
No. of case subjects/No. of control subjects 38/211 27/221 25/227 47/197 5.11
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Odds ratio 1.0 0.5 0.4 0.4 (P 4 .02)
95% confidence interval 0.3-1.0 0.2-0.8 0.2-0.9
Vitamin E§
No. of case subjects/No. of control subjects 72/358 50/373 38/387 34/391 5.2
Odds ratio 1.0 0.4 0.4 0.4 (P 4 .02)
95% confidence interval 0.2-0.7 0.2-0.8 0.2-1.0
Total carbohydrate intake‡
No. of case subjects/No. of control subjects 32/394 48/377 53/373 61/365 29.2
Odds ratio 1.0 2.6 5.6 11.3 (P 4Increased consumption of vitamin B6 (pyridoxine) and vita- (14) Boyle P. SEARCH programme of the International Agency of Research on
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history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Present address: G. R. Howe, Department of Epidemiology, Columbia Uni-
Epidemiol Biomarkers Prev 1994;3:209-12. versity, New York, NY.
Journal of the National Cancer Institute, Vol. 89, No. 15, August 6, 1997 ARTICLES 1137Present address: A. J. McMichael, London School of Hygiene and Tropical Rademaker, and the clinicians and pathologists of regional hospitals and the
Medicine, U.K. Comprehensive Cancer Center ‘‘Midden-Nederland’’ for their participation and
Present address: C. C. Hsieh, Division of Epidemiology and Biostatistics, cooperation in this study. We acknowledge the continual support and encour-
Western Massachusetts Cancer Center, Worcester. agement of Dr. J. Steffen, Director of the Maria Sklodowska-Curie Cancer
This case–control study was conducted within the framework of the SEARCH Centre in this international collaboration, the cooperation in the study of many
Program of the International Agency for Research on Cancer (IARC), Lyon, doctors, nurses, study subjects and their relatives, members of the general popu-
France; the study in Utrecht, The Netherlands, was supported by grant 808 from lation of the Opole Region of southwest Poland, and Drs. K. Drosik, E. Piasecka,
the Ministry of Welfare, Health and Culture (formerly the Ministry of Health and W. Chmielarczyk, M. Krygier, and J. Lissowska. We also thank Dr. J. Baillargeon
Environmental Hygiene) of The Netherlands; the study in Opole, Poland, was and the collaborators within the Reseau Interhospitalier de Cancerologie de
funded by the Polish Cancer Program PR-6; the study in Montréal, Canada, was l’Universitie de Montréal for their support and Ms. C. Perret and M.-C. Goulet. We
supported by the Cancer Research Society, Fondation Hotel-Dieu de Montréal, acknowledge the collaboration of the clinicians and pathologists of the Greater
and Fonds de la Recherche en Santé du Quebec; the study in Toronto, Canada, Toronto region who contributed to this study, Dr. J. Velema and Ms. S. Seuchter,
was supported by the National Cancer Institute of Canada. formerly at the IARC, who contributed to this study, and Mrs. A. Riccardi and Miss
We thank Professors F. De Waard, G. Doornbos, S. Runia, F. C. Bourgeois, S. Cucinotta who helped to prepare the manuscript for publication.
P. E. Steinberger, S. H. Heisterkamp, W. Agterberg, P. W. Dols, J. Dorssers, J. Manuscript received March 1, 1996; revised June 3, 1997; accepted June 4,
van Gorp, M. C. A. Hofstee, A. Liesker, E. Rontgen-Pieper, M. C. E. Stam- 1997.
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