Cancer Letters, 52 (1990) l- 12 Elsevier Scientific Publishers Ireland Ltd
Review Letter
Consumption of methylxanthine-containing of pancreatic cancer
beverages and risk
L. Gordis Department
ofEpidemiology,
Baltimore,
MD 21205
(Received (Accepted
1 March 1990) 9 March 1990)
The Johns Hopkins University School
Summary
Public Health, 615 N. Wolfe St.,
Keywords: pancreatic cancer; epidemiology; coffee; tea; methylxanthines; risk
This paper reviews published studies of a possible relationship of consumption of methylxanthine-containing beverages, primarily coffee, to risk of pancreatic cancer (PC). Certain ecologic studies suggested a possible relation of pancreatic cancer mortality and coffee consumption by country. The findings from case-control studies are not entirely consistent; in general, no significant increased risk with a clear dose-response relationship is reported, but some of the studies suggest the possibility of some increase in risk. The prospective studies reported gererally agree that there is no significant association of coffee consumption with increased risk of PC. The few data auailable on tea consumption do not suggest an increased risk of PC. It seems reasonable to conclude that current epidemiologic evidence does not suggest any significant increased risk of PC with coffee consumption. Further research might clarify whether the divergent results reported for coffee consumption might be a result of confounding or other methodologic problems or might reflect some small but real increase in risk of PC associated with coffee consumption.
0304-3835/90/$03.50 Published and Printed
ofHygiene and
(U.S.A.)
0 1990 Elsevier Scientific Publishers in Ireland
Introduction Cancer of the pancreas is a major cause of cancer mortality in the United States and many other countries. Its cause remains unknown and treatment has been largely ineffective. Few patients survive more than a year after diagnosis. In view of the bleak outlook, intensive efforts have been made to identify causal and risk factors for the disease. The possibility that dietary factors may be involved would seem to be a plausible one given the anatomy and location of the pancreas. The possibility that coffee might be acting as a pancreatic carcinogen was suggested almost twenty years ago. Since coffee consumption is widespread, if an increased risk were indeed demonstrated for coffee, the finding would have major public health and prevention implications. This paper will review the epidemiologic data currently available regarding coffee consumption and pancreatic cancer. The studies will be discussed under three categories: ecologic studies, case-control studies and prospective studies. Ireland Ltd.
2
Ecologic studies
One of the earliest studies which addressed a possible relation of coffee and cancer was that of Stocks (1970) who correlated ageadjusted death rates from different cancers with several variables including coffee consumption in 20 countries. A positive relation of coffee consumption to pancreatic cancer mortality was seen only in males. In 1981, Cuckle and Kinlen reported a study in which data related to coffee consumption were collected for the 16 coffee-importing member countries of the International Coffee Organization for which WHO had adequate pancreatic cancer mortality data. Coffee consumption data related to 1945-49 and 1960 -64 and sex-specific, age standardized pancreatic cancer mortality rates for ages 35-64 for the periods 1955-59 and 1970-74. They found a correlation coefficient of 0.61 for males and 0.68 for females. After excluding Japan which had major post-war changes in both cancer mortality and diet, the correlations were no longer statistically significant. The observed correlations could not be attributed to smoking. Spector et al. (1981) studied coffee consumption in the United Kingdom as reflected in coffee imports from 1948 to 1978 and related these data to pancreatic cancer mortality. From 1948 to 1978 there was a steady increase in pancreatic cancer death rates in men aged 55-64 with a parallel trend in other age groups as well. This corresponded to trends in coffee consumption. Since 1970, imports have been decreasing and it remains to be seen whether pancreatic cancer mortality will also have decreased after an appropriate lag period. Bernarde and Weiss (1982) related data on coffee consumption obtained from the National Coffee Association with pancreatic cancer mortality data obtained from the National Center for Health Statistics. They described a rise and fall in coffee consumption in the United States since 1950 which was followed by a rise and fall in pancreas cancer
mortality after a to-year lag. However, inconsistencies by sex and race led the authors to suggest that the observations were likely to have been confounded by cigarette smoking and occupation. The higher pancreatic cancer incidence repeatedly observed in non-whites is not consistent with the data on coffee consumption by race. In 1983 Binstock et al. reported per capita coffee imports and consumption from 1957 to 1965 in 22 countries and correlated them with pancreatic cancer death rates in those countries in 1971-74. Coffee was significantly correlated with pancreatic cancer mortality in both men and women. Correlations were also noted for lipids and cholesterol. The countries selected for study were based on the availability of data on both coffee consumption and pancreatic cancer mortality. Kato (1985) studied the relation of pancreatic cancer mortality to latitude both in Japan and in several countries. They observed a correlation between Iatitude and pancreatic cancer mortality with a strong negative association with average temperature. The relation held after controlling for per capita consumption of foods including coffee and fat. DeCarIi and LaVecchia (1986) studied mortality from 20 cancer sites in 20 Italian regions and correlated these data with several economic and dietary variables including alcohol, coffee consumption and smoking. Correlation coefficients for coffee and pancreatic cancer mortality were moderately positive in both sexes (0.34 in males and 0.46 in females) but were not statistically significant. The correlations for coffee were lower than those found for other dietary indicators in this study. Among the problems in this study are imprecise temporal correspondence (data for coffee consumption were for a different period than the data for pancreatic cancer mortality) and also the fact that many comparisons were examined. Thus, the ecologic studies have suggested a relationship of coffee consumption to pancreatic cancer mortality, but the problems inherent in ecologic studies preclude any
3
interpretation of more than a suggestion. The basic problem with such ecologic studies is that we are limited to group data: Thus, in an ecologic study, even in a country with high mortality from pancreatic cancer and high coffee consumption, we do not know whether any of those dying from pancreatic cancer were in fact consumers of coffee. Consequently, the issue needs to be addressed through analytic studies in which data on both exposure (coffee consumption) and disease outcome (pancreatic cancer incidence or mortality) are available for each individual as in case-control and prospective studies. Case-control studies
Much of the interest in a possible relation of coffee to risk of pancreatic cancer was stimu-
Case-control
studies of coffee consumption
and pancreatic
lated by the case-control study reported by MacMahon et al. in 1981. By far the largest number of investigations of this relationship have been of a case-control design. These studies are summarized in the accompanying tables. These tables also present general findings regarding tobacco and alcohol for comparative purposes. As seen in these tables, while the findings of several of the studies are suggestive, overall, the results of the case-control studies do not provide strong support for a major risk of pancreatic cancer resulting from coffee consumption. It is often difficult, however, to compare the studies because (a) many do not present enough details of the methodology to permit adequate comparison and (b) there are major methodologic differences among many of the reported studies.
cancer (PC) --I.
Author and year
Jick and Dinan, 1981
Lin and Kessler, 1981
MacMahon,
Study Population/area
Different hospitals in different countries
Boston, Massachusetts and Rhode Island, 1974- 1979
Cases
Patients < 80 years of age admitted for pancreatic cancer (n = 93)
From case-control studies conducted 1972- 1975 in 115 hospitals in 5 U.S. metropolitan areas Adenocarcinomas (n = 94) and islet cell tumors (n = 15)
Controls
Hospital controls with other cancer (n = 78) and hospital controls with other conditions (n = 83)
Matching variables Coffee
No association
Hospital controls matched 1: 1 to cases
Age, sex, martial status and hospital More decaffeinated coffee consumption among cases; No difference in total coffee consumption between cases and controls
et al., 1981
White patients < 79 years of age with histologically confirmed pancreatic cancer in 11 hospitals Hospital controls excluding patients with pancreatic or biliary disease or diseases known to be associated with smoking or alcohol (n = 644) Hospital and physician For decaffeinated coffee, increased risk in men but flat dose-response; Increased risk in women with highly significant dose-response. Consistent trends after adjustment for smoking
4 Table I contd. Author and year
Jick and Dinan, 1981
Lin and Kessler,
Tobacco
Modest association
Alcohol Comments
Not reported Letter to the editor only; Few details given
Case-control
studies of coffee consumption
No association, but female cases were more likely to have smoked heavily than were controls Information on all coffee consumption not given in paper but given in subsequent letter to the editor. If total coffee consumption is the same in cases and controls, would suggest that regular coffee is protective
and pancreatic
Author and year
Goldstein,
Study Population/area
La Jolla, California, 1973-1980
Cases
Controls
Histologically confirmed cases at Scripps Clinic (n = 91) 45 cases of prostate cancer and 48 cases of breast cancer, (1975- 1980)
Matching variables
None reported
Coffee
No association Not reported Not reported Letter to the editor only; Few details given
Tobacco Alcohol Comments
1981
1981
MacMahon,
et al., 1981
Weak association
No association Selection bias in controls: By including many GI patients selected low coffee consumers. Increased risk remained when analyzed separately for GI and other controls. Exclusion of smokingrelated diseases in controls tended to exclude coffee consumers
cancer (PC) - II
Severson,
et al., 1982
From case-control study addressing asbestos in drinking water, Seattle, 1977-1980 Identified from SEER Registry; 40-79 years of age (n = 22) Randomly sleeted from population, ages 40-79 years (n = 22)
No association Positive association Not reported Letter to the editor only; Few details given
Wynder,
et al., 1983
From hospital based case-control study in 18 hospitals in 6 U.S. cities, 1977-1981. Histologically confirmed pancreatic cancer, ages 20-gO years (n = 275) Hospitalized patients at same time-period with non-tobacco related diseases and cancers (r-l = 7,994) Age, sex, race, hospital status (ward vs. private) No association Positive association No association Problem of piggy-backing the study on pre-existing project directed at smoking
Case-control
studies of coffee consumption
Author and year
Study Population/Area Cases
Kinlen and McPherson,
Northwest England and North Wales, Early 1950’s From a case-control study of cancer, 1952-1954 (n = 216) Other cancers (n = 432)
Matching Variables
Sex, age and area of residence
Coffee
No association (but significant positive association for tea)
Tobacco
Positive association, not significant Not reported
Comments
cancer (PC) -
III
Gold, et al., 1985
Hsieh, et al., 1986
Baltimore, 1978-
Boston, Massachusetts and Rhode Island, 1981-1984 Patients in 11 hospitals < 80 years of age. Histologically confirmed (n = 176) Hospital controls < 80 years of age (n = 273)
1984
Controls
Alcohol
and pancreatic
Interpretation difficult given that the controls all had cancer
Maryland, 1980
Incident cases in 16 hospitals (n = 274 interviews of the 392 cases identified) Hospital controls excluded any cancers (n = 392) ; Non-hospital controls were obtained by random digit dialing (n = 392) Hospital controls matched on age, race, sex, hospital and date of admission. Non-hospital controls matched by age, sex, race and telephone exchange No significant association, but suggestive doseresponse in women and not in men Weak association No association, but protective effect for wine Included histologically confirmed cases and those without tissue specimens. No difference found when analyzed separately
Hospital and physician
Slightly increased risk for heaviest consumption, but no dose-response in either sex Positive association No association
This was a repeat study by MacMahon’s group which failed to confirm previously reported association of pancreatic cancer with coffee consumption. Reported only as a letter to the editor
Case-control studies of coffee consumption and pancreatic cancer (PC) - IV. Author and year
Mack, et al., 1986
Norell, et al., 1986
Wynder, et al., 1986
Study Population/area
Los Angeles County
Sweden, 1982-
Cases
All cases of pancreatic adenocarcinoma after April 1, 1976, from cancer registry (n = 490 from a total of 736 eligible cases) ; histologically confirmed Controls obtained by “walking the neighborhood” according to established protocol (n = 490)
People age 40- 79 diagnosed with pancreatic cancer at 3 surgical departments in Stockholm and Uppsala (n = 99)
From hospital based case-control study in 18 hospitals in 6 U.S. cites, 1981-1984 Histologically confirmed pancreatic cancer, ages 20-80 years (n = 238)
Controls
Matching variables
Ages, sex, race and neighborhood or residence
Coffee
Dose-related trend among male nonsmokers, but no consistent relationship among male smokers or females of either smoking status Increased risk No association Attempted to clarify possible coffee association by reinterviewing those reporting high coffee consumption in several subgroups. Did not alter results
Tobacco Alcohol Comments
1984
Population controls from parish registries (n = 133) ; hospital controls from patients with inguinal hernias (n = 163) Population controls by sex, age, parish; hospital controls stratified (age and sex) random sample of patients with inguinal hernias Risk increased (not significantly) only in comparison with hospital controls and not with population controls Increased risk No association Divergent findings using hospital and population controls favors population control comparison. Likelihood of selection bias with hospital controls
Hospitaliied patients in same time period with non tobaccorelated diseases (n = 696) Matched at time of analysis by sex, age, race, hospital and year of interview
No aSbUUdrlOnwith decaffeinated coffee in males, but in females there was increased risk (borderline significance) for l-2 cups per day Positive association No association Problem of piggy-backing a study on a pre-existing project with different objectives. E.g., problem of exclusion of tobacco related diseases from controls
Case-control
studies of coffee consumption
and pancreatic
Author and year
La Vecchia, 1987
Study Population/area
Northern Italy: Data derived from an ongoing case-control study of several GI cancers, 1983- 1986 Patients < 75 years of age with histologically confirmed pancreatic cancer (n = 150) Admissions for acute conditions in patients < 75 years of age. Patients with cancer or other GI disease were excluded. Also excluded were diagnoses presumed to be related to coffee, alcohol or tobacco (n = 605)
Cases
Controls
et al.,
Matching variables Coffee
Estimated RR > 1 (not significant) in coffee drinkers but no dose-response
Tobacco Alcohol Comments
Not reported Not reported
cancer (PC) - V.
Falk, et al., 1988
Gorham,
Hospitalized patients in 29 Louisiana Parishes, from 1979 to 1983
Imperial County, California. 197&3- 1984
427 incident cases identified. Interviews conducted with 368
Identified from death certificates (n = 30)
Hospitaliied patients pooled from 3 studies or different cancer sites (n = 1234)
Selected from death certificates without mention of cancer (n = 47)
Race, sex and age
Age, sex, ethnicity and year of death Positive association limited to smokers
After adjusting for age, smoking, alcohol and other variables, only the risk for males drinking 38 cups per day compared with nondrinkers was greater than 1 but was not significant. No dose-response. Increased risk No association Over 50% of cases were unavailable for direct interview compared to 13% of controls Direct and Surrogate Interviews Analyzed Separately and No Difference Found
et al., 1988
Positive association No association Information by necessity obtained from surrogates
Case-control
studies of coffee consumption
and pancreatic
cancer (PC) - VI
Author and year
Clavel, et al., 1989
Cuzick and Babiker., 1989
Olsen, et al., 1989
Study Population/area
Patients in public hospitals in Paris, 1982- 1985 All patients with diagnosis of pancreatic cancer (n = 161) (102 histologically confirmed)
England: Leeds, London and Oxford, 1983- 1986 Newly diagnosed cases in major teaching and general hospitals in the 3 areas (n = 216)
Minneapolis-St. Area
Patients with cancer outside biliary tree GI system, lung or bladder; second control group of non-cancer patients (n = 268) Age at interview, sex, hospital and interviewer Females: OR 2 2 cups = 2.27 (1.11-4.64) Males: OR > 2 cups = 1.45 (0.82-2.55) Dose-response in both sexes, stronger in females. Coffee effect seems limited to nondrinkers of alcohol in both males and females No association
Hospital controls (n = 212) and controls from general practices (n = 267)
62 white males ages 40-84 who died from 1980- 1983 due to exocrine pancreatic cancer listed on death certificate. 2 12 interviewed (140 pathologically confirmed) White males, ages 40-84 ascertained through random digit dialing (n = 220)
Hospital controls were matched by hospital No association
Age, race and telephone exchange Weakly decreased risk
Positive association in current cigarette smokers Positive association Limited description of case and control selection
Increased
Cases
Matching variables Coffee
Tobacco Alcohol Comments
No association Possible recall bias study published after MacMahon’s 1981 paper. Analyses excluding controls with possibly low coffee intake did not change results. Cases and controls differed by social class and ethnic origin. Although differences were adjusted for in analysis, suggests other unrecognized differences may remain
Paul
risk
Increased risk Information on controls obtained from surrogates to keep process comparable with that for cases - information obtained related to two years prior to death (cases) or prior to interview (controls)
9
Among the major issues which need to be addressed in assessing these studies are the following: 1. Many of the studies excluded from the controls individuals with diseases believed to be related to smoking. Since smoking and coffee drinking are correlated, the result may have indirectly reduced the prevalence of coffee drinking in the controls. 2. Some of the studies include subgroups of patients in the controls, such as those with gastroenterologic disease, who may have reduced their coffee consumption. 3. Many of the studies do not explicitly state what point or period in time was referred to in the questioning regarding coffee consumption. This is compounded by the unceasing regarding the likely latent period between the action of a chemical carcinogen and the development of pancreatic cancer. 4. In seeking a dose-response relationship, studies vary considerably in how coffee doses were categorized. 5. Data on exposure (coffee consumption) are generally self-reported. Problems of recall may be of two types: the general limitations in human ability to recall, and recall bias. Given the limitations of human recall, particularly regarding dietary patterns many years in the past, there is a strong possibility of misclassification error, which if non-differential would serve to reduce the estimated relative risk. Attempts to validate the self-reports are rarely reported. The second problem relating to recall is that of recall bias - a differential pattern of recall in which cases ‘remember’ their exposures better than do the controls. In the case of studies of coffee consumption and pancreatic cancer, recall bias became a potentially important problem particularly after publication of MacMahon’s paper in 1981 which brought the possibility of such a relationship to public attention. 6. In several studies interviewers were not blinded as to case or control status of the interviewee and in other studies, no information on this point is given. It is often not clear whether
or not the interviewer knew or suspected the hypothesis being tested. 7. Some studies were specifically designed and conducted to assess the coffee hypothesis (often with other dietary hypotheses) while others were ‘fishing expeditions’ with no specific hypotheses. Frequently, one cannot tell from the paper whether the study was specifically designed to examine the coffee question or whether the problem of multiple comparisons may need to be considered. 8. Several studies were only reported as ietters to the editor and apparently were not followed by a full paper in a peer reviewed journal. Nevertheless, the studies reported in these letters are frequently cited despite the absence of sufficient methodologic information . 9. In many of the studies, issues of possible selection bias and information bias are not discussed. 10. In general, the specific question or questions which were used for ascertaining coffee consumption in the interview are not presented in the published papers. Prospective studies
Only a limited number of prospective studies have been reported because they generally depend on the availability of a large population for which data on coffee consumption as well as other relevant variables were obtained in the past. In 1983, I-Ieuch et al. reported a prospective study of 16,713 Norwegians from whom dietary data were obtained by questionnaire in 1967. Follow up continued through December, 1978. Sixty three new cases of pancreatic cancer were identified, all in subjects who were 45-74 years old at the start of the follow-up period. Estimated relative risks for coffee consumption were all less than 1.0. Additional data on this study, consistent with the above findings, were provided by Jacobsen et al. in 1986. Snowdon and Phillips (1984) reported a study of 23,912 white male and female Sev-
enth Day Adventists for whom coffee consumption habits and other lifestyle characteristics were ascertained by questionnaire in 1960. Deaths from cancer between 1960 and 1980 were identified. The highest level of coffee consumption in this study was 2 or more cups per day because there were too few subjects who consumed three or more cups to justify a different categorization. They found no significant or suggestive association of coffee consumption and pancreatic cancer mortality. The possibility that an association might have been missed because of misclassification of coffee consumption could not be ruled out; although there was no evidence to support this possibility, the authors suggested it might have occurred as a result of the tendency of respondents to under-report coffee consumption because they knew the church encourages abstinence from caffeine-containing beverages. Mills et al. (1988) reported a prospective study of fatal pancreatic cancer among 34,000 California Seventh-day Adventists from 1976 to 1983. After controlling for cigarette smoking there was no significant increase in risk associated with coffee consumption. In a nested case-control study, Whittemore et al. (1985) studied precursors of different cancers in 50,000 college men and women at Harvard and the University of Pennsylvania recorded at college physical examination and in subsequent questionnaires to alumni. The subjects were followed for periods of 16-50 years. In males, 127 pancreatic cancer deaths occurred, but none occurred in females. Each subject with cancer was matched to 4 control subjects chosen randomly from classmates of the same sex, born in the same year, and known to be alive and free of cancer at the time of the case’s death or diagnosis. Student coffee consumption was unrelated to cancer of the pancreas, and pancreatic cancer decedents reported regular tea consumption less frequently than did their matched controls. Pancreatic cancer mortality was associated with cigarette smoking. Interpretation of the lack of association with coffee consumption is compli-
cated by the fact that data collection for this variable took place over many years, and since it was not carried out for research purposes, the process was not well standardized. In 1986, Nomura et al. reported a prospective study of 7355 Japanese men on Oahu who were clinically examined from 1965 to 1968 at which time coffee consumption was ascertained through a 24-h dietary recall. They were followed through July, 1983; 21 developed pancreatic cancer during this period. Incidence was non-significantly higher in coffee drinkers at different levels of consumption than in non-drinkers. In non-drinkers, incidence was 1.9 per 1000. In those drinking l-2 cups per day, incidence was 3.1, in those drinking 3-4 cups, 4.0, and in those drinking 5 or more cups, 3.4. (P = 0.44) However, after adjustment for cigarette smoking, any relation to coffee was reduced still further: the estimated relative risks for l-2 cups, 3-4 cups and 5 or more cups were 1.16, 2.08 and 1.63, respectively, with P = 0.41. The authors concluded that coffee intake was not associated with any increased risk of pancreatic cancer. Hiatt et al. (1988) studied the incidence of pancreatic cancer in 122,894 men and women who had previously reported their consumption of coffee, tea and alcohol, as part of the multiphasic health check up of the Kaiser Permanente prepaid health program. In the 6 years of follow-up, there was no increase in risk of pancreatic cancer in relation to consumption of coffee, tea or alcohol, although risk was increased in relation to cigarette smoking. Thus, the prospective studies which have been conducted are generally in agreement that there is no significant increase in pancreatic cancer risk associated with coffee consumption. Conclusions
Certain ecologic studies suggested a possible association of pancreatic cancer mortality and coffee consumption by country. The findings from the available case-control studies are
11
not entirely consistent, but in general, no significant increased risk with a clear doseis reported. relationship response Nevertheless, certain of the case-control studies suggest the possibility of some increase in risk with coffee consumption, albeit not a marked one. The prospective studies reported are in general agreement in finding no significant association of coffee consumption with risk of pancreatic cancer. This striking agreement is particularly noteworthy since the prospective study design is free of certain methodological problems such as potential recall bias which could affect case-control studies. The conclusion, therefore, seems justified that current epidemiologic evidence does not suggest any significant increase in risk of pancreatic cancer with coffee consumption. Since the data are not entirely consistent, particularly the data from the case-control studies, further research might clarify whether the divergent results which have been reported might be a result of confounding or other methodologic problems, or whether they may truly reflect some small increase in risk associated with coffee consumption. Acknowledgment
6
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