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Diet in the epidemiology of gastric cancer a
b
a
Saxon Graham , Brenda Haughey , James Marshall , John a
a
a
c
Brasure , Maria Zielezny , Jo Freudenheim , Dee West , d
James Nolan & Gregg Wilkinson
e
a
Department of Social and Preventive Medicine , State University of New York (SUNY) , 2211 Main St., Buffalo, NY, 14214 b
School of Nursing , SUNY at Buffalo ,
c
Bay Area Resource for Cancer Control , Alameda, CA, 94501
d
Department of Medicine , SUNY at Buffalo , Buffalo, NY, 14214
e
Epidemiological Resources , Chestnut Hill, MA, 02167 Published online: 04 Aug 2009.
To cite this article: Saxon Graham , Brenda Haughey , James Marshall , John Brasure , Maria Zielezny , Jo Freudenheim , Dee West , James Nolan & Gregg Wilkinson (1990) Diet in the epidemiology of gastric cancer, Nutrition and Cancer, 13:1-2, 19-34, DOI: 10.1080/01635589009514042 To link to this article: http://dx.doi.org/10.1080/01635589009514042
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Diet in the Epidemiology of Gastric Cancer
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Saxon Graham, Brenda Haughey, James Marshall, John Brasure, Maria Zielezny, Jo Freudenheim, Dee West, James Nolan, and Gregg Wilkinson
Abstract We examined the nutritional epidemiology of gastric cancer in 293 cases and neighborhood-, age-, and sex-matched controls in communities throughout the counties of Niagara, Monroe, and Erie in western New York. The interview was highly detailed, requiring two and one-half hours to complete; it attempted to provide an estimate of total calories ingested as well as of macro- and micronutrients and behaviors that could affect alimentary exposures, such as the use of refrigeration. We found that risk was enhanced by sodium, fat, and retinol. Substantial reductions in risk were associated with ingestion of carotene, especially raw vegetables (including celery, cucumbers, carrots, green peppers, tomatoes, and onions), as well as with increased use of low-temperature food storage. Both refrigeration and carotene could inhibit oxidation products that could act as carcinogens in the stomach. (Nutr Cancer 13, 19-34, 1990)
Introduction
The precipitous decline in incidence of gastric cancer over the last few decades (1), the strong increase in risk with decreases in socioeconomic status (2), and the substantially higher risk in certain ethnic groups [e.g., Japanese and Polynesians (3-5), as well as certain ethnic groups on mainland United States (6)] all suggest that something peculiar to the environment may increase risk. The alimentary environment is a likely candidate. The results of the epidemiological inquiries into diet and gastric cancer completed to date show that a higher risk may be associated with a number of dietary factors: a) low ingestion S. Graham, J. Marshall, J. Brasure, M. Zielezny, and J. Freudenheim are affiliated with the Department of Social and Preventive Medicine, State University of New York (SUNY) at Buffalo, Buffalo, NY 14214. B. Haughey is affiliated with the School of Nursing, SUNY at Buffalo. D. West is affiliated with the Bay Area Resource for Cancer Control, Alameda, CA 94501. J. Nolan is affiliated with the Department of Medicine, SUNY at Buffalo, Buffalo, NY 14214. G. Wilkinson is affiliated with Epidemiological Resources, Chestnut Hill, MA 02167.
Copyright © 1990, Lawrence Erlbaum Associates, Inc.
of carotene, retinol, vitamin C, and raw vegetables and b) high ingestion of sodium, nitrates, meats and fats, and starch (7-10). We studied these factors among approximately 300 gastric cancer cases and matched neighborhood controls in three countries in western New York.
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Methods This study was designed to avoid some of the limitations of previous research. First, we desired to eliminate the biases potentially inherent in studying cases and controls from one or two specific hospitals or communities. Second, we required the substantial numbers of subjects needed to make possible multivariate analyses of risk associated with various foods and nutrients. Third, we needed to ascertain diet histories in considerable detail, including seasonal variation in diet, to provide estimates of several nutrients as well as total calories ingested. To obtain large numbers of subjects from many communities, we designed an inquiry that drew on pathologically confirmed gastric cancer cases from all except five small hospitals in the counties of Erie, Niagara, and Monroe (containing the cities of Buffalo, Lackawana, Niagara Falls, and Rochester, a large number of villages and towns, including Kenmore, Williamsville, Lancaster, Hamburg, East Aurora, and a sizeable rural population) and neighborhood controls. A lengthy (2.5-hr) interview schedule was developed to assess an approximation of total nutrient (including total caloric) intake. Interviews with surrogates for patients unavailable were not undertaken because of the questionable validity of such data, especially in the measurement of diet. This requirement dictated that we limit participants to individuals who in their own opinion and that of their physicians were physically and mentally capable of completing a long interview. Cases were identified by nurse interviewers from 1975 to 1985 via records in hospital pathology departments and surgical services. They were considered eligible for the study if they had been diagnosed less than one year before identification. Their physicians were then contacted for approval of our requesting patients to participate in the extensive interview. About 9.4% of eligible patients refused, but a more important selection factor was the additional 26.5% whose physicians felt they should not be interviewed. The median interval between diagnosis and interview was two months. Because of the inhibiting factors noted, the series we were able to study should not in any way be construed as population based; that is, it was not a representative sample of all of the cases in the three counties in the years during which the inquiry took place. Our case series consists simply of individuals identified in all of the major hospitals in the three counties and successfully interviewed. We will discuss later the implications of our selection process with regard to the ability to generalize from the stomach cancer patients in this series to the universe of such patients in our study communities. But it must be noted here that participants had to be physically capable of the long interview, suggesting that they may have experienced earlier recovery from their therapy. Hence, our cases might have been of higher socioeconomic status than the usual gastric cancer patient. We have no evidence of this. Obviously, the series excluded people who were not mentally competent or who had a language barrier or a hearing problem. Blacks were omitted because they comprise only around 10% of the population of these counties, making a definitive analysis by race impossible. In total, we obtained 293 usable and complete interviews from the patients themselves. Controls were matched with cases on age (within 5 yrs), sex, and neighborhood. We desired to match on neighborhood because this would maximize the similarity between cases and controls in terms of socioeconomic status (SES) and ethnicity, factors shown in the past to be associated with gastric cancer. For example, we had shown that Polish Americans had a higher risk of stomach cancer and Italians of colon cancer than did other ethnic groups in
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Nutrition and Cancer 1990
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western New York (6). By matching on neighborhood we could lessen the effects of SES and ethnicity so that our focus could be more purely on diet. Because of the socioeconomic and ethnic homogeneity of neighborhoods, there was also some homogeneity in diet. Nevertheless, the major socioeconomic and ethnic groups in Buffalo and western New York (being second, third, and earlier generations in this country) vary to a degree that would allow us to detect differences in diets of cases and controls while holding other SES and ethnic traits constant. Differences that were discernable in such a design would be worth important consideration. Controls were selected by a strict protocol requiring the interviewer to visit specified numbers of addresses first on one sidu of the case's residence and then the other, then across the street, and so on, until a suitable participant was found. To maximize the likelihood of a control completing the two and one-half hour interview, interviewers carefully explained to prospective subjects that the interview would require at least two hours. This was an important factor in the high rate of refusals (53.8%) as well as the fact that once initiated most interviews were completed. The interview schedule was developed after a substantial trial period that included a number of pilot tests. We employed the food frequency approach that we had found to be the preferred method in earlier research (11). Information was obtained on demographic traits, factors already known as possible risk factors for cancer of the stomach, diet, and variables associated with alimentation (e.g., oral and dental health). We queried regarding usual frequency and quantity of ingestion of foods in the year before the onset of symptoms. Our analysis took place in several stages. First, because of the complex nature of nutrients, we felt it important to analyze the risk associated with individual foods. In addition, however, we wished to measure ingestion of specific nutrients. To this end, we utilized the tables in US Department of Agriculture Handbooks No. 8 (12) and 456 (13) to estimate the amount of vitamin A, carotene, ascorbic acid, fats, other nutrients, and total calories in the diets of patients and controls. To assess dietary fiber and for estimates of nutrients not available elsewhere, we utilized the tables of Paul and Southgate and Pennington's Dietary Nutrient Guide (14,15). Estimates were obtained by multiplying frequency of ingestion by amount (obtained by reference to pictures during the interview) by nutrient composition of specific foods. Because our study design utilized matched controls, we initially did both matched and unmatched analyses. The use of matched analyses resulted in loss of observations in varying degree because of missing data. Because the results of matched and unmatched analyses did not differ, we used unmatched analyses to minimize the loss of observations. Breslow and Day (16) have shown that if factors on which subjects are matched are controlled analytically, matched analysis can be replaced by unmatched analysis and the loss of observations can be minimized. This we did by adjusting on age and socioeconomic status (via educational level). The wide variation in the amount;; and types of foods ingested by males (compared with females) demanded that odds ratios be calculated for exposure to various nutrients among quartiles and tertiles of cases plus controls whose ranges were specific to males and females, respectively. To assess the likelihood that odds ratios discovered suggest a dose response, we utilized a test of trend in which the p value for the trend is the p value for the exposure as a continuous variable when added to the logistic model. In supplementing our contingency table analyses to control greater numbers of factors, we used logistic regression procedures in which a set of dichotomous dummy variables representing the quantile levels were tested in models containing the continuous; variables of age and years of education as covariates (16,17). Studies of the reliability of data were an integral part of our research. First, as the interviewing was conducted, a 10% random sample of the interviews of each interviewer was
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reinterviewed by telephone utilizing, for part of the interview, a preselected set of questions that was uniformly asked in addition to a random sample of questions chosen specifically for each respondent. The comparison of the original interview with the set of telephone questions posed to all subjects made possible tests of reliability. Analysis of these data, published elsewhere (18), revealed that the average correlations of monthly frequency for 14 food items were 0.42 for male cases, 0.41 for male controls, 0.49 for female cases, and 0.49 for female controls. A different random sample of telephone questions was selected for each telephone reinterview to compare with the answers on each personal interview. Because interviewers were informed of this, they may have been disinclined to devote particular attention to any set of questions that they might have perceived would always be used in a reinterview. A third study of reliability compared the answers of a sample of 158 subjects regarding their diet with those of their spouses regarding the subjects' diets. The results of this inquiry show substantial agreement between spouse and subject reports (19). Moreover, the proportion of misclassification did not differ in the cases compared with the controls. Fourth, in an effort to ascertain the extent to which responses to questions regarding diet at one time are replicable many years later, Byers and co-workers (20) reinterviewed 323 individuals who had been interviewed five to eight years previously (1975-1979). The Pearsonian correlations between current and past exact frequency of use were 0.34 for vegetables, 0.30 for fruits, 0.45 for dairy products, and 0.36 for meats. Agreement within one quintile for responses on fat, vitamin A, and fiber ranged from 66% to 72%. Because of the widespread concern over the adequacy of reports of diet and because of the vital importance of obtaining reliable data to test hypotheses regarding diet and cancer, a number of other reliability studies have been completed by other investigators in the last 10 years. They have used various types of strategies, including interviews of spouses, reinterviews, and data comparisons from diet diaries with food frequency approaches. These investigations lend some confidence that reliability is sufficient to allow estimation of amounts ingested across fairly large categories in groups of cases and controls (19,21-23). To provide absolutely accurate point estimates of ingestion via the food frequency interview or questionnaire approach is not feasible. But our ability to ascertain the quantile of nutrient intake in which groups of subjects fall is adequate to test the hypothesis that there is a dose-response relationship between the ingestion of a given food or nutrient and cancer risk. Results As might be expected in a study with cases and controls matched on neighborhood, cases and controls were very similar on SES as measured by education, and ethnic background. Although cases of both sexes were ligher in weight at the time of interview than were controls, perhaps reflecting effects of their disease, the weights of cases 1 year before the interview, 2 years before the interview, and 10 years before the interview were almost identical to those of controls, as were Quetelet Indices. We found a nonsignificant increase in risk of gastric cancer with an increase of pack-years of cigarettes smoked for males but no difference for females. A logistic regression analysis controlling for age and education revealed no differences in risk associated with the use of any kind of tobacco. We did find a number of risk factors for gastric cancer, some observed previously by us and other investigators and some observed here for the first time. As noted previously, these data were collected over a long period. To ascertain whether the factors identified carried risk in those persons interviewed at different times, we examined the various relationships in logistic regression analyses controlling for year of interview, age, and education. The relationships described below held, regardless of interview year.
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Nutrition and Cancer 1990
Sodium Because a number of previous investigators found increased risk associated with ingestion of salt and salty foods, we examined this factor in a variety of ways. Utilizing nutrient tables on the amount of salt found in all the foods about which we queried, we calculated the monthly milligrams of sodium ingested by male and female cases and controls. As Table 1 shows, there is a dose-response increase in risk for both males and females with increases in amount ingested per month of sodium as found in foods. Note that this logistic regression analysis, adjusting for age and education, showed a statistically significant trend as well as statistically significant differences between the base line value and the higher levels of salt ingestion. We asked other questions as to whether cases and controls added salt while cooking only, eating only, at both times or whether they added no salt at all to their food. Again, risk increased with amount added.
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Vitamins In the highest category of carotene ingestion, there was a substantial decrease in risk of gastric cancer among males, but there was no dose-response relationship. Among females, there was none at all. Table 2 shows the findings concerning retinol; note the increase in risk with increases in ingestion for both sexes. An examination of risk associated with ingestion of vitamins C and E revealed no relationship of interest. Our studies of ingestion of vitamin D and riboflavin showed an increase in risk with an increase in ingestion, but these probably were confounded with the stronger relationship observed for ingestion of meats and fats. The same thing was observed for monthly ingestion of calcium and phosphorous. Here again, we speculate that this could be related to the increase in risk associated with the ingestion of meats and fats from animal sources, which are sources of calcium and phosphorous. Risk was elevated specifically with the ingestion of milk, cheese, butter, and ice cream. It has been hypothesized that antioxidants (e.g., carotene and ascorbic acid) could be associated with lower risk, as could the inhibition of nitrosation. Refrigeration could also Table 1. Odds Ratios Associated With Monthly [ngestion of Sodium as Found in Foods" Cases
Controls
Sodium, g
No.
%
127.3
32 45 53 56 186
17.2 24.2 28.5 30.1 100.0
No.
Odds Ratio
95% CI
33.7 26.0 21.5 18.8 100.0
1.00 1.82 2.62" 3.09*
0.99,3.32 1.43,4.78 1.65,5.79
44.2 34.6 21.2 100.0
1.00 1.76 4.65*
0.89,3.50 2.26,9.55
%
Males 61 47 39 34 181
Trend p = 0.001 Females 88.5
24 34 49 107
22.4 31.8 45.8 100.0
46 36 22 104
Trend p = 0.0001 a: Logistic regression analysis controlled f or age and socioeconomic status. b: Significance was as follows: p < 0.01.
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Table 2. Odds Ratios Associated With Monthly Ingestion of Retinol" Cases Retinol, 1,000 IU
Controls
No.
%
32 42 56 56 186
17.2 22.6 30.1 30.1 100.0
No.
Odds Ratio
95% CI
33.7 27.6 19.9 18.8 100.0
1.00 1.59 3.04* 3.09*
0.88,2.88 1.66,5.56 1.68,5.68
40.4 29.8 29.8 100.0
1.00 1.96 2.08c
0.99,3.90 1.05,4.14
Vo
Males £42.7 42.8-68.3 68.4-108.8 > 108.8
61 50 36 34 181
Trend p = 0.007 Females 28
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73.3
39 40 107
26.2 36.4 37.4 100.0
42 31 31 104
Trend p = 0.02 a: Logistic regression analysis controlled for age and socioeconomic status. b: Significance was as follows: p < 0.01. c: Significance was as follows: p < 0.05.
retard both oxidation and nitrosation; and, consistent with our results on carotene, we found that for males as the number of years of past use of refrigerators increased, the risk of gastric cancer decreased (Table 3), adjusting for age and socioeconomic status. We have some confidence that this finding is not a chance occurrence, not only because of the statistical test results but also, and more importantly, because of the consistent results from a number of different questions we posed on refrigeration. We queried regarding the methods of storing, the duration of use of each method (for 11 different foods), and the use of iceboxes, cold cellars, or electric freezers. All of these results were congruent with those in Table 3. In our previous inquiries, we noted a decrease in risk of gastric cancer when a variety of vegetables were eaten more frequently. For that reason, and also because we found a Table 3. Odds Ratios Associated With Years of Electric Refrigerator Use" Cases
Controls
Years of Use
No.
%
^36
53 53 37 34 177
29.9 29.9 21.0 19.2 100.0
No.
Odds Ratio
95% CI
18.0 28.5 22.1 31.4 100.0
1.00 0.72 0.64 0.41*
0.41,1.27 0.34,1.17 0.22,0.76
23.9 42.4 33.7 100.0
1.00 0.59 0.68
0.31,1.14 0.34,1.37
%
Males 37-42 43-47 £48
31 49 38 54 172
Trend p = 0.001
46
36 31
31 98
36.8 31.6 31.6 100.0
Females 22 39 31 92 Trend p = 0.03
a: Logistic regression analysis controlled for age and socioeconomic status. b: Significance was as follows: p < 0.01
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Nutrition and Cancer 1990
decreasing risk associated with ingestion of carotene, we wished to examine risk associated with specific vegetables. We found that the following vegetables, eaten either cooked or raw, were statistically significantly associated with decreasing risk in regression analyses of monthly frequency of ingestion (adjusted for age and education). For males, the vegetables included celery, cucumbers, carrots, j;reen peppers, tomatoes, and onions. For females, the vegetables were onions and winter squash. Our previous inquiry also found that an increase in the frequency of ingestion of raw vegetables was associated with a decrease in risk (8). A similar result was observed here. In a logistic regression analysis with age and education in the model, the odds ratio among males decreased to 0.19 (CI = 0.09-0.37) for the largest number of different raw vegetables eaten per month and to 0.43 (CI = 0.23-0.78) for the highest monthly frequency of eating any raw vegetables. Analysis of risk associated with ingestion of fruits, either raw or cooked, showed no relationship.
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Macronutrients Tables 4-6 show that for each of the macronutrients, carbohydrates, fats, and protein, there was an increase in risk with an increase in ingestion. In most instances, the risks for females are not as pronounced as foi males, and they are less often statistically significant. Consistent with our finding of increased risk associated with fats and protein was an increase in risk associated with increases in ingestion of meats. We noted that a number of high-starch foods were associated with increased risk of gastric cancer, including potatoes, potato chips, french fries, peas, rice, and pasta. We further examined the role of starch by developing an index of grams ingested per month based on the starch content of all foods. There was a significant dose-response increase in risk among males and females with increases in ingestion of starch per month when age and SES in a logistic regression analysis were controlled. Calories Confounding all of the foregoing analyses is the strong relationship we observed between the risk of stomach cancer and total monthly ingestion of calories from any source. Table 7 Table 4. Odds Ratios Associated With Monthly' Ingestion of Carbohydrates" Controls
Cases No.
«'o
s5,825 5,826-7,825 7,826-9,948 S: 9,949
33 49 51 53 186
17.7 26.3 27.4 281.6 100.0
Males 60 43 41 37 181 Trend p = 0.08
s 5,346 5,347-7,448 a 7,449
27 39 41 107
2;;.2 3(i.4 3!i.4 100.0
Females 43 31 30 104 Trend p = 0.02
Carbohydrates, g
Odds Ratio
95% CI
33.1 23.8 22.7 20.4 100.0
1.00 2.046 2.17* 2.50°
1.13,3.69 1.19,3.95 1.36,4.62
41.4 29.8 28.8 100.0
1.00 2.03* 2.27*
1.03,4.00 1.15,4.49
No.
a: Logistic regression analysis controlled for age and socioeconomic status. b: Significance was asfollows p < 0.05. c: Significance was asfollows: p < 0.01.
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Table 5. Odds Ratios Associated With Monthly Ingestion of Fat'>
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Cases
Controls
Odds Ratio
95% CI
34.3 26.5 18.8 20.4 100.0
1.00 1.87* 3.44C 2.94C
1.01,3.43 1.87,6.35 1.55,5.57
40.4 31.7 27.9 100.0
1.00 1.66 2.33*
0.85,3.25 1.17,4.64
Fat, g
No.
%
No.
%
£1,747 1,748-2,401 2,402-3,179 &3.18O
31 44 58 53 186
16.7 23.7 31.1 28.5 100.0
Males 62 48 34 37 181 Trend p = 0.01
=s 1,489 1,490-2,064 a: 2,065
28 37 42 107
26.2 34.6 39.2 100.0
Females 42 33 29 104 Trend p = 0.004
a; Logistic regression analysis controlled for age and socioeconomic status. b: Significance was as follows: p < 0.05 c: Significance was as follows: p < 0.01
shows that as calories ingested per month increased, so did the risk for both males and females. These relationships were statistically significant and rather substantial in size. Because all of these factors are highly correlated, it is possible that the findings for carbohydrates, proteins, and fats could be confounded with those for calories. Table 8, which deals with male controls, reveals correlations well over 0.90 between total calories ingested and total protein, fat, and carbohydrates. Starch and sodium also were related at a high level (r = 0.71). Fat and retinol were not as highly related at 0.41. Carotene and ascorbic acid were highly correlated (0.79). Correlations for male cases and female cases and controls were similar and may be obtained by inquiry to the authors. The high Table 6. Odds Ratios Associated With Monthly Ingestion of Protein" Cases
Controls Odds Ratio
95% CI
33.1 28.2 16.6 22.1 100.0
1.00 1.39 3.79* 2.24C
0.76,2.52 2.05,6.99 1.20,4.18
45.2 22.1 32.7 100.0
1.00 4.06* 2.37C
2.00,8.26 1.18,4.73
Protein, g
No.
%
No.
%
0.94; see Table 8). However, our analysis of risk associated with proportions of total calories ingested derived
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Table 10. Risk of Gastric Cancer Associated With Dietary Factors in Various Models for Females" Odds Ratio
95% CI
Models assessing single factors Sodium, mg Carotene, IU Retinol, IU Starch, g Carbohydrate, g Fat, g Calories Refrigeration, yrs
1.89 0.97 1.47 1.56 1.42 1.57 1.54 0.71
1.37,2.62 0.74,1.28 1.08,2.01 1.16,2.12 1.09,1.89 1.16,2.12 1.14,2.08 0.52,0.97
Models assessing noncorrelated factors Carotene Retinol Sodium Refrigeration
0.72 1.29 1.95 0.73
0.52,1.00 0.89,1.86 1.34,2.83 0.53,1.00
Carotene Retinol Calories Refrigeration
0.71 1.38 1.57 0.74
0.51,0.99 0.96,1.98 1.09,2.27 0.54,1.02
Carotene Retinol Fat Refrigeration
0.75 1.36 1.52 0.74
0.55,1.04 0.94,1.96 1.07,2.16 0.54,1.01
Carotene Retinol Carbohydrate Refrigeration
0.73 1.48 1.44 0.75
0.52,1.01 1.04,2.11 1.03,2.01 0.54,1.02
a: Logistic regression analysis controlled for age and education. Odds ratio associated with increase of 1 SD of range of exposure.
from fats, calories derived from carbohydrates, and calories derived from protein suggested that as the proportion of total calories derived from fats increases, so does risk. This was not true for carbohydrates or protein. Despite the various caveats we entered with regard to the design and execution of this inquiry, there are a number of congruencies of our findings with those of previous investigators. These may lend credence to our findings. There now have been enough studies which yielded the same results that certain factors could be accepted as likely to play a role in the etiology of cancer of the stomach. Our findings of a dose-response reduction in risk associated with increases in ingestion of carotene and certain vegetables are consistent with previous observations (25,31-38), as shown in Table 11. Our earlier inquiry conducted on Roswell Park Memorial Institute (RPMI) patients also discovered a lower risk of stomach cancer associated with ingestion of certain vegetables, for example, lettuce, tomatoes, carrots, cabbage, and cucumbers (8). These findings were replicated in this study. Similarly, Trichopoulos and colleagues (38) found lower risks associated with eating raw cucumbers, onions, and lettuce in Greece. Most recently, You and co-workers (27) found the same thing in China. Just as carotene may reduce risk by
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Nutrition and Cancer 1990
Table 11. Epidemiological Studies Replicating Principal Findings of This Inquiry on Gastric Cancer Author Vegetables reduce risk Stehr et al. (32)
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Risch et al. (37) Trichopoulos et al. (38) Fontham et al. (34) La Vecchia et al. (33) Graham et al. (8) Bjelke (10) Bjelke (36) Kolonel et al. (25) Correa et al. (35) Haenszel (1) Wynder et al. (42) You et al. (27) High sodium intake increases risk Nazario-Delgado and Szklo (28) Tuyns (50) Haenszel et al. (5) Kolonel et al. (25) Montes et al. (29) Hirayama (49) You et al. (27) Lu and Qin (26) High starch intake increases risk Segi et al. (24) Wynder et al. (42) Graham et al. (8) Trichopoulos et al. (38) La Vecchia et al. (33) Kolonel et al. (25) Modan et al. (9)
Study Design 110 Matched pairs of cases and controls 246 Matched pairs 110 Cases, 100 controls 93 Cases, 186 controls 206 Cases, 474 controls 228 Matched pairs 227 Cases, 1394 controls Prospective study (116 cases from 16,713-person cohort) Eco logic study 1981, vitamin C 391 Matched pairs 220 Cases, 440 matched controls Eco logic and case-control study 564 Cases, 1,131 controls
Place
Pennsylvania Canada Piraeus, Greece Louisiana Metropolitan Milan Buffalo Norway Norway Hawaii South Louisiana Hawaii US, Japan, Iceland, Slovenia Shandong, China
136 Cases, 151 controls 293 Cases, 2,914 controls 220 Patient case, 440 controls, 1972 Ecclogic study 1981, pickled foods, silted fish Ecologic 454 Cases, 454 controls 564 Cases, 1,131 controls Ecclogic
Puerto Rico Belgium Hawaii
2,072 Cases, 4,843 controls Ecologic and case-control study 228 Matched pairs 11C Cases, 100 controls 206 Cases, 474 controls Ecologic study, 1981 166 Cases, matched 1:1 with 3 different sets of controls
Japan US, Japan, Iceland, Slovenia Buffalo Piraeus, Greece Metropolitan Milan Hawaii
Hawaii Colombia Kanagawa, Japan Shandong, China Henan, China
Tel Aviv
inhibiting oxidation, so may refrigeration, and it is significant that we also found a strong risk inhibition association with refrigeration. As we did, You and others (27) found a substantial lowering of risk associated with onions. This is consistent with findings of experiments on animals. Organic sulfides found in onions and other allia are potential inhibitors of carcinogenesis (39-41). Sodium has been found in a few studies to be a risk factor. Kolonel and colleagues (25) in Hawaii, Lu and Qin (26) and You and others (27) in China, and Nazario-Delgado and Szklo (28) in Puerto Rico have more recently reported a similar finding (see Table 11). Montes and co-workers (29) observed a higher urinary excretion of sodium in populations with high gastric cancer rates than in populations with low gastric cancer rates in Colombia, South America. Joosens and Geboers (3), notin;? that salt has been found to be a cocarcinogen and promoter of stomach cancer in many studies of rats, speculate that its caustic action on the
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stomach mucosa could produce atrophic gastritis and ultimately stomach cancer. We observed a higher risk associated with sodium in analyses of data derived from different questions in the interview schedule: a) total sodium derived from foods and b) salt added during cooking, at the table, during both times, or never. We also observed the use of a greater variety of pickled and smoked foods among cases compared with controls, although this difference was unremarkable. Another congruence of these with earlier findings inheres in the observation of a greater risk associated with increased ingestion of starch, specifically with rice, potatoes, potato chips, pasta, baked goods, crackers, noodles, and white bread. Segi's pioneering study (24) found the same thing for rice, and our earlier study, based on the RPMI patient population, found a higher risk associated with the ingestion of potatoes. Kolonel and co-workers (25), Trichopoulos and colleagues (38), Modan and others (9), Wynder and co-workers (42), and Risch and colleagues (37) all have found an increase in risk with an increase in ingestion of such starchy foods. Our finding of higher risks associated with the ingestion of fats is congruent with the finding of Fontham and co-workers (34) for pork and cold cuts. Unlike we did, they did not find an association for meats of any other kind. Trichopolous and colleagues (38) recently found a higher risk associated with ingestion of beef. Risch and others (37) found an increased risk of from two to three for consumption of smoked meats but apparently did not examine risks associated with other meats. We observed an increase in risk for meats in general, for fats, and for smoked meats. When we examined macronutrients, we found an increasing risk with the ingestion of total fats, protein, and carbohydrates. These are each highly correlated with total calorie ingestion and with each other; consequently, we examined whether there was an increased risk with increases in the proportion of calories ingested in the form of fat, protein, or carbohydrates. No such relationship was shown for protein or carbohydrate, and there was only a suspicion of one for fats. In considering the results of this inquiry as a whole and in relation to the results of previous inquiries, a few findings are somewhat conspicuous in the extent to which they have been replicated (Table 11). Thus, in a large number of studies lower risk apparently has been attached to increasing ingestion of vegetables. We replicated the finding for vegetables and found evidence that carotene, an antioxidant, may be particularly related to risk reduction. Refrigeration can retard oxidation, and it is interesting that, consistent with our findings on vegetables (many of which contain carotene), we found a decrease in risk with increases in duration of using refrigeration and consistent findings for other measures of lowtemperature food storage. A possible anomaly inheres in our finding of an enhancement of risk for retinol and a reduction in risk with carotene. Nevertheless, in those few studies where both carotene and retinol have been examined, carotene has often been found to reduce risk and retinol not to affect risk, for example, of lung cancer (18) and, in our own unpublished work, laryngeal cancer. Retinol increased risk of cancer of the esophagus, and carotene had no effect in Tuyns's large study (43) and our smaller one (44). One might speculate that the relationship for retinol is confounded by the fact that it is largely found in animal products. However, we observed correlations in the neighborhood of only 0.40 between retinol and meats, retinol and protein, and retinol and fats; the logistic analyses in Tables 9 and 10 suggest that retinol in itself may be a risk factor. Total vitamin A has been found to increase risk of cancer of the prostate in three studies (45-47). Certainly the potentially different effects of retinol and carotene need further investigation in future research. It has been found in a number of inquiries, including the study of Tatematsu (48) on Wistar rats, that the ingestion of large amounts of sodium increases tumor yield. Also, epidemiological inquiries found increases in risk with salt ingestion, either when studied as total ingestion of sodium in foods or when examined per specific highly salted food item.
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Nutrition and Cancer 1990
Salt has been hypothesized to decrease the viscosity of gastric mucus, thus reducing a potential barrier to alimentary carcinogens. Finally, carbohydrate or starch has been implicated in higher risk in a number of studies, including the one reported here. Inasmuch as the incidence of gastric cancer has dropped drastically, the promulgation of preventive medicine recommendations is less urgent than before. Certainly, however, limiting caloric intake, especially fat, limiting sodium, and increasing vegetable intake, particularly vegetables containing carotene, are suggested as steps toward inhibiting the risk of stomach cancer. The same may be said for the use of refrigeration. A number of other cancers (e.g., colon and lung) in addition to cardiovascular pathologies might also be controlled by these dietary suggestions. Acknowledgments and Notes
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The authors dedicate this paper to the memory of Professor Mitsuo Segi of Sendai University; he was a pioneer researcher in the nutritional epidemiology of gastric cancer. This investigation was supported by Grant CA-11535 from the National Cancer Institute, National Institutes of Health (Bethesda, MD). Address reprint requests to Dr. S. Graham, Dept. of Social and Preventive Medicine, SUNY at Buffalo, 2211 Main St., Buffalo, NY 14214. Submitted 18 May 1989; accepted in final form 1 August 1989.
References 1. Haenszel, W: "Variation in Incidence of and Mortality From Stomach Cancer, With Particular Reference to the U.S." JNCI 21, 213-262, 1958. 2. Graham, S, Levin, M, and Lilienfeld, A: "The Socioeconomic Distribution of Cancer at Various Sites in Buffalo, NY, 1948-1952." Cancer 13, 180-191, 1960. 3. Quisenberry, W: "Gastro-Intestinal Cancer in Hawaii." Acta Int Cancer 17, 324-329, 1961. 4. Smith, R: "Recorded and Expected Mortality Among the Japanese of the U.S. and Hawaii, With Special Reference to Cancer." JNCI 17, 459-473, 1956. 5. Haenszel, W, Kurihara, M, Segi, M, and Lee, R: "Stomach Cancer Among the Japanese in Hawaii." JNCI 49, 969, 1972. 6. Graham, S, Levin, M, Lilienfeld, M, and Sheehe, P: "Ethnic Derivation as Related to Cancer at Various Sites." Cancer 16, 13-27, 1963. 7. Graham, S, Lilienfeld, A, and Tidings, J: "Dietary and Purgation Factors in the Epidemiology of Gastric Cancer." Cancer 30, 2224-2234, 1967. 8. Graham, S, Schotz, W, and Martino, P: "Alimentary Factors in the Epidemiology of Gastric Cancer." Cancer 30, 922-938, 1972. 9. Modan, B, Lubin, F, Barell, V, Greenberg, R, and Modan, M: "The Role of Starches in the Etiology of Gastric Cancer." Cancer 34, 2987-2992, 1974. 10. Bjelke, E: Epidemiologic Studies of Cancer of the Stomach, Colon and Rectum; With Special Emphasis on the Role of Diet (PhD thesis). Ann Arbor, MI: University of Minnesota, University Microfilms, 1973, vols I-IV. 11. Graham, S, Dayal, H, Swanson, M, Mittelman, A, and Wilkinson, G: "Diet in the Epidemiology of Cancer of the Colon and Rectum." JNCI 61, 709-714, 1978. 12. Watt, B, and Merrill, A: Composition of Foods. Washington, DC: Agriculture Research Service, 1962. (USDA Handbook No 8.) 13. Adams, C: Nutritive Value of American Food in Common Units. Washington, DC: Agriculture Research Service, 1963. (USDA Handbook No 456.) 14. Paul, A, and Southgate, D: The Composition of Foods. New York: Elsevier/North-Holland, 1978. 15. Pennington, J: Dietary Nutrient Guide. Westport, CT: Avi, 1976. 16. Breslow, N, and Day, N: Statistical Methods in Cancer Research. The Analysis of Case-Control Studies. Lyon, France: IARC, 1980, vol. 1. 17. Dixon, WJ (ed): BMDP Statistical Software 1981. Berkeley, CA: Univ of California Press, 1981. 18. Byers, T, Graham, S, Haughey, B, Marshall, J, and Swanson, M: "Diet and Lung Cancer Risk: Findings From the Western New York Diet Study." Am J Epidemiol 125, 351-363, 1987. 19. Marshall, J, Priore, R, Haughey, B, Rzepka, T, and Graham, S: "Spouse-Subject Interviews and the Reliability of Diet Studies." Am J Epidemiol 112, 675-683, 1980. 20. Byers, T, Rosenthal, K, Marshall, J, Rzepka, T, and Cummings, M: "Dietary History From the Distant Past: A Methodological Study." Nutr Cancer 5, 60-77, 1983. 21. Kolonel, L, and Lee, J: "Husband-Wife Correspondence in Smoking, Drinking, and Dietary Habits." Am J Clin Nutr 34, 99-104, 1981.
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22. Morgan, RW, Jain, M, Miller, AB, Choi, N, and Matthews, V: "A Comparison of Dietary Methods in Epidemiologic Studies." Am J Epidemiol 107, 488-498, 1978. 23. Willett, WC, Sampson, L, Stampfer, MJ, Rosner, B, and Bain, C: "Reproducibility and Validity of a Semiquantitative Food Frequency Questionnaire." Am J Epidemiol 122, 51-65, 1985. 24. Segi, M, Fukushima, I, Fujisaku, S, Kurihara, M, Saito, S, et al.: "An Epidemiological Study on Cancer in Japan." GANN 48, Suppl, 1-63, 1957. 25. Kolonel, L, Nomura, A, Hirohata, T, Hankin, J, and Hinds, M: "Association of Diet and Place of Birth With Stomach Cancer Incidence in Hawaiian Japanese and Caucasians." Am J Clin Nutr 34, 2478-2485, 1981. 26. Lu, JB, and Quin, YM: "Correlation Between High Salt Intake and Mortality Rates for Oesophageal and Gastric Cancers in Henan Province, China." Int J Epidemiol 16, 171-176, 1987. 27. You, WC, Blot, WJ, Chang, YS, Greshow, A, and Yang, Z: "Diet and High Risk of Stomach Cancer in Shandong, China." Cancer Res 48, 3518-3523, 1988. 28. Nazario-Delgado, C, and Szklo, M: A Case-Control Study of Gastric Cancer in Puerto Rico. Paper presented June 19, 1988, Society for Epidemiologic Research, Vancouver, BC. 29. Montes, G, Cuello, C, Correa, P, Zarama, E, and Liuzza, G: "Sodium Intake and Gastric Cancer." J Cancer Res Clin Oncol 109, 42-45, 1985. 30. Joosens, JV, and Geboers, JF: "Dietary Salt and Risks to Health." Am J Clin Nutr 45, 1277-1288, 1987. 31. Haenszel, W, Correa, P, Lopez, A, Cuello, C, and Zarama, E: "Serum Micronutrient Levels in Relation to Gastric Pathology." Int J Cancer 36, 43-48, 1985. 32. Stehr, P, Gloninger, M, Kuller, L, Marsh, G, and Radford, E: "Dietary Vitamin A Deficiencies and Stomach Cancer." Am J Epidemiol 121, 65-70, 1985. 33. La Vecchia, C, Negri, E, DeCarli, A, D'Avanzo, B, and Franceschi, S: "A Case-Control Study of Diet and Gastric Cancer in Northern Italy." Int J. Cancer 40, 484-489, 1987. 34. Fontham, E, Zavala, D, Correa, P, Rodriguez, E, and Hunter, F: "Diet and Chronic Atropic Gastritis: A Case-Control Study." JNCI 76, 621-627, 1986. 35. Correa, P, Fontham, E, Pickle, LW, Chen, V, and Lin, Y: "Dietary Determinants of Gastric Cancer in South Louisiana Inhabitants." JNCI 75, 645-654, 1985. 36. Bjelke, E: "The Recession of Stomach Cancer: Selected Aspects." Trends in Cancer Incidence, K Magnus (ed). Washington, DC: Hemisphere, 1982, pp 165-181. 37. Risch, H, Jain, M, and Choi, NW: "Dietary Factors and the Incidence of Cancer of the Stomach." Am J Epidemiol 122, 947-959, 1985. 38. Trichopoulos, D, Ouranos, G, Day, NE, Tzonou, A, and Manousos, O: "Diet and Cancer of the Stomach: A Case-Control Study in Greece." Int J Cancer 36, 291-297, 1985. 39. Belman, S: "Onion and Garlic Oil Inhibits Tumor Promotion." Carcinogenesis 8, 1063-1065, 1983. 40. Wargovich, MJ: "Diallyl Sulfide, a Flavor Component of Garlic (Allium sativum) Inhibits DimenthylhydrazineInduced Colon Cancer." Carcinogenesis 8, 487-489, 1987. 41. Niukian, K, Schwartz, J, and Shklar, G: "Effects of Onion Extract on the Development of Hamster Buccal Pouch Carcinomas as Expressed in Tumor Burden." Nutr Cancer 9, 171-176, 1987. 42. Wynder, EL, Kmet, J, Dungal, N, and Segi, M: "An Epidemiological Investigation of Gastric Cancer." Cancer 16, 1461-1496, 1963. 43. Tuyns, AJ: "Protective Effect of Citrus Fruit on Esophageal Cancer." Nutr Cancer 5, 195-200, 1983. 44. Graham, S, Marshall, J, Haughey, B, Brasure, J, and Freudenheim, J: "Nutritional Epidemiology of Cancer of the Esophagus." Am J Epidemiol. In Press. 45. Heshmat, MY, Kaul, L, Kovi, J, Jackson, M, and Jackson, A: "Nutrition and Prostate Cancer: A Case-Control Study." The Prostate 6, 7-17, 1985. 46. Graham, S, Haughey, B, Marshall, J, Priore, R, and Byers, T: "Diet in the Epidemiology of Carcinoma of the Prostate Gland." JNCI 70, 687-692, 1983. 47. Kolonel, L, Yoshizawa, CN, and Hankin, JH: "Diet and Prostatic Cancer: A Case-Control Study in Hawaii." Am J Epidemiol 127, 999-1012, 1988. 48. Tatematsu, M, Takahaski, M, Fukushima, S, Hananouchi, M, and Shirai, T: "Effects of Sodium Chloride on Experimental Gastric Cancers Induced by N-Methyl-N—Nitro-N-Nitrosoguanidine or 4-Nitroquinoline-1Oxide." JNCI 55, 101-106, 1975. 49. Hirayama, T: "Diet and Cancer." Nutr Cancer 1, 67-81, 1979. 50. Tuyns, A: "Salt and Gastrointestinal Cancer." Nutr Cancer 11, 229-232, 1988.
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Nutrition and Cancer Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/hnuc20
Diet in the epidemiology of gastric cancer a
b
a
Saxon Graham , Brenda Haughey , James Marshall , John a
a
a
c
Brasure , Maria Zielezny , Jo Freudenheim , Dee West , d
James Nolan & Gregg Wilkinson
e
a
Department of Social and Preventive Medicine , State University of New York (SUNY) , 2211 Main St., Buffalo, NY, 14214 b
School of Nursing , SUNY at Buffalo ,
c
Bay Area Resource for Cancer Control , Alameda, CA, 94501
d
Department of Medicine , SUNY at Buffalo , Buffalo, NY, 14214
e
Epidemiological Resources , Chestnut Hill, MA, 02167 Published online: 04 Aug 2009.
To cite this article: Saxon Graham , Brenda Haughey , James Marshall , John Brasure , Maria Zielezny , Jo Freudenheim , Dee West , James Nolan & Gregg Wilkinson (1990) Diet in the epidemiology of gastric cancer, Nutrition and Cancer, 13:1-2, 19-34, DOI: 10.1080/01635589009514042 To link to this article: http://dx.doi.org/10.1080/01635589009514042
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Diet in the Epidemiology of Gastric Cancer
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Saxon Graham, Brenda Haughey, James Marshall, John Brasure, Maria Zielezny, Jo Freudenheim, Dee West, James Nolan, and Gregg Wilkinson
Abstract We examined the nutritional epidemiology of gastric cancer in 293 cases and neighborhood-, age-, and sex-matched controls in communities throughout the counties of Niagara, Monroe, and Erie in western New York. The interview was highly detailed, requiring two and one-half hours to complete; it attempted to provide an estimate of total calories ingested as well as of macro- and micronutrients and behaviors that could affect alimentary exposures, such as the use of refrigeration. We found that risk was enhanced by sodium, fat, and retinol. Substantial reductions in risk were associated with ingestion of carotene, especially raw vegetables (including celery, cucumbers, carrots, green peppers, tomatoes, and onions), as well as with increased use of low-temperature food storage. Both refrigeration and carotene could inhibit oxidation products that could act as carcinogens in the stomach. (Nutr Cancer 13, 19-34, 1990)
Introduction
The precipitous decline in incidence of gastric cancer over the last few decades (1), the strong increase in risk with decreases in socioeconomic status (2), and the substantially higher risk in certain ethnic groups [e.g., Japanese and Polynesians (3-5), as well as certain ethnic groups on mainland United States (6)] all suggest that something peculiar to the environment may increase risk. The alimentary environment is a likely candidate. The results of the epidemiological inquiries into diet and gastric cancer completed to date show that a higher risk may be associated with a number of dietary factors: a) low ingestion S. Graham, J. Marshall, J. Brasure, M. Zielezny, and J. Freudenheim are affiliated with the Department of Social and Preventive Medicine, State University of New York (SUNY) at Buffalo, Buffalo, NY 14214. B. Haughey is affiliated with the School of Nursing, SUNY at Buffalo. D. West is affiliated with the Bay Area Resource for Cancer Control, Alameda, CA 94501. J. Nolan is affiliated with the Department of Medicine, SUNY at Buffalo, Buffalo, NY 14214. G. Wilkinson is affiliated with Epidemiological Resources, Chestnut Hill, MA 02167.
Copyright © 1990, Lawrence Erlbaum Associates, Inc.
of carotene, retinol, vitamin C, and raw vegetables and b) high ingestion of sodium, nitrates, meats and fats, and starch (7-10). We studied these factors among approximately 300 gastric cancer cases and matched neighborhood controls in three countries in western New York.
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Methods This study was designed to avoid some of the limitations of previous research. First, we desired to eliminate the biases potentially inherent in studying cases and controls from one or two specific hospitals or communities. Second, we required the substantial numbers of subjects needed to make possible multivariate analyses of risk associated with various foods and nutrients. Third, we needed to ascertain diet histories in considerable detail, including seasonal variation in diet, to provide estimates of several nutrients as well as total calories ingested. To obtain large numbers of subjects from many communities, we designed an inquiry that drew on pathologically confirmed gastric cancer cases from all except five small hospitals in the counties of Erie, Niagara, and Monroe (containing the cities of Buffalo, Lackawana, Niagara Falls, and Rochester, a large number of villages and towns, including Kenmore, Williamsville, Lancaster, Hamburg, East Aurora, and a sizeable rural population) and neighborhood controls. A lengthy (2.5-hr) interview schedule was developed to assess an approximation of total nutrient (including total caloric) intake. Interviews with surrogates for patients unavailable were not undertaken because of the questionable validity of such data, especially in the measurement of diet. This requirement dictated that we limit participants to individuals who in their own opinion and that of their physicians were physically and mentally capable of completing a long interview. Cases were identified by nurse interviewers from 1975 to 1985 via records in hospital pathology departments and surgical services. They were considered eligible for the study if they had been diagnosed less than one year before identification. Their physicians were then contacted for approval of our requesting patients to participate in the extensive interview. About 9.4% of eligible patients refused, but a more important selection factor was the additional 26.5% whose physicians felt they should not be interviewed. The median interval between diagnosis and interview was two months. Because of the inhibiting factors noted, the series we were able to study should not in any way be construed as population based; that is, it was not a representative sample of all of the cases in the three counties in the years during which the inquiry took place. Our case series consists simply of individuals identified in all of the major hospitals in the three counties and successfully interviewed. We will discuss later the implications of our selection process with regard to the ability to generalize from the stomach cancer patients in this series to the universe of such patients in our study communities. But it must be noted here that participants had to be physically capable of the long interview, suggesting that they may have experienced earlier recovery from their therapy. Hence, our cases might have been of higher socioeconomic status than the usual gastric cancer patient. We have no evidence of this. Obviously, the series excluded people who were not mentally competent or who had a language barrier or a hearing problem. Blacks were omitted because they comprise only around 10% of the population of these counties, making a definitive analysis by race impossible. In total, we obtained 293 usable and complete interviews from the patients themselves. Controls were matched with cases on age (within 5 yrs), sex, and neighborhood. We desired to match on neighborhood because this would maximize the similarity between cases and controls in terms of socioeconomic status (SES) and ethnicity, factors shown in the past to be associated with gastric cancer. For example, we had shown that Polish Americans had a higher risk of stomach cancer and Italians of colon cancer than did other ethnic groups in
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Nutrition and Cancer 1990
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western New York (6). By matching on neighborhood we could lessen the effects of SES and ethnicity so that our focus could be more purely on diet. Because of the socioeconomic and ethnic homogeneity of neighborhoods, there was also some homogeneity in diet. Nevertheless, the major socioeconomic and ethnic groups in Buffalo and western New York (being second, third, and earlier generations in this country) vary to a degree that would allow us to detect differences in diets of cases and controls while holding other SES and ethnic traits constant. Differences that were discernable in such a design would be worth important consideration. Controls were selected by a strict protocol requiring the interviewer to visit specified numbers of addresses first on one sidu of the case's residence and then the other, then across the street, and so on, until a suitable participant was found. To maximize the likelihood of a control completing the two and one-half hour interview, interviewers carefully explained to prospective subjects that the interview would require at least two hours. This was an important factor in the high rate of refusals (53.8%) as well as the fact that once initiated most interviews were completed. The interview schedule was developed after a substantial trial period that included a number of pilot tests. We employed the food frequency approach that we had found to be the preferred method in earlier research (11). Information was obtained on demographic traits, factors already known as possible risk factors for cancer of the stomach, diet, and variables associated with alimentation (e.g., oral and dental health). We queried regarding usual frequency and quantity of ingestion of foods in the year before the onset of symptoms. Our analysis took place in several stages. First, because of the complex nature of nutrients, we felt it important to analyze the risk associated with individual foods. In addition, however, we wished to measure ingestion of specific nutrients. To this end, we utilized the tables in US Department of Agriculture Handbooks No. 8 (12) and 456 (13) to estimate the amount of vitamin A, carotene, ascorbic acid, fats, other nutrients, and total calories in the diets of patients and controls. To assess dietary fiber and for estimates of nutrients not available elsewhere, we utilized the tables of Paul and Southgate and Pennington's Dietary Nutrient Guide (14,15). Estimates were obtained by multiplying frequency of ingestion by amount (obtained by reference to pictures during the interview) by nutrient composition of specific foods. Because our study design utilized matched controls, we initially did both matched and unmatched analyses. The use of matched analyses resulted in loss of observations in varying degree because of missing data. Because the results of matched and unmatched analyses did not differ, we used unmatched analyses to minimize the loss of observations. Breslow and Day (16) have shown that if factors on which subjects are matched are controlled analytically, matched analysis can be replaced by unmatched analysis and the loss of observations can be minimized. This we did by adjusting on age and socioeconomic status (via educational level). The wide variation in the amount;; and types of foods ingested by males (compared with females) demanded that odds ratios be calculated for exposure to various nutrients among quartiles and tertiles of cases plus controls whose ranges were specific to males and females, respectively. To assess the likelihood that odds ratios discovered suggest a dose response, we utilized a test of trend in which the p value for the trend is the p value for the exposure as a continuous variable when added to the logistic model. In supplementing our contingency table analyses to control greater numbers of factors, we used logistic regression procedures in which a set of dichotomous dummy variables representing the quantile levels were tested in models containing the continuous; variables of age and years of education as covariates (16,17). Studies of the reliability of data were an integral part of our research. First, as the interviewing was conducted, a 10% random sample of the interviews of each interviewer was
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reinterviewed by telephone utilizing, for part of the interview, a preselected set of questions that was uniformly asked in addition to a random sample of questions chosen specifically for each respondent. The comparison of the original interview with the set of telephone questions posed to all subjects made possible tests of reliability. Analysis of these data, published elsewhere (18), revealed that the average correlations of monthly frequency for 14 food items were 0.42 for male cases, 0.41 for male controls, 0.49 for female cases, and 0.49 for female controls. A different random sample of telephone questions was selected for each telephone reinterview to compare with the answers on each personal interview. Because interviewers were informed of this, they may have been disinclined to devote particular attention to any set of questions that they might have perceived would always be used in a reinterview. A third study of reliability compared the answers of a sample of 158 subjects regarding their diet with those of their spouses regarding the subjects' diets. The results of this inquiry show substantial agreement between spouse and subject reports (19). Moreover, the proportion of misclassification did not differ in the cases compared with the controls. Fourth, in an effort to ascertain the extent to which responses to questions regarding diet at one time are replicable many years later, Byers and co-workers (20) reinterviewed 323 individuals who had been interviewed five to eight years previously (1975-1979). The Pearsonian correlations between current and past exact frequency of use were 0.34 for vegetables, 0.30 for fruits, 0.45 for dairy products, and 0.36 for meats. Agreement within one quintile for responses on fat, vitamin A, and fiber ranged from 66% to 72%. Because of the widespread concern over the adequacy of reports of diet and because of the vital importance of obtaining reliable data to test hypotheses regarding diet and cancer, a number of other reliability studies have been completed by other investigators in the last 10 years. They have used various types of strategies, including interviews of spouses, reinterviews, and data comparisons from diet diaries with food frequency approaches. These investigations lend some confidence that reliability is sufficient to allow estimation of amounts ingested across fairly large categories in groups of cases and controls (19,21-23). To provide absolutely accurate point estimates of ingestion via the food frequency interview or questionnaire approach is not feasible. But our ability to ascertain the quantile of nutrient intake in which groups of subjects fall is adequate to test the hypothesis that there is a dose-response relationship between the ingestion of a given food or nutrient and cancer risk. Results As might be expected in a study with cases and controls matched on neighborhood, cases and controls were very similar on SES as measured by education, and ethnic background. Although cases of both sexes were ligher in weight at the time of interview than were controls, perhaps reflecting effects of their disease, the weights of cases 1 year before the interview, 2 years before the interview, and 10 years before the interview were almost identical to those of controls, as were Quetelet Indices. We found a nonsignificant increase in risk of gastric cancer with an increase of pack-years of cigarettes smoked for males but no difference for females. A logistic regression analysis controlling for age and education revealed no differences in risk associated with the use of any kind of tobacco. We did find a number of risk factors for gastric cancer, some observed previously by us and other investigators and some observed here for the first time. As noted previously, these data were collected over a long period. To ascertain whether the factors identified carried risk in those persons interviewed at different times, we examined the various relationships in logistic regression analyses controlling for year of interview, age, and education. The relationships described below held, regardless of interview year.
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Nutrition and Cancer 1990
Sodium Because a number of previous investigators found increased risk associated with ingestion of salt and salty foods, we examined this factor in a variety of ways. Utilizing nutrient tables on the amount of salt found in all the foods about which we queried, we calculated the monthly milligrams of sodium ingested by male and female cases and controls. As Table 1 shows, there is a dose-response increase in risk for both males and females with increases in amount ingested per month of sodium as found in foods. Note that this logistic regression analysis, adjusting for age and education, showed a statistically significant trend as well as statistically significant differences between the base line value and the higher levels of salt ingestion. We asked other questions as to whether cases and controls added salt while cooking only, eating only, at both times or whether they added no salt at all to their food. Again, risk increased with amount added.
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Vitamins In the highest category of carotene ingestion, there was a substantial decrease in risk of gastric cancer among males, but there was no dose-response relationship. Among females, there was none at all. Table 2 shows the findings concerning retinol; note the increase in risk with increases in ingestion for both sexes. An examination of risk associated with ingestion of vitamins C and E revealed no relationship of interest. Our studies of ingestion of vitamin D and riboflavin showed an increase in risk with an increase in ingestion, but these probably were confounded with the stronger relationship observed for ingestion of meats and fats. The same thing was observed for monthly ingestion of calcium and phosphorous. Here again, we speculate that this could be related to the increase in risk associated with the ingestion of meats and fats from animal sources, which are sources of calcium and phosphorous. Risk was elevated specifically with the ingestion of milk, cheese, butter, and ice cream. It has been hypothesized that antioxidants (e.g., carotene and ascorbic acid) could be associated with lower risk, as could the inhibition of nitrosation. Refrigeration could also Table 1. Odds Ratios Associated With Monthly [ngestion of Sodium as Found in Foods" Cases
Controls
Sodium, g
No.
%
127.3
32 45 53 56 186
17.2 24.2 28.5 30.1 100.0
No.
Odds Ratio
95% CI
33.7 26.0 21.5 18.8 100.0
1.00 1.82 2.62" 3.09*
0.99,3.32 1.43,4.78 1.65,5.79
44.2 34.6 21.2 100.0
1.00 1.76 4.65*
0.89,3.50 2.26,9.55
%
Males 61 47 39 34 181
Trend p = 0.001 Females 88.5
24 34 49 107
22.4 31.8 45.8 100.0
46 36 22 104
Trend p = 0.0001 a: Logistic regression analysis controlled f or age and socioeconomic status. b: Significance was as follows: p < 0.01.
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Table 2. Odds Ratios Associated With Monthly Ingestion of Retinol" Cases Retinol, 1,000 IU
Controls
No.
%
32 42 56 56 186
17.2 22.6 30.1 30.1 100.0
No.
Odds Ratio
95% CI
33.7 27.6 19.9 18.8 100.0
1.00 1.59 3.04* 3.09*
0.88,2.88 1.66,5.56 1.68,5.68
40.4 29.8 29.8 100.0
1.00 1.96 2.08c
0.99,3.90 1.05,4.14
Vo
Males £42.7 42.8-68.3 68.4-108.8 > 108.8
61 50 36 34 181
Trend p = 0.007 Females 28
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73.3
39 40 107
26.2 36.4 37.4 100.0
42 31 31 104
Trend p = 0.02 a: Logistic regression analysis controlled for age and socioeconomic status. b: Significance was as follows: p < 0.01. c: Significance was as follows: p < 0.05.
retard both oxidation and nitrosation; and, consistent with our results on carotene, we found that for males as the number of years of past use of refrigerators increased, the risk of gastric cancer decreased (Table 3), adjusting for age and socioeconomic status. We have some confidence that this finding is not a chance occurrence, not only because of the statistical test results but also, and more importantly, because of the consistent results from a number of different questions we posed on refrigeration. We queried regarding the methods of storing, the duration of use of each method (for 11 different foods), and the use of iceboxes, cold cellars, or electric freezers. All of these results were congruent with those in Table 3. In our previous inquiries, we noted a decrease in risk of gastric cancer when a variety of vegetables were eaten more frequently. For that reason, and also because we found a Table 3. Odds Ratios Associated With Years of Electric Refrigerator Use" Cases
Controls
Years of Use
No.
%
^36
53 53 37 34 177
29.9 29.9 21.0 19.2 100.0
No.
Odds Ratio
95% CI
18.0 28.5 22.1 31.4 100.0
1.00 0.72 0.64 0.41*
0.41,1.27 0.34,1.17 0.22,0.76
23.9 42.4 33.7 100.0
1.00 0.59 0.68
0.31,1.14 0.34,1.37
%
Males 37-42 43-47 £48
31 49 38 54 172
Trend p = 0.001
46
36 31
31 98
36.8 31.6 31.6 100.0
Females 22 39 31 92 Trend p = 0.03
a: Logistic regression analysis controlled for age and socioeconomic status. b: Significance was as follows: p < 0.01
24
Nutrition and Cancer 1990
decreasing risk associated with ingestion of carotene, we wished to examine risk associated with specific vegetables. We found that the following vegetables, eaten either cooked or raw, were statistically significantly associated with decreasing risk in regression analyses of monthly frequency of ingestion (adjusted for age and education). For males, the vegetables included celery, cucumbers, carrots, j;reen peppers, tomatoes, and onions. For females, the vegetables were onions and winter squash. Our previous inquiry also found that an increase in the frequency of ingestion of raw vegetables was associated with a decrease in risk (8). A similar result was observed here. In a logistic regression analysis with age and education in the model, the odds ratio among males decreased to 0.19 (CI = 0.09-0.37) for the largest number of different raw vegetables eaten per month and to 0.43 (CI = 0.23-0.78) for the highest monthly frequency of eating any raw vegetables. Analysis of risk associated with ingestion of fruits, either raw or cooked, showed no relationship.
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Macronutrients Tables 4-6 show that for each of the macronutrients, carbohydrates, fats, and protein, there was an increase in risk with an increase in ingestion. In most instances, the risks for females are not as pronounced as foi males, and they are less often statistically significant. Consistent with our finding of increased risk associated with fats and protein was an increase in risk associated with increases in ingestion of meats. We noted that a number of high-starch foods were associated with increased risk of gastric cancer, including potatoes, potato chips, french fries, peas, rice, and pasta. We further examined the role of starch by developing an index of grams ingested per month based on the starch content of all foods. There was a significant dose-response increase in risk among males and females with increases in ingestion of starch per month when age and SES in a logistic regression analysis were controlled. Calories Confounding all of the foregoing analyses is the strong relationship we observed between the risk of stomach cancer and total monthly ingestion of calories from any source. Table 7 Table 4. Odds Ratios Associated With Monthly' Ingestion of Carbohydrates" Controls
Cases No.
«'o
s5,825 5,826-7,825 7,826-9,948 S: 9,949
33 49 51 53 186
17.7 26.3 27.4 281.6 100.0
Males 60 43 41 37 181 Trend p = 0.08
s 5,346 5,347-7,448 a 7,449
27 39 41 107
2;;.2 3(i.4 3!i.4 100.0
Females 43 31 30 104 Trend p = 0.02
Carbohydrates, g
Odds Ratio
95% CI
33.1 23.8 22.7 20.4 100.0
1.00 2.046 2.17* 2.50°
1.13,3.69 1.19,3.95 1.36,4.62
41.4 29.8 28.8 100.0
1.00 2.03* 2.27*
1.03,4.00 1.15,4.49
No.
a: Logistic regression analysis controlled for age and socioeconomic status. b: Significance was asfollows p < 0.05. c: Significance was asfollows: p < 0.01.
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Table 5. Odds Ratios Associated With Monthly Ingestion of Fat'>
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Cases
Controls
Odds Ratio
95% CI
34.3 26.5 18.8 20.4 100.0
1.00 1.87* 3.44C 2.94C
1.01,3.43 1.87,6.35 1.55,5.57
40.4 31.7 27.9 100.0
1.00 1.66 2.33*
0.85,3.25 1.17,4.64
Fat, g
No.
%
No.
%
£1,747 1,748-2,401 2,402-3,179 &3.18O
31 44 58 53 186
16.7 23.7 31.1 28.5 100.0
Males 62 48 34 37 181 Trend p = 0.01
=s 1,489 1,490-2,064 a: 2,065
28 37 42 107
26.2 34.6 39.2 100.0
Females 42 33 29 104 Trend p = 0.004
a; Logistic regression analysis controlled for age and socioeconomic status. b: Significance was as follows: p < 0.05 c: Significance was as follows: p < 0.01
shows that as calories ingested per month increased, so did the risk for both males and females. These relationships were statistically significant and rather substantial in size. Because all of these factors are highly correlated, it is possible that the findings for carbohydrates, proteins, and fats could be confounded with those for calories. Table 8, which deals with male controls, reveals correlations well over 0.90 between total calories ingested and total protein, fat, and carbohydrates. Starch and sodium also were related at a high level (r = 0.71). Fat and retinol were not as highly related at 0.41. Carotene and ascorbic acid were highly correlated (0.79). Correlations for male cases and female cases and controls were similar and may be obtained by inquiry to the authors. The high Table 6. Odds Ratios Associated With Monthly Ingestion of Protein" Cases
Controls Odds Ratio
95% CI
33.1 28.2 16.6 22.1 100.0
1.00 1.39 3.79* 2.24C
0.76,2.52 2.05,6.99 1.20,4.18
45.2 22.1 32.7 100.0
1.00 4.06* 2.37C
2.00,8.26 1.18,4.73
Protein, g
No.
%
No.
%
0.94; see Table 8). However, our analysis of risk associated with proportions of total calories ingested derived
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Table 10. Risk of Gastric Cancer Associated With Dietary Factors in Various Models for Females" Odds Ratio
95% CI
Models assessing single factors Sodium, mg Carotene, IU Retinol, IU Starch, g Carbohydrate, g Fat, g Calories Refrigeration, yrs
1.89 0.97 1.47 1.56 1.42 1.57 1.54 0.71
1.37,2.62 0.74,1.28 1.08,2.01 1.16,2.12 1.09,1.89 1.16,2.12 1.14,2.08 0.52,0.97
Models assessing noncorrelated factors Carotene Retinol Sodium Refrigeration
0.72 1.29 1.95 0.73
0.52,1.00 0.89,1.86 1.34,2.83 0.53,1.00
Carotene Retinol Calories Refrigeration
0.71 1.38 1.57 0.74
0.51,0.99 0.96,1.98 1.09,2.27 0.54,1.02
Carotene Retinol Fat Refrigeration
0.75 1.36 1.52 0.74
0.55,1.04 0.94,1.96 1.07,2.16 0.54,1.01
Carotene Retinol Carbohydrate Refrigeration
0.73 1.48 1.44 0.75
0.52,1.01 1.04,2.11 1.03,2.01 0.54,1.02
a: Logistic regression analysis controlled for age and education. Odds ratio associated with increase of 1 SD of range of exposure.
from fats, calories derived from carbohydrates, and calories derived from protein suggested that as the proportion of total calories derived from fats increases, so does risk. This was not true for carbohydrates or protein. Despite the various caveats we entered with regard to the design and execution of this inquiry, there are a number of congruencies of our findings with those of previous investigators. These may lend credence to our findings. There now have been enough studies which yielded the same results that certain factors could be accepted as likely to play a role in the etiology of cancer of the stomach. Our findings of a dose-response reduction in risk associated with increases in ingestion of carotene and certain vegetables are consistent with previous observations (25,31-38), as shown in Table 11. Our earlier inquiry conducted on Roswell Park Memorial Institute (RPMI) patients also discovered a lower risk of stomach cancer associated with ingestion of certain vegetables, for example, lettuce, tomatoes, carrots, cabbage, and cucumbers (8). These findings were replicated in this study. Similarly, Trichopoulos and colleagues (38) found lower risks associated with eating raw cucumbers, onions, and lettuce in Greece. Most recently, You and co-workers (27) found the same thing in China. Just as carotene may reduce risk by
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Nutrition and Cancer 1990
Table 11. Epidemiological Studies Replicating Principal Findings of This Inquiry on Gastric Cancer Author Vegetables reduce risk Stehr et al. (32)
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Risch et al. (37) Trichopoulos et al. (38) Fontham et al. (34) La Vecchia et al. (33) Graham et al. (8) Bjelke (10) Bjelke (36) Kolonel et al. (25) Correa et al. (35) Haenszel (1) Wynder et al. (42) You et al. (27) High sodium intake increases risk Nazario-Delgado and Szklo (28) Tuyns (50) Haenszel et al. (5) Kolonel et al. (25) Montes et al. (29) Hirayama (49) You et al. (27) Lu and Qin (26) High starch intake increases risk Segi et al. (24) Wynder et al. (42) Graham et al. (8) Trichopoulos et al. (38) La Vecchia et al. (33) Kolonel et al. (25) Modan et al. (9)
Study Design 110 Matched pairs of cases and controls 246 Matched pairs 110 Cases, 100 controls 93 Cases, 186 controls 206 Cases, 474 controls 228 Matched pairs 227 Cases, 1394 controls Prospective study (116 cases from 16,713-person cohort) Eco logic study 1981, vitamin C 391 Matched pairs 220 Cases, 440 matched controls Eco logic and case-control study 564 Cases, 1,131 controls
Place
Pennsylvania Canada Piraeus, Greece Louisiana Metropolitan Milan Buffalo Norway Norway Hawaii South Louisiana Hawaii US, Japan, Iceland, Slovenia Shandong, China
136 Cases, 151 controls 293 Cases, 2,914 controls 220 Patient case, 440 controls, 1972 Ecclogic study 1981, pickled foods, silted fish Ecologic 454 Cases, 454 controls 564 Cases, 1,131 controls Ecclogic
Puerto Rico Belgium Hawaii
2,072 Cases, 4,843 controls Ecologic and case-control study 228 Matched pairs 11C Cases, 100 controls 206 Cases, 474 controls Ecologic study, 1981 166 Cases, matched 1:1 with 3 different sets of controls
Japan US, Japan, Iceland, Slovenia Buffalo Piraeus, Greece Metropolitan Milan Hawaii
Hawaii Colombia Kanagawa, Japan Shandong, China Henan, China
Tel Aviv
inhibiting oxidation, so may refrigeration, and it is significant that we also found a strong risk inhibition association with refrigeration. As we did, You and others (27) found a substantial lowering of risk associated with onions. This is consistent with findings of experiments on animals. Organic sulfides found in onions and other allia are potential inhibitors of carcinogenesis (39-41). Sodium has been found in a few studies to be a risk factor. Kolonel and colleagues (25) in Hawaii, Lu and Qin (26) and You and others (27) in China, and Nazario-Delgado and Szklo (28) in Puerto Rico have more recently reported a similar finding (see Table 11). Montes and co-workers (29) observed a higher urinary excretion of sodium in populations with high gastric cancer rates than in populations with low gastric cancer rates in Colombia, South America. Joosens and Geboers (3), notin;? that salt has been found to be a cocarcinogen and promoter of stomach cancer in many studies of rats, speculate that its caustic action on the
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stomach mucosa could produce atrophic gastritis and ultimately stomach cancer. We observed a higher risk associated with sodium in analyses of data derived from different questions in the interview schedule: a) total sodium derived from foods and b) salt added during cooking, at the table, during both times, or never. We also observed the use of a greater variety of pickled and smoked foods among cases compared with controls, although this difference was unremarkable. Another congruence of these with earlier findings inheres in the observation of a greater risk associated with increased ingestion of starch, specifically with rice, potatoes, potato chips, pasta, baked goods, crackers, noodles, and white bread. Segi's pioneering study (24) found the same thing for rice, and our earlier study, based on the RPMI patient population, found a higher risk associated with the ingestion of potatoes. Kolonel and co-workers (25), Trichopoulos and colleagues (38), Modan and others (9), Wynder and co-workers (42), and Risch and colleagues (37) all have found an increase in risk with an increase in ingestion of such starchy foods. Our finding of higher risks associated with the ingestion of fats is congruent with the finding of Fontham and co-workers (34) for pork and cold cuts. Unlike we did, they did not find an association for meats of any other kind. Trichopolous and colleagues (38) recently found a higher risk associated with ingestion of beef. Risch and others (37) found an increased risk of from two to three for consumption of smoked meats but apparently did not examine risks associated with other meats. We observed an increase in risk for meats in general, for fats, and for smoked meats. When we examined macronutrients, we found an increasing risk with the ingestion of total fats, protein, and carbohydrates. These are each highly correlated with total calorie ingestion and with each other; consequently, we examined whether there was an increased risk with increases in the proportion of calories ingested in the form of fat, protein, or carbohydrates. No such relationship was shown for protein or carbohydrate, and there was only a suspicion of one for fats. In considering the results of this inquiry as a whole and in relation to the results of previous inquiries, a few findings are somewhat conspicuous in the extent to which they have been replicated (Table 11). Thus, in a large number of studies lower risk apparently has been attached to increasing ingestion of vegetables. We replicated the finding for vegetables and found evidence that carotene, an antioxidant, may be particularly related to risk reduction. Refrigeration can retard oxidation, and it is interesting that, consistent with our findings on vegetables (many of which contain carotene), we found a decrease in risk with increases in duration of using refrigeration and consistent findings for other measures of lowtemperature food storage. A possible anomaly inheres in our finding of an enhancement of risk for retinol and a reduction in risk with carotene. Nevertheless, in those few studies where both carotene and retinol have been examined, carotene has often been found to reduce risk and retinol not to affect risk, for example, of lung cancer (18) and, in our own unpublished work, laryngeal cancer. Retinol increased risk of cancer of the esophagus, and carotene had no effect in Tuyns's large study (43) and our smaller one (44). One might speculate that the relationship for retinol is confounded by the fact that it is largely found in animal products. However, we observed correlations in the neighborhood of only 0.40 between retinol and meats, retinol and protein, and retinol and fats; the logistic analyses in Tables 9 and 10 suggest that retinol in itself may be a risk factor. Total vitamin A has been found to increase risk of cancer of the prostate in three studies (45-47). Certainly the potentially different effects of retinol and carotene need further investigation in future research. It has been found in a number of inquiries, including the study of Tatematsu (48) on Wistar rats, that the ingestion of large amounts of sodium increases tumor yield. Also, epidemiological inquiries found increases in risk with salt ingestion, either when studied as total ingestion of sodium in foods or when examined per specific highly salted food item.
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Nutrition and Cancer 1990
Salt has been hypothesized to decrease the viscosity of gastric mucus, thus reducing a potential barrier to alimentary carcinogens. Finally, carbohydrate or starch has been implicated in higher risk in a number of studies, including the one reported here. Inasmuch as the incidence of gastric cancer has dropped drastically, the promulgation of preventive medicine recommendations is less urgent than before. Certainly, however, limiting caloric intake, especially fat, limiting sodium, and increasing vegetable intake, particularly vegetables containing carotene, are suggested as steps toward inhibiting the risk of stomach cancer. The same may be said for the use of refrigeration. A number of other cancers (e.g., colon and lung) in addition to cardiovascular pathologies might also be controlled by these dietary suggestions. Acknowledgments and Notes
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The authors dedicate this paper to the memory of Professor Mitsuo Segi of Sendai University; he was a pioneer researcher in the nutritional epidemiology of gastric cancer. This investigation was supported by Grant CA-11535 from the National Cancer Institute, National Institutes of Health (Bethesda, MD). Address reprint requests to Dr. S. Graham, Dept. of Social and Preventive Medicine, SUNY at Buffalo, 2211 Main St., Buffalo, NY 14214. Submitted 18 May 1989; accepted in final form 1 August 1989.
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22. Morgan, RW, Jain, M, Miller, AB, Choi, N, and Matthews, V: "A Comparison of Dietary Methods in Epidemiologic Studies." Am J Epidemiol 107, 488-498, 1978. 23. Willett, WC, Sampson, L, Stampfer, MJ, Rosner, B, and Bain, C: "Reproducibility and Validity of a Semiquantitative Food Frequency Questionnaire." Am J Epidemiol 122, 51-65, 1985. 24. Segi, M, Fukushima, I, Fujisaku, S, Kurihara, M, Saito, S, et al.: "An Epidemiological Study on Cancer in Japan." GANN 48, Suppl, 1-63, 1957. 25. Kolonel, L, Nomura, A, Hirohata, T, Hankin, J, and Hinds, M: "Association of Diet and Place of Birth With Stomach Cancer Incidence in Hawaiian Japanese and Caucasians." Am J Clin Nutr 34, 2478-2485, 1981. 26. Lu, JB, and Quin, YM: "Correlation Between High Salt Intake and Mortality Rates for Oesophageal and Gastric Cancers in Henan Province, China." Int J Epidemiol 16, 171-176, 1987. 27. You, WC, Blot, WJ, Chang, YS, Greshow, A, and Yang, Z: "Diet and High Risk of Stomach Cancer in Shandong, China." Cancer Res 48, 3518-3523, 1988. 28. Nazario-Delgado, C, and Szklo, M: A Case-Control Study of Gastric Cancer in Puerto Rico. Paper presented June 19, 1988, Society for Epidemiologic Research, Vancouver, BC. 29. Montes, G, Cuello, C, Correa, P, Zarama, E, and Liuzza, G: "Sodium Intake and Gastric Cancer." J Cancer Res Clin Oncol 109, 42-45, 1985. 30. Joosens, JV, and Geboers, JF: "Dietary Salt and Risks to Health." Am J Clin Nutr 45, 1277-1288, 1987. 31. Haenszel, W, Correa, P, Lopez, A, Cuello, C, and Zarama, E: "Serum Micronutrient Levels in Relation to Gastric Pathology." Int J Cancer 36, 43-48, 1985. 32. Stehr, P, Gloninger, M, Kuller, L, Marsh, G, and Radford, E: "Dietary Vitamin A Deficiencies and Stomach Cancer." Am J Epidemiol 121, 65-70, 1985. 33. La Vecchia, C, Negri, E, DeCarli, A, D'Avanzo, B, and Franceschi, S: "A Case-Control Study of Diet and Gastric Cancer in Northern Italy." Int J. Cancer 40, 484-489, 1987. 34. Fontham, E, Zavala, D, Correa, P, Rodriguez, E, and Hunter, F: "Diet and Chronic Atropic Gastritis: A Case-Control Study." JNCI 76, 621-627, 1986. 35. Correa, P, Fontham, E, Pickle, LW, Chen, V, and Lin, Y: "Dietary Determinants of Gastric Cancer in South Louisiana Inhabitants." JNCI 75, 645-654, 1985. 36. Bjelke, E: "The Recession of Stomach Cancer: Selected Aspects." Trends in Cancer Incidence, K Magnus (ed). Washington, DC: Hemisphere, 1982, pp 165-181. 37. Risch, H, Jain, M, and Choi, NW: "Dietary Factors and the Incidence of Cancer of the Stomach." Am J Epidemiol 122, 947-959, 1985. 38. Trichopoulos, D, Ouranos, G, Day, NE, Tzonou, A, and Manousos, O: "Diet and Cancer of the Stomach: A Case-Control Study in Greece." Int J Cancer 36, 291-297, 1985. 39. Belman, S: "Onion and Garlic Oil Inhibits Tumor Promotion." Carcinogenesis 8, 1063-1065, 1983. 40. Wargovich, MJ: "Diallyl Sulfide, a Flavor Component of Garlic (Allium sativum) Inhibits DimenthylhydrazineInduced Colon Cancer." Carcinogenesis 8, 487-489, 1987. 41. Niukian, K, Schwartz, J, and Shklar, G: "Effects of Onion Extract on the Development of Hamster Buccal Pouch Carcinomas as Expressed in Tumor Burden." Nutr Cancer 9, 171-176, 1987. 42. Wynder, EL, Kmet, J, Dungal, N, and Segi, M: "An Epidemiological Investigation of Gastric Cancer." Cancer 16, 1461-1496, 1963. 43. Tuyns, AJ: "Protective Effect of Citrus Fruit on Esophageal Cancer." Nutr Cancer 5, 195-200, 1983. 44. Graham, S, Marshall, J, Haughey, B, Brasure, J, and Freudenheim, J: "Nutritional Epidemiology of Cancer of the Esophagus." Am J Epidemiol. In Press. 45. Heshmat, MY, Kaul, L, Kovi, J, Jackson, M, and Jackson, A: "Nutrition and Prostate Cancer: A Case-Control Study." The Prostate 6, 7-17, 1985. 46. Graham, S, Haughey, B, Marshall, J, Priore, R, and Byers, T: "Diet in the Epidemiology of Carcinoma of the Prostate Gland." JNCI 70, 687-692, 1983. 47. Kolonel, L, Yoshizawa, CN, and Hankin, JH: "Diet and Prostatic Cancer: A Case-Control Study in Hawaii." Am J Epidemiol 127, 999-1012, 1988. 48. Tatematsu, M, Takahaski, M, Fukushima, S, Hananouchi, M, and Shirai, T: "Effects of Sodium Chloride on Experimental Gastric Cancers Induced by N-Methyl-N—Nitro-N-Nitrosoguanidine or 4-Nitroquinoline-1Oxide." JNCI 55, 101-106, 1975. 49. Hirayama, T: "Diet and Cancer." Nutr Cancer 1, 67-81, 1979. 50. Tuyns, A: "Salt and Gastrointestinal Cancer." Nutr Cancer 11, 229-232, 1988.
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