Int. J . Cancer: 44, 611-616 (1989) 0 1989 Alan R. Liss, Inc.

Publication of the International Union Agalnst Cancer Publication de I'Union lnternationale Contre le Cancer

A CASE-CONTROL STUDY OF GASTRIC CANCER AND DIET IN ITALY

Eva BUIATTI'.~", Domenico PALLI' Adriano DECARLI~, AMADORI~, , Dino Claudio AVELLINP, Simonetta B I A N C H I ~ , Roberta BISERNI~, Francesco CIPRIANI'Pierhigi COCCOh, Attilio GIACOSA', Ettore MARUBINI~, , Riccardo PUNTONI~, JR ~ Carla VINDIGNI~, Joseph FRAUMENI, . and William BLOT^ I Unita di Epidemiologia, Centro per lo Studio e la Prevenzione Oncologica, Florence; 21stituto di Statistica Medica e Biometria, Universita di Milano, Milan; 3Servizio di Oncologia, Forli; 4Servizio di Anatomia Patologica, Imola; 51stituto di Anatomia Patologica, Universita di Firenze, Florence; 61stituto di Medicina del Lavoro, Universita di Cagliari, Cagliari; 71stitutoNazionale per la Ricerca sul Cancro, Genoa; %tituto di Anutomia Patologica II, Universita di Siena, Sienu, Italy; and 9National Cancer Institute, Bethesda, MD, USA.
A case-control study was conducted in high- and low-risk areas of Italy t o evaluate reasons for the striking geographic variation in gastric cancer (GC) mortality within the country. Personal interviews with 1,016 histologically confirmed GC cases and 1,159 population controls of similar age and sex revealed that the patients were more often of lower social class and resident in rural areas and more frequently reported a familial history of gastric (but not other) cancer. After adjusting for these effects, case-control differences were found for several dietary variables, assessed by asking about the usual frequency of consumption of 146 food items and beverages. A significant trend of increasing GC risk was found with increasing consumption of traditional soups, meat, salted/ dried fish and a combination of cold cuts and seasoned cheeses. The habit of adding salt and the preference for salty foods were associated with elevated GC risk, while more frequently storing foods in the refrigerator, the availability of a freezer and use of frozen foods lowered risk. Reduced GC risk were associated with increasing intake of raw vegetables, fresh fruit and citrus fruits. Lowered risk was also related t o consumption of spices, olive oil and garlic. Neither cigarette smoking nor alcoholic beverage drinking were significantly related to GC risk. The case-control differences tended to be consistent across geographic areas, despite marked regional variations in intake levels of certain foods. The high-risk areas tended t o show higher consumption of food associated with elevated risk (traditional soups, cold cuts) and lower consumption of foods associated with reduced risks (raw vegetables, citrus fruits, garlic). Our findings indicate that dietary factors contribute t o the regional variation of stomach cancer Occurrence in Italy, and offer clues for further etiologic and prevention research.

Gastric cancer (GC) is estimated to be the most common cancer worldwide, and the second leading cause of cancer death (Kurihara et al., 1984; Parkin et al., 1988). Among European countries, Italy has one of the highest rates of GC mortality, although there is substantial geographic variation within the country (Cislaghi et al., 1986). Despite recent declines, GC still ranks first in cancer mortality in parts of north central Italy, where some of the world's highest GC rates are found, while rates are comparatively low in the south (ISTAT, 1989; Decarli et al., 1986). To investigate reasons for the regional GC differences, a large multi-center case-control study was conducted in high- and low-risk areas. We now report the results of this investigation, focusing on patterns in food intake that may influence GC risk and contribute to the geographic variation.
SUBJECTS AND METHODS

The case-control study involved 7 centers grouped into 4 areas, 2 with high (1: Forli/Cremona/Imola and 2: Florence/ Siena) and 2 with low (3: Genoa and 4: Cagliari) death rates for GC. The location of centers and their age-adjusted death rates for GC are presented in Figure 1 . Mortality is highest in area 1 and lowest in area 4, with about a 3-fold difference in rates between the areas among both males and females. All patients with histologically confirmed GC first diag-

nosed between June 1985 and December 1987 among residents in the study areas aged 75 or less were eligible as cases and were sought for interview. Cases were identified in surgery and gastroenterology departments and outpatient gastroscopic services of private and public hospitals. Ascertainment of cases was compared in each center with the local cancer registry (CR) wherever available (Florence, Forli and Genoa) or pathology department files to evaluate completeness of reporting. Slides were sought from each case for review and diagnostic classification according to the system of Lauren (1965) previously utilized in two large histopathologic series in these same study areas (Amadori et al., 1986; Amorosi et al., 1988). Non-epithelial neoplasms of the stomach, primarily lymphomas, were excluded from analysis. Controls were randomly selected from 5-year age and sex strata of the general population of each center, approximately in the ratio of 1 :1 to the cases in each stratum. For sampling, municipal computerized lists of residents (which existed for 60% of the population) or National Health Service computerized files (for the remaining 40%) were used. Both sources provide comprehensive coverage of the resident population in the age classes considered. A structured questionnaire, developed and tested during a pilot phase, was used to obtain demographic, socio-economic, residential, occupational, smoking, medical, family and dietary information. Dietary patterns of cases and controls were assessed by asking the usual frequency of intake and portion size (categorized as small, medium or large) of 146 food items and beverages, as consumed in a 12-month period approximately 2 years before the interview. For some items it was asked whether foods were consumed preserved or fresh, cooked or raw, and whether they were prepared at home or purchased. Questions on the habit of adding salt, on preference for salty foods, and on storing methods were also included. Limited data on past diet were obtained by asking about frequency of consumption for 17 major food groups, referring to the time when the subject was aged 15-20 years. A group of professional interviewers was trained centrally in the use of the questionnaire, which was administered with the aid of an instruction manual and an atlas containing pictures of the more frequently consumed foods represented in 3 portion sizes. All cases and controls were interviewed personally. Cases were interviewed at the hospital (94.1%) or at their homes (5.9%); controls were interviewed at their homes (63.2%), at the local Health Department (30.2%) or elsewhere (6.6%). Further details of the data-collecting procedures are presented elsewhere (Buiatti et al., 1989). Intakes of individual food items and of food groups were
'OTo whom reprint requests should be sent, at: Vide Volta 171, Florence 50131, Italy.

Received: April 12, 1989 and in revised form May 31, 1989.

612
e r s arose primarily in the lower parts of the stomach, with

arid biopsy specimen examination for the remainder. The can-

only 7 , S % in the gastric cardia or gastro-esophageal junction. Using the Lauren classification system. SS% were intestinaltype carcinomas, 23% diffuse-type, and 2 2 4 mixed or unclassified. Among the I , 159 controls sampled from rcsidents' lists, 140 (12.1%) refused intcrview and 126 (10.9%) were no longer rcsident, were deceased, or were unavailable because of mental or other health conditions. These subjects were replaced with additional residents randomly selected from the same age and sex stratum, so the total number of interviewed controls was j.lS9. Table I shows the distribution of cases and controls by study area, sex, and age. About 80% of the subjects came from high-risk areas and about 60% were males. The median age was nearly 65. The GC patients more often (34% vs. 23% for controls) lived in rural places within each of the study areas, and tended to be of lower socio-economic status. In the 2 high-risk areas in northern Italy, those who were born in the south of Italy and had migrated north (about 8% of the subjects) experienced a lower risk of GC than did natives of the arca. The cases in all areas also tended to have lower values of itsual adult weight-for-height. The cases also more often reported GC in a first-degree family mcmber; across all areas, 16% had 1 and 5 % had 2 or more relatives with GC, in contrast to 11%1 and 1 % among controls. Cases and controls did not differ with respect to family size or history of other digestivetract cancers in family members. Therc was little overall case-control difference in tobacco simking; ORs for non-, ex-, and current cigarette smokers in categorized into tertiles defincd by wcckiy frequency of con- low and high pack-year catcgories were, respectively, 1 .O, 0.9 sumption among all controls, Cumulative intakc for each food (95%'CI = 0.7- 1 . 1 ), 1 .0 (95% CI = 0.8-1.4) and 1.2 (95% group was obtained by summing thc frcquency of consumption CI = 0.9--1.7). Use of tobacco products other than cigarettes for individual food items in thc group. The food groups, their was uncommon. There was also little trend in risk with inconstituent foods, and thc mcan, 33rd and 67th percentile level creasing alcohol (mostly wine) intake. After adjusting for of consumption are shown in Appcndix 1 . Weighting the frc. smoking and the othcr factors mentioned above, the ORs for qucncics of consumption by portion sire was also conducted. non-drinkers, drinkers of wine less than 2 timesiday, 2 times/ day and 2 + timedday were 1 .0: 0.9 (95% CI = 0.&1.2), 1.2 but results varied littlc and are thus not presented. ociation bctwecri GC risk and the dietary (95% CI -= 0.9-1.S),and 1.3 (95% C1 = l.(b1.8). Table 11 presents ORs according to tertile of recent consumpand other exposure variables was the odds ratio (OR). Adjusted OR estimates and corresponding 95'3 confidence intenals (C1) tion for the 17 major food groups considered. Although the were obtaincd by the Mantel-Haenszel technique and signii'i- levels of consumption of these foods tended to differ among the cance for trends (over the tertiles) was evaluated using the 4 study areas, the ORs were generally similar within each area. Mantel extension chi-squarc test (Breslow and Day. 19x0). Intake of several food categories was associated with increased Multivariate logistic regression analyses were also conducted. GC risk. Strong rising trends in risk with increasing consumpAlways included in the regression models were age (actual agc tion were observed for traditional soups and meats, with ORs in years, age squared) and categorical terms for sex, area (4 equal to or exceeding 1.8 in thc highest tertiles. More moderate study areas) and placc (ruraliurban) of residence, migration rising trends were observed for saltedidried fish, cold cuts, and from the south (,yesino), socio-economic status (low. rncdiurn, seasoned chceses. high, based on a combination of occupation and educational There was little or no association between GC risk and inIcvel), familial history of (iC (0, 1 , 2 + first-degrec family members with GC), and the Quetclet index (tertile catcgories of weightiheight squared). In addition, logistic regression mod'I A B L t 1 - NIJMBLKS OF CASES .4ND CONTROLS BY STUDY AKEA, SEX, AND AGE els including all these terms plus categorical variables for tcrtile levels of consumption of one or more dietary variables Controls were used in ordcr to estimate the effect of food items sepaN _ _ % ~ _ rately or adjusted each one for the others. Models including a (32) 354 (34) 371 term for each of thc 7 centers (instead of the 4 study arecis) were also used for analysis, but no relevant differences werc 4h7 (46) 543 (47) found and these results are not prcsentcd.
KE~IJLi .I

A total of 1,229 patients with histologically confirmed GC were identified as eligible for thc study. Of these, 50 (4. 1 % ) refused to participate and 163 (13.2%) had died or were too ill for interview. The analysis thus included 1,016 GC cascs. ?l'he GC diagnosis was based on surgical specimen review for 7 4 2

122 x2 640 376 46 140 292 538

(12) (8) (63) (37) (5) (14) (29) (53)

137
108

705 454 70 155 322 612

(12) (9) (61) (39) (61 (13) (28) (53)

l _ _ l _ _

GASTRIC C A N C E R A N D D I E T IN I T A L Y

613

TABLE I1 - RELATIVE RISKS OF GASTRIC CANCER ACCORDING TO LEVEL OF CONSUMPTION OF GROUPS OF FOODS. RELATIVE RISKS ADJUSTED FOR AGE. SEX. STUDY AREA. SOCIAL CLASS. RESIDENCE. MIGRATION FROM SOUTH, FAMILY HISTORY OF GASTRIC CANCER, QUETELET INDEX, BUT NOT FOR OTHER GROUPS OF FOODS
Food group Tertile - _ _ _ ~

1 (low) -__

__

Trend p-value

Bread and pasta Traditional soups Meats Cold cuts Salted and dried fish Other fish Milk and dairy products Seasoned cheeses Raw vegetables Cooked vegetables Beans Spices Oniodgarlic Citrus fruit Other fresh fruit Dried and preserved fruit Desserts

1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0

1.0 0.7

1.2 0.8 0.9 0.8 0.7

1.3 1.1 1.1 1.0 1.0

1.1 1.6

0.6
0.8 0.7

1.2 0.6 1.1 0.8 0.7 0.8 0.6

0.4 1.0 0.8

2.4 1.8 1.2 1.4 1.2 1.1

1.0

<0.001 <0.001 0.07 0.001 0.14

<0.001 <0.001 0.04 <0.001 <0.001 0.87 0.02

0.99

0.10 0.58 0.10

0.49

take of bread and pasta (the major staples of the Italian diet), fresh and other fish, milk and dairy products, cooked vegetables, beans and dried/preserved fruit (Table 11). Strong decreasing trends in risk of GC with increasing consumption were seen for raw vegetables, citrus fruit, and other fresh fruit (with risks as low as 40% in the highest compared to lowest tertile), while there were moderate inverse trends for spices, desserts and onion/garlic. Prominent trends in risk associated with individual foods were seen for tomatoes (OR = 1.0, 0.7, 0.7, p < ,001) in the raw vegetable group, grapes (OR = 1.0, 0.8, 0.5, p < ,001) in the fresh fruit group, chili (OR = 1.0, 0.8, 0.6, p < ,001) in the spices group, beef (OR = 1.O, 1.1, 1.6, p = <.001) in the meat group, cooked ham (OR = 1.O, 1.1, 1 .6, p < .01) in the cold-cuts group; and meat soup (OR = 1.0, 1.4, 1.8, p < ,001) in the traditional soups group. Dried fava bean consumption was examined separately from that of other beans, but intake was low, with only 14 cases and 9 controls reporting monthly or greater intake (OR = 2.0, 95% CI = 0.8-4.7). We also asked about oliveoil consumption, the most frequently used fat for dressing foods and cooking. Lower risk was found among those who reported use of olive oil daily as compared with less frequently (OR = 0.8; 95% CI = 0.6-0.9). There was also a reduced G C risk associated with increasing use of garlidonions as condiments (OR = 1.0, 1.0, 0.8, p = .04). Risks also declined with frequency of intake of raw onions, one of the individual food items included in the questionnaire (OR = 1.O, 0.8, 0.8, p < .01) but not with cooked onions (OR for intake more vs. less than once per month 1.1, 95% CI = 0.9, 1.3). During the last year of data collection, an additional question was added to ascertain levels of garlic intake. Among the 27% of participants who were asked this question, a trend of decreasing GC risk with rising consumption of cooked garlic was evident (OR = 1 . 0 , 0 . 6 , 0 . 4 , p < .001). Raw garlic consumption was too low for evaluation. Separate analyses by sex yielded results similar to those described above, except that the association with meat intake was stronger among females than males. In multivariate analyses adjusting the ORs in Table I1 for intake of other food groups associated with positive or negative trends, little change from the ORs presented was found. Independent effects of the various food groups are illustrated in Table 111. Part A shows that the risks of GC declined with increasing fruit intake (citrus + other fresh fruit) within each category of raw vegetable intake (and vice versa); those with high intake of both had

only 30% of the risk as those with low intake of both. Similarly, a nearly 4-fold difference in GC risk was found between those with high vs. low intake of traditional soups and of meat/fish/cold-cutsiseasoned cheeses (Part B). A more than 5-fold difference was found between those reporting a high consumption of traditional soupimeatlfishlcold-cuts/seasoned cheeses and low fruithaw vegetable intake (for whom the OR was = 2.4) vs. those with low traditional soup/meat/fish/ cold-cutsiseasoned cheeses and high fruitfraw vegetable intake (where the OR = 0.4) (Part C). For several main foods, the frequency at ages 15-20 was also sought, but variability was much less than for recent diet, so that effects could not be evaluated for some foods, such as bread, pasta, cooked vegetables and beans. However, high consumption of raw vegetables and fresh fruit (including citrus) at age 15-20 was associated with reduced GC risk. The association persisted after controlling for recent diet. Review of responses to questions on food storage, preservation, and preparation methods revealed that the cases less often had a freezer, purchased a refrigerator at a later age, stored foods in the refrigerator less frequently, and consumed frozen foods less often than controls (Table IV). Increased GC risk was also associated with adding salt to food, and with preference for foods with a salty taste. No association was found with frequency of frying, and a mild positive trend was seen with frequency of broiling. We examined differences between study areas in the prevalence among the controls of the dietary and other variables to see whether they were in accord with differences in G C mortality rates between the four areas, i . e . , whether the risk factors were more prevalent in high-rate areas 1 (ForliKremona/Imola) and 2 (FlorenceISiena) and the protective factors more prevalent in low-rate areas 3 (Genoa) and 4 (Cagliari). This was typically the situation, with consumption of traditional soups and cold cuts higher in high-rate areas and consumption of raw vegetables, citrus fruits, seasonal fresh fruits, and onionigarlic higher in the low-rate areas (Table V). There were also concomitant variations in the availability of freezers (least available in high-rate area 1 ) and use of a refrigerator for storing foods (most often used in low-rate area 4). Exceptions did occur, however, most notably for spices, where increased intake was associated with reduced risk but prevalence of use was highest in the high-risk areas. To estimate what fraction of the variation in GC mortality between areas might be related to dietary practices, we calculated mortality differentials that would be expected between
TABLE 111 - RELATIVE RISKS OF GASTRIC CANCER ASSOCIATED WITH TERTILE LEVEL OF INTAKE OF SELECTED PAIRS OF GROUPS OF FOOD Raw vegetables
1 (low) 2

Fruit

1 (low) 2

1.O 0.7

0.8
0.5

0.5
0.3
3

0.4

3
(8)

0.5
1 (low)

0.5
Meat, fish, cold cuts, seasoned cheeses

Traditional
soups

1 (low) 2
3

1.o 1.6
1.9

1.1 2.1 3.0

1.6 2.4
3.9

Traditional soups, meat fish, cold cuts, seasoned cheeses

I /In\")
7

Fruit and raw vegetables

1 (low) 2
3

0.7 0.4

1.0

2.0 1.1 1.o

2.4 1.9 1.2

614

I< u I A T I 1 E'l ;\I

'TABLE 1%'- KE,1.,4TlVt KlSKS O t GASTRIC (,ANCIX ACCOKOINi; 1'0 RliFRlGER ATION AND SALl-USI: PKACTICES
Varinbie OK

Ever had treerer

Age obtained refrigerator Sraring i n refrigerator

so3

512
30x

618 385 189 3x5

:I I

0 7 0.9

304 404 598

08 1 3 I 0 1 9

-42
'1 1 7 ;74

418 342

1 0 15
0.7 05
0.4-0.9

Add \alt
'Paste for tooth

2 t niediurn) 7 (high) Ycvcr/vAdoin Of tcnialwavs

Yonna! Saltv
Low
4dIt

419

155 629 387 220

1 .o

(!.4-0.6

292

540

175 616 263

I .5 1 .[I i .4 1 .4

1.3 ~ 1 . 9

1.1-1.7 I . i --I .Y

areas due to the -varying consumption of sevcral food items. Thus, we applied the ORs associated with the tertile levels of fniit'raw vegetable intake to the percentages of the general populations of each area in the tertiles (estimated from the percentages among controls), which yielded a prediction that GC risk in areas 1, 2, 3, and 4 would be in the ratio of I . 3 to 1.2 to 1 . i to 1 .O. These predicted ratios are in the same rank order as the observed GC mortality in the 4 areas, although their magnitude is considerably less than the observed ratios of 3.3 to 2.8 to 1.3 to 1.0, possibly because of the misclassification common to all dietary studies. Predicted ratios based on other major food groups, or combinations of food groups, yielded similar findings (with predicted differences between areas I and 4 of 30 to 40%).
I>iSCIJSSIOU

'This casc-control study revealed significant aswciations with dietary factors that appear to contribute to the marked regional variation in GC within Italy. The relatively wide variation in the levels of consumption of specific foods probably enhanced our ability to detect dietary risk factors, despite the difficulties inherent in retrospective studies of diet and cancer (Block, 1982). Perhaps foremost among the limitations of such

investigations is the problem of recall of food intake and the likelihood of misclassification of consumption levels. If this occuned randomly, the odds ratios would be biased towards the null value of 1.0 and we would have underestimated diet both as a risk factor for GC and as a contributor to the geographic patterns of GC in Italy. Since this is the largest casecontrol study of gastric cancer reported to date, the sample size overcomes some of the loss of power due to random exposure misclassification. To reduce the possibility of differential (nonrandom) recall between cases and controls due to changes in diet related to the onset or treatment of gastric cancer, we asked about food intake 2 years prior to interview; the patterns of food consumption suggest no systematic over- or underreporting by thc cases. There also seems little chance for misdiagnosis of cancer, since all cases in this study were identified through histologic tissue examination. Nor did the cases or controls represent selected subsets of the population, since we sought to enroll all patients, and randomly selected controls in the study areas, achieving a high response rate for both. Our data are qualitatively similar to those of several other GC investigations, which found lower risk associated with intake of fruit and vegetables (Nomura, 1982; Correa et ul., 1983. 1985; Risch et ul., 1985; Trichopoulos et al., 1985; La Vecchia et ul., 1987: Hu et al., 1988; You et al., 1988). We found that those consuming high levels of both fresh fruits and vegetables had only 30% of the GC risk of those consuming low levels of both. Reductions in risk were associated with raw but not cooked vegetables and with fresh but not dried or preserved fruits, suggesting that cookingiprocessing may alter any cancer-inhibiting properties of these foods. Protective eftects associated with fruit and/or vegetable intake have been obscrved in Europe. North and South America and Asia, even though intake patterns vary greatly, indicating that components common to fresh fruits and vegetables worldwide are involved. The mechanisms are not clear, although micronutrients have been suspected, particularly vitamin C, which can inhibit endogenous formation of N-nitroso compounds (Mirvish, 1983), thought to be detemiinants of GC in several areas of the world (Cornea et ul., 1975), and also beta-carotene. One of the strongcr associations in our study was with consumption of tomatoes. a source of Iycopene, a carotenoid not efficiently converted to retinol in rivo (Simpson and Chichester, 1981). Furthermore, there were no protective effects associated with liver, dairy products and other sources of retinol. We are currently obtaining data on nutrient content (including retinol and carotcnoids) of various Italian foods to estimate the participants intake of specific vitamins and minerals (Fidanza and Versiglioni, 198l), but the patterns reported here suggest that protective effects may be due to carotenoids and not vitamin A, similar to the situation that appears to hold for lung and perhaps other cancers (Ziegler, 1989). Several investigations in experimental animals have shown that extracts from garlic and onions have strong cancer inhibitory properties (Bclman, 1983; Sparnin et al., 1986; Wargovich, 1987; Wargovich et ul., 1988). Garlic also demonstrates anti-fungal and anti-bacterial properties (Block, 1985), and may limit bacterial growth in the stomach and bacteriacatalyzed conversion of nitrate to nitrite and thus reduce the possibility for in vivo formation of N-nitroso compounds. Investigations in Hawaii and Greece have noted lower GC risk associated with higher consumption of onions (Haenszel et ul., 1972; Trichopoulos et al., 1985). In a case-control study of GC in a high-risk area of northeastern China, reduced risks were associated with intake of each of 5 Allium vegetables, includ1988, 1989). When we became aware of ing garlic (You et d., the Chinese findings, we added a question to our questionnaire to ascertain frequency of intake of garlic (in addition to use of condiments containing onionigarlic). An inverse association between cooked garlic consumption and GC risk was pronounced in this sample, with those in the highest one-third of

GASTRIC CANCER AND DIET IN ITALY

615

intake having only 40% of the G C risk of those in the lowest. Although both garlic and onions are used mostly as flavoring agents for more complex dishes and absolute quantities are small, the findings provide a further incentive for evaluating the effects of garlic and other Allium vegetables in additional populations. An interesting finding is the inverse association of GC with olive-oil consumption, which appeared to be independent of the protective effect of vegetable intake. Experimental data based on mammary and intestinal tumor models have suggested no promotional effect for olive oil, which contains mono-unsaturated fatty acids, in contrast to other types of fats (Cohen et al., 1986; Reddy and Maeura, 1984). Whether olive oil or other mono-unsaturated fats have protective effects for gastric or other cancers deserves further study. We found that more GC patients than controls reported a taste for salty foods and more often added table salt to their food. Other investigations (Nomura, 1982; Correa et al., 1983; Tuyns, 1983; Montes et al., 1985; Lu and Qin, 1987) have also reported that high salt intake increases GC risk. Irritation by salt may lead to gastric atrophy and thus generate lesions which may eventually progress to cancer (Kodama et ul., 1984; Montes et al., 1985). It is difficult to adequately measure total sodium intake because of its varying and sometimes unknown content in many processed foods, so our data on salt consumptiodpreference must be interpreted as crude approximations of intake. Nevertheless, the temporal decline in use of saltpreserved foods and the increase in use of refrigeration tend to coincide with the decline in stomach cancer mortality in many parts of the world. We found direct support of this hypothesis, since risks of G C were higher among those who had a shorter duration of access to a refrigerator, who had never had a freezer, and who used frozen foods less frequently. In areas of the world where refrigerated storage is still uncommon, such as parts of rural China, GC rates have not yet begun to decline (You et al., 1988). Frequent consumption of meats and cold dishes (cold cuts and seasoned cheeses) was related to increased GC risk. The effect for cold dishes was mainly due to preserved meats, most common of which are cooked hams and salami. Meats preserved by nitrates have been linked to increased GC risk in other studies (Nomura, 1982; Risch et al., 1985), with suspicion centering on the potential for endogenous nitrosamine formation. Italian cured meats are often preserved with nitrates

or nitrites, but we do not have precise information on the nitratehitrite concentrations of the cooked meats, which vary greatly in number and variety throughout Italy. Other European studies suggest that meat consumption could be associated with increased G C risk (Trichopoulos et al., 1985; Jedrychowski et al., 1986). In other areas of the world at high risk for GC, meat consumption is very low and the main sources of protein are represented by cereals or fish. We also found a strong positive association with traditional soups. Foods in this broad category, heavily consumed mainly in the high-risk north-central part of Italy, are traditionally prepared once or twice per week and consumed as leftovers after reboiling or heating. Since reboiling reduces bacterial counts, these soups were often left unrefrigerated. Their main components are broth, beans, beef/pork stuffing, bread, corn flour, rice and other starchy foods. No association between GC risk and intake of bread and pasta was observed, in contrast to a previous investigation in northern Italy which implicated starchy foods, including rice and pasta (La Vecchia et al., 1987). Some of these foods are included in the traditional-soups group in our study; however, for bread and pasta there was nearly uniformly high frequency of intake, with even those in the lowest tertile of intake consuming them up to twice per day. We also could not confirm the moderate (4&50%) excess risk of stomach cancer among cigarette smokers, as reported in several cohort and casecontrol studies (Nomura, 1982; You et al., 1988; Surgeon General, 1982), although there was a small (20%) excess among the heaviest smokers. Wine drinking also was not independently associated with elevated risk, contrary to reports from case-control studies in Louisiana (Correa et al., 1985) and France (Hoey et al., 1981). A recent review of epidemiologic evidence of relation of alcohol intake to cancer concluded that there is little to suggest a causal role for drinking of alcoholic beverages in stomach cancer (IARC, 1988). In conclusion, our study indicates that dietary habits are important risk factors for gastric cancer and contribute to the geographic variation within Italy. The series of causative and protective factors in the diet offer clues for further research to clarify the origins of gastric cancer and to help develop preventive strategies.
ACKNOWLEDGEMENTS

This work was supported by: the Italian Consiglio Nazionale

APPENDIX 1 - CONSTITUENT FOODS, TERTILE LEVELS OF WEEKLY CONSUMPTION, AND MEAN VALUES WITHIN TERTILES FOR THE FOOD GROUPS

Tertiles
Food group Constituent foods
. -

1 2 _______
2

3
3
~~~

Mean

33%

Mean

67%

Mean

Bread and pasta Traditional soups Meat Cold cuts Salted and dried fish Other fish Milk and dairy products Seasoned cheeses Raw vegetables Cooked vegetables Beans Spices Oniodgarlic Citrus fruit Other fresh fruit Dried and preserved fruit Desserts

All breads, commercial pasta Meat, bean, bread and rice soup, stuffed pasta, polenta Beef, mutton, pork, chicken, rabbit, offal, liver All kinds of preserved meats Anchovies, cod, herring Fresh and frozen fish, canned tuna Milk, yogurt, dairy cheeses All seasoned cheeses Salad, cucumber, tomatoes, carrots, onions, fennel All cooked vegetables Garbanzo, fava, other beans, peas, lentils Peppers, chili, cloves, cinnamon, nutmeg Onion and garlic as condiments Oranges, grapefruits, citrus juice Apricots, peaches, plums, cantaloupe, figs, grapes Dried figs, grapes, dates, cooked and canned fruit, nuts Cakes, chocolate, pastry, ice cream

15.1 1.5 3.8 0.9 0.0 0.2 0.5 1.1 2.9 3.8 0.1 0.2 1.2 0.2 1.2 0.0 0.2

18.1 2.6 5.2 2.2 0.1 0.5 3.0 2.1 4.1 5.7 0.3 0.8 4.6 1.o 2.4 0.1 0.9

20.7 3.7 6.1 3.5 0.2 0.9 6.4 3.4 6.0 0.7 1.9 4.6 1.8 3.2 0.6 1.9
7.1

23.0 4.9 7.0 5.2 0.4 1.2 7.0 4.7 1.5 8.5 1.0 3.2 4.6 3.0 4.2 1.0 4.5

21.0 1.5 9.3 8.9 1 .o 2.1 10.8 1.6 10.7 11.9 1.9 6.7 7.2 4.9 6.9 3.6 8.7

Weekly frequency of consurnption.-2Dividing point between first and second te~tile.-~Dividing point between second and third tertile

616

lii!lA'l'll E l Al..

dellc Riccrchc, Applied Project "Oncologia"; thc U .S National Cancer Institute; the Istituto Oncologico Rornagnolo in Forli, Italy; the Regione Toscana, Italy; the Rcgione EmiliaRomagna, Italy: and the Italian Lega per la Lotta Contro i Tumori. We are gratcful for the support of the medical, pathology and nursing staff in each Center for case recruitment and diagnosis. We arc indebted to Prof. A. Morettini (Unita di Gastroenterologia, Florence), Dr. B. Lancia (Istituto Nazionale della Nutrizione. Rome), also Dr P Comba and Dr. R .
REFbK
RAGONI,

Pirastu (Istituto Superiore di Sanita, Rome) for suggestions in study design and questionnaire development. We thank Dr. A. Ershow, Dr. B.J. Stone and Dr. M. Gail (NCI) for advice and guidance in study design and analysis, and Dr. C . Dichter (Philadelphia) for helpful suggestions regarding nutrient composition. We also express appreciation to the interviewers Mrs. G . Barni, Mrs. G . Cordopatri and Mrs. D. Tanzini, also Mrs. P. Fallani (CSPO-Florence) and Mrs. H. Brown (NCI) for secretarial assistance.
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