The most recent estimates of the world-wide incidence of cancer indicate that gastric cancer was in 1990 the second most frequent cancer in the world (after lung cancer), with about 900 000 new cases diagnosed every year. Steady declines in the rates have been observed everywhere in the last few decades, but the absolute number of new cases per year is increasing mainly because of ageing of the population. The exact causes of the decline of gastric cancer are not well understood, but must include improvements in diet, food storage (e.g., refrigeration) and, possibly, the decline of Helicobacter pylori infection. Dietary modifications and, possibly, vitamin supplements remain one of the most important tool for the prevention of gastric cancer. Control of H. pylori infection, by means of eradication or immunization, is also likely to offer great potential for the prevention of this important malignancy.
KEY WORDS: stomach neoplasms/prevention & control; Helicobacter pylori; review
Las estimaciones más recientes sobre la incidencia de cáncer a nivel mundial indican que, en 1990, el gástrico fue el segundo más frecuente (después del pulmonar), con aproximadamente 900 000 casos nuevos diagnosticados cada año. Durante las últimas décadas, las tasas de incidencia de esta enfermedad han disminuido en forma constante en casi todo el mundo; sin embargo, el número absoluto de casos nuevos por año continúa en aumento debido, primordialmente, a que la población cuenta con un mayor número de personas de edad avanzada. No se sabe con exactitud a qué se debe esta disminución de casos de cáncer gástrico, pero entre las causas se mencionan: mejoras tanto en la dieta como en la conservación de los alimentos (p.e., por medio de la refrigeración) y una disminución de las infecciones por Helicobacter pylori. Las modificaciones a la dieta y, posiblemente, el consumo de complementos vitamínicos continúan siendo las alternativas más importantes para prevenir el cáncer gástrico. Asimismo, es probable que el control de la infección por H. pylori, mediante la erradicación o la inmunización, tenga grandes posibilidades de contribuir a prevenir este grave padecimiento.
PALABRAS CLAVE: neoplasmas gástricos/prevención & control; Helicobacter pylori; revisión
The most recent estimates of the world-wide incidence of cancer indicate that gastric cancer is the second most frequent cancer in the world after lung cancer, with over 900 000 new cases diagnosed every year.1 Fatality rates are high (the overall mortality incidence ratio is around 85-90%) and, also as a cause of death, gastric cancer ranked second world-wide.2 Large differences in incidence exist also within small geographical areas (e.g., north and south Italy.3 Steady declines have been observed everywhere in the last few decades.
The exact causes of the decline of gastric cancer are not well understood, but must include improvements in the affluence of diet, food storage (e.g., refrigeration) and, possibly, the decline of Helicobacter pylori (HP) infection.4,5
In this review, the geographical distribution and recent trends of gastric cancer will be examined. With respect to the aetiology, priority will be given to the findings concerning dietary habits and HP and their implications for the prevention of this malignancy will be assessed.
Estimated incidence rates of cancer of the stomach, standardized on the world population, ranged, in men in the mid-1980s, from below 10/100 000 in North America, Northern and Western Africa and Southern and South-Eastern Asia to very high rates (i.e., > 40/100 000) in Eastern Asia, most notably in Japan (75/100 000) and in the former Union of Soviet Socialist Republics (USSR)6 (Figure 1).
Data from selected population-based cancer registries indicate that the highest rates (over 40/100 000) are reported from Japan, China, the ex-USSR, Portugal and certain countries in Latin America. The lowest rates (less than 15/100 000) are seen among whites in North America, in India, the Philippines, most African countries, some countries in western Europe, and Australia. Intermediate rates are seen elsewhere (Table I). Substantial variations in gastric cancer incidence can, however, be found also within countries, a good example being Italy where, for instance, male incidence rates ranged from 40.2/100 000 in Florence to 16.1/100 000 in Ragusa3(Table I).
The mortality pattern is very similar to the incidence pattern, on account of the high fatality rates.2 In Latin America, the highest mortality rats in males in 1985-88 are reported from Costa Rica (48.6 per 100 000) and Chile (34.4 per 100 000) and the lowest from Mexico (9.5 per 100 000) and Cuba (7.5 per 100 000).7 The rates of stomach cancer in females are approximately half those in males, particularly in high-risk countries.
Mortality rates, derived from the official World Health Organization (WHO) mortality database, will be chiefly considered, since they have been available on an international scale for a longer period than incidence rates. Stomach cancer mortality declined with the last three or four decades in all European countries, but the falls were quantitatively different in absolute and in relative terms. The downward trends were more marked and started earlier in Northern and Western Europe than in Southern Europe (Figure 2).9
Figure 3 shows time trends in mortality rates for selected countries outside Europe. They provide examples of a general tendency to decline but also of persisting differences in the steepness of downward trends of gastric cancer in the world. Regarding to the Americas, some Central and South American countries had exceedingly high gastric cancer mortality rates that are declining.7 Among males, for instance, Chile had an overall world standardized rate of 69.4/100 000 in 1950-1959, and of 34.4/100 000 in 1985-1989 (i.e., rates similar to the world highest ones, seen in Japan, Figure 3). Comparative figures in Costa Rica were 60.3/100 000 males in 1960-1964 and 48.6/100 000 males in 1985-1989. In Mexico, no variation over the same calendar period was observed: 9.6 in 1960-64 and 9.5 per 100 000 males in 1985-89. Rates for females were lower, but the pattern of geographical differences and trends were similar (Figure 3).
Stomach cancer rates, were, and still are, high in Japan, although during the three decades considered overall age-standardized mortality declined from 71 to 38/100 000 males, and from 37 to 17/100 000 females (Figure 3). The falls were even greater, approaching 60%, in young and middle age (i.e., 35-64 years).
Mortality rates were extremely low in some African and Asian countries, including Egypt, Kuwait, the Philippines and Thailand. Such low values are at least in part, attributable to problems in case ascertainment and certification, although gastric cancer is relatively easy to diagnose. Data concerning mortality in other African and Asian countries are, unfortunately, scanty, and in most instances inaccurate.10
If incidence trends over the last decades, derived from population cancer registries, are examined, gastric cancer shows somewhat less marked declines than for mortality trends.11 Incidence, however, had started to be recorded, in most countries, when the greatest fall of gastric cancer had already taken place. The greatest discrepancy between gastric cancer incidence and mortality rates can be seen in Japan. The incidence/mortality ratio in Japan, in both sexes, is presently around 2, whereas in other developed countries it is generally in the 0.8-1.5 range.11 This high incidence/mortality ratio may partly reflect the spread of screening and early diagnosis by means of gastroscopy in Japan.11
It is important to bear in mind that the aforementioned downward mortality and incidence trends are dominated by the most frequent variant of gastric cancer, namely the so-called intestinal type of adenocarcinoma, usually occupying predominantly the antrum and the antrum-corpus junction. This variant is considered the endstage of a prolonged precancerous process (i.e., from chronic active gastritis, through atrophic gastritis and intestinal metaplasia and dysplasia, to frank carcinoma). The secular decline in diffuse carcinoma has been less clear, if existent, for gastric carcinoma of the diffuse type.12 Conversely, recent increases in incidence rates have been registered for adenocarcinoma of the gastric cardia. In United States whites, for instance, age-adjusted incidence rates of cardiac adenocarcinoma increased, from the mid-1970s to the mid-1980s, from 1.7 to 2.7/100 000 in men and from 0.23 to 0.45/100 000 in women. This increase parallels that of lower oesophageal adenocarcinoma, frequently linked with Barretts oesophagus, reflux oesophagitis, a history of duodenal ulcer and gastric hypersecretion.11
Finally, it should be noted that although the gastric cancer rates are declining in most populations, the absolute number of new cases per year is increasing mainly because of ageing of the populations. This indicates that gastric cancer will still be a major public health problem in the future. The expected number of deaths from stomach cancer for the year 2000 are summarized in Table II. The first column shows the number of deaths estimated for 9 geographical areas in 1985. The second column shows the expected number of deaths for the year 2000 taking into account only the changes in the population resulting from increase and ageing. The third column is the expected number taking into account in addition to the population changes, the decreasing trends assuming that the rates will continue to decrease at the same speed as in the previous 20-30 years and in the last column the same assumptions as in column 3 are made but it is assumed that the decrease will level off (damped trend) which is probably more realistic. These estimates are derived from data published by Pisani et al.2 It is of interest to note that for Latin America (as well as for the other regions), taking the more realistic projection, the number of deaths for stomach cancer in the year 2000 will be higher than those reported in 1985 both for males and females.
Dozens of case-control studies conducted all over the world have shown a remarkably consistent protection from fresh fruits and vegetables.13
Table III shows the types of vegetables and fruits which were significantly associated with gastric cancer risk in case-control investigations which included data on the topic. Studies differed substantially from each other as concerns the type and number of vegetable and fruit items elicited in the dietary questions. However, with only two exceptions, negative associations emerged with high intake of most types of vegetables, most notably fresh green-leaf vegetables, and fruits, especially citrus fruit.
There was also a significant upward trend associated with frequent consumption of traditional foods such as polenta and stuffed pasta, with a RR of 2.4 for the highest tertile of intake in the largest study of gastric cancer published to date, conducted in seven Italian areas with different baseline incidence, and including over 1 000 cases and 1 000 controls.29,32
Two studies from Spain33,34 found that an elevated risk was associated with consumption of preserved fish, salt, and pickled and smoked foods. Old-fashioned ways of food preservation (e.g. smoking of meat) seemed implicated in stomach cancer causation also in a German case-control study.35
Taken together, these foods may represent specific indicators of a less affluent diet, possibly the relevant factor in determining an elevated gastric cancer risk in various populations. Along this line, a Swedish study36 suggested that various indicators of unfavourable socio-economic conditions early in life, such as short height or larger number of siblings, were positively related to subsequent gastric cancer risk. A correlate of unfavourable living conditions in the past, which may well be related to subsequent stomach cancer risk, is the availability of refrigeration, which was inversely related to gastric cancer risk in case-control studies conducted in Italy,29,37 England,38 and Sweden.39
Salt and salty foods have also been consistently incriminated as carcinogenic in relation to gastric cancer. In several studies,27,40-42 questions were asked about taste preferences and amounts of salt usually added to foods during meals. Persons who preferred salty foods had a higher risk of developing gastric cancer, although the difficulty of assessing salt intake accurately certainly led to some underestimation of risk. One hypothesis that might explain a relationship between salt intake and gastric cancer is that excess salt acts as an irritant on the stomach wall, while nitrite and nitrate present in salt-preserved foods may induce the synthesis of N-nitrosamines in the stomach.
An increased risk of gastric cancer associated with a high consumption of chili peppers has also been reported from Mexico.43
Epidemiological data on the relationship between specific micronutrients and the risk of gastric cancer is scantier, but useful in the elucidation of the mechanisms of dietary risk factors.32,35,42,44-41 The main results on selected micronutrients from five European case-control studies are summarized in Table IV. The most consistent pattern of protection emerged for ascorbic acid, followed by b-carotene and a-tocopherol. The carotenoids and ascorbic acid were derived mainly from fruits and vegetables, while the a-tocopherol sources varied in different populations. While a high intake of nitrites seemed to increase gastric cancer risk, results with respect to the intake of nitrates are inconsistent. Ascorbic acid is actively concentrated in the gastric mucosa from the blood and secreted in the gastric cavity, where it can be involved in the detoxification of luminal carcinogens.47 Various investigations have shown that in presence of HP infection, the levels of ascorbic acid in gastric juice are decreased and return to normal after eradication of the infection.48b-carotene may act as scavenger of the radicals and increase cell-to-cell communication, thus inhibiting the expression of malignant phenotypes in transformed cells connected to non-transformed cells.
Since the isolation of Helicobacter pylori in 1982, evidence for this bacteriums causal role in the pathogenesis of gastritis, duodenal ulcers and, possibly, stomach cancer has rapidly accumulated. The evidence linking HP to stomach cancer risk derives from different types of epidemiological studies.5,49
Ecological studies or geographical correlation studies were carried out world-wide, but revealed rather inconsistent results when the incidence or mortality rates of stomach cancer were correlated with prevalence rates of HP antibodies (i.e., the most appropriate measure of HP infection in large-scale studies). In several areas, most notably Africa, high HP prevalence went along with low gastric cancer rates. However, results of these ecological studies can easily have been distorted by variations in the accuracy of cancer registration, recent declines in HP prevalence and lack of allowance for confounding factors (e.g., dietary habits).49
At least ten case-control investigations on gastric cancer included data on HP prevalence (Table V). In these studies, the prevalence of antibodies to HP in patients with gastric cancer has been compared with their prevalence in a control group. Antibodies were measured in sera collected at the time of diagnosis of cancer. Table V includes four studies of this type conducted in low-risk countries for gastric cancer and six from high-risk countries. With respect to low-risk countries, a significant association was reported in the studies conducted in the United States, Finland and Sweden. However, no association was detected in a study carried out in the Netherlands. The higher HP prevalence in the controls compared with the cases and the subsequent lack of association in the Dutch study are not surprising if we consider the nature of the control group (i.e., patients undergoing upper gastrointestinal endoscopy). Although patients with peptic ulcer, gastric atrophy, intestinal metaplasia, or dysplasia were excluded from the control group, the remaining patients had non-ulcer dyspepsia that required upper endoscopy; therefore, it is possible that a considerable proportion of them had non-atrophic chronic gastritis associated with HP infection. In fact, as the authors noted, the HP prevalence in their control group (79%) was higher than that reported in healthy blood donors aged 40-59 years from the same population (47.9%). It is of interest to note that in the Swedish study the odds ratio (OR) increased with decreasing age at cancer diagnosis to reach 9.3 in subjects under 60 years of age, and that the increased risk remained after adjusting for potential confounders. The fraction of stomach cancer attributable to HP infection was about 40% in the studies from the United States and Finland and 50% in the Swedish study.
With respect to the six case-control studies carried out in high-risk countries, all but one study54 did not show a significant positive association between HP and stomach cancer risk. The lack of a significant association in the Japanese study by Igarashi et al.53 is not surprising considering that the control group comprised subjects with chronic gastritis, a condition also associated with HP. Conversely, Kikuchi et al.54 reported a 13-fold elevated risk for early gastric cancer (i.e., below age 40 years). They suggested that the relationship between gastric carcinoma of HP may be stronger at young age, possibly due to a tendency of old cancer patients to develop severe atrophic gastritis and, hence, to lose seropositivity.
In Italy, relatively low HP prevalences were reported in both cases and controls in the Italian study considering that the study subjects came from a high-risk area for stomach cancer. Controls in this study were blood donors matched by sex and age to the cases. In the study from Portugal, controls were blood donors and subjects consulting an orthopaedic outpatient clinic and were matched to the cases by sex and age. In this study, the HP prevalence was higher in controls (81.0%) than in cases (70.0%). The gastric cancer cases from Taiwan were compared with two control groups; a random sample of 276 subjects over 40 years of age from three townships in Taiwan and 92 subjects with a mean age of 52.1 years were chosen among those undergoing a routine health check-up and found normal at endoscopy. In the first case the OR was 0.6 and in the second it was 1.0 (95% CI, 0.6-1.8). In the case-control study that we are conducting in a high-risk area for stomach cancer in Venezuela, the prevalence of HP antibodies was not significantly different in cases (65.7%) from the two control groups; it was 62.0% in the hospital controls and 70.6% in the population controls.5
The inherent limitation of the above case-control studies is the temporal ambiguity. In these studies HP infection and gastric cancer were diagnosed at the same time, thus impeding to determine which came first, especially if HP antibodies are considered indicators of current or ongoing infection. In this context, case-control studies nested in cohort investigations are of particular value in assessing causality, since they document the presence of HP infection years before cancer onset.
Five nested case-control studies have reported consistent results and are summarized in Table VI. In the study conducted in the United Kingdom,58 29 gastric cancer cases were diagnosed in a cohort of 22 000 middle-aged men and were compared with 116 controls matched to the cases by date of birth and date of sera collection. The mean interval between sera collection and cancer diagnosis was 6 years, and the OR for gastric cancer in those with precedent HP antibodies was 2.8 (95% CI, 1.0-8.0). Limitations of this study are its size, the fact that for 13 of the 29 gastric cancer cases the diagnosis was based only on death certificates, and lack of information on other risk factors for stomach cancer.
The second study was nested in a cohort of about 6 000 Japanese-American men living in Hawaii.59 A total of 109 cases of histologically confirmed gastric carcinoma diagnosed in this cohort were compared with 109 controls matched by age at entry and date of serum collection. The average time from serum collection to cancer diagnosis was 13.5 years and the OR of developing stomach cancer was 6.0 (95% CI, 2.1-17.3). The association with gastric cancer was significant for both intestinal and diffuse types of gastric cancer, and it became stronger with increasing antibody titers and with increasing time between serum collection and cancer diagnosis.
The study in California included 109 gastric cancers, 27 carcinomas of the gastro-oesophageal junction, and 120 000 persons.60 The 109 gastric cancer cases included in this study were selected at random from 246 cases of stomach cancer diagnosed in the entire cohort. They were compared with an equal number of controls matched by age at serum donation, sex, race, date of serum donation, and site of recruitment. The mean interval between serum collection and the diagnosis of gastric cancer was 14.2 years. The ORs associated with the presence of preceding HP antibodies were: 3.6 (95% CI, 1.8-7.3 for stomach cancer; 0.8 (0.3-2.1) for tumours of the gastro-oesophageal junction, and 4.0 (0.5-35.8) for gastric lymphoma; only those for stomach cancer were statistically significant. The association was stronger in women and blacks and it was not confounded by either blood group or smoking history. A history of peptic ulcer was negatively associated with subsequent gastric carcinoma in this study.
The study by Lin et al.57 consisted of the comparison of 29 patients with incident gastric cancer and 220 healthy controls, matched by age, sex and residence. They derived from a cohort of 9 777 Chinese subjects. Gastric cancer cases had a slightly higher sero-positive rate (69%) than control subjects (59%), giving an OR of 1.6 (95% CI, 0.7-2.6). The association was weak, possibly on account of the short time interval between serum collection and cancer diagnosis (mean= 3.1 years). Some years before diagnosis, many of the cases would have been likely to have severe atrophic gastritis or intestinal metaplasia. These conditions favour the loss of HP colonization, thus leading to false-negative findings in cases more frequently than in controls. A fifth prospective study is currently being conducted in Shanghai, China,61 including a cohort of 18 244 men aged 45-64 years who provided serum samples between 1986 and 1989. The 87 cases of gastric cancer identified by September 1992 were compared with four to five controls per case, matched by year of birth, month of sample collection and residence. The mean time between sample collection and cancer diagnosis was 2.3 years. No increased risk for gastric cancer was observed (in cases OR= 0.9; 95% CI, 0.5-1.5). For cancer of the cardia the OR was 0.6 (95% CI, 0.2-1.3) and for non-cardia cancer cases it was 1.3 (95% CI, 0.6-2.9).
In conclusion, although there is an impressive body of clinical and experimental data indicating that HP is one of the main causes of acute and chronic gastritis, firm epidemiological evidence linking HP to gastric cancer has been more difficult to obtain. From the review of the formal epidemiological studies carried out so far, the strongest evidence for a causal association is provided by case-control studies carried out in low-risk populations for gastric cancer and from the nested case-control studies in which it could be demonstrated that the HP infection preceded the gastric cancer development. However, the lack of control for potential confounders does not allow to draw definitive conclusions. Especially elevated risk derived from HP infection in younger subjects, although the rarity of gastric cancer before 40 years of age hampers the study of this age group.54,62 The lack of association found in the case-control studies carried out in high-risk areas for stomach cancer might be due to the use of inappropriate serological assays, since assays were based on HP strains most common in Western countries.
The final proof of causality may be provided by intervention studies in which the efficacy of long-term eradication of HP in reducing gastric cancer rates is demonstrated. An important contribution can, however, come from the study of different strains of HP, with, possibly, varying oncogenic potentials. This would provide an essential tool to reassess and, possibly reconcile the aforementioned inconsistencies in the epidemiology of HP world-wide.
There are forty two studies which have examined the effect of tobacco consumption as a risk factor for stomach cancer.63 These consist of twelve cohort studies and thirty case-control studies. Ten of the cohort studies found a positive association between some aspect of tobacco use and gastric carcinoma and two did not find such an association. Eight of the cohort studies examined the presence of a dose-response relationship: three of these found a positive dose- response trend, while five others did not.
Of the thirty case-control studies, nineteen found an association between some aspect of tobacco use and stomach cancer and eleven did not. Seventeen of the studies examined a dose-response relationship between the amount of tobacco consumed and gastric carcinoma risk, and of these, six studies reported that the dose-response trend was positive; in eleven other studies a dose-response trend was not found.
From the mechanisms viewpoint, the direct carcinogenic effect of ingested tobacco or ingested tobacco smoke may include the development of precursor gastric lesions, such as gastritis, gastric peptic ulceration and intestinal metaplasia. Indirect effects of inhaled tobacco smoke in gastric carcinogenesis may involve both the nitrosamines found in smoke, as well as endogenously formed nitrosamines in smokers.
Alcohol drinking is strongly related to cancers of the upper digestive tract, with relative risk estimates around or over tenfold elevated among heavy drinkers as compared to non-drinkers for cancers of the oral cavity, pharynx, and oesophagus. The risk pattern with alcohol drinking is clearly different for gastric cancer,64 but some relation is biologically plausible. Alcohol, in fact, could act as a contributory factor by causing chronic irritation of the gastric mucosa. Chronic gastritis, a disease which is thought to predispose to cancer of the stomach, is very common among alcoholics.
Social class and occupation
An inverse socio-economic gradient has been observed in most populations, the rate in lower socio-economic groups being two to three times higher than in more affluent classes.65 An excess risk has been linked to certain occupations such as coal mining, fishing and agriculture. Since occupations are clearly related to socio-economic background, some of the excess risk observed might be attributable to patterns of lifestyle such as dietary habits.
Although epidemiological evidence indicates that environmental factors play a major role in gastric carcinogenesis, a role of genetic factors is suggested by the study of blood groups and determinants of chronic gastritis.66 Individuals of blood group A have been known for decades to show an approximately 20% excess of gastric cancer than those of group O, B or AB. They also show a similar excess of pernicious anaemia. Some data suggest that group A may be particularly associated with the diffuse type of gastric cancer.66 A genetic aetiology has been reported for chronic atrophic gastritis, a precursor of gastric carcinoma.67 The genetic segregation analysis showed Mendelian transmission of a recessive autosomal gene with penetrance dependent on age and mothers chronic atrophic gastritic status. 48% of individuals with affected mothers were affected as compared to only 7% of those who mother did not have chronic atrophic gastritis.
Finally, a familial tendency to stomach cancer has long been suspected and repeatedly confirmed.66,68,69 Better biomarkers are, however, needed to elucidate the mechanisms of familial susceptibility, including genetic and environmental interactions.
Conclusions and perspectives for prevention
Geographical distribution, time trends and the results of aetiological studies on stomach cancer are consistent in indicating a few major determinants of risk: insufficient fresh fruit and vegetable intake, excessive salt intake and gastric infection with HP, in addition, possibly, to genetic factors. Recent population-based survival data show that, even in Western countries, 5-year relative survival rates for stomach cancer are very low (around 20%) and improvement over time is small.70 In the absence of widely available and effective screening programmes, primary prevention by decreasing exposure to the identified risk factors for the disease or by increasing protection against them might be the most effective way of controlling it. Despite clear improvements in the last decades, dietary modifications and, possibly, vitamin supplements remain the most important tool for the prevention of gastric cancer. However, no intervention trial on diet and stomach cancer is in progress and none is planned.
The main reasons for this are the logistical difficulties associated with changing the diet at a population level, especially in developing countries, and the tendency towards changes in the same direction in the placebo group as in the treatment group. This latter tendency occurs mainly in Eastern countries in which a substantial proportion of the population takes vitamin supplements, and in developing countries that are undergoing rapid economic change, such as China, which is influencing the food supply.
Two chemoprevention trials on the precancerous lesions of the stomach are in progress in high-risk areas of Colombia and Venezuela, while a third one is planned in low/intermediate-risk areas in Europe. The main features of these trials have been described in detail elsewhere.71
Control of HP infection, by means of eradication or immunization, is also likely to have great potential in the prevention of stomach cancer. Our ongoing studies in Venezuela suggest that prevention and/or eradication of HP infection by HP vaccines which are under development are more promising than eradication of the bacteria by antibiotics.72
1. Pisani P, Parkin DM, Muñoz N, Ferlay J. Cancer and infection: Estimates of the attributable fraction in 1990. Cancer Epidemiol Biomarkers Prev (in press).
2. Pisani P, Parkin DM, Ferlay J. Estimates of the worldwide mortality from eighteen major cancers in 1985. Implications for prevention and projections of future burden. Int J Cancer 1993;55:891-903.
3. Parkin DM, Muir CS, Whelan SL, Gao Y-T, Ferlay J, Powell J. Cancer Incidence in Five Continents, (IARC Scientific Publications núm. 120). Lyon: International Agency for Research on Cancer, 1992;vol. VI.
4. Howson CP, Hiyama T, Wynder EL. The decline in gastric cancer: Epidemiology of an unplanned triumph. Epidemiol Rev 1986;8:1-27.
5. Muñoz N. Is Helicobacter pylori a cause of gastric cancer? An appraisal of the seroepidemiological evidence. Cancer Epidemiol Biomarkers Prev 1994;3:445-451.
6. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1995. Int J Cancer 1995;54:594-606.
7. La Vecchia C, Lucchini F, Negri E, Boyle P, Levi F. Trends in cancer mortality in the Americas, 1955-1989. Eur J Cancer 1993;29A:431-470.
8. La Vecchia C, Lucchini F, Negri E, Boyle P, Maisonneuve P, Levi F. Trends of cancer mortality in Europe, 1955-1989. I. Digestive sites. Eur J Cancer 1992;28:132-235.
9. Franceschi S, Levi F, La Vecchia C. Epidemiology of gastric cancer in Europe. Eur J Cancer Prev 1994;3suppl 2:5-10.
10. La Vecchia C, Lucchini F, Negri E, Boyle P, Levi F. Trends in cancer mortality, 1955-1989: Asia, Africa and Oceania. Eur J Cancer 1993;29A: 2168-2211.
11. Correa P, Chen VW. Gastric cancer. Cancer surveys, 19/20, Trends in cancer incidence and mortality. Imperial Cancer Research Fund 1994: 55-76.
12. Muñoz N, Asvall J. Time trends of intestinal and diffuse types of gastric cancer in Norway. Int J Cancer 1971;8:144-157.
13. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control 1991;2:325-357.
14. Graham S, Schotz W, Martino P. Alimentary factors in the epidemiology of gastric cancer. Cancer 1972;30:927-938.
15. Haenszel W, Kurihara M, Segi M, Lee RK. Stomach cancer among Japanese in Hawaii. J Natl Cancer Inst 1972;49:969-988.
16. Bjelke E. Case-control study in Norway. Scand J Gastroenterol 1974;9suppl 31:42-48.
17. Bjelke E. Case-control study in Minnesota. Scand J Gastroenterol 1974;9suppl 31:49-53.
18. Modan B, Lubin F, Barell V, Greenberg RA, Modan M, Graham S. The role of starches in the etiology of gastric cancer. Cancer 1974;34: 2087-2092.
19. Haenszel W, Kurihara M, Locke FB, Shimuzu K, Segi M. Stomach cancer in Japan. J Natl Cancer Inst 1972;56:265-274.
20. Correa P, Fontham E, Pickle LW, Chen V, Lin V, Haenszel W. Dietary determinants of gastric cancer in Louisiana inhabitants. J Natl Cancer Inst 1985;75:645-654.
21. Risch HA, Jain M, Choi NW, Fodor JG, Pfeiffer CJ, Howe GR et al. Dietary factors and the incidence of cancer of the stomach. Am J Epidemiol 1985;122:947-959.
22. Tajima K, Tominaga S. Dietary habits and gastro-intestinal cancers: A comparative case-control study of stomach and large intestinal cancers in Nagoya, Japan. Jpn J Cancer Res 1985;76:705-716.
23. Trichopoulos D, Ouranos G, Day NE, Tzonou A, Manousos O, Papadimitriou C et al. Diet and cancer of the stomach: A case-control study in Greece. Int J Cancer 1985;36:291-297.
24. Jedrychowski W, Wahrendorf J, Popiel T, Rachtan J. A case-control study of dietary factors and stomach cancer risk in Poland. Int J Cancer 1986;37:837-842.
25. La Vecchia C, Negri E, Decarli A, DAvanzo B, Franceschi S. A case-control study of diet and gastric cancer in Northern Italy. Int J Cancer 1987;40:484-489.
26. Hu J, Zhang S, Jia E, Wang Q, Liu S, Liu Y et al. Diet and cancer of the stomach: A case-control study in China. Int J Cancer 1988;41:331-335.
27. You M-C, Blot WJ, Chang Y-S, Ershow AG, Yang Z-T, An Q et al. Diet and high risk of stomach cancer in Shandong, China. Cancer Res 1988;48:3518-3523.
28. You WC, Blot WJ, Chang, Y-S, Ershow AG, Yang Z-T, An Q et al. Allium vegetables and the reduced risk of stomach cancer. J Natl Cancer Inst 1989;81:162-164.
29. Buiatti E, Palli D, Decarli A, Amadori D, Avellini C, Bianchi S et al. A case-control study of gastric cancer and diet in Italy. Int J Cancer 1989;44:611-616.
30. Demirer T, Icli F, Uzunalimoglu O, Kucuk O. Diet and stomach cancer incidence. A case-control study in Turkey. Cancer 1990;65:2344-2348.
31. Kato I, Tominaga S, Ito Y, Kobayashi S, Yoshii Y, Masuura A et al. A comparative case-control analysis of stomach cancer and atrophic gastritis. Cancer Res 1990;50:6559-6564.
32. Buiatti E, Palli D, Decarli A, Amadori D, Avellini C, Bianchi S et al. A case-control study of gastric cancer and diet in Italy. II. Association with nutrients. Int J Cancer 1990;45:896-901.
33. González CA, Sanz JM, Marcos G, Pita S, Brullet E, Seigi E et al. Dietary factors and stomach cancer in Spain: A multi-centre case-control study. Int J Cancer 1991;49:513-519.
34. Ramon JM, Serra L, Cerdo C, Oromi J. Dietary factors and gastric cancer risk. A case-control study in Spain. Cancer 1993;71:1731-1735.
35. Boeing H, Frentzel-Beyme R, Berger M, Berndt V, Gores W, Korner M et al. Case-control study on stomach cancer in Germany. Int J Cancer 1991;47:858-864.
36. Hansson LE, Baron J, Nyrén O, Bergström R, Wolk A, Lindgren A et al. Early-life risk indicators of gastric cancer. A population-based case-control study in Sweden. Int J Cancer 1994;57:32-37.
37. La Vecchia C, Negri E, DAvanzo B, Franceschi S. Electric refrigerator use and gastric cancer risk. Br J Cancer 1990;62:136-137.
38. Coggon D, Barker DJP, Cole RB, Nelson M. Stomach cancer and food storage. J Natl Cancer Inst 1989;81:1178-1182.
39. Hansson LE, Nyrén O, Bergström R, Wolk A, Lindgren A, Baron J et al. Diet and risk of gastric cancer. A population-based case-control study in Sweden. Int J Cancer 1993;55:181-189.
40. Tuyns AJ. Salt and gastrointestinal cancer. Nutr Cancer 1988;11: 229-232.
41. Negri E, La Vecchia C, DAvanzo B, Gentile A, Boyle P, Franceschi S. Salt preference and the risk of gastrointestinal cancers. Nutr Cancer 1990;14:227-232.
42. Boeing H, Jedrychowski W, Wahrendorf J, Popiela T, Tobiasz-Adamczyk B, Kulig A. Dietary risk factors in intestinal and diffuse types of stomach cancer: a multicenter case-control study in Poland. Cancer Causes Control 1991;2:227-233.
43. López-Carrillo L, Hernández Avila M, Dubrow R. Chili pepper consumption and gastric cancer in Mexico: A case-control study. Am J Epidemiol 1994;139:264-271.
44. Ramon JP, Serra-Majem L, Cerdo C, Oromi J. Nutrient intake and gastric cancer risk: a case-control study in Spain. Int J Epidemiol 1993;22:983-988.
45. Hansson LE, Nyrén O, Bergström R, Wolk A, Lindgren A, Baron J et al. Nutrients and gastric cancer risk. A population-based case-control study in Sweden. Int J Cancer 1994;57:638-644.
46. La Vecchia C, Ferraroni M, DAvanzo B, Decarli A, Franceschi S. Selected micronutrient intake and the risk of gastric cancer. Cancer Epidemiol Biomarkers Prev 1994;3:393-398.
47. Correa P. Diet modification and gastric cancer prevention. J Natl Cancer Inst Monogr 1992;12:75-78.
48. Sobala GM, Schorah CJ, Shires S, Lynch DA, Gallacher B, Dixon MF et al. Effect of eradication of Helicobacter pylori on gastric juice ascorbic acid concentrations. Gut 1993;34:1038-1041.
49. Muñoz N, Pisani P. Helicobacter pylori and gastric cancer. Eur J Gastroenterol Hepatol 1994;6:1097-1103.
50. Talley NJ, Zinsmeister AR, Weaver A, DiMagno EP, Carpenter HA, Pérez-Pérez GI et al. Gastric adenocarcinoma and Helicobacter pylori infection. J Natl Cancer Inst 1991;83:1734-1739.
51. Sipponen P, Kosunen TU, Valle J, Riihelä M, Seppälä K. Helicobacter pylori infection and chronic gastritis in gastric cancer. J Clin Pathol 1992;45:319-323.
52. Kuipers EJ, Gracía-Casanova N, Peña AS, Pals G, Van Kamp G, Kurz-Pohlmann E et al. Helicobacter pylori serology in patients with gastric carcinoma. Scand J Gastroenterol 1993;28:433-437.
53. Igarashi H, Takahashi S, Ishiyama N, Nakamura K, Masubuchi N, Saito S, et al. Is Helicobacter pylori a causal agent in gastric carcinoma? (Abstract). Ir J Med Sci 1992;161suppl 10:69.
54. Kikuchi S, Wada O, Nakajima T, Nishi T, Kobayashi O, Konishi T et al. The research group on prevention of gastric carcinoma among young adults. Serum anti-Helicobacter pylori antibody and gastric carcinoma among young adults. Cancer 1995:75;2789-2793.
55. Miglio F, Miglioli M, Mazzeo V, Holton J, Mulè P, Menegatti M et al. Prevalence of Helicobacter pylori (HP) in patients with gastric carcinoma (GC). (Abstract). Ir J Med Sci 1992;161suppl 10:70.
56. Estevens J, Fidalgo P, Tendeiro T, Chagas C, Ferra A, Nobre Leitao C et al. Anti-Helicobacter pylori antibodies prevalence and gastric adenocarcinoma in Portugal: report of a case-control study. Eur J Cancer Prev 1993;2:377-380.
57. Lin J-T, Wang J-T, Wu M-S, Lee TK, Chen C-J. Helicobacter pylori infection in a randomly selected population, healthy volunteers, and patients with gastric ulcer and gastric adenocarcinoma. Scand J Gastroenterol 1993;28:1067-1972.
58. Forman D, Newell DG, Fullerton F, Yarnell JWG, Stacey AR, Wald N et al. Association between infection with Helicobacter pylori and risk of gastric cancer: Evidence from a prospective investigation. Br Med J 1991;302:1302-1305.
59. Nomura A, Stemmermann GN, Chyou P-H, Kato I, Pérez-Pérez I, Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med 1991;325:1132-1136.
60. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 1991;325:1127-1131.
61. Webb PM, Ross R, Yuan J-M, Yu M, Newell D, Gao YT et al. Association between Helicobacter pylori infection, lifestyle and the risk of gastric carcinoma in China. Meeting on Helicobacter pylori: Basic Mechanisms to Clinical Cure, Amelia Island; 1993 noviembre; abstract PO 29.
62. Forman D, Webb P, Parsonnet J. HP and gastric cancer. Lancet 1994;343:243-244.
63. Kune GA, Vitetta L. Smoking and tobacco as an aetiologic factor in gastric carcinoma. GI Cancer 1995;I:33-38.
64. Franceschi S, La Vecchia C. Alcohol and the risk of cancers of the stomach and colon-rectum. Dig Dis 1994;12:276-289.
65. Muñoz N. Descriptive epidemiology of stomach cancer. En: Reed PI, Hill MJ, ed. Gastric carcinogenesis. Amsterdam: Excerpta Medica, 1988: 51-69.
66. Langman MJS. Genetic influences upon gastric cancer frequency. En: Reed PI, Hill MJ, ed. Gastric carcinogenesis. Amsterdam: Excerpta Medica, 1988:81-86.
67. Bonney GE, Elston RC, Correa P, Haenszel W, Zavala DE, Zarama G et al. Genetic association of gastric carcinoma: I. Chronic atrophic gastritis. Genet Epidemiol 1986;3:213-224.
68. Palli D, Galli M, Caporaso NE, Cipriani F, Decarli A, Saieva C et al. Family history and risk of stomach cancer in Italy. Cancer Epidemiol Biomarkers Prev 1994;3:15-18.
69. Zhao L, Blot WJ, Liu W-d, Chang Y-s, Zhang J-s, Hu, Y-r et al. Familial predisposition to precancerous gastric lesions in a high-risk area of China. Cancer Epidemiol Biomarkers Prev 1994;3:461-464.
70. National Cancer Institute. Cancer statistics review 1973-1988. NIH Publication no. 91-2789. Bethesda (MD): Department of Health and Human Services, 1991.
71. Muñoz N, Vivas J, Buiatti E, Oliver W. Chemoprevention trial on precancerous lesions of the stomach in Venezuela: summary of study design and baseline data. En: Stewart BW, McGregor D, Kleihues P, ed. Principles of chemoprevention. (IARC Scientific Publications núm. 139). Lyon: International Agency for Research on Cancer, 1996:125-133.
72. Buiatti E, Muñoz N, Vivas J, Cano E, Peraza S, Carillo E et al. Difficulty in eradicating helicobacter pylori in a population at high risk for stomach cancer in Venezuela. Cancer Causes Control 1994;5:249-254.
(1) Unit of Field and Intervention Studies, International Agency for Research on Cancer, Lyon, France.
(2) Servizio di Epidemiologia, Centro di Riferimento Oncologico, Ariano, Italy.
Fecha de recibido: 24 de marzo de 1997. Fecha de aprobado: 6 de junio de 1997.
Reprint requests to: Dra. Nubia Muñoz. Unit of Field and Intervention Studies, International Agency for Research on Cancer. 150, Cours Albert Thomas, F-69372 Lyon cédex 08, France.