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Epidemiology of gastric cancer

Martyn Plummer, Silvia Franceschi and Nubia Muñoz

Unit of Field and Intervention Studies International Agency for Research on Cancer 150, Cours Albert Thomas F-69372 Lyon cédex 08 France

Keywords: Gastric cancer, epidemiology, prevention

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The most recent estimates of global cancer incidence indicate that stomach cancer was the second most frequent cancer in the world (after lung cancer) in 1990, with about 800,000 new cases diagnosed every year (Parkin, Pisani and Ferlay 1999). Steady declines in gastric cancer incidence rates have been observed everywhere in the last few decades. The exact causes of the decline are not well understood, but may include improvements in diet, food storage and the decline of Helicobacter pylori infection. Dietary modifications remain one of the most important tools for the prevention of gastric cancer. Control of H. pylori infection, by indirect means like improving the general

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sanitary conditions or by direct intervention such as eradication or immunization, is also likely to offer great potential for the prevention of this malignancy.

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According to the most recent available estimates, gastric cancer is the second most common cancer worldwide, following lung cancer (Parkin et al, 1999). Survival from gastric cancer is poor. In the USA, the five-year survival rate is less than 20% and has improved little in the last few decades (Kosary et al, 1995). The poor survival from gastric cancer is reflected in the high mortality: incidence ratio, which is 70-90% in most countries, except Japan where it is 40%.

In this review, the geographical distribution and time trends of gastric cancer will be examined. With respect to the aetiology of gastric cancer, priority will be given to the findings concerning the gastric bacterium Helicobacter pylori. The perspectives for primary prevention gastric cancer will also be discussed.

Two subclassifications of gastric carcinoma have been proposed with possible implications for aetiology. The histological classification of Jarvi and Laurén divides cancers into “intestinal” and “diffuse” types. These are discussed by Tahara (this volume). Gastric cancers may also be classified by subsite within the stomach: the most important distinction being between cardia (the proximal part of the stomach) and noncardia. These two subclassifications will be mentioned where appropriate.

Descriptive epidemiology

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Geographical variation

Gastric cancer incidence shows wide geographical varation. Figure 1 shows a map of the incidence gastric cancer in males, standardized to the world population (Globocan 2000). Incidence rates in females follow a similar pattern, but are about 50% lower. The high risk areas are in Japan, China, Eastern Europe and certain countries in Latin America. Low risk populations are seen among whites in North America, India, the Filipines, most countries in Africa, some western European countries and Australia. There is a 15-20-fold variation in risk between the highest and the lowest risk populations. Substantial variations in gastric cancer incidence may also be found within countries, a good example being Italy where, for instance, male incidence rates range from 36.3/100,000 in Florence to 13.2/100,000 in Ragusa (Parkin et al 1997).

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Time trends

Gastric cancer incidence rates have been declining world wide for several decades (Coleman et al, 1993). Figure 2 shows gastric cancer mortality rates for a selection of countries between 1960 and 1998, using data from the WHO mortality database. The rates are plotted on a log scale to show that the rate of decline is very similar (about 3%) for both high- and low-risk countries. The precise reasons for this decline are unknown, and it has consequently been described as an “unplanned triumph” (Howson, Hiyama and Wynder, 1986).

When cancers of the gastric cardia, the proximal part of the stomach, are analyzed separately, the incidence rates show a strong increase in some industrialized

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countries (Devesa, Blot & Fraumeni, 1998). This may be partly due to changes in diagnostic criteria (Ekström et al 1999), but in the USA at least, it appears to be a genuine increase (Devesa & Fraumeni 1999). The distinct time trend shown by cardia cancer is an indication that it has a different aetiology. There has been a concomitant rise in the incidence of oesophageal cancer, which suggests that gastric cardia shares the same risk factors, namely obesity, gastric reflux and subsequent Barrett's oesophagus.

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Risk factors for gastric cancer

The focus of this review is on H. pylori, but in this section we briefly review other risk factors, referring to more detailed review articles when appropriate.

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A panel of experts recently reviewed the available laboratory and epidemiological evidence evidence on diet and gastric cancer as part of a general review of nutrition and cancer (WCRF 1997). The panel divided levels of evidence into "convincing", "probable", "possible" and "inadequate". The hypotheses that they considered convincing or probable were as follows:  There was convincing evidence that a diet high in vegetables and fruits decreases risk. The most likely anti-carcinogenic compounds contained in vegetables and fruits are anti-oxidant vitamins (e.g. vitamin C, beta-carotene and vitamin E).   Evidence that vitamin C reduces risk was considered probable. Evidence that a diet high in salt intake increases risk was considered probable.

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There was convincing evidence that use of refrigeration to preserve food decreases risk. This effect may be mediated either through an increased intake of fresh fruit and vegetables or a decreased reliance on salted food.

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Trédaniel et al (1997) conducted a review and meta-analysis of the 40 studies that provide a quantitative estimate of the association between tobacco smoking and gastric cancer risk. The results suggest a relative risk of 1.6 in smokers compared to nonsmokers.

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Reviews of alcohol and gastric cancer have consistently rejected an association (IARC 1988; Franceschi and La Vecchia 1994; WCRF 1997). However, a specific association with cancers of the gastric cardia has been suggested by studies in the USA (WuWilliams et al 1990), Italy (Palli et al 1992) and Spain (González et al 1994).

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Socio-economic status

A strong association with socio-economic status (SES) has been frequently observed, with individuals of lower SES having higher risk. SES is, of course, not a causal factor, but is a surrogate for many other factors including sanitary conditions and nutrition.

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Genetic susceptibility

The descriptive epidemiology of gastric cancer strongly indicates that the risk is dominated by environmental causes. There may, however, still be a role for genetic factors. Individuals with blood group A have been known for decades to have an approximately 20% excess of gastric cancer compared with other blood groups (Langman 1988). Germline mutations in a gene encoding the cell adhesion protein Ecadherin (CDH1) have been found in familial diffuse gastric cancer (Guilford et al 1998). A genetic predisposition to precancerous lesions has also been reported (Bonney et al 1986; Zhao et al 1994). Familial clustering of gastric cancer has been reported in a number of case control studies. However, many of these studies rely on unconfirmed reports of gastric cancer in family members, and are therefore potentially subject to recall bias. Two large population-based surveys of familial risk in gastric cancer have been conducted which are free from this source of bias. The first, conducted in Utah (Goldgar et al, 1994) included 800 gastric cancers and gave an estimated familial relative risk (i.e. relative risk given cancer in a first degree relative) of 2.09 (95%CI 0.99-3.58). The second study, conducted in Sweden (Hemminki et al, 2001) included 34 000 gastric cancers and gave an estimated familial relative risk of 1.31 (95%CI 0.97-1.70). Based on this estimate, the population attributable risk due to gastric cancer in Sweden is 0.45%.

Helicobacter pylori

H. pylori is a spiral gram-negative bacterium that colonizes the stomach. It is one of the most common infections in humans with an estimated prevalence of 50% worldwide and

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90% in developing countries. In high-prevalence populations, infection is rapidly acquired in childhood and persists lifelong. Prevalence of H. pylori infection is declining in many developed countries. It is believed that this is a cohort effect, with the prevalence of infection declining in successive birth cohorts. In 1994, an expert working group convened by IARC classified H. pylori as carcinogenic to humans (IARC 1994). This classification was made entirely on the basis of epidemiological evidence. At the time, the evidence from experimental animals was considered inadequate. Since then, the mongolian gerbil has been established as an animal model in which infection with H. pylori alone causes gastric cancer (see Fujioka, Honda and Tokieda (2000) for a review). Further epidemiological studies have also been conducted which clarify the relationship between H. pylori and gastric cancer in humans.

Epidemiological studies can be divided into three categories: ecological studies, retrospective studies and prospective studies. We consider each of these in turn.

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Ecological studies

The limitations of ecological studies are well known. Nevertheless, large variations in gastric cancer risk between different populations have prompted a number of epidemiological studies using aggregate data. Most of these studies have included a small number of areas (Correa et al, 1990; Sierra et al, 1992; Palli et al 1993; Fukao et al, 1993; Tsugane et al, 1993; Lin et al 1995; Perez-Perez et al 1997; Chen et al 1997) or ethnic groups (Fraser et al 1996; Fock et al 1997). With between 2 and 8 groups for

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comparison, these studies are highly susceptible to problems of confounding. Not surprisingly, they have produced equivocal results. Five of the above studies found a significant association between H. pylori and gastric cancer and five did not.

Two large ecological studies have been conducted on H. pylori and gastric cancer. One study of 46 counties in rural China found a correlation of 0.4 between between gastric cancer mortality and H. pylori prevalence. No significant correlation was observed between H. pylori and any other cancer (Forman et al 1990). A follow-up analysis showed that this association was no longer statistically significant (p > 0.10) when serum levels of selected micronutrients were controlled for (Kneller et al 1992). The EUROGAST study group examined 17 populations in 13 countries (EUROGAST study group, 1994). They found significant correlation between H. pylori seropositivity and both cancer incidence (p=0.0002) and mortality (p=0.0002), concluded that a population with 100% prevalence of H. pylori prevalence would have a six-fold increase in gastric cancer risk compared with a population free of H. pylori.

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The “African enigma”

Ecological studies are usually regarded as the lowest level of epidemiological evidence, due to the inability to control for confounding factors. Despite this, discussion of the causal role of H. pylori has been dominated by the so-called “African Enigma” – the observation by Holcombe (1992) that some populations in Africa have high prevalence of H. pylori but low prevalence of diseases associated with H. pylori infection, including gastric cancer. Similar observations are often made about India. The term “African enigma” is unfortunate because it suggests that the African continent is homogeneous.

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However, data from selected cancer registries in Africa shows a four-fold variation in cancer risk. There is also a two-fold variation in cancer risk in India (Parkin et a 1997).

The existence of populations with high H. pylori prevalence but low gastric cancer incidence does not rule out H. pylori as a causal factor. Gastric cancer is a multifactorial disease, and the presence or absence of other risk factors may influence the importance of H. pylori. One hypothesis that has been recently advanced is that progression of helicobacter-induced gastritis and gastric atrophy may be mediated by concurrent parasitic infection (Fox et al 2000). This hypothesis, which comes from an animal model, has generated considerable interest (Feldmeier and Krantz 2000, Gordon 2000, MacDonald 2001). There is currently little evidence from human studies, although one early report (Mitchell et al 2000) supports the hypothesis.

Populations with high prevalence and low gastric cancer risk are a rich source of hypotheses about possible cofactors for H. pylori infection, but some care must be taken over the quality of the prevalence and incidence data. Wabinga (2002) provides a comprehensive review of gastric cancer in Africa, and highlights some of the problems associated with correlating H. pylori prevalence with gastric cancer rates. Firstly, the burden and heterogeneity of gastric cancer in Africa is difficult to assess because its diagnosis requires access to endoscopic facilities that are not always available. Secondly, the prevalence of H. pylori infection is much lower in individuals with gastritis than in those with normal gastric mucosa. The prevalence of gastritis is, however, unknown. These observations suggest that one should be cautious before making generalizations about gastric cancer in Africa.

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Retrospective studies

Retrospective studies of H. pylori and gastric cancer are summarized in figure 3. There is considerable heterogeneity between studies, which makes the results difficult to interpret. Various hypotheses have been put forward to explain the diverse results.

Huang et al (1998) conducted a formal meta-analysis of 14 of these studies, along with 5 cohort studies (Other studies listed here did not meet their inclusion criteria). Their summary odds ratio for gastric cancer in H. pylori infected subjects was 1.92 (95%CI 1.32-2.78). They also examined sources of heterogeneity between studies, concluding that differences in the selection of controls, age of the subjects, and the site and stage of gastric cancer were responsible for the heterogeneity.

Another possible source of heterogeneity is error in the assay used to diagnose H. pylori infection. Based on a comparative study in Thailand, Bodhidatta et al (1994) suggested that the sensitivity of an ELISA may be improved by using antigens derived from local strains of H. pylori instead of using strains from industrialized countries. However, this finding was not reproduced in a study in China, which showed equally high sensitivity for ELISAs based on a pool of Chinese strains and a pool of US strains (Groves et al 1997). A study in Venezuela compared four different ELISAs, including one based on local strains (Plummer et al 2000). This study found good agreement between the different assays when the results were expressed in terms of antibody titres (Spearman correlation coefficient 0.7-0.8). The main reason for disagreement between assays was the choice of cutoff point for determining positivity.

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This observation raises the more general issue of whether classifying subjects as “positive” and “negative” is the best approach in epidemiological studies. An alternative approach is to look at antibody levels. This approach has been successfully used to correlate Epstein Barr virus (EBV) with Hodgkins disease (IARC 1998) and Burkitt’s lymphoma (Geser et al, 1982) in populations with a high prevalence of EBV.

A major methodological problem with retrospective studies of H. pylori is that the disease itself may alter the measurement of exposure. In particular, extensive atropy, which is a precursor of gastric cancer, may lead to a reduced burden of infection in the stomach and consequently lower antibody levels (see Plummer et al (2000) for a review). Measurements of H. pylori taken at the time of cancer incidence, or even a few years previously, may not therefore be a valid measure of the original exposure to H. pylori.

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Prospective studies

Twelve cohort studies on H. pylori and gastric cancer have been published (Aromaa et al, 1991; Forman et al 1991; Parsonnet et al 1991; Nomura et al 1991; Lin et al 1993; Webb et al1996; Siman et al 1997; Watanabe et al 1997; Hansen et al 1999; Yamagata et al 2000; Limburg 2001; Uemura et al 2001). All but two of these were analysed using a nested case-control design, and the results are summarized in figure 4. In these studies H. pylori antibody levels were measured in sera collected years before the cancer diagnosis. This reduces (and for long periods of follow up eliminates) any effect of the carcinogenic process on H. pylori load in the gastric mucosa, and thus, serum antibody levels. All of the studies show an increased risk of gastric cancer for H. pylori

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infection, except for one Japanese study, where there was no association for females (Yamagata et al 2000).

A combined analysis of 10 of these studies and two additional unpublished studies has been undertaken using the original data (Helicobacter and Cancer Collaborative Group 2001). The combined results give an odds ratio of 3.0 (95%CI 2.3-3.8) for non-cardia cancers which was increased (OR=5.9, 95%CI 3.4-10.3) when the when the blood sample for H. pylori serology was collected more than 10 years before diagnosis. H. pylori was not associated with an increased risk of gastric cardia cancer (OR=1.0, 95%CI 0.7-1.4). Seven of the 12 studies included in the meta-analysis included data on histological type. Among these studies, the association did with H. pylori did not differ by histological type (p=0.5).

This combined analysis represents the strongest epidemiological evidence for the association between H. pylori and gastric cancer. It is interesting to note that the relative risk estimate of 5.9 is almost identical to the prediction of the EUROGAST study (EUROGAST study group, 1994) although there is considerable uncertainty in the estimate.

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Prevention of gastric cancer

The two major changes that could be made at a population level to reduce gastric cancer incidence are improvement in diet and reduction in the prevalence of H. pylori. These changes are already taking place in many populations, and may explain the observed decline in gastric cancer incidence. Active intervention in a population

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requires proof that the intervention is effective, and this can only come from randomized trials.

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Trials of vitamin supplementation

There have been no interventions trial on diet using cancer as an endpoint. However, several trials have been conducted using supplementation with selected vitamins as an intervention. Vitamin supplementation can simulate improved diet in a population with low vitamin intake levels, assuming that the protective micronutrients in a healthy diet have been correctly identified.

An intervention trial was conducted in the general adult population of Linxian, China, an area with high incidence of esophageal and gastric cardia cancer. Four different interventions were tested (A) retinol and zinc; (B) riboflavin and niacin; (C) vitamin C and molybdenum; and (D) beta-carotene, vitamin E, and selenium. During the 5.25-year follow-up period a significant reduction in gastric cancer mortality (RR = 0.79; 95% CI = 0.64-0.99) was observed in those receiving treatment (D). Reductions in total mortality and total cancer mortality were also observed in this group (Blot et al, 1993).

Gastric cancer is preceded by a sequence of changes to the gastric mucosa that may be identified histologically (Correa, this volume). Several trials have used changes in precancerous lesions as an endpoint. In the Linxian trial, an endoscopic survey was conducted at the end of follow-up to compare the prevalence of gastric dysplasia and cancer between the different treatment groups. No significant differences were observed (Wang et al 1994). The ATBC study was a trial of alpha-tocopherol and/or beta-

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carotene in subjects at high risk of lung cancer. The main endpoint of the ATBC study was lung cancer mortality, but an endoscopic survey was also conducted at the end of the 5-8 year follow up period in a subsample. No diffference in the prevalence of gastric dysplasia was found between the different treatment groups (Varis et al, 1998). A chemoprevention trial on precancerous lesions of the stomach has been conducted in Colombia (Correa et al, 2000). The trial compared treatment with ascorbic acid, betacarotene and anti-H. pylori treatment in a factorial design. Unlike the trials described above, the Colombian trial was specifically designed to look at precancerous lesions and included a gastroscopy at the beginning and the end of the 6 year follow-up period. All 7 groups receiving treatment showed higher regression of precancerous lesions (19-29% regression) than the control group (7% regression).

Other chemoprevention trials are underway or being completed in Venezuela (Muñoz et al 1996), the Shandong province of China (Gail et al 1998) and Europe (Biasco and Paganelli 1999).

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Trials of H. pylori eradication

Several treatment regimens have been used to eradicate H. pylori infection, but triple therapy including bismuth salts, amoxicillin and clarithromycin is currently the regimen of choice.

The only randomized trial to examine the effect of H. pylori eradication on precancerous lesions of the stomach is the chemoprevention trial in Colombia (Correa et al, 2000) described above. This showed a protective effect of H. pylori eradication which, like the

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anti-oxidant vitamin treatment, increased the rate of regression of precancerous lesions. However, a combination of H. pylori eradication and vitamin supplementation did not show an increased benefit over either intervention given separately. One possible interpretation of this finding is that the anti-oxidant treatment blocks the effect of H. pylori. However, the require confirmation from other trials that are currently under way.

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Issues with large scale H. pylori eradication

Moving from the results of randomized trials to population intervention requires consideration of several issues. The first is effectiveness of anti-H. pylori treatment in eradicating H. pylori. Difficulties in eradicating H. pylori have been reported in Venezuela (Buiatti et al 1994) and Costa Rica (Sierra et al 1998), two countries with high risk of gastric cancer, although these studies used an H. pylori therapy that may be considered suboptimal. In the Colombian intervention trial, the prevalence of H. pylori infection was reduced from 96% to 26% over six years using two episodes of anti-H. pylori treatment (Correa et al 2000). A trial of H. pylori eradication in Iran showed eradication rate of only 24% from a one week course of triple therapy. The rate was higher (36%) when treatment was given for two weeks and was higher still (63%) when an H2-receptor antagonist was administered at the same time (Kaviani et al 2001). These contrasting results highlight the need to find an effective treatment in the local population before widespread use of anti-H. pylori therapy can be considered.

H. pylori eradication using triple therapy may not be effective in the long term if subjects are rapidly reinfected. This possibility has led to an interest in vaccines against H. pylori which could offer lasting protection. Vaccines against H. pylori are currently under

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development and will soon be tested in humans. The current status of H. pylori vaccine development is reviewed by Alsahli, Farrell & Michetti P (2001).

A theoretical problem with H. pylori eradication is the possibility of harmful side effects. It has been suggested that, on account of its pH-raising action, H. pylori is negatively associated with gastric reflux, Barrett’s oesophagus and cancer of the gastric cardia and oesophagus, with the implication that eradication of H. pylori might increase the risk of these diseases (Blaser, 1998; Chow et al 1998). This issue clearly has cost/benefit implications for eradication of H. pylori by any method.

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Geographical distribution and time trends suggest that the risk of gastric cancer is strongly determined by environmental factors. Aetiological studies point to infection with H. pylori and a poor diet as the main determinants of gastric cancer risk. Despite the long term decline of gastric cancer incidence in many populations there is plenty of scope for active intervention to reduce the risk of gastric cancer, notably by eradication of H. pylori.

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Figure legends

Figure 1. Incidence of stomach cancer in males. Age standardized rate (world population)

Figure 2. Mortality from gastric cancer 1968-1998

1 2 3 4 5 Figure 4. Prospective studies of gastric cancer Figure 3. Case-control studies of gastric cancer

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