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Helicobacter pylori: the gastric cancer problem

Gastric cancer is the second most common fatal malignancy in the world and is the cause of more than 750 000 deaths annually. In 1990, it was the fourteenth most frequent cause of death globally and, despite a general decline in the incidence, projections indicate that the annual number of new cases will increase significantly in the developing world during the next few decades as a result of adult population growth. Most gastric cancer is diagnosed at an advanced stage and survival is uniformly poor, usually no more than 15% at five years. There is now considerable evidence in support of an aetiological association between Helicobacter pylori infection and gastric cancer. Infection causes gastritis and the natural history of H pylori associated gastritis over a period of decades is one of increasing degenerative changes and evolution towards atrophy, metaplasia and dysplasia. One prospective study has established that there is a significantly increased risk, in the order of ninefold, of developing precancerous gastric conditions when H pylori positive patients were compared with those without infection. In addition, most of the descriptive epidemiology of gastric cancer parallels that for H pylori infection, especially the strong association with poor socioeconomic conditions. Studies carried out within the Peoples Republic of China and internationally have shown a significant geographical correlation between gastric cancer mortality rates and the prevalence of H pylori infection. The most persuasive evidence indicative of an association is that from prospective serological studies of gastric cancer. These consistently show that there is roughly a threefold increased risk of cancer in H pylori positive subjects and this can be translated into a worldwide burden of at least 300 000 new cases of gastric cancer annually attributable to the infection. Very few established causes of cancer have been associated with an attributable risk of this magnitude. Understanding of the mechanistic basis of the H pylori–cancer relation is also advancing rapidly and most evidence suggests that it is the chronic nature of the host inflammatory response and upregulation of various metabolites, such as reactive oxygen and nitric oxide, that are critical to the carcinogenic process. There is much that remains to be established about the relation, in particular the reasons why certain populations (notably in Africa) or patient groups (such as those with duodenal ulcers) have relatively low gastric cancer rates despite high levels of infection. The interaction between H pylori infection and host factors in the development of gastric cancer also requires further investigation. Such host factors may consist of genetic predisposition (for example, HLA haplotype) or dietary diVerences (for example, vitamin C intake). Researchers are also endeavouring to discover whether there are specific H pylori strains associated with cancer. Most studies to date have looked at CagA status and several have reported a stronger risk of both gastric atrophy and intestinal-type gastric cancer in subjects infected with CagA positive strains of H pylori. These data do not, however, show that subjects infected with CagA negative strains have no excess risk. In particular, they seem to be at an equivalent increased risk of diVuse-type gastric cancer as those with CagA positive infections. Thus, at the current time, no strains of H pylori have been identified that are unambiguously cancer related. A further important question is the extent to which H pylori induced precancerous changes will regress or be prevented from progressing after eradication. There is very little peerreviewed literature on this subject and, although a number of preliminary reports have been published in abstract form, none of these studies are randomised and the results are remarkably inconsistent. The most optimistic data, from a Japanese study, indicate that patients with early gastric cancers which have been resected endoscopically show significantly less recurrence after H pylori eradication. Without quantitative information addressing this question, it will be impossible to estimate the benefit in terms of cancer prevention that would occur from testing asymptomatic individuals for infection and treating those who are positive. It has, however, been shown in modelling studies that even with limited eYcacy (preventing 30% of gastric cancers in those treated), a test and treat strategy would be economically cost-eVective. As the background cancer rate increases, so does the relative cost-eVectiveness of such a strategy, although populations with the highest rates are frequently from developing countries where gastric cancer is one disease amongst many competing for limited health care resources and where high rates of adult reinfection may be a problem. Perhaps the optimal populations for employment of such a strategy, at least initially, are in countries such as Japan with high cancer rates and which are relatively aZuent. There are those who would advocate that a policy of screening for H pylori within the general population and treating those found to be positive is now an appropriate strategy for gastric cancer prevention on the basis that it must be of some value and that there would be few adverse side eVects. There are, however, several concerns about such a policy that can only be Gut 1998;43 (suppl 1):S33–S34 S33