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Chemoprevention for gastric cancer

https://doi.org/10.1016/j.bpg.2011.09.002Get rights and content

Gastric cancer remains the fourth commonest cancer, and the second commonest cause of cancer death, globally. Chemopreventive strategies to reduce the incidence of gastric cancer are required, particularly as the number of deaths per year is likely to rise for the foreseeable future. There is some evidence that population screening and treatment for Helicobacter pylori in high-risk populations may reduce incidence of gastric cancer. Trials studying the effect of anti-oxidants and selenium are conflicting. A recent meta-analysis demonstrated that aspirin use led to a reduced risk of gastric cancer after 10–20 years of follow-up. There is little convincing evidence that statins have any effect on risk of gastric cancer. More trials on chemoprevention for gastric cancer are therefore urgently required.

Introduction

Gastric cancer is common. According to the latest estimates of the worldwide burden of cancer produced by GLOBOCAN for 2008 [1], the disease is the fourth commonest cancer in terms of incidence, and it remains the second commonest cause of cancer death worldwide, responsible for almost three quarters of a million deaths annually. This is an increase in global mortality from the disease, compared with an estimated two thirds of a million deaths per year in 2002 [2]. Despite a declining incidence in many countries in the developed world, the total number of deaths from gastric cancer may well continue to rise for the foreseeable future [3], due to an increase in the average age of the world’s population.

Unfortunately, many patients are diagnosed at a late stage, meaning that the efficacy of treatment for gastric cancer is unsatisfactory. Almost half of patients’ disease is inoperable at the time of presentation [4], and 5-year survival in this group of individuals is close to zero. Even among those who are suitable for surgical treatment, extensive surgery is often required, and 5-year survival rates are in the order of 20%–30%. [5].

Survival may be improved if the disease were able to be diagnosed at an earlier stage [6]. Population screening for gastric cancer, via upper gastrointestinal (GI) endoscopy, is feasible, but the costs of adopting such a strategy are likely to be prohibitive in many countries, as thousands of asymptomatic people would need to undergo endoscopy in order to detect one case of cancer. Even if only those with upper GI symptoms that may be indicative of an occult gastric cancer, such as dyspepsia, were screened by endoscopy the cost of detecting one malignant lesion has been estimated to be as high as $83,000 [7].

As a result, chemoprevention strategies to reduce the incidence of, and therefore mortality from, gastric cancer may be an attractive alternative to mass screening of the general population, or subgroups of the population who may be at increased risk of gastric cancer. The remainder of this article will focus on the available evidence for any efficacy of a variety of proposed chemopreventive agents for gastric cancer.

Section snippets

Rationale for use of eradication therapy for Helicobacter pylori in the prevention of gastric cancer

In early models of the natural history and evolution of gastric cancer an unknown environmental factor was thought to induce a chronic inflammatory response in the gastric mucosa, causing a superficial gastritis, which eventually progressed to gastric atrophy, and ultimately intestinal metaplasia [8], [9]. Both atrophy and intestinal metaplasia have been proposed as potential precursor lesions of gastric cancer, with atypical changes then taking place within the gastric mucosa, resulting in

Rationale for use of aspirin and non-steroidal anti-inflammatory drugs in the prevention of gastric cancer

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis via the cyclo-oxygenase (COX) enzyme. There are two isoforms of cyclo-oxgenase, COX-1 and COX-2 [46]. COX-2 is induced by cytokines, tumour promoters, and hormones [47], and is involved in the early stages of carcinogenesis in the human colon [48]. Investigators have demonstrated that NSAIDs reduce epithelial proliferation [49], and inhibit tumour growth and tumour-induced angiogenesis. Some NSAIDs

Rationale for use of anti-oxidants and selenium in the prevention of gastric cancer

The declining incidence of gastric cancer in the developed world has been proposed, by some, to be due to an improvement in living conditions and diet in the last 50 years. Epidemiological studies have suggested that a diet high in fresh fruit and vegetables is associated with a reduction in the risk of gastric cancer [65], [66], perhaps due to the large number of anti-oxidants, such as β-carotene and vitamin C, present in these foods. Nutritional surveys of individuals indigenous to

Rationale for use of statins in the prevention of gastric cancer

The statin drugs inhibit cholesterol biosynthesis via inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A. As a result, mevalonate, a precursor of cholesterol, is depleted, leading to a reduction in activity of the Ras protein, which is involved in cell differentiation and proliferation [79]. A significant proportion of tumours in the GI tract demonstrate mutations of the k-Ras oncogene. Statins may have the potential to inhibit activation of Ras, and therefore lead to restoration of normal

Summary

There is clear evidence that H. pylori plays a causal role in the development of gastric cancer, and eradication therapy may yet be shown to reduce the incidence of gastric cancer in infected individuals. However, no country has adopted a screening and treatment strategy. Aspirin and NSAIDs may also have chemopreventive properties, and a meta-analysis of RCTs has demonstrated a reduction in gastric cancer with aspirin use after 10–20 years of follow-up. Selenium and anti-oxidants may also have

Role of the funding source

Not applicable.

Conflict of interest

None.

Acknowledgements

None.

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