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© 2003 American Society for Clinical Oncology
Chemoprevention of Gastric Cancer: Has the Time Come?
From the Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA. Address reprint requests to Pelayo Correa, MD, Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112; e-mail: correa{at}lsuhsc.edu.
ALTHOUGH THE gastric cancer incidence rates have been declining,1,2 recent estimates show that it is the fourth most common cancer and the second most common cause of cancer deaths worldwide.3 Among etiologic factors, high salt intake has been considered an important causative factor.4 In contrast, adequate intake of fresh fruits and vegetables is associated with decreased risk.5,6 Currently, it is accepted that Helicobacter pylori infection plays a prominent causative role.7 The bacterial infection is acquired in childhood and persists for many decades unless treated with antibiotics.8 The clinical outcome of H pylori infection is variable.9 In most subjects, it is asymptomatic. Symptomatic patients usually fall in one of two distinct categories: nonatrophic gastritis and multifocal atrophic gastritis. The former category, mostly localized in the gastric antrum, is associated with hyperacidity and duodenal ulcer, and does not carry an increase in gastric cancer risk.10 In the latter category, the chronic gastritis involves the antrum and the corpus in multiple foci characterized by loss of glands (atrophy), usually leading to their replacement by glands with intestinal phenotype (intestinal metaplasia).
Sequential changes of the gastric mucosa take place before neoplasia develops (Fig 1
Recent focus has been directed to the possibility that "oxidative stress" may be a crucial mechanism in the chain of preneoplastic events.15 H pylori infection leads to gastric mucosa inflammation, with increased expression of inducible nitric oxide synthase16 and nitric oxide. Reactive nitrogen oxides species may damage DNA and induce changes in the epithelial cell cycle.17 Antioxidant enzymes (catalase and superoxide dismutase) may prevent the cellular damage induced by the oxidative stress.16 It thus appears that opposing forces of oxidation and antioxidation interact to either induce or prevent neoplastic transformation. H pylori strains show a high grade of genetic diversity. Two bacterial genes, cagA and vacA are determinants of virulence. cagA gene presence is associated with more severe pro-inflammatory response and to increased oxidative stress in gastric mucosa.18 cagA positive genotypes predominate in gastric cancer patients.19 Genotypic variations in the vacA gene, specifically s1 and m1 genotypes, are also related to higher cancer risk.20
Human polymorphisms associated with increased gastric cancer risk are related to cytokines expressed during the inflammatory process: interleukin-1-ß and its receptor antagonist, interleukin-10, and tumoral necrosis factor- Combining high virulence bacterial genotypes with high-risk (pro-inflammatory) host polymorphisms results in a remarkable increase in cancer risk.20 It becomes, therefore, possible to select subjects from the general population with a very high-risk of developing gastric cancer. Several intervention trials have shown reduction in the progression of gastric preneoplastic lesions administrating anti-H pylori therapy.22,23 A trial in China reported reduction in gastric cancer mortality in subjects taking antioxidant supplements.24 A 6-year trial in Colombia tested the effect of anti-H pylori treatment and dietary supplementation with antioxidants.25 Disease progression/regression was evaluated by comparing pre- and postintervention gastric biopsies. Eradication of the infection and/or dietary supplementation with beta-carotene, ascorbic acid, or both agents independently resulted in significant regression of lesions. No additive effects for any of the combinations were detected. These results support the hypothesis that oxidative stress may represent the final common path of Helicobacter pylori carcinogenesis. The current understanding of the complex interaction between host and H pylori permits the reformulation of prevention strategies in gastric cancer. What is needed at the present time is to develop rapid and inexpensive tests to detect bacterial genotypes and host polymorphisms that increase the risk of cancer. Screening programs will identify individuals at risk, who should receive effective anti-H pylori treatments, and adequate amounts of antioxidants. Endoscopic follow-up will monitor the efficiency of the intervention.
The author indicated no potential conflicts of interest.
This work was supported by grants CA 28804 from the National Cancer Institute, National Institutes of Health, and by the Health Excellence Fund (2000–05)-03 of the Louisiana Board of Regents.
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20. Figueiredo C, Machado JC, Pharoah P, et al: Helicobacter pylori and interleukin 1 genotyping: An opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 94:1680–1687, 2002 21. El Omar EM, Rabkin CS, Gammon MD, et al: Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 124:1193–1201, 2003[CrossRef][Medline] 22. Sung JJ, Lin SR, Ching JY, et al: Atrophy and intestinal metaplasia one year after cure of H. pylori infection: A prospective, randomized study. Gastroenterology 119:7–14, 2000[CrossRef][Medline] 23. Wong BCY, Lam S, Wong W-M, et al: Eradication of Helicobacter pylori infection significantly slows down the progression of precancerous lesions in high risk population: A 5-year prospective randomized study. Gastroenterology 122:A588, 2002 (abstr W215)
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25. Correa P, Fontham ET, Bravo JC, et al: Chemoprevention of gastric dysplasia: Randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. J Natl Cancer Inst 92:1881–1888, 2000 Submitted August 5, 2003; accepted August 5, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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