Current best practices and rationalistic perspectives in causation-based prevention, early detection and multidisciplinary treatment of breast and gastric cancer

Volume 1- Number 2 -October/December 2002



Chemoprevention Studies in Gastric Cancer: Results - Comments

Epameinondas V. Tsianos, MD and Dimitrios H. Roukos, MD
From the Department of Internal Medicine (EVT) and Surgery (DHR), Ioannina University School of Medicine, 45110 Ioannina, Greece,

Previous studies indicated that screening for and treating H. pylori infection to prevent gastric cancer was potentially cost effective in the prevention of gastric cancer, particularly at high-risk population.[1] The authors strongly recommended cancer prevention trials. However, intervention studies utilizing cancer diagnosis as the primary end point are not feasible because they require following thousands of subjects for several decades. Thus, most available current studies have used intermediate steps in the progression of gastric carcinogenesis as end points which allows inferences based on observations of a smaller number of subjects followed over a shorter time period.

Analysis of chemoprevention studies

Table 1 summarizes the results of chemoprevention studies available which all have used intermediate steps as end points

Table 1. Effect of chemoprevention with anti-H. pylori therapy and/or vitamin supplementation* on the outcome (regression, no change, progression) of persons with gastric atrophy (GA) or intestinal metaplasia (IM) at baseline of studies with more than 100 subjects.


Year of Publication, Ref. Nr.

No. of


Improvement**of GA or IM

Conclusive results

Randomized trials 


2000 [7]






2000 [2]





 Non randomized studies


2001 [3]






2001 [5]





 van der Hulst

1997 [4]





*Chemoprevention interventions include, apart of H. pylori eradication, also dietary supplementation of ascorbic acid and -carotene.

** Histological assessment at the end of follow-up after successful eradication of H. pylori or vitamin supplementation.

The critical analysis reveals that although promising, the findings are inconclusive. In generally a long follow up and a large sample size is needed for a valid assessment but the studies either they are randomized but with a short (1-year only) follow-up[2] or they are nonrandomized with small sample size[3-5] and/or short follow-up.[2,4,5] These weakness and the methological difficulties and disagreement in the interpretation of regression of premalignant lesions among pathologists[6] explain the conflicting and inconclusive results.

The most promising findings have been reported by a recent randomized intervention trial that evaluates the effects of H pylori eradication and dietary supplementation with vitamin C or b-carotene.[7]This was carried out in a high incidence gastric cancer region (in Colombia) on 852 infected subjects who had atrophic gastritis and/or intestinal metaplasia at entry and who were biopsied at 36 and 72 months following intervention treatment. Correa and colleagues concluded that elimination of H pylori produced "a marked and statistically significant increase in the rate of regression of the precursor lesions". But similar relative risks were obtained for the other treatments alone and, as it was pointed out in the related editorial, it is disturbing that anti-H pylori treatment was effective when given alone but conveyed no (added) benefit when given with vitamin C or b-carotene.[8] Although the results are promising, Blot[8] concluded that in view of the lack of consistency, the findings should be interpreted with caution. Further caution about the protective effect of b-carotene is suggested by the end results of a study[9] which did not confirm earlier findings[10] for an inverse association between serum b-carotene levels and the risk of developing gastric cancer. Furthermore, disappointing were the results with b-carotene previously reported for lung cancer.[11]

Promising findings for gastric cancer prevention curing H. pylori infection provides another most recent Japanese nonrandomized study.[3] However, although none among 253 infected patients developed gastric cancer 8 years after H. pylori eradication, the number of subjects at really high-risk was very small (only 12 patients with corpus predominant gastritis and 15 with pangastritis), to drawn conclusions..

Can atrophy and intestinal metaplasia be reversible lesions once they have been established?

That remains to be proved. Dixon[6] supports the view that the hope that intervention by elimination of H pylori will by itself lead to substantial reversal of atrophy and intestinal metaplasia is an unrealistic expectation, because certain forms of atrophy and intestinal metaplasia have passed to a "point of no return" and reversal becomes impossible. It is expected that the ongoing intervention trials will determine whether chemoprevention strategy on persons with established pre-malignant lesions is effective.

Until then, logically, interventions targeting at earlier, more reversible stages seem to offer higher protective potential. Curing H. pylori infection -the causative factor for the initiation of carcinogenic process- before establishment of precancerous lesions, it could eliminate the risk of H. pylori-attributable gastric cancer. Because infection occurs during childhood -50% prevalence at age 2 years and 90% at age 9 years12 and young age at H. pylori infection has been suggested as a risk factor for cancer,[13] interventions in childhood present the most promising effective prevention. Because little is known about the time needed for the progression from infection to atrophy or intestinal metaplasia development, the younger the age at H. pylori eradication the higher is the probability for more effective gastric cancer prevention.

However, conduction of clinical trials to confirm this view has two major limitations. First, the screening endoscopy needed for the assessment of premalignant lesions is a complicated, invasive and rather unrealistic procedure in asymptomatic children. Second, a simple test-and-treat of H. pylori infection-population study without endoscopy, requires a very long-term follow-up since the median age at gastric cancer diagnosis is over 60 years.

Therefore, vaccines are an attractive option[14,15] especially when we take into account that antimicrobial therapy currently used as the method of choice for curing H. pylori infection, presents several disadvantages including complex dosing, inconsistent efficiency, development of antibiotic resistance, costs and various side effects that compromise widespread use. Commercial development of products for clinical trial is underway, but many important issues, such as lack of a suitable mucosal adjuvant, and prevention of potential side effects, such as postimmunization gastritis, need to be resolved.[14]

Subsite-specific risk of gastric cancer

Unlike previous works [16], most recent findings [3,17,18] indicate a revised substantially higher risk of gastric cancer associated with H. pylori infection. The magnitude of this risk varies with the tumor site and histological type according to Lauren classification [19,20]. Although credible evidence indicates an excess risk for non-cardia, intestinal-or diffuse-type cancer [21,3,17,22,23], the effect of H. pylori infection on the development of cardia and esophageal cancer is highly controversial. In a recent combined analysis of 12 case-controlled prospective studies there was no relationship between H. pylori and risk of cardia cancer [18], other studies suggested an increased risk [22,23], whereas others suggest a protective effect against development of cardia and esophageal cancer [24]. Although this protective effect of H. pylori is less possible [18,25], it needs further prospective evaluation.

Prognosis of gastric cancer remains even currently poor with overall 5-year survival rate of only 22% in the USA.[27] In early-stages cancer or localized disease with appropriate surgical treatments excellent survival rates have been reported not only from Japan[28] but also now from the Western world.[29] Current evidence urgently suggests the need for a change of current management of gastric cancer in the western societies. Now, is an exciting time to move on from treatment of advanced stages-cancer to early detection and prevention of gastric cancer.[30]

Given the recent major advances in our understanding of the biology of gastric carcinogenesis there is promise that an era of truly rational chemoprevention has arrived.[31] At the present time a science-based recommendation for chemoprevention by curing H. pylori infection cannot be made. However, it is rational that patients with atrophic gastritis or intestinal metaplasia need surveillance and an anti-H. pylori therapy. Since these pre-malignant lesions usually produce no symptoms and their diagnosis requires endoscopic biopsies, the major challenge today is how to identify these persons for endoscopic evaluation.

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30. Roukos DH. Time to move on from current strategy in gastric cancer? Gastric Breast Cancer 2002; 1(3): 51-52.
31. Roukos DH, Tsianos EV. Background of chemoprevention in gastric cancer: four reasons towards optimism. Gastric Breast Cancer 2002; 1(3): 53-55.

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last update: 22 May 2003