Description of the Evidence
Incidence and mortality
The age-adjusted incidence rate for gastric cancer in the United States for the years 2004 to 2008 was 7.7 persons per 100,000 population. Incidence among men is twice as high as among women. Mortality rates for gastric cancer have been declining worldwide in recent decades, most prominently in the United States.[2,3] Mortality rates for white males in the United States were approximately 40 deaths per 100,000 population in 1930, compared with 4.6 deaths per 100,000 population for the years 2003 to 2007. The death rate from gastric cancer for black males was 2.3 times higher than for whites for the years 2003 to 2007. The annual number of new cases seems to be steady in recent years; in 2015, it is estimated that 24,590 Americans will be diagnosed with gastric cancer and 10,720 persons will die of it. Gastric cancer is the fourth most common cancer in the world.[6,7] Worldwide, the estimated number of cases per year in 2008 was 988,000, and the estimated number of deaths was 736,000. Age-standardized annual incidence rates vary widely across the world: from 3.9 to 42.4 cases per 100,000 in men, and from 2.2 to 18.3 cases per 100,000 in women. More than 70% of cases occur in developing countries, and 50% of the cases occur in Eastern Asia.
Most cancers in the United States are advanced at diagnosis, which is reflected in an overall 5-year survival rate of 27.1% from 2001 to 2007. Carcinomas localized to the mucosa or submucosa (“early” cancers) have a much better prognosis; the 5-year survival rate is more than 95% in Japan and more than 65% in the United States. In high-risk populations, secondary prevention measures linked to screening programs have been instituted. In Japan, endoscopic resection techniques have been refined and could possibly be responsible for drastic reductions in mortality rates in the presence of steady incidence rates. This hypothesis, however, has not been tested in clinical trials. (Refer to the PDQ summary on Stomach (Gastric) Cancer Screening for more information.)
Understanding the pathogenesis of gastric cancer has advanced over the years. A lengthy precancerous process has been identified in which the gastric mucosa is slowly transformed from normal to chronic gastritis, to multifocal atrophy, to intestinal metaplasia of various degrees, to dysplasia, and then to invasive carcinoma. The process is apparently driven by forces acting on the gastric epithelium for many years, such as excessive dietary salt and most prominently, infection with H. pylori.
Interventions for Reduction of Stomach (Gastric) Cancer Risk
A systematic review and meta-analysis showed a 60% increase in gastric cancer in male smokers and a 20% increase in gastric cancer in female smokers compared with nonsmokers. A systematic review of studies addressing the relationship between cigarette smoking and gastric cancer to estimate the magnitude of the association for different levels of exposure to cancer provides solid evidence to classify smoking as the most important behavioral risk factor for gastric cancer.[10-12] Compared with persistent smokers, the risk of stomach cancer decreases among former smokers with time since cessation. The pattern that emerges from these observations makes it reasonable to infer that cigarette smoking prevention or cessation would result in a decreased risk of gastric cancer.
H. pylori infection eradication
H. pylori infection is an accepted cause of gastric adenocarcinoma.[13,14] Questions remain concerning the natural history of H. pylori infection; the mechanism of transmission and the rates of reinfection or recrudescence for different populations are unknown.[15,16] A small randomized trial of antibiotic eradication in 140 H. pylori-infected people suggests the possibility of transmission among close family members. In 70 participants, only the participant received eradication therapy; in the other 70 participants, all H. pylori-infected family members living with the primary participant also received the eradication therapy. Nine months after the therapy, the positivity rates in the index participants in each group were 38.6% and 7.1%, respectively (odds ratio = 8.61; 95% confidence interval [CI], 2.91–22.84), suggesting the possibility of transmission from untreated, infected family members.
Since about half of the world population is infected with H. pylori, antibacterial treatment for all people who are chronically infected may be impractical and could trigger antimicrobial resistance. Vaccination against H. pylori has been shown effective in experimental animal models, but thus far, such efficacy has not been studied in humans.
A randomized controlled trial (RCT) showed that short-term treatment with amoxicillin and omeprazole reduced the incidence of gastric cancer by 39% during a period of 15 years following randomization, with similar but not statistically significant reductions for gastric cancer mortality.
A meta-analysis of seven randomized studies, all conducted in areas with high-risk gastric cancer populations, and all but one study conducted in Asia, suggests that treatment of H. pylori may reduce gastric cancer risk (from 1.7% to 1.1%; relative risk [RR] = 0.65; 95% CI, 0.43–0.98). Only two studies assessed gastric cancer incidence as the primary study outcome, and two different studies were double blinded. It is unclear how generalizable the results may be to the North American population. It would be useful to know which subgroups of persons with H. pylori are particularly likely to develop cancer in order to decide which subgroups might be appropriate to consider for targeted screening and eradication. However, studies in H. pylori-infected subjects have been underpowered for determining progression to invasive cancer. Even studies of associations between baseline characteristics (such as age, alcohol use, and well water used as the source of drinking water in rural China) and histologic progression of intestinal metaplasia to more severe grades of metaplasia show associations of insufficient magnitude to be useful in clinical decision making.
Interventions With Inadequate Evidence as to Whether They Reduce the Risk of Stomach (Gastric) Cancer or Evidence of No Effect
Excessive salt intake has been identified as a possible risk factor for gastric cancer in correlation and case-control studies.[21,22] The daily intake of salt has decreased drastically in most western countries and in Japan, in part due to public health campaigns to reduce hypertensive diseases. This may be at least partially responsible for declines in gastric cancer rates. There is a consistent association between high salt intake and the risk of gastric cancer.
Epidemiologic evidence from case-control and cohort studies suggests that increased intake of fresh fruits and vegetables is associated with decreased gastric cancer rates.[22,23] However, no RCTs have been done to establish a causal association.
Because of the evidence for an inverse association between gastric cancer and dietary intake of fruits and vegetables, especially those rich in antioxidants, there has been interest in dietary supplementation with antioxidants.
Dietary indices of micronutrient intake have been calculated and indicate possible protective effects of beta carotene, vitamin A, vitamin E, selenium, vitamin C or foods that contain these compounds. A chemoprevention trial in China reported a statistically significant reduction in the gastric cancer mortality rate after supplementation with beta carotene, vitamin E, and selenium. The population studied, however, may have been nutritionally deficient, raising questions of generalizability to other populations such as that of the United States. In addition, the experimental design did not permit assessment of the relative effects of beta carotene, vitamin E, and selenium.
Likewise, there was a randomized placebo-controlled trial of 200 mg of oral allitridium (a component of garlic) every day combined with 100 mcg of oral selenium every other day for 1 month of each year over a 3-year period in Qixia County (Shandong Province, China), an area with low intake of garlic and low selenium content in their garlic compared with other areas of China. Although designed as a double-blinded trial, allitridium causes a distinctive odor of garlic. A total of 5,033 people, who met at least one of the following criteria: (1) medical history of stomach disorder, (2) family history of tumor, (3) history of smoking, or (4) history of alcohol consumption, were randomly assigned. The study, published in a Chinese medical journal, was not well described. After a follow-up for as many as 11 years, there were a total of 23 gastric cancer cases in the allitridium/selenium group and 30 cases in the placebo group (RR after adjustment for a number of baseline characteristics = 0.48; 95% CI, 0.21–1.06). Only 60% of the gastric cancers were diagnosed by histopathology. There was a qualitative difference in outcome by sex: RRmen = 0.36 (95% CI, 0.14–0.92); RRwomen = 1.14 (95% CI, 0.22–5.76). Given the problems with design and reporting of the study, the evidence of benefit (including men) is weak and may not be generalizable to Western countries.
In a randomized, double-blind, chemoprevention trial in Venezuela among a population at increased risk for gastric cancer, a combination of antioxidant vitamins (vitamins C, E, and beta carotene) failed to modify progression or regression of precancerous gastric lesions. Another potential explanation for the lack of benefit of vitamin supplementation in this trial was the high prevalence of advanced premalignant lesions and the high H. pylori infection rate.
A secondary analysis of the Alpha-Tocopherol Beta Carotene trial conducted on male smokers in Finland evaluated the effect of supplementation on gastric cancer incidence. No protective effects for these supplements against gastric cancer were observed. Six-year follow-up results of a study of 976 Colombian patients have been reported. Patients were randomly assigned to receive eight different treatments that included vitamin supplements and anti-Helicobacter therapy either alone or in combination versus placebo. Among the 79 patients who received anti-Helicobacter therapy, a borderline statistically significant regression of intestinal metaplasia when compared with a placebo (15% vs. 6%; RR = 3.1; 95% CI, 1.0–9.3) was noted. However, the combinations of antibiotics and vitamins did not confer additional benefits. More importantly, the progression rate of intestinal metaplasia was comparable irrespective of the treatments received. The progression rate was 23% in the placebo group and 17% in antibiotic recipients.
A systematic review examined randomized trials of antioxidant dietary supplements for the prevention of gastrointestinal cancers, including gastric cancer. Twenty trials were identified that assessed the preventive effects of antioxidant supplements or vitamin C on gastrointestinal cancer. With regard to gastric cancer, there were 12 comparisons of one or more micronutrients with placebo: beta-carotene alone (4 trials); vitamin C alone (1 trial); vitamin E alone (1 trial); vitamin A plus beta-carotene (1 trial); beta-carotene plus vitamin C (1 trial); beta-carotene plus vitamin E (1 trial); beta-carotene plus vitamins C and E (1 trial); selenium plus vitamins C and E (1 trial); and beta-carotene, vitamins C and E, and selenium (1 trial). None of the comparisons showed a statistically significant effect on the incidence of gastric cancer. The overall summary estimate across all trials of antioxidants showed no statistically significant effect (RR of gastric cancer = 1.14; 95% CI, 0.97–1.33). Approximately 0.51% of participants in the combined antioxidant groups developed gastric cancer versus 0.38% in the placebo groups after treatment of 2.1 to 12 years and follow-up for as many as 14.1 years. In the combined analysis of all 20 trials of antioxidants for the prevention of gastrointestinal cancers, a fixed effects model showed an increase in overall mortality of antioxidants compared with a placebo (RR for mortality = 1.04; 95% CI, 1.02–1.07) but not in a random effects model (RR for mortality = 1.02; 95% CI, 0.97–1.07)
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