Description of the Evidence
Incidence and mortality
In 2014, it is estimated that 22,220 Americans will be diagnosed with gastric cancer and 10,990 will die of it. Two-thirds of people diagnosed with gastric cancer are older than 66 years. The disease is much more common in other countries, principally Japan, Central Europe, Scandinavia, Hong Kong, South and Central America, the Soviet Union, China, and Korea. Gastric cancer is a major cause of death worldwide, especially in developing countries.
The major type of gastric cancer is adenocarcinoma (95%). The remaining malignant tumors include lymphomas, sarcomas, carcinoid tumors and other rare types. Distinguishing the common adenocarcinoma from the uncommon lymphoma may sometimes be difficult but is important, due to major differences in staging, treatment, and prognosis. Gastric adenocarcinomas can be further categorized into an intestinal type and a diffuse type. Intestinal-type lesions are frequently ulcerative and occur in the distal stomach more often than the diffuse type. Diffuse-type lesions are associated with a worse prognosis than the intestinal type. The intestinal type tends to be predominant in geographic regions with a high incidence of gastric carcinoma. The decline in the incidence of gastric cancer worldwide is largely due to a decrease in the number of intestinal-type lesions.
The incidence of gastric cancer in the United States has decreased fourfold since 1930 to approximately seven cases per 100,000 people. The reasons for this striking decrease in incidence are not fully understood but are suspected to be related to improved storage of food and changes in diet, such as decreased salt intake. Some populations of Americans are at elevated risk, including elderly patients with atrophic gastritis or pernicious anemia, patients with sporadic gastric adenomas, familial adenomatous polyposis, or hereditary nonpolyposis colon cancer, and immigrant ethnic populations from countries with high rates of gastric carcinoma.[9,10]
Risk factors for gastric cancer include the presence of precursor conditions such as chronic atrophic gastritis and intestinal metaplasia, pernicious anemia, and gastric adenomatous polyps. Genetic and environmental factors include a family history of gastric cancer; low consumption of fruits and vegetables; consumption of salted, smoked, or poorly preserved foods; and cigarette smoking.[11,12] There is consistent evidence that Helicobacter pylori infection of the stomach is strongly associated with both the initiation and promotion of carcinoma of the gastric body and antrum, and of gastric lymphoma.[13-15] The International Agency for Research on Cancer (IARC) classifies H. pylori infection as a cause of noncardia gastric carcinoma and low-grade B-cell mucosa-associated lymphatic tissue gastric lymphoma (i.e., a Group 1 human carcinogen).[16,17] Compared with the general population, people with duodenal ulcer disease may have a lower risk of gastric cancer.
Evidence of Benefit Associated With Screening
Several screening techniques, including barium-meal photofluorography, gastric endoscopy, and serum pepsinogen have been proposed as screening methods for the early detection of gastric cancer. No randomized trials evaluating the impact of screening on mortality from gastric cancer have been reported.[12,19] Even in very high-risk areas, the positive predictive value (PPV) of the screening tests may be very low. In a screening program of 17,647 men aged 40 to 60 years in Wakayama City, Japan, the PPV of combined serum pepsinogen and barium meal with digital radiography over the 7-year period was 0.85%. The positive test rates were 19.5% for serum pepsinogen and 22.5% for radiography, with a cancer detection rate of 0.28%. Over the 7-year period, there was no reduction in gastric cancer mortality compared with an age-matched surrounding population.
Barium-meal gastric photofluorography
A national program of population-based screening for gastric cancer using barium-meal photofluorography has been ongoing since the 1960s in Japan. Participation rates have been in the range of only 10% to 20%.[12,20] Although there has been a coincident decrease in mortality from gastric cancer in Japan, mortality rates have been decreasing in many developed countries despite the lack of screening programs. Case-control studies from Japan show decreases in gastric mortality in people who have undergone screening, but results from prospective studies were not consistent.[12,19]
A pilot study of community-based photofluorography was conducted in Costa Rica using the same techniques as those used in Japan’s national program (with consultation from Japanese experts). People were invited by letter from a population registry to attend two rounds of screening, and a total of 6,200 eligible screened participants (of a planned 12,000) were analyzed. Their gastric cancer mortality from 2 to 7 years after screening was compared with four control groups that had not been invited to be screened, and the relative risk was about 0.5 (no p-value reported). The study was, however, prone to strong biases, including selection bias, and likely differential exclusion of people with previously diagnosed gastric cancer favoring the screened population. In addition, unlike the community controls, patients diagnosed with gastric cancer through the screening program were treated at a single referral center. The PPV of a suspicious fluorograph was 3%; the specificity in the two rounds was 67% and 80%; and the positivity rates were 34% and 20%. Despite the authors’ belief that their results provided substantial evidence that routine screening would decrease gastric cancer mortality, they concluded that the costs of screening with photofluorography would be far too high in their country.
A screening study was begun in Venezuela in 1980, using radiographic fluorography. The efficacy of this program in reducing mortality from stomach cancer was evaluated by means of a case-control study, and there was no detectable reduction in mortality from gastric cancer.
Endoscopy appears to be more sensitive than photofluorography for the detection of gastric cancer. Time-trend analysis and case-control studies of gastric endoscopy suggest a twofold decrease in gastric cancer mortality in screened versus unscreened individuals;[24-28] however, this stands in contrast to studies of stronger design.
A cohort study of endoscopic screening was conducted in Linqu County, China, where gastric cancer rates are high, in which 4,394 adult residents aged 35 to 64 years were screened. Individuals were screened at an average of 4.5-year intervals, except for a high-risk subset (689 individuals) that was screened 2 years after the initial examination. Of the 85 cases of gastric cancer occurring in the cohort, 58 were detected with screening. No impact on gastric cancer mortality was observed among screened individuals. The standardized mortality ratio (SMR) for gastric cancer 10 years after the initial screen was 1.01 (95% confidence interval, 0.72–1.37). The SMR for all-cause mortality was significantly lower among participants because individuals with hypertension, liver disease, and chronic obstructive pulmonary disease were not eligible to participate. The data were observational, and not primarily collected to evaluate the effect of screening on gastric cancer mortality. In addition, the intervals between screens may have been too long.
There are no studies evaluating the effect of screening with serum pepsinogen on gastric cancer mortality, and there are important limitations to its use as a screening test. Low serum pepsinogen levels indicate the presence of atrophic gastritis and are therefore applicable to the detection of presumed precursors for intestinal type gastric cancer rather than the diffuse type. In addition, there are no standard cut-off values of abnormality.[12,30] Finally, eradication of H. pylori and use of proton pump inhibitors for the management of indigestion change pepsinogen levels, making interpretation of results difficult in the setting of widespread use of these interventions.[12,20]
In Japan, measurement of serum pepsinogen levels I and II (PGI and PGII) in 5,113 subjects also screened by endoscopy (13 gastric cancers detected), used cut-off points for identifying risk for gastric cancer of less than 70 ng/mL for PGI and less than 3 ng/mL for the PGI:PGII ratio. This combination provided a sensitivity of 84.6%, a specificity of 73.5%, a PPV of 0.81%, and a negative predictive value of 99.6%.
Clinical considerations for high risk groups
There may be justification for screening some populations of Americans at higher risk, although there is considerable discussion about how much incidence would make the examination worthwhile. Potential subgroups might include elderly patients with atrophic gastritis or pernicious anemia, patients with partial gastrectomy, patients with the diagnosis of sporadic adenomas, familial adenomatous polyposis, or hereditary nonpolyposis colon cancer, and immigrant ethnic populations from countries with high rates of gastric carcinoma.[9,10]
Evidence of Harm Associated With Screening
Harms of routine screening for gastric cancer are poorly quantitated or reported, and derive chiefly from screening experiences in very high-risk areas such as Japan. The most frequent harm is the occurrence of false-positive tests. Exposure to the low doses of radiation (about 0.6 mSv in photofluorography) carries a theoretical but poorly quantified risk of carcinogenesis. Additional rare complications of screening may include adverse effects of premedication (used for endoscopy and sometimes photofluorography), and bleeding or perforation from endoscopy. As with any screening test, there is a possibility of overdiagnosis with attendant overtreatment. Since harms such as perforation and bleeding may vary with the experience of the screening center, they may be higher in populations at low risk for gastric cancer, such as the United States, than in mass screening programs in Japan.
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- Lauren P: The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma: an attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64(1): 31-49, 1965.
- Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). Bethesda, Md: National Cancer Institute, 2012. Also available online. Last accessed December 15, 2014.
- Ming SC, Goldman H: Gastric polyps: a histogenetic clasification and its relation to carcinoma. Cancer 18: 721-6, 1965. [PUBMED Abstract]
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- Aarnio M, Salovaara R, Aaltonen LA, et al.: Features of gastric cancer in hereditary non-polyposis colorectal cancer syndrome. Int J Cancer 74 (5): 551-5, 1997. [PUBMED Abstract]
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- Parsonnet J, Hansen S, Rodriguez L, et al.: Helicobacter pylori infection and gastric lymphoma. N Engl J Med 330 (18): 1267-71, 1994. [PUBMED Abstract]
- Ando T, Goto Y, Maeda O, et al.: Causal role of Helicobacter pylori infection in gastric cancer. World J Gastroenterol 12 (2): 181-6, 2006. [PUBMED Abstract]
- Aromaa A, Kosunen TU, Knekt P, et al.: Circulating anti-Helicobacter pylori immunoglobulin A antibodies and low serum pepsinogen I level are associated with increased risk of gastric cancer. Am J Epidemiol 144 (2): 142-9, 1996. [PUBMED Abstract]
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- Hamashima C, Shibuya D, Yamazaki H, et al.: The Japanese guidelines for gastric cancer screening. Jpn J Clin Oncol 38 (4): 259-67, 2008. [PUBMED Abstract]
- Ohata H, Oka M, Yanaoka K, et al.: Gastric cancer screening of a high-risk population in Japan using serum pepsinogen and barium digital radiography. Cancer Sci 96 (10): 713-20, 2005. [PUBMED Abstract]
- Rosero-Bixby L, Sierra R: X-ray screening seems to reduce gastric cancer mortality by half in a community-controlled trial in Costa Rica. Br J Cancer 97 (7): 837-43, 2007. [PUBMED Abstract]
- Pisani P, Oliver WE, Parkin DM, et al.: Case-control study of gastric cancer screening in Venezuela. Br J Cancer 69 (6): 1102-5, 1994. [PUBMED Abstract]
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