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Gastric cancer is the fifth most common cancer and third leading cause of cancer-related death worldwide.1 In 2013, 841 000 people worldwide died due to gastric cancer.2 Eastern Asia, Eastern Europe and some regions in Central and South America have the highest incidence of stomach cancer, whereas Western Europe and North America have lower rates. The majority of gastric malignancies are intestinal type adenocarcinomas.3 These cancers develop according to a multistep process, in strong association with Helicobacter pylori infection. This bacterium causes chronic gastritis, which can slowly progress via atrophy, intestinal metaplasia and dysplasia to gastric adenocarcinoma.4 This process takes decades3 and provides an excellent window of opportunity for early detection and prevention of gastric cancer.
Several strategies have been proposed for gastric cancer screening. These include H. pylori screening and treatment, endoscopy with random or targeted biopsy sampling, serological testing for pepsinogens, gastrin and H. pylori antibodies and breath testing for volatile organic compounds.5 A test-and-treat approach for H. pylori has been proposed as the preferred strategy for population screening in high gastric cancer-risk populations in the Asia–Pacific region.6 ,7 This test-and-treat approach benefits from availability of non-invasive tests (serology, breath and stool tests) and is a single screen and treat strategy without the need for further surveillance. This is based on the low risk of recurrent H. pylori infection after successful eradication, and the low risk of gastric cancer in H. pylori negatives without premalignant lesions. Disadvantages include the risk of increased antibiotic resistance in the community and the lack of preventive effect in people who have already developed more advanced precancerous lesions. Screening for the presence of atrophic gastritis by means of serum pepsinogen testing is an attractive alternative and can be combined with H. pylori screening.8 ,9 Subjects with negative H. pylori serology and normal pepsinogens have a low risk for cancer, and do not need intervention or surveillance. Positive H. pylori serology in combination with increased pepsinogens is compatible with active, non-atrophic H. pylori gastritis. In these subjects, eradication therapy can cure gastritis and prevent progression to cancer. The combination of positive H. pylori serology and decreased pepsinogens is compatible with atrophic H. pylori gastritis. In these subjects, eradication therapy can reduce mucosal inflammation, but cannot prevent further progression to cancer. Finally, the combination of negative H. pylori serology and low pepsinogens is compatible with end-stage atrophy having led to spontaneous clearance of H. pylori. These subjects are at the highest risk for progression to cancer and may benefit from surveillance with endoscopic treatment of early dysplastic and cancerous lesions.10
In this edition of Gut, Yeh et al11 have explored the cost-effectiveness of one-time screening of US men by means of serum pepsinogen testing. They compared this approach with strategies of endoscopy and H. pylori screening, using decision-analytic modelling. Their model suggests that serum pepsinogen testing may prevent one in four gastric cancers. This approach was more effective and cheaper than either endoscopy or H. pylori screening. However, since the costs of serum pepsinogen screening of the general population exceeded $100 000 per quality-adjusted life-year gained (QALY), it was not cost-effective as strategy for the complete population. An important strength of the study by Yeh et al is that they also considered targeted screening of higher-risk subgroups, in particular current and former smokers. In them, serum pepsinogen testing continued to dominate the other screening strategies. However, because of the higher benefits of screening in these high-risk groups, costs per QALY gained decreased. Consequently, serum pepsinogen testing was cost-effective especially for the highest risk group of current male smokers.
These findings may have important implications for current practice. First, it suggests that there may be a role for pepsinogen screening in high-risk countries, such as Japan and Korea, next to initiatives based on imaging and endoscopy.12 ,13 Pepsinogen testing in these countries could potentially increase benefits, as well as participation, of their current programmes, while at the same time reduce costs. Second, a more targeted screening, for example, aimed at male smokers and other high-risk subgroups could also be considered,14 ,15 could potentially make gastric cancer screening worthwhile in the lower risk Western population. As Yeh et al11 rightfully pointed out, still more than 22 000 gastric cancer cases occur in the USA each year. Targeted screening may prevent a substantial proportion of these cases. This is even more relevant in the USA because of the marked interracial differences in gastric cancer incidence16 and also strongly affects indigenous populations both in the USA and worldwide.17 The acceptability of targeted screening is demonstrated by the US Preventive Services Task Force recommendations to only screen for abdominal aortic aneurysm and lung cancer in smokers.
The study by Yeh et al underlines the potential for serum pepsinogen testing, even in lower risk areas like Western Europe and the USA. The authors have carefully constructed their model, synthesising the best available evidence from multiple data sources. Meticulous sensitivity analyses support the robustness of their results. Still, modelling can never replace randomised controlled trials.
Their model found H. pylori eradication to be ineffective in reducing gastric cancer mortality, even though this is the only strategy for which there is evidence from randomised controlled trials that it decreases gastric cancer incidence. The other evaluated screening strategies in their study depend on the ability of endoscopy to detect dysplasia and cancer and the effectiveness of subsequent treatment of those lesions. Data on the effectiveness of endoscopy screening were based on Japanese data primarily coming from observational studies, without adjustment for confounding factors.18 Since the Japanese screening studies also showed an association between endoscopy and lower all-cause mortality, healthy screenee bias cannot be excluded. Data from Western countries are limited. A recent study from the England reported that the higher use of diagnostic gastroscopy was associated with earlier detection and improved outcome of oesophagogastric cancer.19 A previous Danish study, however, suggested that endoscopists missed 10% of oesophagogastric cancers, leaving significant room for improvement.20
The study by Yeh et al should thus be seen as a stimulus towards generating further evidence for the effectiveness of gastric cancer screening. This study comes at a time that the worldwide average life expectancy continues to increase, but healthy life years do not increase at simultaneous pace and healthcare costs rise exponentially. Against that background, clinicians, public health experts and governments realise that we have to substantially increase our efforts for prevention and early detection of disease. Gastric cancer in Western countries tended to become a ‘forgotten disease’ despite remaining to affect many patients, mostly diagnosed at advanced stage with dismal outcome. This is illustrated by the fact that gastric cancer is the most commonly occurring cancer of the GI tract, and has a worldwide mortality rate close to 90%.2 ,21 We now have solid evidence that the disease can be prevented by early treatment of H. pylori, and endoscopic techniques for detection and treatment of early lesions have also revolutionised. If the performance characteristics of pepsinogen testing hold up in clinical practice, the balanced modelling by Yeh et al supports the conduct of randomised controlled trials on pepsinogen testing, also in Western populations. Such trials would give the final verdict on the comparative effectiveness and cost-effectiveness of pepsinogen testing and other screening modalities.
Contributors Both authors contributed to the conception and design of the work; and drafting the work and revising it critically for important intellectual content. Both authors gave final approval of the version to be published.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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