The Wilson and Junger criteria
The Wilson and Junger criteria for screening, established in 1968, outline key requirements for the development of an effective screening programme. These criteria include that the condition being screened for is an important health concern, that it has a recognizable early symptomatic stage, and that we understand the condition’s natural course. It also requires the availability of a suitable test that is acceptable to the population and the availability of treatment and facilities for diagnosis and treatment.8 In the case of gastric cancer, the disease pathway is detailed by the Correa cascade,9 which describes the progression from normal mucosa through intestinal metaplasia, gastric atrophy, and ultimately, cancer. A significant promoter along this carcinogenic cascade is the presence of H. pylori. While H. pylori infection is not necessary for cancer development, it significantly promotes progression along this pathway. H. pylori can be tested for non-invasively using urea breath testing, stool antigen testing, or serology. Fortunately, effective treatment exists for this pathogen.10 Notably, in countries with reducing H. pylori prevalence, there has been a corresponding reduction in gastric cancer cases (Figs. 2 and 3).11
Screening mechanisms
Three potential screening strategies have been suggested to target gastric cancer: primary prevention, secondary prevention, and opportunistic screening. A primary preventive strategy focuses on screening individuals for this carcinogenic bacteria before the development of preneoplastic lesions and treating it where present; this is known as a ‘screen and treat’ strategy.12 A substantial body of evidence supports this approach, at reducing the risk of gastric cancer mortality and incidence. However, debate exists around the optimal age to begin screening. Recent studies have suggested the potential role of screening school-aged children, while others argue that infection in childhood rarely causes complications such as peptic ulcer disease.13–15 A recent meta-analysis of randomized controlled trials using this ‘screen and treat’ approach in adult populations estimated the number needed to treat to prevent one case of gastric cancer as 72 and one cancer-related death as 135.16 A significant body of observational data in Asia also supports this approach. The most notable of these is the Matsu Islands study. In this study, 7,000 adults over the age of 30 were screened and treated for H. pylori. Compared to the historical period from 1995 to 2003, there was a 53% reduction in gastric cancer incidence and a 23% reduction in mortality.17 While limited, observational population data exists in a European population to support this approach. A systematic review conducted by Doorakkers et al.18 on the Swedish database provided data associating H. pylori eradication with a reduction in gastric cancer in a Western population. The most significant benefit was observed when H. pylori infection was treated earlier, with a reported standardized incidence ratio over 5–7 years of 0.87.19
Secondary preventive strategies involve screening those in a high-risk age cohort when a pre-neoplastic or early neoplastic lesion has already occurred and endoscopically treating these before progression. Research on secondary prevention has primarily focused on endoscopic screening, the role of X-rays as part of an upper gastrointestinal series (UGIS), and serological markers. While both endoscopic screening and UGIS have limitations, meta-analysis supports the role of endoscopic screening over UGIS.20 UGIS carries concerns over radioactivity, lack of biopsy capability, and low sensitivity and specificity compared to endoscopy, potentially resulting in lost opportunities to treat early-stage cancers endoscopically. Endoscopy, while both a screening and diagnostic test, is costly, comes with a small risk of significant complications, and requires considerable training to perform at a high quality. Despite these factors, UGIS has largely been replaced by endoscopic screening in national gastric cancer screening programmes in East Asian countries. However, in areas lacking facilities and trained endoscopy staff, UGIS can still be considered based on the patient’s clinical situation.21
Research has been ongoing on the role of serological markers as a potential screening mechanism for decades.22,23H. pylori antibodies, pepsinogen I & II levels, gastrin-17, and anti-parietal cell antibodies have been studied for their potential role as a pre-screening tool to determine who requires a gastroscopy. Support currently exists for the potential use of pepsinogen and H. pylori antibodies as a screening mechanism from the Kyoto Global Consensus; however, limitations exist in their application across populations.24 Four key models have been proposed using these markers, including the ABC, ABCD, five-markers study, and the seven variables study. All scoring systems incorporate serology, with the more recent seven variables study also including recognized gastric cancer risk factors. The ABC and ABCD methods measure serum pepsinogen I, II, I/II ratio, and H. pylori antibody status.25,26 The five-markers and seven variables methods measure H. pylori antibody status, pepsinogen I & II levels, gastrin-17 levels, and anti-parietal cell antibodies. The seven variables method also assesses exposure to nitroso compounds such as pickled and fried food.27,28 Out of these scoring systems, the seven variables method suggests a better discriminative ability to identify patients with gastric cancer than the other methods.29 However, it is important to note differences in baseline risk in these study groups and variations in reproducibility of results in different populations. In Europe, a retrospective review by Gašenko et al.30 found a poor correlation between changes in pepsinogen and gastrin-17 levels and gastric cancer, suggesting these serological markers have an uncertain application in a Caucasian population. Despite this, in countries where these markers are validated in the population being screened, they could potentially be used to select those who require gastroscopy, allowing for a ‘work smart’ approach to screening.