A Systematic Review of Cost-Effectiveness Studies on Gastric Cancer Screening

Simple Summary This research set out to systematically review available cost-effectiveness studies on gastric cancer (GC) screening across the world. Of the studies reviewed, the majority were model-based, while fewer were prospective observational-based studies. The results of the review point to a distinction between Asian-based and non-Asian-based studies. The data revealed a higher risk of GC in Asian countries and their diasporas because of the elevated prevalence of one of the main risk factors within this population group, i.e., Helicobacter pylori (Hp) infections, compared with non-Asian populations. GC screening was mainly cost-effective in these high-risk groups, with a probability of at least 85% compared to no screening. Primary intervention, which involves Hp screening with eradication, was a preferred strategy as it addresses the main causative factor and limits the development of GC. Secondary intervention, which involves endoscopic screening, was also cost-effective but is typically used to identify adenocarcinomas rather than precancerous conditions. GC screening was generally not cost-effective among Western countries. Abstract Gastric cancer (GC) poses notable economic and health burdens in settings where the incidence of disease is prevalent. Some countries have established early screening and treatment programs to address these challenges. The objectives of this systematic review were to summarize the cost-effectiveness of gastric cancer screening presented in the literature and to identify the critical factors that influence the cost-effectiveness of screening. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Economic evaluation studies of gastric cancer screening were reviewed from SCOPUS and PubMed. The Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) was used to assess the quality of reporting presented in the selected articles. Only primary economic evaluation studies addressing the cost-effectiveness, cost–utility, and cost–benefit of gastric cancer screening were selected. Two reviewers scrutinized the selected articles (title, abstract, and full text) to determine suitability for the systematic review based on inclusion and exclusion criteria. Authors’ consensus was relied on where disagreements arose. The main outcome measures of concern in the systematic review were cost, effectiveness (as measured by either quality-adjusted life years (QALY) or life-years saved (LYS)), and incremental cost-effectiveness ratio (ICER) of screening versus either no screening or an alternative screening method. Thirty-one studies were selected for the final review. These studies investigated the cost-effectiveness of GC screening based on either primary, secondary, or a combination of primary and secondary interventions. The main primary intervention was Helicobacter pylori (Hp) screening with eradication, while the main secondary intervention was endoscopic screening. Cost-effectiveness was evaluated against no screening or screening using an alternative method in both observational and model-based studies. Screening was mainly cost-effective in Asian countries or their diasporas where the prevalence of GC was high. GC screening was generally not cost-effective among Western countries. GC screening can be cost-effective, but cost-effectiveness is dependent on context-specific factors, including geographical location, the prevalence of GC in the local population, and the screening tool adopted. However, there is benefit in targeting high-risk population groups in Asian countries and their diaspora for GC screening.


Introduction
Gastric cancer (GC) is one of the most common cancers in the world.In 2022, there were approximately one million newly diagnosed cases worldwide, the fifth highest among all newly diagnosed cases of cancer that year [1].In terms of mortality, gastric cancer was also the fifth leading cause of cancer-related mortality globally, with approximately 659,936 deaths in 2022 [1].New cases and deaths are disproportionately more prevalent among Asian countries and their diasporas, with China, Japan, India, and the Russian Federation accounting for approximately 60% of new cases globally in 2022 [1].Similarly, these countries combined accounted for approximately 59% of total gastric cancer-related deaths across the world [1].China alone accounted for approximately 37% and 40% of global GC cases and global GC deaths, respectively, in the same year [1].
Early screening, diagnosis, and treatment can potentially reduce the cost of care and notably improve clinical outcomes with a greater chance of survival and lower mortality, especially since early gastric cancer tends to be either asymptomatic or minimally symptomatic with epigastric discomfort and dyspepsia [2].When detected at a later stage, the 5-year survival rate of gastric cancer is less than 30%, but early detection is associated with a 90% survival rate with appropriate treatment [3,4].Treatment costs are exorbitant, and increasingly so with greater levels of intervention, posing a strain on limited healthcare resources [5].In China, for example, the estimated cost of GC treatment was CNY 23.508 billion in 2018, representing the third-highest treatment cost among all types of cancers in that country [2].Also, in the USA, the average monthly out-patient cost for GC patients was estimated to be between USD 34,002 and USD 72,778 (2017 USD) [5].
Generally, there are two approaches to the prevention of GC: primary prevention and secondary prevention methods.Primary prevention mainly involves Helicobacter pylori (H.pylori/Hp) screening and eradication, which potentially lowers GC incidence and mortality rates as the main risk factor is removed [6][7][8].Meanwhile, secondary prevention commonly involves endoscopic screening (endoscopic screening here refers to gastroscopy/upper gastrointestinal endoscopy/esophagogastroduodenoscopy (EGD)) to detect GC, especially after gastric atrophy has been identified [9,10].Other strategies along the continuum of screening tools include serological screening using pepsinogen, upper gastrointestinal series (UGI), tumor markers, microRNAs (miRNAs) in human serum, and Gastrin-17 [2,11,12].
Screening guidelines recommend a focus on high-risk populations, which typically includes those with high rates of Hp infections [2,13,14].Hp is a group I carcinogen and known risk factor for the development of GC, particularly non-cardia gastric adenocarcinoma (NCGA), which is the most common type of GC [2,12,[15][16][17].In fact, up to 75% of all NCGA cases have an H. pylori histology [18] and approximately 50% of the Chinese population carries this infection with no visible symptoms [2].Both gastric atrophy and intestinal metaplasia, which may stem from chronic inflammation caused by Hp infections, are also contributors to the development of GC [19][20][21].Other notable risk factors for GC are smoking, diet, and genetics [12].
The Working Group of the International Agency for Research on Cancer (IARC) cautioned that GC will continue to be of global concern in the absence of effective control and prevention strategies [22].This is even more likely in countries with higher incidence rates of Hp infections.The Working Group, however, acknowledged that with known interventions to prevent GC that target its risk factors, the burdens associated with the disease can be alleviated [22].
The objective of this study, therefore, is to perform a systematic review of the current literature on the cost-effectiveness of gastric cancer screening and to determine the key factors that impact cost-effectiveness.This review may prove useful to policy makers within and across both developed and developing countries to inform appropriate GC screening intervention strategies based on cost, effectiveness, and risk factors.

Materials and Methods
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for reporting a systematic review [23].The research protocol began with a broad search of the literature on health-economic evaluation studies on the cost-effectiveness of screening for esophageal, liver, pancreatic, and gastric cancers.However, for this systematic review, only gastric cancer is highlighted.The research protocol was registered on 14 October 2023 through PROSPERO, registration no.CRD42023467167.SCOPUS and PubMed were the electronic databases used to perform the literature search.With the aid of two university-level health sciences librarians, search strategies were developed and tailored for each database.Key search terms included "stomach neoplasms", "stomach cancer", "gastric cancer", "screening", "early detection", "economic evaluation", and "cost-effectiveness analysis".The literature search was restricted to studies published up to September 2023.The Supplementary Materials provide the complete search strategy along with mesh combinations for each database.(see the Supplementary Material File S1).
COVIDENCE was used as a repository for all articles identified from the initial literature search.This was also where the PRISMA flow chart was generated.The literature search was not restricted to any particular country or group of countries.The authors recognized that the cancer of concern in this review is less prevalent in North America and Europe and more prevalent in Southeast Asia.
The specific inclusion criteria were as follows: 1.
Studies that focused on the screening of stomach cancers through primary and/or secondary methods compared to no screening or screening using alternative methods; 2.
Studies that focused on populations at average risk or above average risk for gastric cancer; 3.
Studies that reported on patient outcomes measured in terms of quality-adjusted life-years (QALY) or life-years gained (LYG); 4.
Studies based on decision-analytic modeling assessing both the long-term effectiveness and the cost-effectiveness of different early detection; 5.
Studies that reported the incremental cost-effectiveness ratio (ICER) or provided data for ICER calculation; 6.
Studies that outlined cost per quality-adjusted life-year (QALY) or cost per life-year gained, or cost per utility gained; 7.
Studies that had full economic evaluations; 8.
Studies published in English.
The exclusion criteria were as follows: 1. Non-original studies; 2.
Studies not published in English; 3.
Systematic reviews, editorials, letters, abstracts, and studies that are not full health economic evaluations or evaluated only follow-up or treatment strategies.
In selecting the final articles for the systematic review, firstly, two authors (L.J. and D.L.) completed title-abstract screening of all the studies generated from the literature search in SCOPUS and PubMed.This screening process was guided by the inclusion and exclusion criteria described above and presented in Figure 1.Authors' consensus was relied on where disagreements arose.
Following the selection of relevant articles through the initial screening process, a full-text review was conducted to extract all pertinent pieces of data from each of the remaining articles.The reviewers applied the inclusion and exclusion criteria to form the final list of studies.From the final list of studies, the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) [24] was used to assess the adequacy/quality of reporting of each study.The following information were also extracted from each study: study settings, target populations, study objectives, screening strategies, economic evaluation model and its features (namely, model type, study perspective, discount rate, time horizon, sensitivity analysis, and willingness to pay (WTP) threshold), clinical outcomes, costs associated with screening, and study recommendations.The main outcome indicators were quality-adjusted life years (QALY), life-years saved (LYs), incremental cost-effectiveness ratio (ICER), and incremental cost-utility ratio (ICUR).

Results
Thirty-one studies were ultimately selected for this review based on the inclusion-exclusion criteria.This selection process is illustrated in the PRISMA diagram, Figure 1.Tables 1-3 provide a summary of the data extracted from the selected studies.Notable variations across the selected studies can be identified, particularly with respect to country setting, target population, time horizon, discount rate, study perspective, study objective, age range, cancer risk, screening compliance, screening strategies, and willingness to pay threshold.
Generally, studies conducted economic evaluations of GC screening methods using cost-effectiveness analyses that report on the ratios (ICERs) as the principal outcome measure.ICER was typically measured as cost per quality-adjusted life year (QALY), except for a few studies that estimated cost per life-year saved (LYS) [14,[25][26][27].Cho et al. (2013) estimated cost per survival, while Wei et al. (2011) performed a cost-benefit analysis [28,29].Economic evaluations were conducted from several perspectives, namely, societal, healthcare system, healthcare payer, third party payer, ministry of health, healthcare provider, and public healthcare.The specific aims of this case study of gastric cancer screening in Japan were to (a) determine the most cost-effective strategy; (b) decide on the optimal target ages stratified by sex; and (c) identify the change of cost-effectiveness between the 1980s and 1990s

Interventions Identified from the Systematic Review
The studies identified in this systematic review either focused on primary, secondary, or both primary and secondary intervention strategies.The most common primary interventions sought to identify GC risk factors like Hp infection, gastric atrophy, intestinal metaplasia, and dysplasia using either, or a combination of, Helicobacter pylori IgG antibody (HPA), 14C-urea breath test (UBT), Gastrin-17 (G-17), MiRNA screening, or serum pepsinogen (PG) I and I/II (pepsinogen levels at or below 70 mg L −1 (≤70 µg/L) for pepsinogen I and 3.0 for the pepsinogen ratio I/II warrant follow-up gastric cancer screening and diagnosis [12]).Some studies even developed a scoring method to determine the risk of developing GC based on combinations of the aforementioned indicators.In fact, two studies investigated the cost-effectiveness of the new gastric cancer screening scoring system (NGCS) in China, which is a scoring system that assesses a person's status with respect to Hp infection, PG levels, G-17 levels, age, and sex in order to determine GC risk levels where risk is classified as high, moderate, or low [2,30].In a similar study, the gastric cancer risk score scale (GCRSS) was evaluated-this however determined risk based on Hp infection, PG levels, and G-17 levels [31].Another study focused on the "ABC method", which combines both Hp and PG screening to assess GC risk [32].
Endoscopy, particularly, gastrointestinal endoscopy, otherwise known as gastroscopy or esophagogastroduodenoscopy, was identified as the main secondary intervention among the studies, albeit at different frequencies, including one-time, annual, biennial, triennial, every 5 years, and every 10 years.Other radiographic procedures like upper gastrointestinal series (UGI) were less commonly considered [14,29,33,34].
The aforementioned interventions were compared to no screening in most cases and, in some cases, against an alternative strategy: either the next most effective screening strategy or a previous less costly strategy.
There was general consensus across the studies on the outcomes of the economic evaluations.Studies that focused on primary interventions found these interventions to generally be cost-effective compared to no screening in the prevention of GC, with a probability of at least 85% (across various study perspectives and willingness to pay (WTP) thresholds) [2,11,12,[30][31][32]35,36].These primary interventions range from Hp screening and treatment only to composite risk measurement tools like NGCS, ABC, and GCRSS.Even further, studies that compared both primary and secondary interventions demonstrated that primary interventions involving Hp screening were more cost-effective at least 85% of the times [11,[30][31][32][33]35,37,38].Four of these studies were based on the Japanese population [32,33,37,38], another three were based on the Chinese population [11,30,31], and one was based on the Mexican population [35].In contrast, one study on a US-based population did not find population-wide Hp screening to be cost-effective at a WTP of USD 100,000/QALY, although cost-effectiveness was more likely (85-97%) among former and current smokers using serum pepsinogen in the USA from a societal perspective compared to no screening [12].
For studies that investigated only secondary interventions, endoscopic screening was found to be cost-effective, particularly in high-risk regions, with a probability between 92 and 100% compared to no screening [13,[38][39][40][41].In regions with intermediate risk, like Europe and the USA, endoscopic screening was cost-effective among high-risk ethnic groups and when performed during a colonoscopy (ICER: USD 71,451-USD 80,278/QALY (2015 USD) at a WTP of USD 100,000/QALY in the USA and ICER: EUR 15,407/QALY (2016 EUR) at a WTP of EUR 37,000/QALY in Portugal [15,42,43].See Tables 1-3.

Cost-Effectiveness Analysis of Asian-Based Versus Non-Asian-Based Studies
The studies selected for the systematic review were grouped into one of two categories based on geographical location of each respective study population.These categories are Asian-based studies and non-Asian-based studies.
Among Japanese-based studies, primary intervention, in particular, Hp screening and treatment, was found to be cost-effective compared to either no screening or endoscopic screening 100% of the times at a WTP threshold of USD 50,000/QALY from a healthcare payer perspective [33,37].In one Chinese-based study, Hp was shown to be a dominant strategy [44], while in other Chinese-based studies, Hp had at least a 99% probability of being cost-effective compared to no screening at a WTP of USD 31,315/QALY (2020 USD) from a healthcare provider perspective [36] and a WTP of CNY 80,976/QALY (perspective not reported) [2].
In other studies that considered primary intervention based on a combination of risk factors (including Hp infection, serum pepsinogen levels, G-17 levels, sex, and age), the intervention strategy was also proven to be cost-effective.These interventions include NGCS and GCRSS in China and the "ABC method" in Japan [2,[30][31][32].NGCS was a dominant strategy compared with no screening [2] and had an 86.3% probability of being cost-effective when screening started at age 40 years compared with no screening at a WTP of USD 17,922/QALY (2021 USD) from a societal perspective [30].GCRSS was cost-effective with ICER ranging between USD 10,315 and 27,446/QALY at a WTP of USD 37,655/QALY from a healthcare system perspective [31].ABC was also a dominant strategy with a 99.7% probability of being cost-effective at a WTP of USD 10,000/QALY compared to no screening from a healthcare payer perspective [32].
Meanwhile, for studies that compared endoscopic screening to no screening, the former was consistently the preferred strategy [13,25,29,34,38,40,45].Biennial endoscopy had a 98% and a 100% probability of being cost-effective in China and Japan, respectively, from a healthcare system perspective compared to no screening [13,38].Triennial screening was preferred 92.6% of the time compared with no screening among persons 50-75 years old (ICER: USD 45,665/QALY at a WTP of USD 50,000/QALY from a societal perspective [39].For South Korea, at a WTP of USD 19,162 (2008 USD), endoscopic screening was cost-effective (ICER: USD 4820/QALY for males and USD 6073/QALY for females) from a societal perspective [34].Similarly, in Singapore, screening was cost-effective (ICER: USD 26,836/QALY) at a WTP of USD 28,000 (2003 USD) from a societal perspective [45].
Among studies that focused on Western countries, two (one US-based study and one Portugal-based study) found that endoscopic GC screening performed during a colonoscopy was cost-effective compared to no screening (ICER: USD 74,329/QALY (2015 USD) at a WTP of USD 100,000/QALY, and ICER: EUR 30,908/QALY (2016 EUR) at a WTP of EUR 37,000/QALY [15,43].An earlier US-based study, however, did not find this intervention to be cost-effective at a WTP of USD 50,000/QALY from a third-party payer perspective [46].When considering only endoscopic screening, studies demonstrated that this strategy was cost-effective mainly for high-risk ethnic groups (Hispanics, non-Hispanic blacks, and Asians) in the USA (ICER: USD 71,451-USD 80,278/QALY (2015 USD) at a WTP of USD 100,000/QALY [15,42].Screening using serum pepsinogen was only cost-effective among current and former smokers and not so for the general population in the USA compared to no screening [12].This strategy had a 97% probability of being cost-effective at a WTP of USD 100,000/QALY from a societal perspective [12].However, in a study based on a Mexican population, both serum pepsinogen and endoscopic screening were cost-effective (ICER: USD 1590/QALY and USD 129/QALY, respectively, at a WTP of USD 9000/QALY from a public healthcare perspective) [35].
Although the country settings of the selected studies varied widely across the world, most studies focused on GC cancer screening in China (n = 9).This was followed by Japan (n = 7), USA (n = 6), Republic of Korea (n = 3), and Singapore (n = 3).There was also one study that evaluated screening in Mexico [35] and another in Portugal [43], while another compared screening across countries in Asia, Europe, Africa, and South America [47].
The majority of these studies targeted high-risk populations within their respective jurisdictions including Japan, Republic of Korea, and regions within China that have higher incidence of GC compared to the general population.Studies based on Singapore, Mexico, and Portugal were assumed to have intermediate risk [35,40,41,43,45].For the Singaporean studies, in particular, focus was on the Chinese subpopulation because of the higher risk of GC among that group [40,41,45].Meanwhile, all the US-based studies proposed an average-risk general population with elevated risk among selected sub-population groups like, Asian Americans, non-Hispanic white, non-Hispanic blacks, and Hispanics [12,15,26,42,46,48].See Tables 1-3.

Study Type and Model Parameters
Two types of cost-effectiveness studies were identified from the literature search: prospective observational cost-effectiveness studies and model-based cost-effectiveness studies.Five studies were observational in nature [25,28,29,49,50], while the remaining 26 studies presented model-based simulations (25 studies were state transition Markov models and 1 was a decision tree).
Regardless of the modeling approach adopted, the general consensus among the studies reviewed is that GC screening is cost-effective compared with no screening.Among the observational studies, focus was on high-risk populations in China and Republic of Korea [25,28,29,49,50].GC (endoscopic) screening was cost-effective in Republic of Korea (ICER: KRW 119,099,000-17,870,000 KW/survival (WTP not reported) [29], and ICER: USD 20,309/LYS at a WTP of USD 20,565/LYS) [25].Meanwhile, Wei et al. (2011) demonstrated that GC screening using endoscopy had a benefit-cost ratio ranging from 4.49 to 10.37 in Linzhou, China [28].The other Chinese-based observational studies also reported that a comprehensive intervention inclusive of an epidemiology survey, serum pepsinogen testing, endoscopy, and a pathological examination with a positive identification was costeffective (ICER: USD 459/QALY [49] and ICER: CNY 1370/QALY [50] (WTP not reported in both studies).With respect to model-based studies, the results are also consistent and can be gleaned from previous Sections 3.1 and 3.2.
With observational studies, the cost-effectiveness of an actual population-based screening program was investigated; meanwhile, with model-based studies, hypothetical cohort groups were examined.Moreover, model-based studies implemented state transition models, typically of one-year cycle length, to investigate the impact of screening intervention on disease progression, clinical outcomes, and cost.
The state transition models adopted in most studies were based on Correa's Cascade [20], which maps the stages towards the development of gastric cancer starting from normal mucosa to chronic gastritis, atrophic gastritis, and intestinal metaplasia and then to dysplasia.Some studies further captured the various stages of gastric carcinoma from stages I to IV in their proposed models and, in some cases, distinguished between clinical and preclinical health states based on whether a clinical diagnosis was established [2,[12][13][14][15]30,31,35,39,42,44].Yet, other studies focused on Hp screening and eradication and then transitioned cohort members to GC stages without accounting for the other precancerous health stages [32,33,[36][37][38]48].Another group of studies focused solely on GC screening and the related cascading GC health states, not accounting for precancerous stages [34,40,43,47].Meanwhile, Gupta et al. (2011) modeled the precancerous states that precede GC but had no explicit account of the stages of GC [46].
For observational studies, the time horizon ranged between 2 and 10 years, while for model-based studies, the time horizon ranged from 15 years to a lifetime.Moreover, among the model-based studies, 21 used a time horizon of at least 25 years.The starting age for screening was generally either 40 or 50 years and continued until at least age 69 years in most cases, or death, whichever occurred first.
Screening compliance rates also differed across studies, ranging from 13% to 100%.Studies that adopted a rate less than 100% either reflected current screening rates or a minimum ideal rate to establish cost-effectiveness.Meanwhile, those with full screening compliance sought to express the maximum potential benefit of the screening program [2,30,31,41,[45][46][47][48][49][50].
The input parameters were sourced mainly from the existing literature; clinical databases and registries; clinical trials; perspective data from the study population; health insurance databases; and the National Cancer Institute-Surveillance, Epidemiology, and End Results Program.Discount rates were either 3% or 5%.
While most studies focused on populations at higher risk of GC, fewer studies investigated populations at average and intermediate risk, where risk was primarily measured by the presentation of Hp infection, gastric atrophy, and/or intestinal metaplasia.Other risk factors considered were familial exposure to Hp and smoking history.See Tables 1-3.

Willingness-to-Pay Thresholds and Sensitive Variables
In terms of the willingness-to-pay (WTP) threshold, studies either used the World Health Organization's recommendation of less than three time the annual national gross domestic product (GDP) per capita or a typical threshold level, such as USD 50,000/QALY or USD 100,000/QALY, or a level recommended within a particular local setting [51,52].See Table 1.
For some models, ICER was sensitive to transition probabilities, prevalence of disease and risk factors, distribution of cancer at screening, screening age, utility scores, discount rate, cost of screening and cost of follow-up procedures, compliance with treatment, and sensitivity and specificity of the screening test.Notwithstanding, most models were stable and ICER did not vary significantly when parameters were allowed to change independently.See Table 3.

Results on Quality of Reporting
The results of the 28-item CHEERS 2022 [24] checklist for the 31 selected studies are presented in Supplementary Table S1 in the ESM.Based on the CHEERS checklist, the quality of reporting was generally consistent among the selected articles, although a number of studies pre-dated the updated CHEERS 2022 [24] reporting guidelines and so some checklist items were not included.For example, of the 28 items, no study reported on criteria 21 and 25, which address patient and other study stakeholder engagements.Although some studies mentioned that the CHEERS checklist was used for reporting, albeit the previous version (CHEERS 2013) [53], many studies did not provide this list either in the main text or Supplementary Materials.Also, some studies did not report conflicts of interest and source of funding.See Table 3 and Supplementary Table S1 in the ESM.

Discussion
This systematic review revealed that screening for GC is always preferred to no screening, as demonstrated by cost-effectiveness analyses.Notwithstanding this, there was some variability in the results, mainly because the intervention strategies differed notably from one study to the next.These strategies included different combinations of primary and secondary GC screening tests, and follow-up treatments.Cost-effectiveness was also influenced by the incidence of GC in a given location; the type of screening intervention; and the prevalence of risk factors, mainly Hp infections.Overall, there was general agreement that GC screening is likely to be cost-effective in countries or regions or among high-risk populations where the incidence of disease is relatively high and the cost of screening is relatively low.This sentiment was expressed by Ascherman and Hur (2021) in an economic evaluation of endoscopic GC screening among Brazil, France, Japan, Nigeria, and the United States [47].
As a primary intervention, Hp screening and treatment is potentially cost-effective in high-risk regions.Lansdorp-Vogelaar et al. (2021) had a similar conclusion in a review of model-based studies that investigated the cost-effectiveness of GC screening and surveillance in Western countries [54].Meanwhile, secondary interventions that involve endoscopic screening are also cost-effective, but they only address disease malignancies rather than precancerous conditions.For countries with average to intermediate risk of GC, endoscopic screening of subpopulations with elevated risk of disease was also cost-effective.This was evident predominantly in the Chinese diaspora in other Asian countries and in the USA.Other high-risk diaspora groups include Hispanics and non-Hispanic blacks in the USA [42].
The value of primary intervention is that it allows for the detection and treatment of precancerous conditions, and it stymies, if not prevents, progression to malignancy and, ultimately, death [6][7][8].It also helps to identify those at varying degrees of gastric cancer risk based on serological findings, Hp infection, smoking history, age, and ethnicity.This facilitates a more tailored approach with respect to surveillance and treatment of each case [40].Primary intervention strategies including screening, early detection, and surveillance are also practical given the window of opportunity between gastric atrophy and tumor presentation [42,55,56].
Guidelines for primary intervention typically recommend mass Hp screening and eradication therapy (in asymptomatic persons) for the prevention of GC in populations at elevated risk of developing GC [22, [57][58][59].The full benefits of Hp eradication strategies are only realized in the long-run, manifesting in fewer cases of GS, fewer related deaths, and cost-savings [31,60].This long-run effect also accounts for the disparity in results among studies with longer versus shorter time horizons.It is also a critical factor to consider in deciding on Hp intervention across different populations, especially since Hp screening has higher sensitivity and specificity than UGI and endoscopy [33].
Meanwhile, according to one meta-analysis, endoscopic screening programs have the potential to reduce GC deaths by 40% and is therefore considered the golden standard of GC screening and detection [47,61].However, this tool is relatively invasive and may be associated with lower compliance rates [40].Nonetheless, the combination of Hp screening and eradication and follow-up endoscopy is an effective strategy for addressing the burdens associated with GC [37,62].
The findings from the studies highlighted in this systematic review are instructive to policy makers in deciding on GC intervention strategies for their respective jurisdictions.These findings suggest that interventions for GC are best tailored to a specific country setting and local context related to the incidence of disease, the prevalence of risk factors, and the cost and benefit of screening.A similar view was echoed by the Working Group of the International Agency for Research on Cancer (IARC) in its recommendation for countries, particularly those with a high incidence of GC, to assess their need for a gastric cancer program in light of the potential benefits and costs of such a program over time [22].The Working Group further advised that in developing a national Hp screening and treatment program, a country should account for factors such as local disease incidence and distribution, cost, effectiveness, and other competing health challenges, while ensuring that interventions are evidence-based [17].Furthermore, the outcome of an economic evaluation of a cancer screening program, especially for gastric cancer, hinges largely on the quality of parameter estimates, model specification, the diagnostic performance of screening tools, and the level of risk of cancer among the target population.
The level of cancer risk is important because it influences cancer incidence rates.As Hp infection is the primary risk factor for GC, particularly of the non-cardia type, populations with the highest infection rates tend to also have a greater incidence of GC [2,12,[15][16][17].This is true for Asian countries like China and Japan, as well as their diaspora, where Hp infection and GC are more prevalent [1].Furthermore, although the number of cases of GC has lowered over the years, the projected incident rate is expected to remain high in the future [63].Notwithstanding, the risk of GC is expected to decrease over time in countries at higher risk with successful Hp eradication strategies and also among high-risk diaspora populations in the absence of other environmental and extrinsic risk factors [42,64].This reality also has implications for the cost-effectiveness of screening strategies as they are expected to erode after each successive generation [42,64].
Countries at higher risk of GC have an age-standardized rate (ASR) of ≥20 per 100,000 and are ideal candidates for nationwide screening programs [43,65].In 2020, the countries with the highest risk, as measured by ASR, included Mongolia (32.5),Japan (31.6), the Republic of Korea (27.9),Tajikistan (23.4),China (20.6), and Kyrgyzstan (19.7) [1].National gastric cancer screening programs using radiographic screening and endoscopic examination currently exist in Japan and Republic of Korea, while in China, screening programs have emerged predominantly in regions where the incidence of disease is particularly high [13].Relatedly, Japan and Republic of Korea have experienced declines in the incidence and burden of GC linked to their respective national screening programs, while China continues to grapple with these challenges due in part to an aging population, limited resources given the scale of intervention needed to implement a national screening program, and notable regional diversity [44,66].These factors may account for the fact that <10% of diagnosed cases are at the early stage of the disease in China, while in Japan and Republic of Korea, early-stage diagnoses account for 50-70% of all diagnosed cases [9,10,16,67].As a comparison, in the USA, where no screening program exists, 75% of diagnosed cases occur at later stages of disease [42].
For countries with low and intermediate risk of GC (ASR < 10 per 100,000), populationwide screening is nonexistent because it is not cost-effective, and what is often recommended is surveillance and treatment of those with precancerous conditions like H pylori infections, atrophic gastritis, and intestinal metaplasia [43,58,68,69].In fact, in the USA, researchers found that among 50-year-old men, endoscopic mucosal resection (EMR) with endoscopic surveillance either every 1, 5, or 10 years for gastric dysplasia was costeffective (ICER: USD 18,600, USD 20,900, and USD 39,800/QALY, respectively, at a WTP: USD 100,000/QALY, (2007 USD) from a societal perspective [70].Although this intervention potentially reduces the risk of developing GC by at least 60%, its cost-effectiveness was less favorable on less advanced precancerous condition like intestinal metaplasia, with the possible exception of migrant populations from high-risk countries [70].
One meta-analysis demonstrated that even though immigrants may move from a country with a high incidence of GC to one with low incidence, they still maintain an inherent elevated risk of developing GC [71].Building on this, Shah et al. recounted the fact that the incidence of GC is notably greater in certain minority groups in the US, namely Hispanic and non-Hispanic blacks, and some Asian American groups, which have incidence rates two and six times that of non-Hispanic whites, respectively [15].Further investigation found that for these minority groups, a one-time GC screening using esophagogastroduodenoscopy/upper GI endoscopy (EGD) during a colonoscopy, with follow-up EGDs only if indicated, is cost-effective [42].
One region where further research is needed to confirm the cost-effectiveness of gastric cancer screening is Africa.While the continent has the highest prevalence of Hp infections globally, with about 70% of the population infected, the incidence of gastric adenocarcinoma remains relatively low compared to other regions (the age-standardized incidence rates per 100,000 of GC in 2022 for Africa, North America, Oceania, Europe, Latin America and the Caribbean, and Asia were 4, 4.1, 5.5, 7.9, 8.5, and 11, respectively [1])-a phenomenon called the "African Enigma" [72,73].The enigma is prefaced on the fact that the clinical presentation of patients in Africa with gastrointestinal conditions, particularly gastric atrophy, stemming from Hp infection is similar to that of patients in Western and Asian countries; however, progression to GC is less common [72,74,75].Researchers proffered several reasons for this epidemiological puzzle.Some credit under-resourced health systems and the absence of cancer registries for under-reporting of cancer cases [76].Others argue that the virulence of the strain of the Hp bacteria most prevalent in Africa (HpAfrica2) is less severe than those found in other regions, lacking the Cag Pathogenicity Island, which is linked to the development of GC [77].Relatedly, it has also been argued that the development of GC from Hp infections can be stymied in cases of co-parasitic infections that may alter the progression of disease by delaying atrophic gastritis [78].The impact of a diet consisting of fresh fruits and vegetables, which helps with reducing the risk of GC, has also been credited to be responsible for the enigma [79].
This systematic review has limitations.The main limitation is the exclusion of studies not written in English.The authors recognize that there are a number of economic evaluation studies written in languages other than English that were not included in this research.However, we anticipate that the conclusion of this review would not change even if those studies were included.We also acknowledge that the treatment strategies for Hp infection and GC would impact the cost-effectiveness of screening.However, these various strategies were not explicitly accounted for in this analysis.We are of the opinion that this analysis is beyond the scope of this review.

Conclusions
Gastric cancer (GC) screening can be cost-effective, but cost-effectiveness is dependent on context specific factors, including geographical location, the prevalence of GC in the local population, and the screening tool adopted.There is some benefit to targeting highrisk population groups like Asians and their diaspora for screening, as well as current and former smokers.Primary interventions (including Hp screening and screening based on multiple risk factors) and secondary intervention (endoscopic screening) were found to be cost-effective in high-risk regions compared with no screening.However, primary interventions were preferred to secondary interventions when both types of strategies were compared.In studies that focused on countries with intermediate-and average-risk regions, population-wide screening was not cost-effective, but screening was cost-effective when special population groups were targeted, e.g., Hispanics and non-Hispanic blacks in the USA, the Asian diaspora in the USA and Singapore, as well as current and former smokers.

Table 1 .
Characteristics of included studies.
To conduct a cost-utility analysis to determine whether endoscopic screening for stomach cancer in an intermediate-risk population would be cost-effective and to better define the high-risk groups in the population who would benefit from such a strategyCho et al., 2013 [29]

Table 2 .
Summary of study methods of included studies.
CDC-Centers for Disease Control and Prevention; SEER-Surveillance, Epidemiology, and End Results.

Table 3 .
Summary of outcomes of included studies.