Article Text

Original article
Gastric adenocarcinoma screening and prevention in the era of new biomarker and endoscopic technologies: a cost-effectiveness analysis
1. Jennifer M Yeh1,
2. Chin Hur2,
3. Zachary Ward1,
4. Deborah Schrag3,
5. Sue J Goldie1
1. 1Center for Health Decision Science, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
2. 2Massachusetts General Hospital Institute for Technology Assessment, Boston, Massachusetts, USA
3. 3Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
1. Correspondence to Dr Jennifer M Yeh, Center for Health Decision Science, Harvard T. H. Chan School of Public Health, 718 Huntington Avenue, Boston, MA 02115, USA; jyeh{at}hsph.harvard.edu

## Statistics from Altmetric.com

### Significance of this study

#### What is already known on this subject?

• Gastric cancer rates are declining, but more than 20 000 cases are diagnosed each year in the US and noncardia gastric adenocarcinoma (NCGA) remains the leading subtype.

• Screening for precursors of NCGA may be an effective strategy for preventing disease and reducing cancer deaths among US men, yet long-term benefits associated with new biomarkers and endoscopic technologies are uncertain.

#### What are the new findings?

• Although a one-time serum pepsinogen screen at age 50 years may prevent one in four intestinal-type NCGAs among men, population-based screening for the general population is unlikely to be a high-value approach for improving cancer outcomes.

• However, targeting high-risk smokers may be a cost-effective strategy to reduce NCGA deaths and warrants consideration.

#### How might it impact on clinical practice in the foreseeable future?

• Our model-based findings suggest screening current smokers with a serum pepsinogen test may be an effective and cost-effective strategy to identify men at elevated risk for NCGA who may benefit from endoscopic follow-up and treatment.

## Introduction

Gastric cancer is the third leading-cause of cancer-related mortality worldwide.1 Despite declines in recent decades, 22 000 individuals in the US are diagnosed each year, less than 30% of these individuals survive more than 5 years, and noncardia gastric adenocarcinoma (NCGA) remains the predominant phenotype.2 Screening efforts have primarily focused on detecting gastric cancer at earlier stages with more favourable prognosis in countries with high gastric cancer incidence.3–5 Recent advances in biomarker and endoscopic technologies to detect and treat precancerous and cancerous lesions may offer alternative strategies for NCGA control.

In contrast to other histological subtypes, epidemiological studies have well-established the precancerous development process for intestinal-type NCGA and the role of Helicobacter pylori infection and smoking. Normal gastric mucosa progresses to invasive cancer through a series of precancerous lesions.6 By initiating the precancerous process, H. pylori increases disease risk by as much as sixfold7 and is estimated to be responsible for approximately 75% of noncardia cancers.8 Elevating the risk of progression of existing precancerous lesions to more advanced lesions, smoking increases NCGA risk by approximately twofold.9–12 Other risk factors include diet and genetic factors.

As serum levels for pepsinogen I and II reflect the functional and morphologic status of the gastric mucosa, biomarker-based serum pepsinogen screening may identify individuals at higher risk for gastric cancer.13 ,14 A stepwise screening strategy, starting with a serum pepsinogen test followed by endoscopic biopsy sampling for positive test results, can help to distinguish low-risk individuals from high-risk individuals who are more likely to benefit from subsequent surveillance.15 The generalised use of the test has been limited despite clinical studies on its potential usefulness.16–18 Gastric cancer control efforts may be further enhanced by advances in endoscopic technology, including endoscopic mucosal resection (EMR), to detect and remove dysplastic/precancerous or cancerous lesions without surgery, which may potentially reduce intestinal-type NCGA risk by 90% among individuals with dysplasia.19 Findings from a randomised clinical trial suggest that H. pylori treatment may only reduce cancer incidence among individuals without existing precancerous lesions (defined as atrophy, intestinal metaplasia or dysplasia) at time of treatment.20 The estimated benefits associated with population-based H. pylori screening in the US are therefore likely much lower than previously estimated.21

Screening for precursors of NCGA may be an effective strategy for preventing invasive cancer, yet long-term benefits associated with new biomarker and endoscopic technologies are uncertain. Model-based analyses provide a framework for estimating potential benefits and risks associated with screening, extrapolating existing randomised clinical trial results, and guiding the design of future clinical studies by highlighting areas where better data are needed. We therefore employed a decision-analytic simulation-based modelling approach to synthesise the best available epidemiologic, clinical and economic data to assess the potential clinical benefits and cost-effectiveness of alternative screening strategies to reduce intestinal-type NCGA incidence and mortality.

## Methods

Using a mathematical simulation model of intestinal-type NCGA natural history among US men, we estimated the benefits, costs and cost-effectiveness associated with the following screening-based cancer control strategies: (1) serum pepsinogen screening, (2) endoscopic-based screening and (3) H. pylori screening. Described in detail elsewhere,22 the model is based on natural history parameters derived via empirical model calibration to age-specific precancerous lesions prevalence23 and Surveillance, Epidemiology, and End Results (SEER) cancer incidence24 to ensure model outputs are consistent with US epidemiologic data (see online supplementary materials). For each strategy, we estimated screening test performance, complication rates and treatment effectiveness from the published literature. Costs were based on US Medicare reimbursement rates and SEER-Medicare linked database estimates. Model outcomes included lifetime risk of intestinal-type NCGA, life expectancy, quality-adjusted life expectancy, lifetime costs and number of cause-specific deaths. To evaluate the relative performance of each strategy, we calculated incremental cost-effectiveness ratios (ICERs), defined as the additional cost of a specific strategy divided by its additional clinical benefit, compared with the next least expensive strategy, and expressed as cost per quality-adjusted-life-year (QALY) gained. We adopted a societal perspective and discounted all costs and clinical consequences at 3% annually.25 All costs are reported in 2012 dollars. To identify subgroups for targeted screening, we conducted subgroup analyses based on smoking status at time of screening: never, current and former smokers.

ICERs were more attractive for current smokers ($76 000 per QALY gained) and former smokers ($94 500 per QALY gained), and less attractive for never smokers ($137 800) (table 2). ### Sensitivity and uncertainty analysis For the overall cohort, results for the serum pepsinogen screening strategy were most sensitive to H. pylori prevalence, screen age, serum pepsinogen test sensitivity, and costs associated with endoscopic follow-up (figure 3). Results were moderately sensitive to serum pepsinogen screening costs and test specificity. Results remained largely unchanged over the plausible range for endoscopic sensitivity for dysplastic and cancerous lesions, EMR treatment effectiveness and complication risks, and proportion of EMR-eligible localised cancers. Figure 3 Tornado diagram on one-way sensitivity analysis for serum pepsinogen screening strategy: select model parameters. Based on one-way sensitivity analyses, this figure depicts the relative influence of select model parameters on results for serum pepsinogen screening for the overall cohort. The x-axis shows the effect of changes in selected variables on the incremental cost-effectiveness ratio (ICER) for serum pepsinogen screening at age 50 years (compared to no assessment). The y-axis shows selected model parameters, with the base case value and range used in the sensitivity analysis shown in parentheses. The shaded bars indicate the variation in the ICER caused by changes in the value of the indicated variable while all other variables were held constant. The dotted vertical black line indicates the ICER for the base case. The solid vertical grey line represents the commonly used$100 000 per quality-adjusted-life-year cost-effectiveness threshold. *The first number in the range indicates value yielding the lowest ICER; the second indicates value yielding the highest ICER. H. pylori, Helicobacter pylori; EMR, endoscopic mucosal resection.

We conducted scenario analyses for the overall cohort to explore alternative model assumptions. In our base case, we used estimates for surgical mortality risks among asymptomatic individuals in good health; if age-specific risks for symptomatic patients undergoing surgery were used instead,65 the ICER for serum pepsinogen screening increased to $128 400 per QALY gained. If 5% of endoscopic procedures required hospitalisation (related to complications or incidental findings that required follow-up care), the ICER increased to$120 600 per QALY gained. Similarly, if follow-up endoscopic surveillance was based on only macroscopic findings (ie, no gastric biopsies were taken), both the reduction in cancer risk (21% vs 26% in base case) and attractiveness of serum pepsinogen screening ($130 000 vs$105 400 per QALY gained in base case) declined. If we assumed that after EMR treatment, individuals still harboured intestinal metaplastic lesions (which could progress to invasive cancer), serum pepsinogen screening was also less attractive (ICER=$116 000 per QALY gained). For all these scenarios, ICERs remained less than$93 000 per QALY gained for current smokers.

To assess the impact of H. pylori prevalence, we determined the threshold value needed for serum pepsinogen screening to be considered cost-effective. At a $100 000 per QALY gained threshold, 40% of the cohort would need to be H. pylori infected (base case=31%) (see online supplementary figure S1). For current smokers, screening was considered cost-effective at nearly all prevalence levels. In contrast, for never smokers, the ICER exceeded the$100 000 per QALY threshold at all prevalence levels.

Two-way threshold analysis on serum pepsinogen test characteristics similarly found that the range of possible values for which serum pepsinogen would be preferred was much broader for current smokers compared to the other subgroups (figure 4). For current smokers, if sensitivity was greater than 60%, serum pepsinogen screening was the preferred strategy as long as test specificity was greater than 94%. For never smokers, serum pepsinogen screening was preferred only if the test had nearly perfect performance.

Figure 4

Two-way threshold analysis on serum pepsinogen test characteristics for the overall cohort and smoking subgroups. The preferred strategy based on serum pepsinogen screening test sensitivity and specificity are shown for the overall cohort (Panel A) and smoking subgroups (never smokers (Panel B), current smokers (Panel C), and former smokers (Panel D)). In each panel, the shaded grey region indicates the range of values over which serum pepsinogen screening would be considered the preferred strategy at a cost-effectiveness threshold of $100 000 per quality-adjusted-life-year gained. For example, for never smokers, serum pepsinogen screening would be the preferred strategy only with nearly perfect test sensitivity and specificity. For all possible test characteristic values depicted, serum pepsinogen screening dominated all other screening strategies, in that it was either less costly and more effective (endoscopic screening) or more effective and more cost-effective (Helicobacter pylori screening). A positive serum pepsinogen screen was defined as: pepsinogen I levels ≤70 µg/L and pepsinogen I/II ratio ≤3.0. For the overall cohort, probabilistic sensitivity analysis suggested that at a cost-effectiveness threshold of$100 000 per QALY gained, the probability that serum pepsinogen screening was the preferred strategy was 0.47 (table 2 and figure 5). The probability was 0.97 for current smokers and 0.85 for former smokers.

Figure 5

Cost-effectiveness acceptability curves for the overall cohort and smoking subgroups. To illustrate the uncertainty surrounding incremental cost-effectiveness ratio estimates, the cost-effectiveness acceptability curves depict the probability that a given strategy is the preferred strategy across a range of cost-effectiveness ratios. Results are depicted for the overall cohort (black solid lines) and subgroups, including never smokers (grey dotted line), current smokers (grey long dashed line), and former smokers (grey short dashed line). Results are based on 1000 second-order Monte Caro simulations in which model variables were simultaneously varied. The solid black vertical line indicates the $100 000 per quality-adjusted-life-year willingness-to-pay threshold commonly used as a benchmark in the US. ## Discussion Although intestinal-type NCGA incidence has declined over the past century, disease risk is largely determined by H. pylori infection acquired in childhood and the number of cases is projected to remain considerable for decades.22 To provide insight into this important public health and clinical problem and explore options for secondary prevention, we employed a model-based approach to estimate the comparative benefits and cost-effectiveness associated with several screening strategies. Our findings suggest that although a one-time serum pepsinogen screening (with endoscopic follow-up and EMR treatment if needed) at age 50 years can prevent as many as one in four intestinal-type NCGAs among US men, general population-wide screening is unlikely to be a high-value strategy for improving cancer outcomes. However, screening targeted to current smokers who are at elevated risk for premature death66 may be an effective and cost-effective strategy to reduce NCGA mortality. Our study is the first simulation model-based analysis to evaluate the clinical benefits and economic consequences of serum pepsinogen screening in the US. Previous model-based studies have focused on high-risk populations in Asia,67 or estimated the short-term economics of serum pepsinogen testing as a follow-up strategy for individuals diagnosed with atrophy or intestinal metaplasia.68 Neither study estimated the clinical benefits associated with serum pepsinogen screening in terms of a reduction in cancer risk, or provided estimates for smoking subgroups which can be used as the basis for targeting screening efforts. Consistent with published studies (see online supplementary table S2),45 ,69–74 our model-based estimates of serum pepsinogen screening performance underscore the potential usefulness of the test to detect and distinguish individuals at higher risk for developing cancer from those at lower risk.75 ,76 Furthermore, our estimates of the NNS to prevent one intestinal-type NCGA death (1157 US male smokers) suggest that serum pepsinogen screening may have similar benefits to mammography screening among 50–59-year-old women (NNS=1339 to prevent 1 breast cancer death), albeit smaller benefits than low-dose computed tomography (NNS=320 to prevent 1 lung cancer death)77–79 or flexible sigmoidoscopy (NNS=871 to prevent 1 colorectal cancer death).80 However, our findings should be cautiously considered given the notable uncertainty surrounding serum pepsinogen test performance,17 limited evidence in low-risk populations,18 and concerns surrounding the translation of clinical findings in high-risk populations to low-risk populations.81 As better data become available, our model can be refined and recalibrated to reflect these data, and as such, can serve as an iterative tool to provide updated assessments of the likely health and economic outcomes associated with secondary gastric cancer control efforts. The serum pepsinogen test has also been proposed as the basis for screening for intestinal-type NCGA itself (in contrast to identifying individuals with atrophy who are at elevated risk for NCGA as in our analysis). Our model found, however, that such a strategy, with a 77% sensitivity and 73% specificity for dysplastic and cancerous lesions,17 would not be cost-effective in the US, even among current smokers (see online supplementary table S3). While such a test would lead to similar reductions in cancer risk as atrophy screening, nearly 30% as opposed to 2% would have a false positive test and receive treatment unnecessarily leading to higher costs and possible harm without a commensurate gain in benefits. Similar to our threshold analyses on screening test characteristics (figure 4), these results highlight the importance of accurately detecting the absence of atrophy or precancerous lesions for any serum pepsinogen test-based screening strategy. Previous studies have concluded H. pylori screening is cost-effective in the US.21 ,82 Our findings provide updated estimates of the cost-effectiveness of population-based H. pylori screening based on randomised trial evidence that only individuals without existing precancerous lesions benefit from H. pylori treatment.20 Under this assumption, we found that targeting screening to 20-year-old individuals (who are less likely to have precancerous lesions) may be more effective in reducing cancer risk (1.6% vs 0.2%). However, even with the greater benefit, the strategy would remain unattractive compared to no screening (ICER=$2.7M per QALY) and dominated by serum pepsinogen screening. Recent results from another randomised trial in China suggest that all individuals, regardless of the presence of advanced lesions, may benefit from H. pylori treatment,83 potentially as a result of eradicating non-H. pylori bacteria that influence the later stages of gastric carcinogenesis.84 If we assumed that the risk of dysplasia was reduced by 50% among all treated individuals, H. pylori screening was indeed more attractive compared to no screening (21% reduction in cancer risk at an ICER of $85 000 per QALY). Yet, H. pylori screening was still dominated by serum pepsinogen screening as the reduction in cancer risk was also greater for serum pepsinogen screening (44%) and at a more favourable ICER ($70 700 per QALY). As such, despite the considerable uncertainty in H. pylori treatment effectiveness, our findings suggest that serum pepsinogen is likely to be a more effective and cost-effective NCGA screening strategy in the US.

Limitations to our study include using data from multiple sources with varying study designs. We conducted extensive probabilistic sensitivity analyses to account for the uncertainty in variables and assumptions, including disease natural history. We focused on only men, and made the simplifying assumption that the prevalence of H. pylori and smoking were independent because data regarding interactions are not available. We also only focused on one gastric cancer subtype. If we assumed that diffuse and other noncardia tumours (detectable for 24 months on average before becoming clinically symptomatic) were also detected via follow-up endoscopy for a positive serum pepsinogen screen, results were largely unchanged (ICER=$104 100 vs$105 400 in the base case). This was consistent with our finding that the majority of serum pepsinogen screening benefit was derived from the detection and removal of dysplastic lesions before they progressed to invasive cancer. We found however, that serum pepsinogen screening was less attractive if treated individuals still harboured intestinal metaplastic lesions (common in settings where H. pylori-related atrophy is frequently multifocal) or if endoscopic sensitivity for dysplasia was considerably lower. However, as long as sensitivity was greater than 60% (base case=81%), serum pepsinogen screening remained attractive for current smokers (ICER=\$99 400).

Notably, we based estimates of serum pepsinogen test performance and EMR treatment effectiveness on clinical studies from Japan given the limited data in Western populations. EMR is relative new, availability of and expertise with EMR technology is limited; additional training (and resources) will be needed to realise the projected screening benefits. Not all biopsy-detected dysplasia may be macroscopically visible and therefore, eligible for EMR. We found however that even if the large majority of individuals with dysplasia (60–70%) would require annual or biannual endoscopic surveillance before undergoing EMR treatment, results were largely unchanged. We also did not include the impact of endoscopy-related incidental findings and their downstream effects in our analysis; further analysis of their long-term effects is needed. Proton-pump inhibitors, widely used in the general population, may reduce serum pepsinogen test sensitivity by altering intragastric acidity and biomarker levels.85 Sensitivity analyses found that even if sensitivity fell to 60% (base case=71%), as long as test specificity was greater than 94%, the ICER remained attractive for current smokers.

Last, our model focused on NCGA screening in the US. Estimates of the clinical benefits and cost-effectiveness associated with screening strategies will vary in high-risk countries, such as Japan, where risk factor prevalence and influence on the multifactorial aetiology of gastric carcinogenesis may differ. As the projective validity of our model was consistent with data on precancerous lesions prevalence and cancer risk from the Netherlands, our findings are likely generalisable to this setting and other low-risk European countries with similar H. pylori and smoking profiles.86

Our model-based findings suggest that serum pepsinogen screening to reduce NCGA risk is not warranted for the general population. However, targeting high-risk smokers for screening may be an effective and cost-effective strategy to reduce intestinal-type NCGA mortality. Further, the marginal benefits associated with H. pylori screening, even among high risk subgroups, underscore the need for future clinical studies on alternative secondary gastric cancer control strategies, including serum pepsinogen screening, to improve cancer outcomes and overall survival.

View Abstract

• ## Supplementary Data

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Files in this Data Supplement:

## Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.