Dear Editors,
Gastric cancer (GC) is a prevalent digestive tract tumor. The Global Cancer Statistics Report (GLOBOCAN 2020) reveals 1,089,103 new cases globally, ranking fifth in incidence and fourth in mortality, with a case fatality rate of nearly 0.7 (769,000/1,089,000).1 If uncontrolled, GC could see 1.8 million new cases and 1.3 million deaths by 2040, significantly increasing the disease burden.2Helicobacter pylori (H. pylori) infection is a critical risk factor for GC, with strong evidence linking it to non-cardia gastric cancer.3,4 However, its association with cardia gastric cancer remains inconsistent, particularly in Western populations where correlations are often absent or negative. In contrast, East Asian studies frequently show an increased cardia cancer risk with H. pylori infection.5 Eradicating H. pylori is the most definitive and controllable factor in preventing gastric cancer, as shown by multiple clinical trials (Table 1),4,6–11 and meta-analyses have confirmed this conclusion.5,12–14 A meta-analysis of 10 global, randomized controlled trials observed that H. pylori eradication could decrease gastric cancer incidence (risk ratio = 0.54, 95% confidential interval (CI): 0.40–0.72) and mortality (risk ratio = 0.61, 95% CI: 0.40–0.92).12 Another meta-analysis recruiting eight randomized controlled studies and 16 cohort studies reached a similar conclusion, indicating a 46% reduction in gastric cancer risk.14 However, most studies included in these two meta-analyses come from East Asia, particularly China, where the baseline risk for healthy populations is relatively high. Additionally, many studies have an insufficient scale, leading to limited combined events.
Table 1Clinical studies on Helicobacter pylori eradication for GC prevention
| Authors | Study type | Region | Sample size | Intervention | Follow-up (years) | Primary endpoint | Results |
|---|
| Li et al,9 2019 | Blinded randomized placebo controlled trial | China | 3,365 | Helicobacter pylori treatment; vitamin supplementation; garlic supplementation | 22.3 | GC incidence; GC mortality | The risk of GC incidence was reduced by 52% and the risk of gastric cancer mortality was reduced by 38%. |
| Kumar et al,11 2020 | Retrospective cohort study | United States | 371,813 | Helicobacter pylori treatment | 20 | Gastric cancer incidence | The risk of GC was reduced among patients with confirmed eradication of Helicobacter pylori (sHR: 0.24, 95% CI: 0.15–0.41, p < 0.001) |
| Chiang et al,7 2020 | Long-term cohort study | Taiwan, China | 6,512 | Helicobacter pylori treatment | 14 | GC incidence; GC mortality | The incidence of GC was reduced by 53% (95% CI: 30–69%, p < 0.001) and the mortality rate was reduced by 25% (95% CI: −14–51%, p = 0.18) |
| Piazuelo et al,6 2021 | Prospective cohort study | United States | 356 | Helicobacter pylori treatment; placebo treatment | 20 | GC incidence | The GC risk was not reduced. Progression of the Correa score was reduced (OR: 0.59, 95% CI: 0.38–0.93) |
| Yan et al,10 2022 | Randomized controlled trial | China | / | Helicobacter pylori treatment; placebo treatment | 26.5 | GC incidence; GC mortality | The incidence of GC was reduced (HR: 0.57, 95% CI: 0.33–0.98) |
| Li et al,4 2023 | retrospective cohort study | United States | 29,543 | Helicobacter pylori treatment | 21 | NCGA incidence | The incidence of NCGA was reduced after a follow-up of ≥eight years (sHR: 0.37, 95% CI: 0.14-0.97). |
| Pan et al,8 2024 | Cluster-randomized controlled trial | China | 180,284 | Helicobacter pylori treatment; Symptom alleviation treatment | 11.8 | GC incidence | The incidence of GCr was reduced (HR: 0.86, 95% CI: 0.74–0.99) |
A recently published article in Nature Medicine has provided new evidence. Pan et al.8 designed a prospective, randomized, controlled study. Starting in 2011 in Linqu, Shandong, this study followed 180,284 individuals aged 25–54 for up to 11.8 years. Participants with positive C13 urea breath test results were randomly assigned to undergo a standard 10-day quadruple therapy for H. pylori eradication (with 20 mg omeprazole, 750 mg tetracycline, 400 mg metronidazole, and 300 mg bismuth citrate). The control group received symptom relief treatment once daily using omeprazole and bismuth citrate. Over the 11.8 years of follow-up, 1,035 new gastric cancer cases were recorded. An intention-to-treat analysis revealed a significant decline in gastric cancer incidence among individuals who received anti-H. pylori therapy (hazard ratio 0.86). There was a significant decrease in those who successfully eradicated H. pylori using the quadruple treatment (hazard ratio = 0.81). Subgroup analysis suggested that successfully eradicating H. pylori reduced the incidence (hazard ratio = 0.65) and mortality (hazard ratio = 0.57) of gastric cancer among individuals under 45. However, this reduction was only significant in the non-cardia gastric cancer subtype. For individuals aged 45 and above, the effect of H. pylori eradication treatment on the incidence and mortality of gastric cancer was insignificant. However, the cumulative incidence curves indicated that the group receiving anti-H. pylori treatment had lower incidence and mortality rates. Throughout the trial, the incidence of moderate adverse events within the anti-H. pylori treatment group was only 1.8%. No serious intolerance events were observed. This is the largest-scale follow-up interventional study on H. pylori to date. It confirms the importance of starting large-scale H. pylori screening and treatment within high-risk community settings immediately after reaching adulthood. These findings remain significantly consistent with the interventional trials undertaken in Changle, Fujian, with a 26.5-year follow-up,10 which reported a 43% reduced risk of GC after H. pylori treatment.
The study by Pan et al.8 has clarified the effectiveness and feasibility of H. pylori eradication for gastric cancer prevention in large-scale community populations and supports the implementation of H. pylori screening and treatment from early adulthood as an important public health policy in high-incidence areas of GC. The current research was conducted in high-incidence gastric cancer populations within China, and it is not appropriate to apply these findings to Western populations with lower gastric cancer incidence rates. A cohort study in the South American region found that H. pylori therapy was not associated with a reduction in GC risk, possibly because of the minimal number of outcome events.6 However, the risk of disease progression after H. pylori treatment was reduced by 41% in individuals who had precancerous gastric lesions at baseline. Recently, a large retrospective study from the United States evaluated the impact of H. pylori eradication treatment on the incidence of non-cardia gastric adenocarcinoma (NCGA).4 Compared to untreated H. pylori-positive individuals, treated individuals had a significantly decreased adjusted subdistribution hazard ratio for NCGA after eight years (0.37, 95% CI: 0.14–0.97). Therefore, H. pylori eradication treatment has a sustained protective effect on NCGA. This study provides a scientific basis for implementing H. pylori screening and treatment strategies in regions with low incidence of gastric cancer, like the United States.
Moreover, H. pylori eradication in high-incidence areas of gastric cancer demonstrates significant cost-effectiveness. Wang et al.15 compared various strategies for GC prevention and found that H. pylori eradication therapy is a cost-effective strategy to reduce the gastric cancer burden in the long run. In this research, annual endoscopic screening was the most effective for the general population, but it was less cost-effective compared to H. pylori eradication, with costs exceeding 70,000 yuan per gained quality-adjusted life year. Similarly, European SAPEA (Science Advice for Policy by European Academies) experts do not recommend annual gastroscopy for gastric cancer screening. Instead, they regard H. pylori eradication as the most viable solution for reducing GC incidence in Europe.16 Although nationwide endoscopic screening does not provide a cost-effective advantage, combining H. pylori eradication therapy with screening for risk subgroups may improve the balance between cost and effectiveness. In summary, we recommend implementing a “screen and treat” strategy for H. pylori in populations from high-incidence areas of GC, while adopting a “test and treat” strategy in low-incidence areas. In addition to H. pylori screening, improving the rate of H. pylori eradication is also an important strategy for gastric cancer prevention and control. H. pylori infection has a familial clustering tendency and can be transmitted among family members. Therefore, we emphasize the management of H. pylori at the family level to reduce the risk of reinfection.17 Future studies aimed at comparing the H. pylori eradication benefits in various gastric cancer risk populations can improve the precise prevention of gastric cancer. Meanwhile, better screening models for accurately differentiating the high-risk levels of gastric cancer populations will globally advance screening efforts.
Declarations
Funding
This research was supported by The Science and Technology Project of Shenzhen under Grant No. KCXFZ20211020163558024.
Conflict of interest
Prof. Ye Chen has been an editorial board member of Cancer Screening and Prevention since March 2022. The authors declare that they have no other conflict of interests.
Authors’ contributions
Article design, writing (YC), and literature review (BL). All authors have read and approved the final manuscript.