Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands

Tsung-Hsien Chiang, Wei-Jung Chang, Sam Li-Sheng Chen, Amy Ming-Fang Yen, Jean Ching-Yuan Fann, Sherry Yueh-Hsia Chiu, Yi-Ru Chen, Shu-Ling Chuang, Chun-Fu Shieh, Cheng-Ying Liu, Han-Mo Chiu, Hung Chiang, Chia-Tung Shun, Ming-Wei Lin, Ming-Shiang Wu, Jaw-Town Lin, Chang-Chuan Chan, David Y Graham, Hsiu-Hsi Chen, Yi-Chia Lee, Tsung-Hsien Chiang, Wei-Jung Chang, Sam Li-Sheng Chen, Amy Ming-Fang Yen, Jean Ching-Yuan Fann, Sherry Yueh-Hsia Chiu, Yi-Ru Chen, Shu-Ling Chuang, Chun-Fu Shieh, Cheng-Ying Liu, Han-Mo Chiu, Hung Chiang, Chia-Tung Shun, Ming-Wei Lin, Ming-Shiang Wu, Jaw-Town Lin, Chang-Chuan Chan, David Y Graham, Hsiu-Hsi Chen, Yi-Chia Lee

Abstract

Objective: Although mass eradication of Helicobacter pylori has been proposed as a means to eliminate gastric cancer, its long-term effects remain unclear.

Design: Mass eradication of H. pylori infection was launched in 2004 and continued until 2018 for a high-risk Taiwanese population aged 30 years or older dwelling on Matsu Islands with prevalent H. pylori infection. Test positives for the 13C-urea breath test underwent eradication therapy. We evaluated the effectiveness of the mass eradication in reducing two main outcomes, incidence and mortality rates of gastric cancer, until the end of 2016 and 2018, respectively.

Results: After six rounds of mass screening and eradication, the coverage rate reached 85.5% (6512/7616). The referral rate for treatment was 93.5% (4286/4584). The prevalence rates of H. pylori fell from 64.2% to 15.0% with reinfection rates of less than 1% per person-year. The presence and severity of atrophic gastritis and intestinal metaplasia also decreased with time. Compared with the historical control period from 1995 to 2003, the effectiveness in reducing gastric cancer incidence and mortality during the chemoprevention period was 53% (95% CI 30% to 69%, p<0.001) and 25% (95% CI -14% to 51%, p=0.18), respectively. No significant changes were noted in the incidence rates of other digestive tract cancers or the antibiotic resistance rate of H. pylori.

Conclusion: Population-based eradication of H. pylori has significantly reduced gastric cancer incidence with no increase in the likelihood of adverse consequences. A significant reduction in mortality is likely to be achieved with a longer follow-up period.

Trial registration number: NCT00155389.

Keywords: cancer prevention; gastric cancer; helicobacter pylori.

Conflict of interest statement

Competing interests: DYG is a consultant for RedHill Biopharma and Phathom Pharmaceuticals regarding novel H. pylori therapies and has received research support for culture of Helicobacter pylori. The rest authors have no conflicts of interest.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Timeline of the gastric cancer prevention programme implemented on the Matsu Islands, Taiwan. EGD, oesophagogastroduodenoscopy; UBT, urea breath test.
Figure 2
Figure 2
Prevalence rates and reinfection rates of Helicobacter pylori (HP).
Figure 3
Figure 3
The presence and severity of premalignant gastric lesions according to the operative link for gastritis assessment of atrophic gastritis (OLGA) and operative link for gastritis assessment of intestinal metaplasia (OLGIM) grading systems. over 2004–2018, for the presence of atrophic gastritis and intestinal metaplasia (ie, grade ≥1), the prevalence rates declined from 55.9% to 15.9% and from 31.7% to 21.4%, respectively (both p

Figure 4

Incidence rates of gastric cancer…

Figure 4

Incidence rates of gastric cancer between 1995 and 2016, correlated with the start…

Figure 4
Incidence rates of gastric cancer between 1995 and 2016, correlated with the start of the mass eradication programme in 2004. The dash line indicates the predicted trend to 2025. The Gamma-Poisson regression model was internally validated by using data on the incidence rate of gastric cancer between 1995 and 2003 with the goodness-of-fit test (χ²=4.95; p=0.84). The magnitude of risk reduction was determined by comparing the expected number of cases with the number observed during the chemoprevention period.

Figure 5

Rates of mortality from gastric…

Figure 5

Rates of mortality from gastric cancer between 1995 and 2018, correlated with the…

Figure 5
Rates of mortality from gastric cancer between 1995 and 2018, correlated with the start of the mass eradication programme in 2004. The dash line indicates the predicted trend to 2025. The Gamma-Poisson regression model was internally validated by using data on the mortality rate of gastric cancer between 1995 and 2003 with the goodness-of-fit test (χ²=3.88; p=0.92). The magnitude of mortality reduction was determined by comparing the expected number of cases with the number observed during the chemoprevention period.
Figure 4
Figure 4
Incidence rates of gastric cancer between 1995 and 2016, correlated with the start of the mass eradication programme in 2004. The dash line indicates the predicted trend to 2025. The Gamma-Poisson regression model was internally validated by using data on the incidence rate of gastric cancer between 1995 and 2003 with the goodness-of-fit test (χ²=4.95; p=0.84). The magnitude of risk reduction was determined by comparing the expected number of cases with the number observed during the chemoprevention period.
Figure 5
Figure 5
Rates of mortality from gastric cancer between 1995 and 2018, correlated with the start of the mass eradication programme in 2004. The dash line indicates the predicted trend to 2025. The Gamma-Poisson regression model was internally validated by using data on the mortality rate of gastric cancer between 1995 and 2003 with the goodness-of-fit test (χ²=3.88; p=0.92). The magnitude of mortality reduction was determined by comparing the expected number of cases with the number observed during the chemoprevention period.

References

    1. Bray F, Ferlay J, Soerjomataram I, et al. . GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;2018:394–424.
    1. Tan MC, Balakrishnan M, Graham DY. Gastric cancer worldwide except Japan : Shiotani A, Gastric cancer with special focus on studies from Japan. Singapore: Springer, 2018: 17–28.
    1. Hunt RH, Camilleri M, Crowe SE, et al. . The stomach in health and disease. Gut 2015;64:1650–68. 10.1136/gutjnl-2014-307595
    1. Graham DY. Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits. Gastroenterology 2015;148:719–31. 10.1053/j.gastro.2015.01.040
    1. IARC Helicobacter pylori Working Group (2014) Helicobacter pylori Eradication as a Strategy for Gastric Cancer Prevention. Lyon, France: International Agency for Research on Cancer (IARC Working Group Reports, No. 8). Available: [Accessed 6 Aug 2019].
    1. Fukase K, Kato M, Kikuchi S, et al. . Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 2008;372:392–7. 10.1016/S0140-6736(08)61159-9
    1. Choi IJ, Kook M-C, Kim Y-I, et al. . Helicobacter pylori therapy for the prevention of metachronous gastric cancer. N Engl J Med 2018;378:1085–95. 10.1056/NEJMoa1708423
    1. Li W-Q, Zhang J-Y, Ma J-L, et al. . Effects of Helicobacter pylori treatment and vitamin and garlic supplementation on gastric cancer incidence and mortality: follow-up of a randomized intervention trial. BMJ 2019;366:l5016. 10.1136/bmj.l5016
    1. Choi IJ, Kim CG, Lee JY, et al. . Family History of Gastric Cancer and Helicobacter pylori Treatment. N Engl J Med 2020;382:427–36. 10.1056/NEJMoa1909666
    1. Sugano K, Tack J, Kuipers EJ, et al. . Kyoto global consensus report on Helicobacter pylori gastritis. Gut 2015;64:1353–67. 10.1136/gutjnl-2015-309252
    1. Malfertheiner P, Megraud F, O'Morain CA, et al. . Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 2017;66:6–30. 10.1136/gutjnl-2016-312288
    1. Rabeneck L, Lansdorp-Vogelaar I. Assessment of a cancer screening program. Best Pract Res Clin Gastroenterol 2015;29:979–85. 10.1016/j.bpg.2015.09.009
    1. Lee Y-C, Lin J-T, Wu H-M, et al. . Cost-Effectiveness analysis between primary and secondary preventive strategies for gastric cancer. Cancer Epidemiol Biomarkers Prev 2007;16:875–85. 10.1158/1055-9965.EPI-06-0758
    1. Doorakkers E, Lagergren J, Santoni G, et al. . Helicobacter pylori eradication treatment and the risk of Barrett's esophagus and esophageal adenocarcinoma. Helicobacter 2020;25:e12688. 10.1111/hel.12688
    1. Hu K-C, Wu M-S, Chu C-H, et al. . Decreased colorectal adenoma risk after Helicobacter pylori eradication: A retrospective cohort study. Clin Infect Dis 2019;68:2105–13. 10.1093/cid/ciy591
    1. Megraud F, Coenen S, Versporten A, et al. . Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut 2013;62:34–42. 10.1136/gutjnl-2012-302254
    1. Sung JJY. Population-based screening and mass eradication of Helicobacter pylori infection to prevent gastric cancer: There are more questions than answers. J Gastroenterol Hepatol 2020;35:521–2. 10.1111/jgh.15024
    1. Lee Y-C, Wu H-M, Chen TH-H, et al. . A community-based study of Helicobacter pylori therapy using the strategy of test, treat, retest, and re-treat initial treatment failures. Helicobacter 2006;11:418–24. 10.1111/j.1523-5378.2006.00432.x
    1. Lee Y-C, Chen TH-H, Chiu H-M, et al. . The benefit of mass eradication of Helicobacter pylori infection: a community-based study of gastric cancer prevention. Gut 2013;62:676–82. 10.1136/gutjnl-2012-302240
    1. Chiang T-H, Chiu SY-H, Chen SL-S, et al. . Serum pepsinogen as a predictor for gastric cancer death: a 16-year community-based cohort study. J Clin Gastroenterol 2019;53:e186–93. 10.1097/MCG.0000000000000992
    1. Liou J-M, Chen C-C, Chang C-Y, et al. . Sequential therapy for 10 days versus triple therapy for 14 days in the eradication of Helicobacter pylori in the community and hospital populations: a randomised trial. Gut 2016;65:1784–92. 10.1136/gutjnl-2015-310142
    1. Cook TD, Campbell DT. Quasi-Experiments Interrupted Time-Series Designs : Quasi-Experimentation: Design & Analysis Issues for Field Settings. Boston: Houghton Mifflin Co, 1979: 207–32.
    1. Dixon MF, Genta RM, Yardley JH, et al. . Classification and grading of gastritis. The updated Sydney system. International workshop on the histopathology of gastritis, Houston 1994. Am J Surg Pathol 1996;20:1161–81. 10.1097/00000478-199610000-00001
    1. Rugge M, Meggio A, Pennelli G, et al. . Gastritis staging in clinical practice: the OLGA staging system. Gut 2007;56:631–6. 10.1136/gut.2006.106666
    1. Capelle LG, de Vries AC, Haringsma J, et al. . The staging of gastritis with the OLGA system by using intestinal metaplasia as an accurate alternative for atrophic gastritis. Gastrointest Endosc 2010;71:1150–8. 10.1016/j.gie.2009.12.029
    1. Chiang CJ, Chen YC, Chen CJ, et al. . Taiwan cancer registry Task force. cancer trends in Taiwan. Jpn J Clin Oncol 2010;40:897–904.
    1. National Cancer Registry On-Line interactive data acquisition system, health promotion administration, Ministry of health and welfare, Taiwan. Available: [Accessed 20 Feb 2020].
    1. Cancer Registry Annual Report Health promotion administration, Ministry of health welfare, Taiwan, 2017. Available: [Accessed 6 Jul 2020].
    1. Department of Household Registration, Ministry of the Interior, Taiwan . Household registration statistics data analysis. Available: [Accessed 20 Feb 2020].
    1. Bosman FT, Carneiro F, Hruban RH. WHO classification of tumours of the digestive system. Lyon: IARC, 2010.
    1. Congdon PD. Bayesian hierarchical models: with applications using R. Second edn Chapman and Hall/CRC Press, 2019.
    1. Arnold M, Park JY, Camargo MC, et al. . Is gastric cancer becoming a rare disease? a global assessment of predicted incidence trends to 2035. Gut 2020;69:823–9. 10.1136/gutjnl-2019-320234
    1. Jun JK, Choi KS, Lee H-Y, et al. . Effectiveness of the Korean National cancer screening program in reducing gastric cancer mortality. Gastroenterology 2017;152:1319–28. 10.1053/j.gastro.2017.01.029
    1. Lee Y-C, Chiang T-H, Chou C-K, et al. . Association between Helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta-analysis. Gastroenterology 2016;150:1113–24. 10.1053/j.gastro.2016.01.028
    1. Ford AC, Yuan Y, Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer: systematic review and meta-analysis. Gut 2020;69:2113–21. 10.1136/gutjnl-2020-320839
    1. Chen Q, Liang X, Long X, et al. . Cost-effectiveness analysis of screen-and-treat strategy in asymptomatic Chinese for preventing Helicobacter pylori-associated diseases. Helicobacter 2019;24:e12563. 10.1111/hel.12563
    1. Wong BC-Y, Lam SK, Wong WM, et al. . Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 2004;291:187–94. 10.1001/jama.291.2.187
    1. Leung WK, Lin S-R, Ching JYL, et al. . Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication. Gut 2004;53:1244–9. 10.1136/gut.2003.034629
    1. Liou J-M, Malfertheiner P, Lee Y-C, et al. . Screening and eradication of Helicobacter pylori for gastric cancer prevention: the Taipei global consensus. Gut 2020;69:2093–112. 10.1136/gutjnl-2020-322368
    1. Blaser MJ. Antibiotic use and its consequences for the normal microbiome. Science 2016;352:544–5. 10.1126/science.aad9358
    1. Bair M-J, Chuang S-L, Lei W-Y, et al. . Planning mass eradication of Helicobacter pylori infection for indigenous Taiwanese peoples to reduce gastric cancer. J Gastroenterol Hepatol 2020;35:609–16. 10.1111/jgh.14898
    1. Graham DY, Lee Y-C, Wu M-S. Rational Helicobacter pylori therapy: evidence-based medicine rather than medicine-based evidence. Clin Gastroenterol Hepatol 2014;12:177–86. 10.1016/j.cgh.2013.05.028
    1. Liou JM, Chen CC, Chang CM, et al. . Taiwan Gastrointestinal Disease and Helicobacter Consortium. Long-term changes of gut microbiota, antibiotic resistance, and metabolic parameters after Helicobacter pylori eradication: a multicentre, open-label, randomised trial. Lancet Infect Dis 2019;19:1109–20.
    1. Guo Y, Zhang Y, Gerhard M, et al. . Effect of Helicobacter pylori on gastrointestinal microbiota: a population-based study in Linqu, a high-risk area of gastric cancer. Gut 2020;69:1598–607. 10.1136/gutjnl-2019-319696
    1. Rugge M, Meggio A, Pravadelli C, et al. . Gastritis staging in the endoscopic follow-up for the secondary prevention of gastric cancer: a 5-year prospective study of 1755 patients. Gut 2019;68:11–17. 10.1136/gutjnl-2017-314600
    1. Chiang Tsung‐Hsien, Maeda M, Yamada H, et al. . Risk Stratification for Gastric Cancer after Helicobacter pylori Eradication: A Population‐based Study on Matsu Islands. J Gastroenterol Hepatol 2020. 10.1111/jgh.15187

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