Best Practice & Research Clinical Gastroenterology 28 (2014) 1107e1114
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
13
The fight against gastric cancer e the IARC Working Group report Rolando Herrero, MD, PhD, Group Head *, Jin Young Park, PhD, Scientist, David Forman, PhD, Senior Visiting Scientist International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France
a b s t r a c t Keywords: Gastric cancer Helicobacter pylori Eradication Prevention
Gastric cancer is the third cause of cancer death worldwide, and Helicobacter pylori infection causes almost 90% of non-cardia cancers, the predominant type. H. pylori infection is treatable, and in clinical trials there is evidence of a 30e40% reduction in incidence of gastric cancer among treated subjects. However, with a few exceptions, there are no public health programmes for gastric cancer prevention. In December 2013, the International Agency for Research on Cancer (IARC), organized a Working Group of international experts to discuss and make recommendations for gastric cancer control. The Working Group considered that the enormous burden of disease, which is not expected to decline in the coming decades, requires decisive public health action to include gastric cancer in cancer control programmes. Interventions should be tailored to the local conditions and consider populationbased screening and eradication of H. pylori, in the context of evaluation of feasibility, efficacy and adverse consequences. © 2014 Elsevier Ltd. All rights reserved.
The International Agency for Research on Cancer (IARC) of the World Health Organization organized a Working Group Meeting in December 2013 to review evidence regarding H. pylori treatment as a strategy for preventing gastric cancer, including discussions on existing regional gastric cancer prevention efforts, health effects, cost and feasibility of H. pylori screening and treatment programmes,
* Corresponding author. Head, Prevention and Implementation Group, Section of Early Detection and Prevention, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France. Tel.: þ33 4 72 73 86 83. E-mail address: [email protected] (R. Herrero).
http://dx.doi.org/10.1016/j.bpg.2014.10.003 1521-6918/© 2014 Elsevier Ltd. All rights reserved.
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and current and planned studies on the topic. The Working Group members included 19 external experts and 11 IARC participants and produced a report and recommendations [1] (Fig. 1). Gastric cancer is the third leading cause of cancer mortality, with more than 700,000 deaths per year worldwide [2]. Incidence and mortality from this malignancy are characterized by declining trends in most countries, predominance of males and extreme regional variations between and within countries (Fig. 2). In addition, the burden of the disease is higher in less developed countries, where 70% of the cases occur. Despite declining incidence trends in the last few decades, ageing of the population prevents overall reductions in the burden of disease. Infection with H. pylori is a recognized cause of gastric cancer, as has been determined by IARC in two consecutive evaluations, and recent estimates indicate that 90% of all non-cardia gastric cancers are caused by H. pylori [2]. The prevalence of H. pylori has been declining in the last few decades in many countries around the world, and this is likely to explain a large part of the decline in gastric cancer [3]. The Working Group noted that gastric cancer, despite its important morbidity and mortality burden has not been a public health priority, and very few countries have established control efforts. The Republic of Korea is one of the exceptions, with an established nationwide screening programme, which provides upper gastrointestinal series or endoscopy every 2 years to individuals aged 40 years and older [4]. Among participants in this programme, a large fraction of the cancers are detected early and patients benefit from high survival rates. In Japan, screening with barium contrast imaging has had limited coverage. In 2013, the Japanese government approved national health insurance coverage for antibiotic treatment for H. pylori infection in patients with endoscopically diagnosed chronic gastritis [5]. A regional programme in Taiwan, China, provides H. pylori stool antigen testing together with faecal immunochemical testing for colorectal cancer screening. Subjects positive for H. pylori are offered endoscopic screening and antibiotic treatment [6]. In Latin America, Chile has introduced an opportunistic gastric cancer screening programme for symptomatic adults aged 40 years and older, including endoscopic examination for H. pylori detection, biopsy, and treatment [7]. There are very few public health programmes for gastric cancer prevention and control in other areas of the world [8,9]. Several trials have investigated the role of H. pylori eradication on incidence of gastric cancer [10]. In a recent meta-analysis of randomized clinical trials the estimated relative risk was 0.66
Fig. 1. H. pylori eradication as a strategy for preventing gastric cancer. IARC Working Group met on 4e6 December 2013 in IARC, Lyon-France.
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Fig. 2. a: Male age-standardized incidence rates of gastric cancer by country in 2012 (Globocan 2012) ASR: age-standardized rates b: Female age-standardized incidence rates of gastric cancer by country in 2012 (Globocan 2012) ASR: age-standardized rates.
(95% confidence interval, 0.46e0.95), and a trial in Japan investigated impact of H. pylori treatment after endoscopic resection of early gastric cancer, reporting a statistically significant reduction in risk of metachronous tumors. Despite the results of these trials and the possibility of a 30e40% reduction in gastric cancer incidence by helicobacter eradication, several unresolved issues were discussed by the Working Group, including the difficulty of precise estimation of overall benefits and the possibility of adverse consequences.
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In addition to prevention of gastric cancer, H. pylori treatment significantly reduces risk of new ulcer development and visits to medical facilities for dyspepsia symptoms. However, some studies have suggested that H. pylori may have immunological and physiological benefits [11] and therefore that treatment to eradicate the organism might have deleterious effects. Despite inconsistent findings, epidemiologic studies have demonstrated that the absence of H. pylori infection correlates with gastro-oesophageal reflux disease (GORD), Barrett oesophagus and oesophageal adenocarcinoma. In addition, there is some evidence for negative associations between H. pylori infection and asthma, eczema, and other immunological conditions. There are also data associating H. pylori treatment with weight gain, although the magnitude of the association is unlikely to explain the current obesity trends. One of the important concerns when considering mass-eradication of H. pylori, which affects more than 50% of the adult population in high incidence areas, is the development of antibiotic resistance and alterations of the intestinal microbiota [12]. A programme of population screening and treatment for H. pylori could increase antibiotic-resistant pathogens within the community, although it may be difficult to identify the impact of the intervention against the background of resistance due to widespread use of antibiotics for other purposes (including veterinary). The problem may be more serious if the H. pylori treatment regimen includes antibiotics that are essential against serious human infections. Treatment for H. pylori infection selects for resistant organisms and can alter the intestinal microbiome, with yet unknown possible health consequences. H. pylori screening and treatment as a mass intervention is probably feasible and affordable. An inexpensive blood test can select subjects for treatment; with sufficient sensitivity and specificity for a screening programme. The urea breath test and stool antigen test are also highly sensitive and more specific for active infection and have been recommended for clinical management [13], but are more expensive and complex to administer. Some of the basic principles to take into account for the establishment of preventive interventions were also discussed [14], emphasizing that strategies must be tailored to local conditions and that care should be taken to prevent widespread implementation before sufficient knowledge about their efficacy, safety, and economic impact. The multisectorial approach and community participation were also emphasized. Treatment regimens with two or three inexpensive, generic antibiotics plus a proton pump inhibitor for 7e14 days can achieve greater than 80% success in eliminating H. pylori infection, although effectiveness will vary according to the profile of antibiotic resistance in the target population [15]. Although the ideal approach would be a treatment chosen based on culture and susceptibility testing, for population-based treatment programmes the most reasonable will be to use regimens proven reliably effective in the area or based on the observed population pattern of antimicrobial resistance. Health economic models reported to date show that population H. pylori screening and treatment strategies in developed countries are cost-effective at a threshold of US$ 50,000 per life-year saved [16]. However, published models are based on observational epidemiological data rather than on randomized trials evaluating H. pylori treatment to prevent gastric cancer and most did not evaluate impact on added benefits or possible deleterious effects of treatment. Also, the absence of data from low-income countries limits the utility of the analyses. Gastric cancer is a multifactorial disease, and a combination of markers including host genetic factors, H. pylori virulence factors (e.g., cagA), markers of gastric atrophy (e.g., pepsinogens) and environmental factors such as diet may identify patients at risk and could potentially help stratify subjects for treatment decisions. However, the value of using markers to guide public health interventions is not established [17]. Novel approaches to improve the predictive value of existing biomarkers and new biomarkers, including ghrelin, a gastric hormone involved in appetite control and energy balance regulation, are actively being investigated by the US National Cancer Institute [18]. Several clinical trials under way should help clarify whether and how to implement populationbased H. pylori screening and treatment programmes. The largest is a randomized cluster trial in Linqu County in China initiated in 2011 [19], which is enrolling 200,000 participants aged 25e64 years from a high-risk population. Participants are allocated to treatment with anti-H. pylori quadruple therapy or to control (low-dose omeprazole and bismuth citrate) and will be followed up for 10 years.
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The H. pylori Screening Study (HPSS) in the United Kingdom started in 1997, and was designed to assess whether screening and eradication of H. pylori infection in men aged 35e69 years and women aged 45e69 years reduces the incidence of gastric cancer [20]. The number of participants recruited in the study was 28,000 per arm, with a planned follow-up of 15 years or more after recruitment. Results should be available within the next few years. Additional work is underway in the Matsu Islands of Taiwan since 2004 [21]. During three consecutive phases, eradication rates associated with a test-treat-retest-retreat strategy, effectiveness of H. pylori treatment to modify prevalence of H. pylori and neoplastic lesions, reinfection rates and impact on drug-resistance patterns are being investigated in detail. The GISTAR study, a multicentre randomized study is planned for Latvia, Belarus, and the Russian Federation [22] in collaboration with IARC. The objective is to evaluate whether serum pepsinogen and H. pylori testing are effective in identifying high-risk subjects to be referred for appropriate treatment with subsequent reduction in gastric cancer mortality. A pilot study in Latvia was launched in 2013 to test the study procedures, assumptions, and acceptability of the methods. Another randomized controlled trial started in 2014 in the Republic of Korea as a collaboration between the Korean National Cancer Centre and IARC. It will evaluate the preventive efficacy and effectiveness of H. pylori treatment in reducing gastric cancer incidence among participants aged 40e60 years recruited from the national cancer screening programme [23]. The trial is scheduled to run for 10 years, with biennial endoscopic follow-up. Conclusions and recommendations The Working Group recognizes that gastric cancer remains a condition of high importance for global health despite the decline in incidence in several areas of the world, and it is likely to remain so for the foreseeable future unless effective control measures are implemented [24]. The continuing high global burden of gastric cancer and the feasibility of treating its principal cause thus make it a logical target for intervention. There is an acute need to commit more public health resources to gastric cancer control. The Working Group recommends that all countries consider including gastric cancer in their national cancer control programmes and that they conduct detailed assessments of its current and future human and economic impacts and of the potential value of prevention strategies. Collecting standardized data on H. pylori prevalence will be useful for predicting the future burden of gastric cancer and other H. pylori-associated conditions and may help to identify subpopulations that appear most likely to benefit from interventions. Randomized clinical trials have found that H. pylori treatment is effective in preventing gastric cancer, and models indicate that H. pylori screening and treatment strategies would be cost-effective. However, uncertainties remain about the generalizability of results and about the costeeffectiveness and possible adverse consequences of programmes applied in community settings. The Working Group therefore recommends that countries explore the possibility of introducing population-based H. pylori screening and treatment programmes, but cautions that decisions as to whether and how to implement H. pylori testing and treatment must hinge on local considerations of disease burden, other health priorities, and costeeffectiveness analyses that are relevant to the particular country. Moreover, these programmes should be implemented in conjunction with a scientifically valid assessment of programme processes, feasibility, effectiveness, and possible adverse consequences. Participants Working Group Members Dr Christian C. Abnet. Division of Cancer Epidemiology & Genetics, National Cancer Institute Bethesda, MD, USA. [email protected]. Dr Masahiro Asaka. Department of Cancer Preventive Medicine, Hokkaido University Graduate School of Medicine Sapporo, Japan. [email protected].
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Dr Il Ju Choi. Gastric Cancer Center, National Cancer Center, Goyang, Republic of Korea. cij1224@ncc. re.kr. Dr Pelayo Correa. Division of Gastroenterology, Hepatology, and Nutrition Vanderbilt University, Nashville, TN, USA. [email protected]. Dr Catterina Ferreccio. Departamento de Salud Pública/Escuela de Medicina Pontificia Universidad lica de Chile Santiago, Chile. [email protected]. Cato Dr Javier P. Gisbert Department of Gastroenterology Hospital Universitario de La Princesa Instituto n Sanitaria Princesa and CIBEREHD Madrid, Spain. [email protected]. de Investigacio Dr Karen J. Goodman Department of Medicine & School of Public Health University of Alberta Edmonton, AB, Canada. [email protected]. Dr Vadim M. Govorun Research Institute of Physico-Chemical Medicine, Moscow, Russian Federation. [email protected]. Dr E. Robert Greenberg. Fred Hutchinson Cancer Research Center, Seattle, WA, USA. E.Robert. [email protected]. Dr Yi-Chia Lee. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, China. [email protected]. rcis Leja. Faculty of Medicine, University of Latvia, Riga, Latvia. [email protected]. Dr Ma Dr Reza Malekzadeh. Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran. [email protected]. graud. INSERM U853 & Bacteriology Laboratory, University of Bordeaux, Bordeaux, Dr Francis Me France. [email protected]. Dr Paul Moayyedi. Department of Medicine, McMaster University, Hamilton, ON, Canada. [email protected]. ~ oz. National Cancer Institute of Colombia (Emeritus Professor), Lyon, France. nubia. Dr Nubia Mun [email protected]. Dr Julie Parsonnet. Departments of Medicine and of Health Research and Policy Stanford University, Stanford, CA, USA. [email protected]. n en, Enfermedades Infecciosas, Instituto Mexicano del Dr Javier Torres Unidad de Investigacio Seguro Social, Mexico City, Mexico. [email protected]. Dr Nicholas J. Wald. Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, London, United Kingdom. [email protected]. Dr Wei-Cheng You. Peking University Cancer Hospital & Institute, Beijing, China. weichengyou@ yahoo.com. IARC Secretariat Ms Karima Abdedayem. Prevention and Implementation Group, Section of Early Detection and Prevention, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Maria Constanza Camargo. Prevention and Implementation Group, Section of Early Detection and Prevention, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Catherine de Martel. Infections and Cancer Epidemiology Group, Section of Infections International Agency for Research on Cancer, Lyon, France. [email protected]. Dr David Forman. Head, Section of Cancer Information, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Silvia Franceschi. Head, Infections and Cancer, Epidemiology Group, Section of Infections, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Paula Gonzalez. Prevention and Implementation Group, Section of Early Detection and Prevention, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Rolando Herrero. Head, Prevention and Implementation Group, Section of Early Detection and Prevention, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Jin Young Park. Prevention and Implementation Group, Section of Early Detection and Prevention International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Martyn Plummer. Infections and Cancer Epidemiology Group, Section of Infections, International Agency for Research on Cancer, Lyon, France. [email protected].
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nica S. Sierra. Section of Cancer Information, International Agency for Research on Cancer, Dr Mo Lyon, France. [email protected]. Dr Massimo Tommasino. Head, Infections and Cancer Biology Group and Section of Infections, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Christopher P. Wild. Director, International Agency for Research on Cancer, Lyon, France. [email protected]. References [1] IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014 (IARC Working Group Reports, No. 8). Available from: http:// www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [2] Forman D, Sierra MS. The current and projected global burden of gastric cancer (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 5e15. Available from:, http://www.iarc.fr/en/publications/ pdfs-online/wrk/wrk8/index.ph. [3] Peleteiro B, Bastos A, Ferro A, Lunet N. Prevalence of Helicobacter pylori infection worldwide: a systematic review of studies with national coverage. Dig Dis Sci 2014;59:1698e709. [4] Choi IJ. The role of endoscopic screening in gastric cancer control in the Republic of Korea (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 16e20. Available from:, http://www.iarc.fr/en/ publications/pdfs-online/wrk/wrk8/index.ph. [5] Asaka M. Strategy to eliminate gastric cancer deaths in Japan (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 21e7. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/ wrk8/index.ph. [6] Lee Y-C. The regional status of current or planned gastric cancer prevention strategies in Taiwan, China (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 28e36. Available from:, http:// www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [7] Ferreccio C. The regional status of current or planned gastric cancer prevention strategies in Latin America (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 37e43. Available from:, http:// www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [8] Leja M. The regional status of current or planned gastric cancer prevention strategies in Europe (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 44e55. Available from:, http://www. iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [9] Malekzadeh R. Effect of Helicobacter pylori eradication on different subtypes of gastric cancer: perspective from a Middle Eastern country (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 55e63. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [10] Greenberg ER, Park JY. Effectiveness of Helicobacter pylori eradication (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 64e71. Available from:, http://www.iarc.fr/en/publications/pdfsonline/wrk/wrk8/index.ph. [11] Parsonnet J. Are there benefits of Helicobacter pylori infection? (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 72e9. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/ index.ph. graud F. Potential impact of bacterial resistance after population-based Helicobacter pylori treatment (IARC Working [12] Me Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 80e7. Available from:, http:// www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [13] Malfertheiner P, Megraud F, O'Morain CA, Atherton J, Axon AT, Bazzoli F, et al. Management of Helicobacter pylori infection e the Maastricht IV/Florence Consensus report. Gut 2012;61:646e64. [14] Goodman KJ, Colquhoun A. Principles of evidence-based cancer prevention strategies (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 88e94. Available from:, http://www.iarc.fr/en/ publications/pdfs-online/wrk/wrk8/index.ph. [15] Gisbert JP, Greenberg ER. Potential regimens for the mass eradication of Helicobacter pylori infection (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 95e110. Available from:, http://www. iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [16] Moayyedi P. Feasibility and cost-effectiveness of population-based Helicobacter pylori eradication (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 111e21. Available from:, http://www. iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph.
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[17] Torres J. The role of biomarkers of gastric cancer risk to target interventions (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 122e35. Available from:, http://www.iarc.fr/en/publications/pdfsonline/wrk/wrk8/index.ph. [18] Abnet CC. Current and ongoing research projects related to gastric cancer prevention: perspective of the United States National Cancer Institute (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 136e42. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [19] You W-C. Current gastric cancer prevention strategies in Linqu County, a high-risk area in Shandong Province, China (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 143e6. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [20] Wald NJ. The treatment of Helicobacter pylori infection of the stomach in relation to the possible prevention of gastric cancer (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 174e80. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [21] Lee Y-C. Community-based Helicobacter pylori eradication with two sequential antibiotic regimens for the residents and migrants in a high-risk area for gastric cancer (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 161e73. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [22] Leja M, Park JY, Plummer M, Herrero R. Multicentre randomized study of Helicobacter pylori eradication and pepsinogen testing for prevention of gastric cancer mortality (Gastric cancer prevention study by predicting atrophic gastritis; GISTAR) (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 147e53. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [23] Choi IJ, Park JY, Herrero R. Effect of Helicobacter pylori eradication on gastric cancer prevention in the Republic of Korea: a randomized controlled clinical trial (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 154e60. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [24] Park JY, Greenberg ER, Parsonnet J, Wild CP, Forman D, Herrero R. Summary of IARC Working Goup Meeting on Helicobacter pylori eradication as a strategy for preventing gastric cancer (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 1e4. Available from:, www.iarc.fr/en/publications/pdfs-online/wrk/ wrk8/index.ph.
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
13
The fight against gastric cancer e the IARC Working Group report Rolando Herrero, MD, PhD, Group Head *, Jin Young Park, PhD, Scientist, David Forman, PhD, Senior Visiting Scientist International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France
a b s t r a c t Keywords: Gastric cancer Helicobacter pylori Eradication Prevention
Gastric cancer is the third cause of cancer death worldwide, and Helicobacter pylori infection causes almost 90% of non-cardia cancers, the predominant type. H. pylori infection is treatable, and in clinical trials there is evidence of a 30e40% reduction in incidence of gastric cancer among treated subjects. However, with a few exceptions, there are no public health programmes for gastric cancer prevention. In December 2013, the International Agency for Research on Cancer (IARC), organized a Working Group of international experts to discuss and make recommendations for gastric cancer control. The Working Group considered that the enormous burden of disease, which is not expected to decline in the coming decades, requires decisive public health action to include gastric cancer in cancer control programmes. Interventions should be tailored to the local conditions and consider populationbased screening and eradication of H. pylori, in the context of evaluation of feasibility, efficacy and adverse consequences. © 2014 Elsevier Ltd. All rights reserved.
The International Agency for Research on Cancer (IARC) of the World Health Organization organized a Working Group Meeting in December 2013 to review evidence regarding H. pylori treatment as a strategy for preventing gastric cancer, including discussions on existing regional gastric cancer prevention efforts, health effects, cost and feasibility of H. pylori screening and treatment programmes,
* Corresponding author. Head, Prevention and Implementation Group, Section of Early Detection and Prevention, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France. Tel.: þ33 4 72 73 86 83. E-mail address: [email protected] (R. Herrero).
http://dx.doi.org/10.1016/j.bpg.2014.10.003 1521-6918/© 2014 Elsevier Ltd. All rights reserved.
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and current and planned studies on the topic. The Working Group members included 19 external experts and 11 IARC participants and produced a report and recommendations [1] (Fig. 1). Gastric cancer is the third leading cause of cancer mortality, with more than 700,000 deaths per year worldwide [2]. Incidence and mortality from this malignancy are characterized by declining trends in most countries, predominance of males and extreme regional variations between and within countries (Fig. 2). In addition, the burden of the disease is higher in less developed countries, where 70% of the cases occur. Despite declining incidence trends in the last few decades, ageing of the population prevents overall reductions in the burden of disease. Infection with H. pylori is a recognized cause of gastric cancer, as has been determined by IARC in two consecutive evaluations, and recent estimates indicate that 90% of all non-cardia gastric cancers are caused by H. pylori [2]. The prevalence of H. pylori has been declining in the last few decades in many countries around the world, and this is likely to explain a large part of the decline in gastric cancer [3]. The Working Group noted that gastric cancer, despite its important morbidity and mortality burden has not been a public health priority, and very few countries have established control efforts. The Republic of Korea is one of the exceptions, with an established nationwide screening programme, which provides upper gastrointestinal series or endoscopy every 2 years to individuals aged 40 years and older [4]. Among participants in this programme, a large fraction of the cancers are detected early and patients benefit from high survival rates. In Japan, screening with barium contrast imaging has had limited coverage. In 2013, the Japanese government approved national health insurance coverage for antibiotic treatment for H. pylori infection in patients with endoscopically diagnosed chronic gastritis [5]. A regional programme in Taiwan, China, provides H. pylori stool antigen testing together with faecal immunochemical testing for colorectal cancer screening. Subjects positive for H. pylori are offered endoscopic screening and antibiotic treatment [6]. In Latin America, Chile has introduced an opportunistic gastric cancer screening programme for symptomatic adults aged 40 years and older, including endoscopic examination for H. pylori detection, biopsy, and treatment [7]. There are very few public health programmes for gastric cancer prevention and control in other areas of the world [8,9]. Several trials have investigated the role of H. pylori eradication on incidence of gastric cancer [10]. In a recent meta-analysis of randomized clinical trials the estimated relative risk was 0.66
Fig. 1. H. pylori eradication as a strategy for preventing gastric cancer. IARC Working Group met on 4e6 December 2013 in IARC, Lyon-France.
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Fig. 2. a: Male age-standardized incidence rates of gastric cancer by country in 2012 (Globocan 2012) ASR: age-standardized rates b: Female age-standardized incidence rates of gastric cancer by country in 2012 (Globocan 2012) ASR: age-standardized rates.
(95% confidence interval, 0.46e0.95), and a trial in Japan investigated impact of H. pylori treatment after endoscopic resection of early gastric cancer, reporting a statistically significant reduction in risk of metachronous tumors. Despite the results of these trials and the possibility of a 30e40% reduction in gastric cancer incidence by helicobacter eradication, several unresolved issues were discussed by the Working Group, including the difficulty of precise estimation of overall benefits and the possibility of adverse consequences.
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In addition to prevention of gastric cancer, H. pylori treatment significantly reduces risk of new ulcer development and visits to medical facilities for dyspepsia symptoms. However, some studies have suggested that H. pylori may have immunological and physiological benefits [11] and therefore that treatment to eradicate the organism might have deleterious effects. Despite inconsistent findings, epidemiologic studies have demonstrated that the absence of H. pylori infection correlates with gastro-oesophageal reflux disease (GORD), Barrett oesophagus and oesophageal adenocarcinoma. In addition, there is some evidence for negative associations between H. pylori infection and asthma, eczema, and other immunological conditions. There are also data associating H. pylori treatment with weight gain, although the magnitude of the association is unlikely to explain the current obesity trends. One of the important concerns when considering mass-eradication of H. pylori, which affects more than 50% of the adult population in high incidence areas, is the development of antibiotic resistance and alterations of the intestinal microbiota [12]. A programme of population screening and treatment for H. pylori could increase antibiotic-resistant pathogens within the community, although it may be difficult to identify the impact of the intervention against the background of resistance due to widespread use of antibiotics for other purposes (including veterinary). The problem may be more serious if the H. pylori treatment regimen includes antibiotics that are essential against serious human infections. Treatment for H. pylori infection selects for resistant organisms and can alter the intestinal microbiome, with yet unknown possible health consequences. H. pylori screening and treatment as a mass intervention is probably feasible and affordable. An inexpensive blood test can select subjects for treatment; with sufficient sensitivity and specificity for a screening programme. The urea breath test and stool antigen test are also highly sensitive and more specific for active infection and have been recommended for clinical management [13], but are more expensive and complex to administer. Some of the basic principles to take into account for the establishment of preventive interventions were also discussed [14], emphasizing that strategies must be tailored to local conditions and that care should be taken to prevent widespread implementation before sufficient knowledge about their efficacy, safety, and economic impact. The multisectorial approach and community participation were also emphasized. Treatment regimens with two or three inexpensive, generic antibiotics plus a proton pump inhibitor for 7e14 days can achieve greater than 80% success in eliminating H. pylori infection, although effectiveness will vary according to the profile of antibiotic resistance in the target population [15]. Although the ideal approach would be a treatment chosen based on culture and susceptibility testing, for population-based treatment programmes the most reasonable will be to use regimens proven reliably effective in the area or based on the observed population pattern of antimicrobial resistance. Health economic models reported to date show that population H. pylori screening and treatment strategies in developed countries are cost-effective at a threshold of US$ 50,000 per life-year saved [16]. However, published models are based on observational epidemiological data rather than on randomized trials evaluating H. pylori treatment to prevent gastric cancer and most did not evaluate impact on added benefits or possible deleterious effects of treatment. Also, the absence of data from low-income countries limits the utility of the analyses. Gastric cancer is a multifactorial disease, and a combination of markers including host genetic factors, H. pylori virulence factors (e.g., cagA), markers of gastric atrophy (e.g., pepsinogens) and environmental factors such as diet may identify patients at risk and could potentially help stratify subjects for treatment decisions. However, the value of using markers to guide public health interventions is not established [17]. Novel approaches to improve the predictive value of existing biomarkers and new biomarkers, including ghrelin, a gastric hormone involved in appetite control and energy balance regulation, are actively being investigated by the US National Cancer Institute [18]. Several clinical trials under way should help clarify whether and how to implement populationbased H. pylori screening and treatment programmes. The largest is a randomized cluster trial in Linqu County in China initiated in 2011 [19], which is enrolling 200,000 participants aged 25e64 years from a high-risk population. Participants are allocated to treatment with anti-H. pylori quadruple therapy or to control (low-dose omeprazole and bismuth citrate) and will be followed up for 10 years.
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The H. pylori Screening Study (HPSS) in the United Kingdom started in 1997, and was designed to assess whether screening and eradication of H. pylori infection in men aged 35e69 years and women aged 45e69 years reduces the incidence of gastric cancer [20]. The number of participants recruited in the study was 28,000 per arm, with a planned follow-up of 15 years or more after recruitment. Results should be available within the next few years. Additional work is underway in the Matsu Islands of Taiwan since 2004 [21]. During three consecutive phases, eradication rates associated with a test-treat-retest-retreat strategy, effectiveness of H. pylori treatment to modify prevalence of H. pylori and neoplastic lesions, reinfection rates and impact on drug-resistance patterns are being investigated in detail. The GISTAR study, a multicentre randomized study is planned for Latvia, Belarus, and the Russian Federation [22] in collaboration with IARC. The objective is to evaluate whether serum pepsinogen and H. pylori testing are effective in identifying high-risk subjects to be referred for appropriate treatment with subsequent reduction in gastric cancer mortality. A pilot study in Latvia was launched in 2013 to test the study procedures, assumptions, and acceptability of the methods. Another randomized controlled trial started in 2014 in the Republic of Korea as a collaboration between the Korean National Cancer Centre and IARC. It will evaluate the preventive efficacy and effectiveness of H. pylori treatment in reducing gastric cancer incidence among participants aged 40e60 years recruited from the national cancer screening programme [23]. The trial is scheduled to run for 10 years, with biennial endoscopic follow-up. Conclusions and recommendations The Working Group recognizes that gastric cancer remains a condition of high importance for global health despite the decline in incidence in several areas of the world, and it is likely to remain so for the foreseeable future unless effective control measures are implemented [24]. The continuing high global burden of gastric cancer and the feasibility of treating its principal cause thus make it a logical target for intervention. There is an acute need to commit more public health resources to gastric cancer control. The Working Group recommends that all countries consider including gastric cancer in their national cancer control programmes and that they conduct detailed assessments of its current and future human and economic impacts and of the potential value of prevention strategies. Collecting standardized data on H. pylori prevalence will be useful for predicting the future burden of gastric cancer and other H. pylori-associated conditions and may help to identify subpopulations that appear most likely to benefit from interventions. Randomized clinical trials have found that H. pylori treatment is effective in preventing gastric cancer, and models indicate that H. pylori screening and treatment strategies would be cost-effective. However, uncertainties remain about the generalizability of results and about the costeeffectiveness and possible adverse consequences of programmes applied in community settings. The Working Group therefore recommends that countries explore the possibility of introducing population-based H. pylori screening and treatment programmes, but cautions that decisions as to whether and how to implement H. pylori testing and treatment must hinge on local considerations of disease burden, other health priorities, and costeeffectiveness analyses that are relevant to the particular country. Moreover, these programmes should be implemented in conjunction with a scientifically valid assessment of programme processes, feasibility, effectiveness, and possible adverse consequences. Participants Working Group Members Dr Christian C. Abnet. Division of Cancer Epidemiology & Genetics, National Cancer Institute Bethesda, MD, USA. [email protected]. Dr Masahiro Asaka. Department of Cancer Preventive Medicine, Hokkaido University Graduate School of Medicine Sapporo, Japan. [email protected].
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Dr Il Ju Choi. Gastric Cancer Center, National Cancer Center, Goyang, Republic of Korea. cij1224@ncc. re.kr. Dr Pelayo Correa. Division of Gastroenterology, Hepatology, and Nutrition Vanderbilt University, Nashville, TN, USA. [email protected]. Dr Catterina Ferreccio. Departamento de Salud Pública/Escuela de Medicina Pontificia Universidad lica de Chile Santiago, Chile. [email protected]. Cato Dr Javier P. Gisbert Department of Gastroenterology Hospital Universitario de La Princesa Instituto n Sanitaria Princesa and CIBEREHD Madrid, Spain. [email protected]. de Investigacio Dr Karen J. Goodman Department of Medicine & School of Public Health University of Alberta Edmonton, AB, Canada. [email protected]. Dr Vadim M. Govorun Research Institute of Physico-Chemical Medicine, Moscow, Russian Federation. [email protected]. Dr E. Robert Greenberg. Fred Hutchinson Cancer Research Center, Seattle, WA, USA. E.Robert. [email protected]. Dr Yi-Chia Lee. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, China. [email protected]. rcis Leja. Faculty of Medicine, University of Latvia, Riga, Latvia. [email protected]. Dr Ma Dr Reza Malekzadeh. Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran. [email protected]. graud. INSERM U853 & Bacteriology Laboratory, University of Bordeaux, Bordeaux, Dr Francis Me France. [email protected]. Dr Paul Moayyedi. Department of Medicine, McMaster University, Hamilton, ON, Canada. [email protected]. ~ oz. National Cancer Institute of Colombia (Emeritus Professor), Lyon, France. nubia. Dr Nubia Mun [email protected]. Dr Julie Parsonnet. Departments of Medicine and of Health Research and Policy Stanford University, Stanford, CA, USA. [email protected]. n en, Enfermedades Infecciosas, Instituto Mexicano del Dr Javier Torres Unidad de Investigacio Seguro Social, Mexico City, Mexico. [email protected]. Dr Nicholas J. Wald. Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, London, United Kingdom. [email protected]. Dr Wei-Cheng You. Peking University Cancer Hospital & Institute, Beijing, China. weichengyou@ yahoo.com. IARC Secretariat Ms Karima Abdedayem. Prevention and Implementation Group, Section of Early Detection and Prevention, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Maria Constanza Camargo. Prevention and Implementation Group, Section of Early Detection and Prevention, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Catherine de Martel. Infections and Cancer Epidemiology Group, Section of Infections International Agency for Research on Cancer, Lyon, France. [email protected]. Dr David Forman. Head, Section of Cancer Information, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Silvia Franceschi. Head, Infections and Cancer, Epidemiology Group, Section of Infections, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Paula Gonzalez. Prevention and Implementation Group, Section of Early Detection and Prevention, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Rolando Herrero. Head, Prevention and Implementation Group, Section of Early Detection and Prevention, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Jin Young Park. Prevention and Implementation Group, Section of Early Detection and Prevention International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Martyn Plummer. Infections and Cancer Epidemiology Group, Section of Infections, International Agency for Research on Cancer, Lyon, France. [email protected].
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nica S. Sierra. Section of Cancer Information, International Agency for Research on Cancer, Dr Mo Lyon, France. [email protected]. Dr Massimo Tommasino. Head, Infections and Cancer Biology Group and Section of Infections, International Agency for Research on Cancer, Lyon, France. [email protected]. Dr Christopher P. Wild. Director, International Agency for Research on Cancer, Lyon, France. [email protected]. References [1] IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014 (IARC Working Group Reports, No. 8). Available from: http:// www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [2] Forman D, Sierra MS. The current and projected global burden of gastric cancer (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 5e15. Available from:, http://www.iarc.fr/en/publications/ pdfs-online/wrk/wrk8/index.ph. [3] Peleteiro B, Bastos A, Ferro A, Lunet N. Prevalence of Helicobacter pylori infection worldwide: a systematic review of studies with national coverage. Dig Dis Sci 2014;59:1698e709. [4] Choi IJ. The role of endoscopic screening in gastric cancer control in the Republic of Korea (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 16e20. Available from:, http://www.iarc.fr/en/ publications/pdfs-online/wrk/wrk8/index.ph. [5] Asaka M. Strategy to eliminate gastric cancer deaths in Japan (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 21e7. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/ wrk8/index.ph. [6] Lee Y-C. The regional status of current or planned gastric cancer prevention strategies in Taiwan, China (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 28e36. Available from:, http:// www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [7] Ferreccio C. The regional status of current or planned gastric cancer prevention strategies in Latin America (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 37e43. Available from:, http:// www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [8] Leja M. The regional status of current or planned gastric cancer prevention strategies in Europe (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori Working Group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 44e55. Available from:, http://www. iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [9] Malekzadeh R. Effect of Helicobacter pylori eradication on different subtypes of gastric cancer: perspective from a Middle Eastern country (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 55e63. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [10] Greenberg ER, Park JY. Effectiveness of Helicobacter pylori eradication (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 64e71. Available from:, http://www.iarc.fr/en/publications/pdfsonline/wrk/wrk8/index.ph. [11] Parsonnet J. Are there benefits of Helicobacter pylori infection? (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 72e9. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/ index.ph. graud F. Potential impact of bacterial resistance after population-based Helicobacter pylori treatment (IARC Working [12] Me Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 80e7. Available from:, http:// www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [13] Malfertheiner P, Megraud F, O'Morain CA, Atherton J, Axon AT, Bazzoli F, et al. Management of Helicobacter pylori infection e the Maastricht IV/Florence Consensus report. Gut 2012;61:646e64. [14] Goodman KJ, Colquhoun A. Principles of evidence-based cancer prevention strategies (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 88e94. Available from:, http://www.iarc.fr/en/ publications/pdfs-online/wrk/wrk8/index.ph. [15] Gisbert JP, Greenberg ER. Potential regimens for the mass eradication of Helicobacter pylori infection (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 95e110. Available from:, http://www. iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [16] Moayyedi P. Feasibility and cost-effectiveness of population-based Helicobacter pylori eradication (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 111e21. Available from:, http://www. iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph.
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[17] Torres J. The role of biomarkers of gastric cancer risk to target interventions (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 122e35. Available from:, http://www.iarc.fr/en/publications/pdfsonline/wrk/wrk8/index.ph. [18] Abnet CC. Current and ongoing research projects related to gastric cancer prevention: perspective of the United States National Cancer Institute (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 136e42. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [19] You W-C. Current gastric cancer prevention strategies in Linqu County, a high-risk area in Shandong Province, China (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 143e6. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [20] Wald NJ. The treatment of Helicobacter pylori infection of the stomach in relation to the possible prevention of gastric cancer (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 174e80. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [21] Lee Y-C. Community-based Helicobacter pylori eradication with two sequential antibiotic regimens for the residents and migrants in a high-risk area for gastric cancer (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 161e73. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [22] Leja M, Park JY, Plummer M, Herrero R. Multicentre randomized study of Helicobacter pylori eradication and pepsinogen testing for prevention of gastric cancer mortality (Gastric cancer prevention study by predicting atrophic gastritis; GISTAR) (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 147e53. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [23] Choi IJ, Park JY, Herrero R. Effect of Helicobacter pylori eradication on gastric cancer prevention in the Republic of Korea: a randomized controlled clinical trial (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 154e60. Available from:, http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.ph. [24] Park JY, Greenberg ER, Parsonnet J, Wild CP, Forman D, Herrero R. Summary of IARC Working Goup Meeting on Helicobacter pylori eradication as a strategy for preventing gastric cancer (IARC Working Group Reports, No. 8). In: IARC Helicobacter pylori working group. Helicobacter pylori eradication as a strategy for preventing gastric cancer. Lyon, France: International Agency for Research on Cancer; 2014. p. 1e4. Available from:, www.iarc.fr/en/publications/pdfs-online/wrk/ wrk8/index.ph.
