There is an urgent need for optimising primary prevention and early detection for gastric cancer, and infection with Helicobacter pylori imparts the highest risk of developing this disease
Jan Bornschein MD
Peter Malfertheiner MD
Deptartment of Gastroenterology,
Hepatology and Infectious Diseases,
Otto-von-Guericke University of
Gastric cancer is mostly diagnosed at an advanced stage. Recurrence rates after surgical resection are high, and palliative treatment still results in poor prognosis. Cure can only be offered at early stages of gastric cancer. Thus, there is urgent need for optimising primary prevention as well as early detection of the disease. Infection with Helicobacter pylori carries the highest risk for developing gastric cancer, and the risk is further increased in the presence of more virulent bacterial strains. Because incidence rates of gastric cancer in many parts of the Western world are decreasing, a general population-based screen and eradicate scheme is not recommended.
However, test-and-treat should be offered to individuals at high risk, such as first degree relatives of gastric cancer patients as well as patients with history of peptic ulcer disease. If patients undergo an upper gastrointestinal endoscopy and premalignant mucosal conditions such as intestinal metaplasia or glandular atrophy are detected, a regular follow-up is recommended. Up to today, the ‘point of no return’ from which eradication of H. pylori no longer has the potential to halt further progression towards gastric cancer is not clearly defined. Non-invasive screening for premalignant alteration can be carried out by testing for serum pepsinogens and anti-H. pylori antibodies. An effective vaccine against H. pylori infection would be an optimal option for primary prevention but is not available at present.
Epidemiological background and risk factors
In 80% of patients, diagnosis of gastric cancer is made at advanced stage of disease when curative treatment options can no longer be offered. In many patients, there is only a short period of symptoms preceding the diagnosis such as unintentional weight loss, anaemia, epigastric pain, nausea and vomiting or dyspeptic symptoms. In 40% patients, there may be no dyspeptic symptoms at any time.
General population screening facilitates the detection of early gastric cancer, but this is only implemented on a large scale in Japan and Korea. In regions with low incidence as in many parts of Europe and in North America, the risk conditions have to be defined to allow a cost-beneficial identification of individuals who need special attention for either primary preventive measures or adequate surveillance. Risk factors are grouped as environmental, hereditary or acquired host-related factors (see Table 1). The major risk factor is infection with H. pylori, representing in the majority of gastric cancer cases the ‘motor’ of the disease by linking the environmentally acquired bacterial infection with the characteristics of the host-specific immune response.
H. pylori as a major risk factor: epidemiological evidence
In 1994, the World Health Organization (WHO) classified H. pylori as a Class I carcinogen based mainly on epidemiological data; in 2010, this was updated by the International Agency for Research on Cancer (IARC) with evidence available at that time. Animal studies on Mongolian gerbils were the first to indicate H. pylori as a complete carcinogen capable of inducing gastric adenocarcinomas without the requirement of any co-carcinogens.(1,2)
Numerous studies have assessed the attributable risk to H. pylori for gastric carcinogenesis in humans. In 2001, the Helicobacter and Cancer Collaborative Group presented the combined data from available case control studies nested with prospective cohorts to evaluate the relative risk for gastric cancer. In this meta-analysis, 1228 patients were included and a clear association of H. pylori infection to non-cardia gastric cancer (odds ratio (OR) 3.0; 95% confidence interval (CI): 2.3–3.8) was reported. Other meta-analyses from Asia and the Western world demonstrated comparable results.(3,4) The OR was 5.9 (95% CI: 3.4–10.3) when blood samples for H. pylori serology were obtained ten years or longer before cancer diagnosis.(5) This is explained by the loss of H. pylori colonisation in the presence of atrophic gastritis and intestinal metaplasia (IM), so that gastric cancer patients have a loss of anti-H. pylori antibodies at the time of disease manifestation. When a combination of diagnostic methods for H. pylori detection is applied, the prevalence of H. pylori-negative gastric cancer decreases to 0.66% (95% CI: 0.41–1.01), as shown in a recent Japanese cohort.(6)
Several studies have shown that the risk of gastric cancer is further increased if bacterial virulence factors are present; for example, the cytotoxin-associated antigen A (CagA). Antibodies against CagA persist longer in the serum as compared to general H. pylori antibodies. The assessment of the CagA status by immunoblot analysis can lead to a further 2–10-fold increase of the H. pylori attributable OR for non-cardia cancer.(7,8)
Most studies claim that H. pylori infection is related to distal gastric cancer only. The same holds true for proximally located adenocarcinomas at or below the gastric cardia. Approximately 80% of patients with proximal gastric cancer revealed positive evidence for an actual or past infection with H. pylori if correct allocation of the primary tumour is performed and adenocarcinomas of the distal oesophagus are excluded.(9) The risk for gastric carcinogenesis by H. pylori infection is similar in intestinal and diffuse type gastric cancer.(9)
There is a documented synergistic effect of carcinogenic agents, such as salt, tobacco and red meat, with H. pylori infection.(10)
Eradication of H. pylori for gastric cancer prevention
Eradication of H. pylori has the potential to prevent gastric cancer. In 6695 patients included from various studies, H. pylori eradication reduced gastric cancer risk (relative risk (RR) 0.65; 95% CI: 0.43–0.98). Overall, 56 of 3307 (1.7%) untreated (control) participants developed gastric cancer compared with 37 of 3388 (1.1%) treated patients.(11)
The effect of H. pylori eradication on gastric cancer prevention was nearly exclusively studied in high incidence regions in Asia. In a retrospective study of more than 3000 patients after H. pylori eradication, the incidence of gastric cancer was analysed for five years of follow-up in 23 centres in Japan.(12) Gastric cancer developed in 1% of patients who had been successfully eradicated and in 4% of patients with persistent infection (OR 0.36; 95% CI: 0.22–0.62). In an observational study from Japan, gastric cancer developed only in patients infected with H. pylori, but not in uninfected patients.(13) In 1526 patients with dyspeptic symptoms and an endoscopy-based diagnosis followed-up for 7.8 years, 36 of the H. pylori-positive patients (2.9%) developed gastric cancer, and gastric malignancy was not detected among the H. pylori -negative patients.(13)
The only prospective, randomised, placebo-controlled, population-based study to demonstrate primary gastric cancer prevention by eradication of H. pylori was performed in China.(14) In total, 1630 healthy individuals were recruited for randomisation to either H. pylori eradication or placebo treatment. In the period of 7.5 years follow-up, there were 18 new cases of gastric cancer, seven in the eradication group and 11 in the placebo group. Subgroup analysis revealed that all patients who developed gastric cancer presented with preneoplastic mucosal conditions (gastric atrophy, IM) at baseline whereas no case of gastric cancer was diagnosed in patients without baseline mucosal changes (p=0.02).(14) Therefore, the major challenge is to treat the H. pylori infection before changes develop that can no longer be stopped in the progression towards gastric cancer.
The point of no return
Patients with the highest risk for gastric cancer after eradication therapy present with atrophic gastritis at baseline, mainly in the gastric corpus.
Regression of atrophic gastritis is possible to a limited extent but does not occur for IM. It has been suggested that the decisive factor determining whether or not there is an effect of H. pylori eradication on regression of premalignant conditions of the gastric mucosa is the duration of follow-up. Improvement of mucosal inflammation occurs within the first 6–12 months after eradication, whereas atrophic changes may require a follow-up period longer than one year. To challenge the ‘point of no return’ in the progression of premalignant gastric changes towards invasive gastric cancer, a recent Japanese study demonstrated that it is never too late to eradicate; eradication of H. pylori significantly reduced the incidence of metachronous gastric cancer in patients who had undergone endoscopic mucosal resection of early gastric cancer.(15)
Risk gastritis is currently best assessed by histological staging systems such as the Operative Link for Gastritis Assessment (OLGA) or the more recently adapted Operative Link on Gastric Intestinal Metaplasia assessment (OLGIM) for inclusion of IM.(16,17)
Cost-effectiveness of gastric cancer prevention
Expenses for prior diagnostic procedures and the costs for antibiotic treatment taken into account, cost-effectiveness of a ‘screen and eradicate’ schedule for the prevention of gastric cancer is low.(18) Estimations from the US suggest costs for H. pylori screening and treatment between €6300 to €25,000 per life year saved(19,20); data from the UK suggest a maximum cost of €8,500 if a positive effect on dyspeptic symptoms and peptic ulcer disease is included.(21) With this, the definition of criteria to identify individuals at high risk of gastric cancer who should be tested for H. pylori positivity is crucial. This includes at present state of knowledge, first-degree relatives of gastric cancer patients and patients with positive history of gastric or duodenal ulcer disease. Screening and surveillance strategies have to be properly developed according to individual circumstances (see Figure 1).(22)
In a decision model, the cost-effectiveness of yearly endoscopy for a period of ten years after new diagnosis of IM in the stomachs of a cohort of 10,000 American patients was compared to no surveillance.(23) With an estimated gastric cancer incidence of 1.8% per year, 556 and 3738 endoscopies were needed to detect one case of gastric cancer and to prevent one cancer-related death, respectively. The incremental cost-effectiveness ratio of endoscopic surveillance compared to non-surveillance was US$72,519 per life year gained.
For non-invasive stratification of patients at high risk of gastric cancer development, the analysis of serum pepsinogens combined with anti-H. pylori antibodies remains the best option. In a study from Italy on approximately 1400 patients, the serological test and the results of the histological analysis were in concordance in 94% for corpus-prevalent chronic atrophic gastritis (sensitivity 80%, specificity 96%).(24) The serological assessment of pepsinogen I is a reliable method to assess gastric atrophy as a preneoplastic condition but is not a tumour marker and not useful for the detection of invasive adenocarcinoma.(25) Pepsinogen I is therefore more suitable to identify the premalignant conditions of intestinal than of diffuse type gastric cancer.
An effective vaccine against H. pylori would eliminate the necessity of screening and furthermore lead to an improvement of cost-effectiveness in the fight against gastric cancer. A prediction model estimates that a ten-year vaccination program would cause a decrease of H. pylori prevalence in the US down to 0.07% by the end of the 21st century.(26) This would not only have an effect on gastric cancer but on all H. pylori-related diseases. Animal studies have demonstrated that vaccination against H. pylori can be effective, although there are no data yet on an effective vaccine for humans. Trials are ongoing and more sophisticated understanding of the host’s immune response mechanisms may lead to further innovations in this area.(27–29)
Because of the low incidence of gastric cancer in most regions of Europe and North America, a general population based ‘screen and eradicate’ regime is not applicable. However, it would be feasible to apply serological testing for the identification of individuals at high risk that would need further diagnostic work-up and eventually a follow-up. Eradication of H. pylori infection should be offered, even in case of premalignant mucosal changes since the so-called ‘point of no return’ in each individual is not yet clearly defined. Development of an effective vaccine against H. pylori will remain a mirage. At present, the authors recommend screening of the general population for individuals at high risk as delineated in Figure 1.
- Honda S et al. Development of Helicobacter pylori-induced gastric carcinoma in Mongolian gerbils. Cancer Res 1998;58(19):4255–9.
- Watanabe T et al. Helicobacter pylori infection induces gastric cancer in Mongolian gerbils. Gastroenterology 1998;115(3):642–8.
- Huang JQ et al. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 1998;114(6):1169–79.
- Eslick GD et al. Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis. Am J Gastroenterol 1999;94(9):2373–9.
- Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001;49(3):347–53.
- Matsuo T et al. Low prevalence of Helicobacter pylori-negative gastric cancer among Japanese. Helicobacter 2011;16(6):415–19.
- Ekstrom AM et al. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 2001;121(4):784–91.
- Huang JQ et al. Meta-analysis of the relationship between CagA seropositivity and gastric cancer. Gastroenterology 2003;125(6):1636–44.
- Bornschein J et al. H. pylori infection is a key risk factor for proximal gastric cancer. Dig Dis Sci 2010;55(11):3124–31.
- Gonzalez CA, Lopez-Carrillo L. Helicobacter pylori, nutrition and smoking interactions: their impact in gastric carcinogenesis. Scand J Gastroenterol 2010;45(1):6–14.
- Fuccio L et al. Meta-analysis: can Helicobacter pylori eradication treatment reduce the risk for gastric cancer? Ann Intern Med 2009;151(2):121–8.
- Kato M et al. Helicobacter pylori eradication prevents the development of gastric cancer – results of a long-term retrospective study in Japan. Aliment Pharmacol Ther 2006;24(Suppl. 4):203–6.
- Uemura N et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001;345(11):784–9.
- Wong BC et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomised controlled trial. JAMA 2004;291(2):187–94.
- Fukase K 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(9636):392–7.
- Rugge M et al. Gastritis OLGA-staging and gastric cancer risk: a twelve-year clinico-pathological follow-up study. Aliment Pharmacol Ther 2010;31(10):1104–11.
- Capelle LG 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(7):1150–8.
- Malfertheiner P et al. Helicobacter pylori eradication has the potential to prevent gastric cancer: a state-of-the-art critique. Am J Gastroenterol 2005;100(9):2100–15.
- Parsonnet J et al. Modelling cost-effectiveness of Helicobacter pylori screening to prevent gastric cancer: a mandate for clinical trials. Lancet 1996;348(9021):150–4.
- Sonnenberg A, Inadomi JM. Review article: Medical decision models of Helicobacter pylori therapy to prevent gastric cancer. Aliment Pharmacol Ther 1998;12(Suppl 1):111–21.
- Mason J et al. The cost-effectiveness of population Helicobacter pylori screening and treatment: a Markov model using economic data from a randomised controlled trial. Aliment Pharmacol Ther 2002;16(3):559–68.
- Malfertheiner P, Bornschein J, Selgrad M. Role of Helicobacter pylori infection in gastric cancer pathogenesis: a chance for prevention. J Dig Dis 2010;11(1):2–11.
- Hassan C et al. Cost-effectiveness of endoscopic surveillance for gastric intestinal metaplasia. Helicobacter 2010;15(3):221–6.
- Lombardo L et al. Prevalence of atrophic gastritis in dyspeptic patients in Piedmont. A survey using the GastroPanel test. Clin Chem Lab Med 2010;48(9):1327–32.
- Miki K. Gastric cancer screening using the serum pepsinogen test method. Gastric Cancer 2006;9(4):245–53.
- Rupnow MF et al. Quantifying the population impact of a prophylactic Helicobacter pylori vaccine. Vaccine 2001;20(5–6):879–85.
- Malfertheiner P et al. Safety and immunogenicity of an intramuscular Helicobacter pylori vaccine in noninfected volunteers: a phase I study. Gastroenterology 2008;135(3):787–95.
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- Velin D et al. PAR2 promotes vaccine-induced protection against Helicobacter infection in mice. Gastroenterology 2011;141(4):1273–82.