Abstract
Introduction
The principal effect of Helicobacter pylori infection is lifelong chronic gastritis, affecting up to 20% of younger adults but 50% to 80% of adults born in resource-rich countries before 1950.
Methods and outcomes
We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of H pylori eradication treatment on the risk of developing gastric cancer? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2014 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).
Results
At this update, searching of electronic databases retrieved 208 studies. After deduplication and removal of conference abstracts, 166 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 124 studies and the further review of 42 full publications. Of the 42 full articles evaluated, one systematic review was added at this update. We performed a GRADE evaluation for two PICO combinations.
Conclusions
In this systematic overview, we categorised the efficacy for one intervention based on information about the effectiveness and safety of H pylori eradication treatment for the prevention of gastric cancer.
Key Points
The principal effect of Helicobacter pylori infection is lifelong chronic gastritis, affecting up to 20% of younger adults but 50% to 80% of adults born before 1950 in resource-rich countries.
H pylori infection can be identified indirectly by the C13 (or C14) urea breath test and stool antigen tests, which are more accurate than serology.
Transmission and prevalence rates are higher in areas of childhood poverty. Adult re-infection rates are less than 1% a year.
In people with H pylori infection, about 15% will develop a peptic ulcer and 1% will develop gastric cancer during their lifetime.
Gastric cancer is the fourth most frequent cancer worldwide in men and the fifth in women, although the incidence varies widely among countries.
For this overview, we evaluated evidence from RCTs and systematic reviews of RCTs. We found one systematic review and meta-analysis showing:
H pylori eradication treatment is likely to be more effective than placebo or no treatment at reducing the risk of developing gastric cancer within the subsequent 4 to 15 years in healthy H pylori-infected individuals (relative risk 0.66; 95% CI 0.46 to 0.95).
The quality of evidence was low because of methodological limitations of the RCTs (lack of masking, factorial design) and also because of indirectness, as five out of six RCTs were conducted in East Asia, while the sixth RCT was conducted in Central America.
Clinical context
General background
Gastric cancer is the fourth most frequent cancer worldwide in men and the fifth in women, but the incidence varies widely among countries. A large number of observational studies have shown a consistent association of gastric cancer, especially non-cardia gastric cancer, with Helicobacter pylori infection, a chronic infection of the gastric mucosa that affects approximately half of all humans worldwide.
Focus of the review
Given the epidemiological association between gastric cancer and H pylori infection, it is of major clinical importance to assess through RCTs whether the risk of this malignancy is reduced when the infection is eradicated.
Comments on evidence
We found a systematic review and meta-analysis showing that H pylori eradication treatment is likely to be more effective than placebo or no treatment at reducing the risk of developing gastric cancer within the subsequent 4 to 15 years in healthy H pylori-infected individuals. The quality of evidence was low because of methodological limitations of the RCTs (lack of masking, factorial design), and also because of indirectness, as five out of six RCTs had been conducted in East Asia, while the sixth RCT had been conducted in Central America. In fact, if our population of interest had been healthy H pylori-infected individuals who live in East Asia, the quality of evidence for the results would have been moderate (i.e., one level higher).
Search and appraisal summary
The update literature search for this overview was carried in July 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 208 studies. After deduplication and removal of conference abstracts, 166 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 124 studies and the further review of 42 full publications. Of the 42 full articles evaluated, one systematic review was added at this update.
Additional information
The systematic review cited above found no significant difference between eradication therapy and control in all-cause mortality. The systematic review included subgroup analyses according to the presence or absence of pre-cancerous lesions at baseline, and found no evidence that the eradication therapy had a different effect on the risk of gastric cancer in any of the subgroups (contrary to widely publicised preliminary results of one of the RCTs).
About this condition
Definition
Helicobacter pylori is a gram-negative flagellated spiral bacterium found in the stomach. Infection with H pylori is predominantly acquired in childhood. It is the fourth most frequent cancer worldwide in men, and fifth in women, but incidence varies widely among countries. H pylori infection is not associated with a specific type of dyspeptic symptom. The organism is associated with lifelong chronic gastritis and may cause other gastroduodenal disorders. A large number of observational studies have shown a consistent association of gastric cancer, especially non-cardia gastric cancer, with H pylori infection, a chronic infection of the gastric mucosa that affects approximately half of all humans. Diagnosis H pylori can be identified indirectly by serology or by the C13 urea breath test. The urea breath test is more accurate than serology, with a sensitivity and specificity greater than 95%, and indicates active infection, whereas serology may lack specificity and cannot be used reliably as a test of active infection. Thus, the urea breath test is the test of choice where prevalence (and hence predictive value of serology) may be low, or where a 'test of cure' is required. In some areas, stool antigen tests that have a similar performance to the urea breath test are now available. Population This overview focuses on healthy asymptomatic H pylori-positive people throughout.
Incidence/ Prevalence
In the developed world, H pylori prevalence rates vary with year of birth and social class. Prevalence in many resource-rich countries tends to be much higher (50%–80%) in individuals born before 1950 compared with prevalence (<20%) in individuals born more recently. In many resource-poor countries, the infection has a high prevalence (80%–95%) irrespective of the period of birth. Adult prevalence is believed to represent the persistence of a historically higher rate of infection acquired in childhood, rather than increasing acquisition of infection during life.
Aetiology/ Risk factors
Overcrowded conditions associated with childhood poverty lead to increased transmission and higher prevalence rates. Adult re-infection rates are low — less than 1% a year.
Prognosis
H pylori infection is believed to be causally related to the development of duodenal and gastric ulceration, B cell gastric lymphoma, and distal (i.e., non-cardia) gastric cancer. About 15% of people infected with H pylori will develop a peptic ulcer, and 1% of people will develop gastric cancer during their lifetime.
Aims of intervention
Reduction of risk of gastric cancer; improvement in quality of life.
Outcomes
Incidence of or mortality from gastric cancer; regression of pre-cancerous lesions; adverse effects.
Methods
Search strategy BMJ Clinical Evidence search and appraisal date July 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to July 2014, Embase 1980 to July 2014, The Cochrane Database of Systematic Reviews 2014, issue 7 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, at least single-blinded, and containing more than 20 individuals (at least 10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' sections (see below). Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following previously reported questions: What are the effects of H pylori eradication treatment in people with a confirmed duodenal ulcer, a confirmed gastric ulcer, confirmed gastro-oesophageal reflux disease (GORD), confirmed non-ulcer dyspepsia, uninvestigated dyspepsia, localised B cell lymphoma of the stomach, and non-steroidal anti-inflammatory drug (NSAID)-related peptic ulcers? What are the effects of H pylori eradication treatment for preventing NSAID-related peptic ulcers in people with or without previous ulcers or dyspepsia? Do H pylori eradication treatments differ in their effects? Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Helicobacter pylori eradication: gastric cancer prevention.
| Important outcomes | Incidence of or mortality from gastric cancer, Regression of pre-cancerous lesions | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of Helicobacter pylori eradication treatment on the risk of developing gastric cancer? | |||||||||
| 6 (6497) | Incidence of or mortality from gastric cancer | H pylori eradication treatment versus placebo or no treatment for the prevention of gastric cancer in asymptomatic, healthy H pylori-infected individuals | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for methodological limitations of RCTs included in the analysis (lack of masking, factorial design); directness point deducted for generalisability (of the 6 RCTs, 5 were carried out in East Asia and 1 in Central America; eradication regimen used varied across studies) |
| 1 (852) | Regression of pre-cancerous lesions | H pylori eradication treatment versus placebo or no treatment for regression of pre-cancerous lesions | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for methodological limitations (incomplete reporting of results, factorial design); directness point deducted for generalisability (the study was conducted in Colombia) |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Grigorios I Leontiadis, Division of Gastroenterology, McMaster University, Hamilton, ON, Canada.
Alexander Charles Ford, Leeds Gastroenterology Institute, St James’s University Hospital, Leeds, UK.
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