Meta-analysis: Can Helicobacter pylori Eradication Treatment Reduce the Risk for Gastric Cancer?

The incidence of and mortality from gastric cancer are progressively decreasing worldwide (1, 2), but gastric cancer remains a major public health problem in several developed and developing countries, especially in Asia (3). Many risk factors for gastric cancer have been identified, most of which are related to lifestyle and dietary habits, such as high salt intake (4), alcohol consumption (5), and tobacco smoking (6). In the past 2 decades, the association between Helicobacter pylori infection and gastric cancer has been firmly established (7); indeed, the International Agency for Research on Cancer (8) categorized H. pylori as a group 1 carcinogen for gastric cancer. However, H. pylori eradication has not been clearly demonstrated to reduce the risk for gastric cancer (9). We performed a meta-analysis of randomized, controlled trials (RCTs) to determine whether H. pylori eradication treatment is an effective preventive strategy to reduce the risk for gastric cancer. Methods Data Sources and Searches Our review followed a prespecified protocol and standard reporting guidelines (10). We identified relevant trials by searching PubMed, EMBASE, Google Scholar, and the Cochrane Library. We also searched online clinical trial registers, such as the Cochrane Central Register of Controlled Trials, metaRegister of Controlled Trials, and National Institutes of Health. We searched the literature without language restriction through 31 January 2009 by using combinations of the terms Helicobacter pylori, gastric cancer, intestinal metaplasia, gastric atrophy, dysplasia, prevention, treatment, and eradication. In addition, we identified relevant trials from the reference list of each selected article. We also hand-searched abstracts presented through 2008 at the United European Gastroenterology Week meeting, Digestive Disease Week, and the Asian Pacific Digestive Week. Selection criteria were established a priori to minimize bias (11). To be eligible for this analysis, RCTs had to compare an eradication treatment group with an untreated group among H. pyloripositive patients and provide the number of gastric cancer cases detected during follow-up. When we found multiple articles for a single study, we used the latest publication and supplemented it, if necessary, with data from the previous publications. We did not exclude ongoing and unpublished studies. Study Selection We assessed the relevance of the studies by using a hierarchical approach based on title, abstract, and full article. Two investigators independently reviewed all studies, and discrepancies were resolved by consensus of all investigators. Data Extraction and Quality Assessment Two investigators independently extracted data on the following items from the selected trials: study design; number of patients enrolled in the study and in each treatment group; eradication therapy and number of eradication attempts; diagnostic testing used to assess H. pylori status after eradication attempts; H. pylori eradication rate in treatment and control groups; type of control (placebo or no intervention); mean and age range of patients at enrollment; ratio of men to women in each group; alcohol use, daily smoking, and salty fish intake in each group (because salty fish was the only measure of salt intake assessed by the trials, all but 1 of which were conducted in Asia); histologic details (baseline histopathologic characteristics, number of biopsies for histologic evaluation, use of a biopsy protocol, sites from which biopsy samples were obtained, histologic classification used, number of pathologists who confirmed the diagnosis, validation of diagnosis by external reviewers, inter- or intraobserver agreement among the pathologists); definition of gastric cancer used to assess diagnosis; timing and diagnostic methods used to detect gastric lesions; enrollment period; year of publication, format (abstract or journal article), and country in which the trial was performed; outcomes (primary and secondary); length of follow-up; gastric cancer cases diagnosed in each group; number of patients lost to follow-up; and report of intention-to-treat results. We obtained further information, if necessary, directly from authors. Two independent investigators evaluated the quality of each study according to quality criteria suggested for RCTs (12). The quality of each study was assessed by evaluating the following items: randomization, generation of allocation sequence and allocation concealment, blinding (open study, single- or double-blind), description of follow-up (number of or reasons for patient withdrawal), presence of a control group, definition of outcome measures, adequate power for clinically significant effect size, intention-to-treat analysis, baseline assessment of all treatment group characteristics, and description of treatment regimens (dosage, route of administration, and duration of treatment). We used a score to measure the strength of agreement between the 2 investigators at all stages (selection process, data extraction, and quality assessment) and resolved disagreements by consensus of all investigators. Data Synthesis and Analysis The outcome of the meta-analysis was the risk for gastric cancer, analyzed on an intention-to-treat basis. We used relative risks and 95% CIs to compare the risk for gastric cancer between the treatment and control groups. We pooled the relative risks for all studies into a summary relative risk by using both MantelHaenszel fixed-effects (13) and random-effects models (14). Analyses using fixed-effects and random-effects models produced identical overall estimates. Therefore, we report results from the fixed-effects model. We provide P values and 95% CIs for the summary relative risks. A sensitivity analysis was performed to examine the influence of individual studies on the pooled estimate. All analyses were performed with Stata software, version 10 (StataCorp, College Station, Texas). Results Search Results Figure 1 shows the study selection process. Two authors selected the studies, extracted the data, and assessed study quality; this resulted in high interobserver agreement (= 0.86). The initial search identified 5488 reports, and we excluded 5472 because of the title or abstract. Of the remaining 16 articles, 9 were excluded: Four had a nonrandomized design (1518), 1 did not report the number of gastric cancer cases (19), and 3 were previous reports of studies already included in our analysis (2022). We included the study by Correa and colleagues (23), although the study presented a factorial design: Patients were randomly assigned to 4 antiH. pylori treatment groups, with or without dietary supplementation, or to 4 placebo groups, with or without dietary supplementation; multiple variables were examined; and their degree of interaction was evaluated. However, we excluded the latest publication of the same trial (24), because after 6 years of follow-up, the trial was unblinded, and eradication therapy was offered to patients not previously treated. Figure 1. Study flow diagram. APDW = Asian Pacific Digestive Week; DDW = Digestive Disease Week; UEGW = United European Gastroenterology Week. Seven RCTs ultimately met our inclusion criteria (23, 2530). Table 1 lists the characteristics of the 7 reviewed studies. Table 1. Gastric Cancer Cases in Groups Treated for Helicobacter pylori and Control Groups Study Characteristics and Quality All studies were performed in areas with high incidence of gastric cancer, defined as an incidence rate greater than 20 cases per 100000 persons per year (33). Four trials were performed in China (25, 26, 29, 30), 2 in Japan (27, 28), and the only study outside Asia was done in Colombia (23). The median follow-up was 6 years (range, 3 to 10 years). Helicobacter pylori eradication was adequately assessed in all studies (Table 2) (34). Eradication rates ranged from 73% to 88.9% in treatment groups and from 5% to 15.2% in control groups. Table 2. Helicobacter pylori Eradication Treatment Treated patients and control participants in each study had similar baseline histologic findings (Tables 3 and 4), ranging from superficial gastritis to dysplasia. At enrollment, most patients had either gastric atrophy or intestinal metaplasia. One study (27) included patients who already had early gastric cancer. To evaluate histology, all studies but 1 (28) used a biopsy protocol, and a minimum of 4 biopsy specimens were obtained from each patient (Table 5). Five studies (23, 25, 26, 29, 30) blinded pathologists to the treatment allocation, and for 3 of these studies (23, 25, 26), 2 or more experienced pathologists confirmed all diagnoses. Five studies (23, 25, 26, 29, 30) defined gastric cancer as a tumor that invaded the lamina propria or the muscularis mucosae. In the study by Fukase and colleagues (27), gastric cancer was defined as categories 4 and 5 of the Vienna classification (39), which includes both invasive and noninvasive tumors. Table 3. Trial Quality Measures Table 4. Baseline Histologic Characteristics Table 5. Histologic Assessment Participants' mean age at enrollment ranged from 42 to 51 years (Table 6) in all studies except the trial by Fukase and colleagues (27), which included patients older than 60 years (range, 62 to 73 years). The malefemale ratio of this study was 3:1, which differed from all the other studies, in which the malefemale ratios were equal. In all studies but 1 (25), treated patients and control participants had similar baseline characteristics. In the study by Wong and colleagues (25), the treatment group differed in alcohol and fish sauce intakes compared with the placebo group; however, these variables did not show any statistically significant effect on the number of gastric cancer cases diagnosed during follow-up. In most studies, data on daily smoking, alcohol use, and salty fish intake were lacking (Table 6). Table 6. Baseline Patient Characteristics No study fulfilled all o