Chemoprevention may form the cornerstone in the management of gastric adenocarcinoma of the future. Helicobacter pylori eradication and aspirin and/or nonsteroidal anti-inflammatory drug therapy have emerged as front-runner chemotherapeutic agents due to the putative pathogenic mechanisms that they address. Before a population-based chemopreventive strategy can be recommended on a large scale, randomized controlled trials with follow-up of more than 10 years of these 2 agents in populations at high gastric adenocarcinoma risk is urgently awaited.
Key points
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Chemoprevention may form the cornerstone in the management of gastric adenocarcinoma (GC) in the future.
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Helicobacter pylori (HP) eradication and aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs) therapy have emerged as front-runner preventive strategies due to the putative pathogenic mechanisms that they address.
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Before a population-based chemopreventive strategy can be recommended on a large scale, randomized controlled trials (RCTs) with follow-up of more than 10 years of these 2 agents in populations at high GC risk are urgently awaited.
GC is the fourth most common cancer worldwide but the second leading cause of cancer deaths. GC is a major public health burden internationally, especially in parts of the Asia-Pacific region, where this burden varies due to the heterogeneity of the ethnic populations that reside in this region. The risk of GC varies from high-risk areas in East Asia, including China, Japan, and Korea, where the age-standardized incidence rate (ASR) is greater than 20 per 100,000, to low-risk areas, such as Australia, India, and Thailand, where the ASR is less than half that. This pattern of risk explains the types of clinical GC studies undertaken in the Asia-Pacific region, which have been focused on preventive strategies, early GC screening strategies, and endoscopic management of early GC.
The particular interest in GC-chemopreventive strategies in this region is driven by several factors. First, as discussed previously, some of the highest ASRs of GC internationally are in the Asia-Pacific region. Second, in the absence of screening programs to detect early GC, GC tends to present in an advanced stage because early GC is usually silent and symptoms are nonspecific. Third, treatment outcomes for patients with advanced GC are poor with the currently available chemotherapy regimens and even the newer biologics, with 5-year survival rates between 0% and 30%. Finally, although population screening for occult GC in asymptomatic subjects may seem an appealing strategy, the costs associated with the program, suggested as high as $83,000 to detect 1 occult malignant lesion, may prove unsustainable. By comparison, modeling on the chemoprevention of GC through therapy, such as HP eradication, suggests that the costs compare favorably to other well-established screening programs. Although population-based chemoprevention seems an attractive option as a primary prevention for GC, for the strategy to be successful there needs to be an identifiable therapy that is low cost, easily implementable, and well tolerated by the target population. Two such agents have been identified, and this review examines the evidence for HP eradication and NSAIDs as chemoprophylactic agents. Other chemopreventive agents in GC also are discussed briefly.
Helicobacter pylori
Justification for Use of HP Eradication in the Prevention of GC
The most accepted model of gastric carcinogenesis is that GC, like colonic cancers, progresses through a cancer cascade. This is particularly true for intestinal-type GC, where evidence shows there is a multistep progression from gastritis to glandular atrophy, intestinal metaplasia (IM), dysplasia, and ultimately cancer. In early observational studies of the natural history of GC, it seemed that an unknown inciting agent triggered the start of this carcinogenesis cascade, which ultimately resulted in cancer. Since 1982, when Marshall and Warren identified HP and causally linked the bacterium with chronic gastritis and peptic ulcer disease, it has become evident that the putative pathogenic agent causing chronic gastritis in the majority of cases is HP. The hypothesis that prevention of GC may be achieved through HP eradication is based on the results of large-scale epidemiologic studies, experimental models, and meta-analysis of case-control studies.
In 1991, 3 seminal prospective case-control studies involving 324 GC subjects with matched controls were published, which demonstrated that the odds ratio (OR) for HP in subjects with GC was between 2.77 and 6.0, with the pooled analysis of the 3 prospective epidemiologic studies demonstrating a relative risk (RR) of 3.8, which was significant. This led to the 1994 classification by the International Agency for Research on Cancer/World Health Organization of HP as a definite carcinogen based on the inference that HP causes histologic gastritis, which, when prolonged, may induce atrophic gastritis, considered the first step in the gastritis-metaplasia-carcinoma sequence of the stomach. Unfortunately, subsequent studies found conflicting results, which prompted several meta-analyses to try to resolve the issue. Of these, 2 meta-analyses used more rigorous entry criteria, including only prospective case-control studies, and both demonstrated pooled ORs for gastric cancer in HP-positive individuals of between 2 and 3. So, in summary, several meta-analyses have found that HP infection is moderately to strongly associated with the risk of GC development. Coupled with the long lead times presumed involved in the transition between stages in the GC cascade, observational studies showing that nonatrophic gastritis progresses to glandular atrophy and IM over a period of 12 years, make HP eradication a natural choice for chemopreventive strategies, with a large window of opportunity during which to institute therapy. However, not all individuals infected with HP develop GC and the reason why certain individuals have a greater propensity to develop GC is most certainly a multi factorial process. So, although it may seem biologically plausible that HP eradication would result in a reduction in GC incidence, given these complex interactions between host factors, HP infection, and environmental factors, such as diet, it is critical that the evidence for the efficacy of HP eradication in GC prevention is examined.
Evidence for Effectiveness of HP Eradication on Gastric Cancer Incidence
Interventional studies of HP eradication would confirm whether eradication of this infection could prevent GC. Large population-based studies have not been performed, however, and are difficult to undertake for the following reasons. First, the incidence of GC is low, and second, the natural history of GC development is long, so that some investigators have projected that more than 35,000 subjects need to be enrolled and followed for more than 10 years to demonstrate a 50% reduction in the GC incidence after HP eradication. This represents a possibly insurmountable issue in the design, execution, and financing of any proposed study, and these problems are demonstrated in the RCTs performed to examine this issue (discussed later). Finally, there are ethical issues involved in randomizing subjects from a high-risk GC region to placebo when there is strong evidence of HP’s putative pathologic role in the development of GC. For these reasons, the authors believe both major cohort studies as well as all RCTs examining the efficacy of HP eradication on GC incidence warrant discussion. Table 1 details the 6 major cohort studies examining the efficacy of HP eradication on GC incidence. Three of the studies are retrospective studies, which included more than 80,000 subjects and found that HP eradication was consistently and significantly associated with reduced GC incidence. The largest of these studies was conducted in Taiwan and demonstrated that in patients with peptic ulcer disease, HP eradication within an arbitrarily defined time frame (defined by the investigators as within a year of hospitalization for peptic ulcer disease) was associated with GC incidence rates similar to those of the general population. Moreover, this effect seemed time dependent, so that as the years posteradication of HP increased, this had the effect of decreasing the GC standardized incidence ratios (SIRs). The remaining 3 cohort studies were prospective interventional studies, which again found benefit for HP eradication in reducing GC incidence. A study by Uemura and colleagues is important because it was one of the first prospective studies to demonstrate that HP eradication caused a reduction in GC incidence and the subjects with duodenal ulcers seemed protected from GC development. The study’s major flaws, however, are the significantly reduced follow-up time in the HP-eradicated cohort (mean 4.8 vs 8.5 years, respectively; P <.001) compared with the untreated cohort, meaning that GC developing later may have been missed in the HP-eradicated/negative group. Moreover, this study was never intended as an interventional study. The study by Yanaoka and colleagues used pepsinogen levels as a surrogate marker of gastric atrophy, which probably would be more cost effective and less invasive if used in a GC chemoprevention program. The investigators suggest that there seems to be a point of no return in the stomach carcinogenesis cascade when HP eradication is of limited benefit. Similarly, the study by Take and colleagues suggests HP eradication was most efficacious before the onset of significant atrophy. They noted, however, that HP eradication even in patients with mild gastric atrophy did not completely prevent GC.
| Uemura et al, 2001 | Aims: to determine the relationship between HP infection and the development of GC |
| Design: prospective, observational single-center study in Japan (N = 1526; 1246 with HP and 280 without HP) recruiting subjects with upper gastrointestinal disorders. HP status determined by positive histology, urease test, and/or serology. Subgroup of N = 253 who received HP eradication. Endoscopy performed at 1 y and 3 y post enrollment. | |
| Results: no cancers developed in HP-negative cohort; 36 cancers in the HP-positive cohort. Risk of GC by Kaplan-Meier analysis was 5% at 10 y. No cancers developed in the 253 patients who received HP eradication, although there were 36 cases of GC among 993 untreated patients (mean duration of follow-up 4.8 vs 8.5 y, respectively; P <.001); 63.9% of GC intestinal type and 36.1% diffuse type. | |
| Conclusions: HP-negative patients did not develop GC. HP infection is associated with development of both intestinal and diffuse GC, particularly when IM and/or corpus predominant gastritis is in conjunction with severe atrophy. By contrast, patients with HP infection and duodenal ulcer seemed protected from the development of GC. | |
| Limitations: nonrandomized. Not placebo controlled. Different follow-up between case and control groups. | |
| Takenaka et al, 2007 | Aims: to determine the effect of HP eradication on GC incidence. |
| Design: retrospective, multicenter, cohort study of 1807 subjects with HP positivity who received HP eradication (1519 HP eradicated; the rest had persistent infection). Subjects drawn from 11 hospitals in Japan. No uniform endoscopy at enrollment or post–HP eradication treatment. HP status posteradication determined by urea breath test or endoscopically. Median follow-up of patients was 3 y. | |
| Results: 11 subjects developed GC (6 in HP eradicated group and 5 in persistent infection group; P <.01). 3 Cases of diffuse and 8 cases of intestinal-type GC noted. On multivariate analysis, age >60 y (OR 5.5; 95% CI, 1.4–21) and successful HP eradication (OR 0.20; 95% CI, 0.061–0.66) were significant independent factors in the development of GC. | |
| Conclusions: HP eradication prevents, in particular, the development of the intestinal-type gastric cancer. | |
| Limitations: retrospective design and lack of control cohort. Short follow-up period. Histology at time of HP eradication unknown. 3% of patients lost to follow-up. | |
| Ogura et al, 2008 | Aims: to determine the effect of HP eradication on GC incidence. |
| Design: retrospective, open-label, interventional study of HP eradication. 1476 Subjects had a history of gastroduodenal disease, were HP positive, and were drawn from a single center in Japan with a high incidence of GC. Subjects were given HP eradication as an opt-in option (n = 853); subjects declining HP eradication were followed as the persistent HP infection cohort. HP eradication confirmed by urea breath test. 222 Subjects were withdrawn from the HP eradication cohort after a refusal or failure to eradicate HP on a second course of HP eradication. Subjects followed with yearly endoscopies, for a mean of 3 y. | |
| Results: a total of 19 cases of GC was reported during follow-up, 6 in the treatment group and 13 in the persistent HP infection group ( P = .019). HR of GC development was 0.335 (95% CI, 0.114–0.985). Female gender and older age group also had significant associations with GC development. | |
| Conclusions: GC prevention through HP eradication is of benefit. | |
| Limitations: retrospective, open-label study. Small cohort study and short follow-up time may miss gastric cancer diagnoses. | |
| Wu et al, 2009 | Aims: to determine GC risk in patients with peptic ulcer diseases who received early HP eradication (defined as within 1 y of hospitalization for peptic ulcer disease). |
| Design: retrospective study of 80,255 subjects who were hospitalized with peptic ulcer disease and received HP eradication therapy. Data drawn from a Taiwanese database that covers 99% of the country’s population. Follow-up for a mean of 5.92–7.22 y. | |
| Results: early HP eradication was associated with GC incidence rates similar to the general public (SIR 1.05; 95% CI, 0.96–1.14), but late eradication resulted in increased risk (SIR 1.36; 95% CI, 1.24–1.49). Early eradication in subjects with gastric ulcers demonstrated decreasing GC SIRs (1.60–1.05, 3–4 y vs 7–10 y, respectively) with increasing accumulated years post–HP treatment. Late eradication demonstrated a similar trend (SIRs decreased from 2.14 to 1.32, 3–4 y vs 7–10 y, respectively). Frequent aspirin or NSAID use (HR 0.65) was an independent protective factor for gastric cancer. | |
| Conclusions: early HP eradication before the onset of significant gastric atrophy decreases risk of gastric cancer in patients with known peptic ulcer disease, with incidence rates comparable to the general population. | |
| Limitations: retrospective study with varied follow-up, between 2 y and 10 y. No confirmation of outcome of HP eradication. Baseline HP status of cohort that received no HP eradication unknown (presumed HP negative). Finally, GC diagnosis abstracted from the database and uncertain of accuracy. | |
| Yanaoka et al, 2009 | Aims: to determine the effect of HP eradication on chronic atrophic gastritis monitored by serum pepsinogen levels. |
| Design: prospective, open-label cohort study of 4129 HP-positive male subjects. Follow-up for 9.3 y. Subjects were healthy factory workers recruited from a single province in Japan with high GC incidence. Subjects opted in for HP eradication and 473 successfully eradicated the HP infection. GC diagnosed through barium meal and/or pepsinogen levels, and confirmed with endoscopy. | |
| Results: 60 GC developed during the follow-up period, 5 in the HP-eradicated group, with no significant difference in GC incidence between HP eradication and persistent infection cohorts. Significant reduction in cancer incidence after HP eradication was observed only in pepsinogen test–negative subjects ( P <.05). Pepsinogen test–positive subjects possibly represent the point of no return in stomach carcinogenesis for most GC development and HP eradication will have little impact on the incidence of GC development within 10 y of treatment. | |
| Conclusions: HP eradication is of most benefit in subjects with mild chronic atrophic gastritis as measured by pepsinogen levels. | |
| Limitations: GC incidence as secondary outcome measure. Surrogate measures of chronic atrophic gastritis used. Unblinded and no placebo control. Predominantly male subjects. Screening for GC with barium meal and/or pepsinogen level could miss some early GCs. | |
| Take et al, 2011 | Aims: to determine the GC incidence over up to 14.1 y of follow-up in subjects with peptic ulcer disease who have had their HP eradicated. |
| Design: prospective, uncontrolled, interventional study of 1674 subjects who were HP positive. HP eradication was given to every subject and eradication confirmed on a urea breath test within 2 mo of treatment. Yearly endoscopy followed thereafter to assess the histology. 96.7% Had peptic ulcer disease, because the original subjects studied by this group were patients with peptic ulcer disease and HP infection. Japanese single-center study. Subjects followed for up to 14.1 y (mean 5.6 y). | |
| Results: 28 GC developed during the follow-up period; 16 were intestinal type and 12 were diffuse type. The risk of GC post–HP eradication was 0.30% per year. All GCs developed in the absence of histologic inflammation. Baseline mucosal atrophy (HR 14.4; 95% CI, 1.9–110.2; P = .01) was an independent risk factor on multivariate analysis for development of GC. | |
| Conclusions: HP eradication reduced GC incidence to 1/3 in patients with peptic ulcer disease (with no GC on enrollment endoscopy) and was most efficacious before significant gastric atrophy had developed, but HP eradication did not completely prevent GC even in patients with mild mucosal atrophy at time of treatment. The risk of intestinal and diffuse type GC was identical in subjects with HP eradication in this cohort. GC also developed in 2 subjects who initially presented with duodenal ulcers. Periodic follow-up of patients post–HP eradication should be for 10 y or more. | |
| Limitations: single-center study recruiting predominantly male factory workers. The majority of the cohort had peptic ulcer disease, with 61.4% had gastric ulcers with or without concomitant duodenal ulcers. |
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