Helicobacter pylori Eradication for Metachronous Gastric Cancer: An Unsuitable Methodology Impeding Broader Clinical Usage

Abstract

Recently, a study reported significant reductions in metachronous gastric cancer after H. pylori eradication therapy in patients with previously resected early gastric cancer. These results indicated that H. pylori infections benefit from treatment at any stage, thus refuting the conventional concept of the “point of no return”. Unfortunately, several methodological problems may exist in the aforementioned study that may influence the generalizability of results and conclusions and impede its broader clinical use. In this study, we discuss in detail methodological problems and rationale for caution by analyzing reported studies, aiming to help the promotion of future well-powered trials. Helicobacter pylori infection is a major health concern worldwide, especially in many resource-poor countries, particularly in Africa and Latin America/Caribbean, such that more than half of the global population was infected with the pathogen H. pylori in 2015 (1). Gastric cancer (for which stomach adenocarcinoma accounts for around 90% of cases) is a life-threatening disease, which may be prevented by pharmacological approaches such as aspirin and non-pharmacological approaches such as gastric endoscopy (1). Basic and clinical studies have demonstrated strong associations between oncogenesis and the presence of H. pylori bacteria in the stomach; this includes the progression of pre-cancerous lesions (2). Remarkably, the proportion of non-cardia gastric cancer attributable to H. pylori increased from 74.7 to 89.0% from 2008 to 2014 (3). Furthermore, other epidemiologic factors, such as metabolic syndrome, are increasingly implicated in the etiology of gastric cancer (4). Importantly, H. pylori infection has also been linked to non-gastric diseases, including Parkinson's disease (5). The eradication of H. pylori using antibiotic therapy may prevent gastric cancer; such treatment has been implemented with varying levels of success globally (6). The timing of interventions is often considered a key factor in determining whether cancer therapy is successful or not and whether H. pylori eradication is beneficial. A recent review of clinical studies revealed that H. pylori eradication is associated with a significantly lower risk of gastric cancer, particularly in patients with atrophic and non-atrophic gastritis, rather than in those with intestinal metaplasia; however, maximal benefit is obtained when eradication is performed during the early stages of infection (7). While this might be challenging because the infection is not typically targeted in childhood, a recent review of clinical studies confirmed that there is a general belief among healthcare practitioners that H. pylori eradication can prevent gastric cancer when it is administered in pre-cancerous or early cancerous stages (i.e., before a “point of no return”) (8). In a remarkable and highly visible clinical study, Choi et al. (9) reported significant reductions in the incidence of metachronous gastric cancer after H. pylori eradication therapy in patients with previously resected early gastric cancer, indicating that H. pylori infections can benefit from treatment at any stage, thus refuting the conventional concept of the “point of no return” (1). This exciting finding seems important in convincing physicians, patients, and stakeholders, in favor of preventive H. pylori eradication, who might be otherwise skeptical of such measures; moreover, it generally aligns with the findings of similar recently published studies in the literature (10). Previous critiques of this landmark study were focused on its scientific aspects (11). Unfortunately, we have identified several methodological problems in the study, which may impact the generalizability of the results and conclusion, regardless of whether the study is robust and/or can be replicated. Hence, there is a need for further evidence (or more rigorous clinical trials) regarding the promising role of H. pylori eradication in the prevention of metachronous gastric cancer. More precisely, the study by Choi et al. (9) was a clinical trial in which ~10% of the patients developed gastric cancer, and a statistically significant difference was noted between the treated and untreated groups (P = 0.03). The authors reported a highly significant (P < 0.001) change in the atrophy grade within the corpus lesser curvature, thereby fulfilling their primary objective. A consistent limitation of clinical studies is the inability to replicate results (frequently known as the “reproducibility crisis”); this often occurs due to low statistical power and a tendency to overinterpret statistically significant results. The researchers (9) did not report whether multiplicity corrections were used, although such statistical analyses are increasingly used in leading scientific journals (12). Combined with the reports of individual patient data, despite opposing opinions (13), we suspect that this could have helped readers to evaluate whether there is a causal association between H. pylori eradication and metachronous cancer reduction more accurately. A recent study demonstrated that clinical study participants are typically amenable to sharing of their individual patient data (14); the provision of such additional data would help promote detailed meta-analyses and evaluate the robustness of important results. The corpus lesser curvature, which showed significantly less atrophy in patients who underwent H. pylori eradication therapy, is one of many regions where stomach adenocarcinomas exist. In the Japanese Gastric Cancer Association classification system, the corpus lesser curvature comprises three of the 12 possible lymph node stations; together with the corpus upper curvature, it is considered a part of the N1 region (15). Cancer...