Long journey to prevent metachronous gastric cancer after endoscopic resection

The “Perspective” by Drs. Cho et al. (1) is a very interesting and informative article for the readers. They have summarized the recent issues regarding the effects of Helicobacter pylori (H. pylori) on the prevention of metachronous gastric cancer (MGC) after endoscopic resection (ER), including our study (2). We thank them for their kind comments and interest in our article.

Does H. pylori eradication actually prevent MGC from the perspective of basic and clinical evidence?

As Cho et al. (1) mention in their paper, there has been great debate about whether H. pylori eradication actually prevents MGC. Our recent open-label, randomized, controlled trial (RCT) demonstrated that H. pylori eradication did not produce significant changes in the molecular alterations related to carcinogenesis in patients once gastric cancer had occurred in the stomach (2). To date, only a few studies investigated the effects of eradication on molecular alterations in the background mucosa with gastric cancer (3,4). Shin et al. (4) reported that a decrease in the MOS methylation level was not observed among patients with intestinal metaplasia (IM) or those with gastric cancer, and the methylation level in MOS was persistently increased in patients with gastric cancer even after H. pylori eradication (mean follow-up duration, 26.0 months). Choi et al. (5) postulated that a long-term investigation (over 5 years) could clarify the exact role of H. pylori eradication. One of the limitations in our study was that the intervention period of the RCT was short (1 year), and thus it may be necessary to conduct follow-up for a long time. In Japan, it has been only 3 years since the government approved health insurance coverage for the treatment of H. pylori in chronic gastritis in 2013. Therefore, future studies of molecular events with a long-term investigation following eradication are expected to resolve this matter in Japan.

Cancer risk is generally higher in patients who underwent ER than in those with chronic gastritis, because the patients who develop gastric cancer enter the state of “field cancerization”. To date, there have been a few meta-analyses regarding the effects of H. pylori eradication on MGC after ER (6,7). These studies concluded that H. pylori eradication is associated with a reduction of the incidence of gastric cancer. A recent meta-analysis by Chen et al. (8) showed that, for patients without IM at baseline diagnosis, H. pylori eradication may halt the progression to a precancerous lesion including IM and reduce the risk of gastric cancer, whereas when IM presents, no preventive effect was observed after eradication, neither in the risk of gastric cancer nor in the progression to a precancerous lesion. This result supports the study by Wong et al. (9).

H. pylori infection may be a promoter for gastric carcinogenesis

In the animal model, H. pylori infection alone never causes gastric tumorigenesis, and other factors including methyl N-nitrosourea or salt are needed to develop stomach cancer (10). In addition, the lesions that developed in H. pylori-infected models are heterotopic proliferative glands, similar to mucinous adenocarcinoma, different from gastric adenocarcinoma. Therefore, the results from animal models highlight that H. pylori is not an initiator, but it might be a promoter of gastric carcinogenesis (11). Taken together, it makes sense to us that H. pylori eradication alone cannot prevent the development of gastric cancer, including MGC. Additionally, it may be true that the elimination of the bacteria delays the development of gastric cancer if H. pylori infection plays a role as a promoter of gastric carcinogenesis. In any case, it will be best to provide eradication for the chronic gastritis patients who did not pass the “point of no return”.

Beyond H. pylori eradication for MGC prevention

The number of molecular alterations related to gastric carcinogenesis may be approximately 20 at most. However, we still cannot identify the indisputable biomarkers heralding the “point of no return” in H. pylori-associated carcinogenesis despite the efforts of many investigators worldwide. Thus, additional efforts are needed for a secondary prevention study of MGC for patients whose H. pylori has been eradicated. Actually, a combination of anti-oxidative or anti-inflammatory agents, dietary or nutritional intervention activating molecular mechanisms for cancer prevention, reversion of premalignant lesions, and even ablation of cancer stem cells rather than H. pylori treatment is needed, as Cho et al. state, as short-term interventions to revert premalignant lesions (siTRP) (1).

In conclusion, patients with IM may not benefit from H. pylori eradication with respect to the risk of MGC. Additionally, in view of the present situation, in which we cannot identify a definite biomarker for gastric cancer development, it is appropriate that surrounding break-up should be considered, such as siTRP, rather than H. pylori treatment to prevent MGC.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Zi-Guo Yang, MM (Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University; Shandong University School of Medicine, Jinan, China).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2016.07.31). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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