Many factors, including autoimmune gastritis Citation[1], Epstein–Barr virus infection Citation[2], a high-salt diet Citation[3], hyperglycemia Citation[4] and genetic abnormality Citation[5], have been reported concerning gastric carcinogenesis; however, it is clear that Helicobacter pylori infection is the most important gastric carcinogen Citation[6]. Clinically, gastric cancer is the second most common cancer in the world and the number of newly diagnosed cases was calculated as 750,000 persons per year Citation[7]; in Japan, more than 50,000 people die of gastric cancer every year. The mechanisms inducing gastric carcinogenesis following H. pylori infection have been clarified by many basic research studies. The most important carcinogenic factor of H. pylori infection may be cytotoxin-associated gene product (CagA) toxin, which is injected by the bacteria into the host’s gastric epithelial cells Citation[8]. Recent studies by Hatakeyama et al. have demonstrated direct evidence that CagA actually led to the development of gastric cancer Citation[9]. The next step is the clinical application of these important findings.
Clinical trials of gastric cancer prevention by eradication therapy
Clinically, H. pylori-uninfected people seldom develop gastric cancer. Theoretically, therefore, eradication therapy should be beneficial for cancer prevention. However, attention should be drawn to the fact that the gastric cancer risk is not similar between noninfected and eradicated people. Until now, many human studies have demonstrated that some patients develop gastric cancer even if they have undergone successful eradication therapy Citation[10]. The next important issue is the actual clinical prevention of gastric cancer by H. pylori eradication therapy. Interestingly, studies in Japan have demonstrated the effectiveness of cancer prevention through eradication therapy in approximately a third of patients treated; however, most studies from outside Japan concluded that there is no effect of eradication therapy on gastric cancer prevention Citation[11].
It should be emphasized that the clinical stage of gastric cancer is significantly different between Japan and other countries. Previously, we carried out a systematic review and clarified that the prevalence of early gastric cancer was 94% in Japan and 16% overseas Citation[11]. This indicates not only the superior diagnostic ability in Japan but also the limited effect of eradication therapy. In other words, eradication therapy may have an effect on cancer prevention if the therapy is administrated before a single cancer cell has transformed or before cancer tissue shows invasive growth. It is likely that eradication therapy has no effect if the cancer has progressed to an advanced stage.
Eradication therapy reduced the prevalence of gastric cancer
A Japanese multicenter randomized controlled trial by the Japan Gast Study Group enrolled patients undergoing previous endoscopic therapy for gastric cancer and demonstrated that eradication therapy significantly reduced the prevalence of secondary gastric cancer in a 3-year follow-up period Citation[12]. It should be emphasized that the study design was superior to previous studies and so the conclusions of this study are strongly supported. However, this study does not show that eradication therapy can prevent newly developed gastric cancer even in secondary cancer, because the follow-up period was too short. Our previous study demonstrated that the doubling time of gastric cancer at an early stage was 16.6 months Citation[13], and another study supported this result Citation[14]. These findings suggest that it will take more than 10 years from the transformation of a single cancer cell until the endoscopic detection of a gastric cancer lesion. Subsequently, the mechanism may be as follows: first, eradication therapy influences the growth or invasive ability of early (occult) gastric cancer; and second, cancer morphology may change and escape discovery by routine endoscopic examination.
What is the true effect of eradication therapy on gastric carcinogenesis?
In the first hypothesis, we should discuss the difference in biological behavior between occult and clinical cancer. It is well known that the malignant potential increases if cancer cells invade the submucosal layer and interact with interstitial stromal cells Citation[15]. However, it is still unclear whether occult cancer cells have a different character compared with those limited to the mucosal layer, which are clinically detectable. If the cancer cells in occult cancer tissue show poor autonomous growth, eradication therapy will be beneficial for these lesions. In the second hypothesis we previously demonstrated that morphology of gastric neoplasms, including gastric cancer, changed, especially in elevated-type tumors Citation[16]. Moreover, non-neoplastic epithelium appears at the surface of tumor tissue microscopically on short-term follow-up Citation[16]. Gotoda et al. initially demonstrated the endoscopic disappearance of gastric adenoma by eradication therapy, which is consistent with our results Citation[17]. The actual mechanism may be clarified by the long-term follow-up of these subjects. If the difference in cancer prevalence becomes distinct, the first hypothesis may be likely. However, if the difference becomes indistinct, the second may be possible.
Cancer prevention program in the next step
For the prevention of gastric cancer, it is clear that eradication therapy at an earlier age should be strongly recommended, and a recent paper supports this Citation[18]. Moreover, the cancer-preventive effect of eradication therapy may be prominent at the stage when the host’s gastric mucosa shows a non-neoplastic or premalignant status. In Japan, the prevalence of H. pylori infection is markedly decreasing and the prevalence at a younger age (<20 years) has fallen below 10% Citation[19]. In addition, the spread of eradication therapy and elucidation of infection routes should accelerate the decreasing trend of H. pylori infection. Intervention (eradication therapy) will become realistic and a national strategy may become possible.
Previous studies have demonstrated that H. pylori-negative gastric cancer was rare, with a prevalence of less than 3% among all gastric cancers Citation[20,21]. We have also demonstrated that the prevalence of H. pylori-negative gastric cancer is less than 1% [Ito et al., Unpublished Data]. Gastric cancer is the most common neoplasm in Japan (53.4 per 100,000 people in 2003) Citation[22]. If we can treat and cure H. pylori infection, the rate of gastric cancer should reduce by approximately 1 in 100, meaning that occurrence of gastric cancer would become similar to that of more rare cancers. Recent cancer screening systems in Japan are based on the early detection of cancer (secondary prevention). However, future strategies may be based on the primary prevention of cancer, which represents a shift from the early detection of gastric cancer to the early eradication of H. pylori.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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