Elsevier

The Lancet

Volume 372, Issue 9636, 2–8 August 2008, Pages 392-397
The Lancet

Articles
Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial

https://doi.org/10.1016/S0140-6736(08)61159-9Get rights and content

Summary

Background

The relation between Helicobacter pylori infection and gastric cancer has been proven in epidemiological studies and animal experiments. Our aim was to investigate the prophylactic effect of H pylori eradication on the development of metachronous gastric carcinoma after endoscopic resection for early gastric cancer.

Methods

In this multi-centre, open-label, randomised controlled trial, 544 patients with early gastric cancer, either newly diagnosed and planning to have endoscopic treatment or in post-resection follow-up after endoscopic treatment, were randomly assigned to receive an H pylori eradication regimen (n=272) or control (n=272). Randomisation was done by a computer-generated randomisation list and was stratified by whether the patient was newly diagnosed or post-resection. Patients in the eradication group received lansoprazole 30 mg twice daily, amoxicillin 750 mg twice daily, and clarithromycin 200 mg twice daily for a week; those in the control group received standard care, but no treatment for H pylori. Patients were examined endoscopically at 6, 12, 24, and 36 months after allocation. The primary endpoint was diagnosis of new carcinoma at another site in the stomach. Analyses were by intention to treat. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000001169.

Findings

At 3-year follow-up, metachronous gastric carcinoma had developed in nine patients in the eradication group and 24 in the control group. In the full intention-to-treat population, including all patients irrespective of length of follow-up (272 patients in each group), the odds ratio for metachronous gastric carcinoma was 0·353 (95% CI 0·161–0·775; p=0·009); in the modified intention-to-treat population, including patients with at least one post-randomisation assessment of tumour status and adjusting for loss to follow-up (255 patients in the eradication group, 250 in the control group), the hazard ratio for metachronous gastric carcinoma was 0·339 (95% CI 0·157–0·729; p=0·003). In the eradication group, 19 (7%) patients had diarrhoea and 32 (12%) had soft stools.

Interpretation

Prophylactic eradication of H pylori after endoscopic resection of early gastric cancer should be used to prevent the development of metachronous gastric carcinoma.

Funding

Hiroshima Cancer Seminar Foundation.

Introduction

Helicobacter pylori has an important role in gastric carcinogenesis, since almost all non-cardiac gastric cancers develop from a background of H pylori-infected mucosa.1 WHO has categorised the bacterium as a group 1 carcinogen for gastric cancer on the basis of results from epidemiological studies.2, 3, 4, 5, 6, 7, 8, 9, 10 Animal models clearly show the causal link between H pylori and gastric cancers.11, 12, 13, 14 In experimental studies, H pylori eradication has been shown to have a prophylactic effect on gastric cancer.15, 16, 17 However, the prophylactic effect of such eradication in human beings remains controversial. Non-randomised intervention studies, in which eradicated and non-eradicated patients underwent endoscopic follow-up to assess the development of gastric cancer, have suggested that eradication of H pylori has an inhibitory effect on gastric cancer incidence.18 However, a large-scale, double-blind randomised study in China showed that gastric cancer still occurred after successful eradication of H pylori and that eradication did not lead to a significant decrease in the incidence of gastric cancer.19 Meta-analysis of four randomised intervention studies with gastric cancer incidence as a secondary outcome showed a non-statistically significant overall odds ratio of 0·67 (95% CI 0·42–1·07).20

In Japan, mucosal gastric cancer without concomitant lymph node metastasis is usually treated with endoscopic resection. Guidelines for the treatment of gastric cancer state that intestinal type mucosal cancer less than 20 mm in diameter with no evidence of ulcer or ulcer scar is an indication for endoscopic resection.21 Endoscopic resection removes the tumour and surrounding mucosa such that metachronous gastric cancer could develop at sites other than that of the endoscopic resection.22, 23 A non-randomised Japanese study involving 132 patients with early gastric cancer and a multi-centre historical cohort study reported that eradication of H pylori after endoscopic resection reduced the development of metachronous gastric cancer.24, 25

We did this multi-centre, open-label, randomised controlled trial to determine the effect of eradication of H pylori on the subsequent development of metachronous gastric carcinoma after endoscopic resection for early stage gastric cancer—ie, in patients at high risk for developing such cancers.

Section snippets

Patients

The details of the study design have been published elsewhere.26 Briefly, 51 hospitals affiliated with the Japan Gast Study Group participated. Patients were eligible for enrolment if they were aged 20–79 years and had been diagnosed with early gastric cancer, either newly diagnosed and planning to have endoscopic treatment (newly diagnosed), or in a follow-up phase after endoscopic resection (post-resection). Exclusion criteria were the absence of active H pylori infection, the development of

Results

The trial profile is shown in figure 1. The intention-to-treat population consisted of 544 patients, while the modified intention-to-treat population consisted of 505 patients. The baseline characteristics of the patients in the modified intention-to-treat population are shown in table 1; there were no significant differences between groups in terms of sex, age, characteristics of the endoscopically resected lesions, or the background gastric mucosa. Length of time between endoscopic resection

Discussion

The results of this multi-centre, open-label, randomised controlled trial suggest that treatment to eradicate H pylori reduces the risk of developing new gastric carcinoma in patients who have a history of such disease and are thus at high risk for developing further gastric cancers.

Although randomisation was used to reduce potential bias at baseline, one patient in each group voluntarily left the study at allocation, and 21 patients in the control group and 16 in the eradication group left the

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