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Risk Assessment of Metachronous Gastric Neoplasm after Endoscopic Resection for Early Gastric Cancer According to Age at Helicobacter pylori Eradication

Seunghan Lee , Soo-Jeong Cho , Hyunsoo Chung , Bokyung Kim , Mi Jin Oh , Yun Suk Na , Jun Hee Lee , Jiyoon Kim , Sang Gyun Kim

Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea

Correspondence to: Sang Gyun Kim
ORCID https://orcid.org/0000-0003-1799-9028
E-mail harley1333@hanmail.net

Received: September 25, 2023; Revised: November 14, 2023; Accepted: December 5, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver.

Published online March 21, 2024

Copyright © Gut and Liver.

Background/Aims: Helicobacter pylori eradication can reduce the incidence of metachronous gastric neoplasm (MGN) after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). This study evaluated the risk of developing MGN after ESD for EGC based on age at H. pylori eradication.
Methods: Data of patients who underwent curative ESD for EGC with H. pylori infection between 2005 and 2018 were retrospectively analyzed. The patients were allocated to four groups according to age at H. pylori eradication: group 1 (<50 years), group 2 (50–59 years), group 3 (60–69 years), and group 4 (≥70 years).
Results: All patients were followed up for at least 5 years after ESD. The 5-year cumulative incidence of MGN was 2.1%, 7.0%, 8.7%, and 16.7% in groups 1, 2, 3, and 4, respectively (p<0.001), and groups 3 and 4 showed a significant increase in the risk of MGN (hazard ratio [HR], 4.66; 95% confidence interval [CI], 1.09 to 19.92 and HR, 10.75; 95% CI, 2.45 to 47.12). After adjustments for moderate to severe intestinal metaplasia based on the updated Sydney system, groups 3 and 4 remained significantly associated with MGN (HR, 4.40; 95% CI, 1.03 to 18.84 and HR, 10.14; 95% CI, 2.31 to 44.57).
Conclusions: The incidence of MGN after ESD for EGC increased with age at H. pylori eradication. Age at H. pylori eradication ≥60 years was an independent risk factor for MGN, even after adjusting for the presence of advanced intestinal metaplasia.

Keywords: Early gastric cancer, Endoscopic submucosal dissection, Metachronous neoplasm, Helicobacter pylori

Gastric cancer is the fifth most common malignancy worldwide and the fourth leading cause of cancer-related death.1 Recently, endoscopic submucosal dissection (ESD) has emerged as a curative treatment modality for early gastric cancer (EGC), demonstrating favorable long-term clinical outcomes when performed under specific indications.2-4

However, ESD accompanies risk for developing metachronous gastric neoplasm (MGN) in the remaining gastric mucosa after treatment.5 According to a recent meta-analysis for MGN, the pooled 5-year and 10-year cumulative incidence rates of MGN after ESD for EGC were 9.5% and 14.9%, respectively.6 In addition, previous studies have reported annual incidence rates of MGN ranging from 2.4% to 4.7%.7-9 Therefore, the risk of MGN has become a major concern for patients who underwent ESD for EGC.10

To date, previous studies have identified several risk factors of the development of MGN after endoscopic resection for EGC. These risk factors include old age, male sex, atrophic gastritis, intestinal metaplasia, synchronous neoplasm, and persistent Helicobacter pylori infection.11-17 Among these factors, H. pylori infection is the only modifiable factor and a number of studies have investigated the effect of H. pylori eradication on prevention of metachronous recurrence after ESD for EGC. Several randomized controlled trials demonstrated that H. pylori eradication reduced the incidence of metachronous gastric cancer (MGC).18-20 In one study, H. pylori eradication led to improvement in the grade of glandular atrophy and intestinal metaplasia based on the updated Sydney system.18 Considering the association between H. pylori infection and the sequential progression from atrophic gastritis and intestinal metaplasia to adenoma and cancer in the stomach,21 it is plausible to infer that H. pylori eradication at a younger age may potentially be associated with a lower incidence of MGN.

To the best of our knowledge, no previous studies have specifically investigated the effect of age at H. pylori eradication on the incidence of MGN. In this retrospective cohort study, we aimed to assess the risk of developing MGN after ESD for EGC according to the age at H. pylori eradication.

1. Study population and design

We performed a retrospective study using data from patients who underwent ESD for EGC with H. pylori infection at Seoul National University Hospital between January 2005 and April 2018. Patients with a follow-up period of less than 5 years were excluded from the analysis, and the data up to April 2023 were analyzed. Information on age, sex, endoscopic findings, histology, H. pylori test results, and medication of the study population was collected from electronic medical records. Patients who underwent non-curative ESD were also excluded.

In the main analysis, we included patients who received curative ESD for EGC, had a follow-up duration of at least 5 years, and achieved eradication of H. pylori through antibiotic therapy. Based on the age at which H. pylori eradication was confirmed, the patients were divided into four groups: group 1 (<50 years), group 2 (50–59 years), group 3 (60–69 years), and group 4 (≥70 years). Additionally, the patients were alternatively categorized into four groups according to age at which ESD was performed: group 1’ (<50 years), group 2’ (50–59 years), group 3’ (60–69 years), and group 4’ (≥70 years).

This study was performed according to the Declaration of Helsinki and was approved by the Institutional Review Board of Seoul National University Hospital (IRB number: 2306-099-1438). The requirement to obtain informed consent from the patients was waived due to the retrospective nature of this study.

2. ESD procedure

The indications for ESD included the following conditions: (1) differentiated-type EGC with tumor size ≤2 cm; (2) high-grade dysplasia; or (3) some cases of low-grade dysplasia, depending on tumor size and patient preference.12 Patients underwent endoscopic ultrasonography and abdominal computed tomography to preclude evidence of submucosal invasion and lymph node or distant metastasis before ESD.

All ESD procedures followed a standardized protocol as described in our previous study.12 Initially, indigo-carmine dye was applied to demarcate the area, marking a boundary 5 mm beyond the lesion. Subsequently, a mixed solution containing indigo carmine, diluted epinephrine (1:100,000), and normal saline was injected to lift the submucosal layer. An initial incision was made outside the marked boundary, and submucosal dissection was conducted using an insulation-tipped knife (H260; Olympus Optical, Tokyo, Japan).

For evaluation of H. pylori infection, mucosal atrophy, and intestinal metaplasia, two random biopsy samples were taken from non-tumorous mucosa: one from the lesser curvature of the antrum, and another from the lesser curvature of the body. Furthermore, a rapid urease test was performed using a tissue sample from the antrum to determine the presence of H. pylori infection.

3. Histopathological evaluation

After ESD, resected specimens were prepared into 2-mm thick sections, followed by hematoxylin and eosin staining. Histopathological evaluation was performed according to the 3rd edition of the Japanese classification of gastric carcinoma.22 In cases of mixed-type cancers, the classification was determined by the differentiation status of the tumor components that constituted more than 50% of the cancer. For tumors with synchronous EGC, the lesion with a deeper invasion depth was selected for evaluation.

Curative ESD was defined as an en bloc resection of a lesion with negative lateral and vertical resection margins, within the curative criteria based on the 2021 Japanese gastric cancer treatment guidelines.3 The curative criteria were defined as one of the following: (1) differentiated type cancer of any size, mucosal invasion, without ulceration; (2) differentiated type cancer of size ≤3 cm, mucosal invasion, with ulceration; (3) differentiated type cancer of size ≤3 cm, with submucosal invasion <500 µm from the muscularis mucosa (SM1); or (4) undifferentiated type cancer of size ≤2 cm with mucosal invasion.

Biopsy specimens taken from non-tumorous mucosa were evaluated based on the updated Sydney system.23 Mucosal atrophy and intestinal metaplasia were graded on a scale of four categories: none, mild, moderate, and severe.

4. H. pylori infection

The positive status of H. pylori infection was determined based on positive results from any of the following tests at the time of ESD: rapid urease test, histologic examination of the antrum, or the body. Successful eradication of H. pylori was defined as negative conversion on follow-up with rapid urease test, histologic examination of the antrum, and the body. In cases where there was a discrepancy between follow-up tests, a positive result was adopted.

The first-line eradication therapy consisted of a triple regimen, including omeprazole, clarithromycin, and amoxicillin, taken for 7 days. The second-line therapy consisted of a quadruple regimen comprising rabeprazole, metronidazole, tetracycline, and bismuth, taken for 7 days. If H. pylori infection was detected during the follow-up after confirmed eradication, it was considered a recurrence of the infection.

5. Follow-up after ESD

Patients underwent upper endoscopy at 3, 6, and 12 months after the initial ESD, and then every 12 months thereafter. During these visits, rapid urease tests and random biopsies were performed to monitor the status of H. pylori infection. The follow-up period was defined as the time between the initial ESD and the last endoscopy documented in the medical records. The development of MGN was defined as the detection of cancer or adenoma distant from the site of ESD, at least 1 year after resection. Any lesion diagnosed within 1 year after resection was considered to be a synchronous neoplasm.5

6. Statistical analysis

Categorical variables were expressed as percentages and compared using the chi-square test or Pearson exact test, as appropriate. Continuous variables were described with median and interquartile ranges and compared using the Student t-test, Mann-Whitney U test, one-way analysis of variance, or Kruskal-Wallis test, as indicated. The cumulative incidence of MGN was assessed using the Kaplan-Meier method and compared by applying log-rank test. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using the Cox proportional hazard regression model. p-values below 0.05 were considered statistically significant. All statistical analyses were conducted with R software version 4.2.3 for Windows (R Foundation, Vienna, Austria).

1. Baseline characteristics

A total of 2,310 patients underwent ESD for EGC between January 2005 and April 2018. Among them, 1,178 patients were initially diagnosed as positive H. pylori infection at the time of ESD. Subsequently, 369 patients with follow-up period less than 5 years and 62 patients who underwent non-curative ESD were excluded from the analysis. After applying the information of H. pylori infection, 322 patients who did not receive eradication therapy, 54 patients with persistent infection after eradication therapy, 16 patients with recurrence of the infection during follow-up, and eight patients with no H. pylori evaluation after eradication therapy were further excluded. Finally, a total of 347 patients who achieved successful H. pylori eradiation and had no recurrence during the follow-up period were included in the main analysis (Fig. 1).

Figure 1.Flow diagram of patient enrollment. ESD, endoscopic submucosal dissection; EGC, early gastric cancer; H. pylori, Helicobacter pylori.

According to the age at H. pylori eradication, 47 patients were categorized into group 1, 114 patients into group 2, 126 patients into group 3, and 60 patients into group 4. Alternatively, based on the age at ESD, 56 patients were classified into group 1’, 121 patients into group 2’, 121 patients into group 3’, and 49 patients into group 4’.

In baseline characteristics, there were no significant differences between the groups for sex (p=0.664), H. pylori eradication (p=0.664), tumor location (p=0.441), tumor size (p=0.436), depth of tumor invasion (p=0.839), histologic type (p=0.124), grade of mucosal atrophy (p=0.136), grade of intestinal metaplasia (p=0.082), pre-existing adenoma (p=0.774), synchronous adenoma (p=0.428), and synchronous EGC (p=0.374). The median follow-up durations for groups 1, 2, 3, and 4 were 93.0, 92.5, 90.5, and 77.5 months, respectively (p=0.171) (Table 1).

Table 1. Baseline Characteristics of the Patients According to Age at Helicobacter pylori Eradication

CharacteristicGroup (<50 yr) (n=47)Group 2 (50–59 yr) (n=114)Group 3 (60–69 yr) (n=126)Group 4 (≥70 yr) (n=60)p-value
Age at eradication, yr46.0 (43.0–48.0)56.0 (53.0–58.0)65.0 (63.0–68.0)72.0 (71.0–74.5)<0.001
Age at ESD, yr46.0 (42.0–47.5)54.0 (52.0–57.0)64.0 (62.0–67.0)71.0 (70.0–73.0)<0.001
Sex0.664
Male36 (76.6)81 (71.1)98 (77.8)44 (73.3)
Female11 (23.4)33 (28.0)28 (22.2)16 (26.7)
H. pylori eradication0.664
Triple therapy46 (97.9)114 (100)124 (98.4)59 (98.3)
Quadruple therapy1 (2.1)02 (1.6)1 (1.7)
Location0.441
Upper2 (4.3)5 (4.4)5 (4.0)2 (3.3)
Middle22 (36.8)36 (31.6)39 (31.0)16 (26.7)
Lower23 (48.9)73 (64.0)82 (65.1)42 (70.0)
Tumor size0.436
<20 mm35 (74.5)89 (78.1)99 (78.6)41 (68.3)
≥20 mm12 (15.1)25 (21.9)27 (21.4)19 (31.7)
Depth of tumor invasion0.839
Mucosa41 (87.2)102 (89.5)115 (91.3)55 (91.7)
Submucosa6 (12.8)12 (10.5)11 (8.7)5 (8.3)
Histologic type0.124
Differentiated42 (89.4)100 (87.7)120 (95.2)57 (95.0)
Undifferentiated5 (10.6)14 (12.3)6 (4.8)3 (5.0)
Mucosal atrophy0.136
Absent/mild42 (89.4)93 (81.6)94 (74.6)45 (75.0)
Moderate/severe5 (10.6)21 (18.4)32 (25.4)15 (25.0)
Intestinal metaplasia0.082
Absent/mild40 (85.1)83 (72.8)87 (65.1)38 (63.3)
Moderate/severe7 (14.9)31 (27.2)39 (34.9)22 (36.7)
Additional lesion
Pre-existing adenoma3 (6.4)13 (11.4)11 (8.7)6 (10.0)0.774
Synchronous adenoma3 (6.4)14 (12.3)14 (11.1)10 (16.7)0.428
Synchronous EGC1 (2.1)3 (2.6)8 (6.3)4 (6.7)0.374
Follow-up duration, mo93.0 (70.5–133.5)92.5 (70.0–131.0)90.5 (70.0–130.0)77.5 (69.0–113.5)0.171

Data are presented as median (interquartile range) or number (%).

ESD, endoscopic submucosal dissection; EGC, early gastric cancer.



2. Incidence of MGN according to age at H. pylori eradication

In a total of 347 enrolled patients, the 5-year and 10-year incidences of MGN were 8.6% and 17.1%, respectively. The 5-year incidence of MGN was 2.1%, 7.0%, 8.7%, and 16.7 % in groups 1, 2, 3, and 4, respectively. The 10-year incidence of MGN was 2.1%, 11.7%, 19.9%, and 35.1% in groups 1, 2, 3, and 4, respectively. There was significant difference in the cumulative incidence of MGN between the groups according to age at H. pylori eradication (p<0.001). Based on age at ESD, the 5-year incidence of MGN was 5.4%, 6.6%, 9.1%, and 16.3% in groups 1’, 2’, 3’, and 4’, respectively. The 10-year incidence of MGN was 5.4%, 15.5%, 20.9%, and 25.1%, in groups 1’, 2’, 3’, and 4’, respectively. A significant difference was also observed in the cumulative incidence of MGN between the groups according to age at ESD (p=0.016) (Fig. 2).

Figure 2.Cumulative incidence of metachronous gastric neoplasm (MGN) after endoscopic submucosal dissection (ESD) for early gastric cancer. (A) According to age at Helicobacter pylori eradication. (B) According to age at ESD.

For the patients in groups 1’, 2’, and 3’ whose age at ESD was less than 70 years, there was no significant difference in the cumulative incidence of MGN (p=0.307). However, when these patients were classified based on the age at H. pylori eradication, the cumulative incidence of MGN significantly increased with the age (p=0.013) (Fig. 3).

Figure 3.Cumulative incidence of metachronous gastric neoplasm (MGN) after endoscopic submucosal dissection (ESD) for, early gastric cancer in patients with age at ESD below 70 years. (A) According to age at Helicobacter pylori eradication. (B) According to age at ESD.

When MGN was divided into metachronous gastric adenoma and MGC for further analysis, there was no significant difference in the cumulative incidence of metachronous gastric adenoma between the groups. (p=0.291) (Supplementary Fig. 1). On the other hand, the cumulative incidence of MGC increased with the age at H. pylori eradication, and there was a significant difference between the groups (p=0.013) (Supplementary Fig. 2).

3. Characteristics and treatment outcomes of MGN

During the follow-up period, MGN occurred in 2, 12, 21, and 17 patients for groups 1, 2, 3, and 4, respectively. Among them, MGC was diagnosed in 0, 6, 14, and 11 patients for groups 1, 2, 3, and 4, respectively. No significant difference was observed in the histologic type of metachronous gastric adenoma across the groups (p=0.759). Most of the lesions diagnosed as MGC were of differentiated histology, smaller than 2 cm, confined to mucosa, without lymphovascular invasion, and were subsequently treated with additional ESD. There was no significant difference in histologic type (p=0.477), tumor size (p=0.149), depth of tumor invasion (p=0.969), lymphovascular invasion (p=0.683), treatment strategy (p=0.244), and proportion of R0 resection (p=0.253) for MGC between the groups (Table 2).

Table 2. Characteristics and Treatment Outcomes of Metachronous Gastric Neoplasm after Endoscopic Resection for EGC

Metachronous gastric neoplasmGroup 1 (<50 yr)
(n=2)
Group 2 (50–59 yr)
(n=12)
Group 3 (60–69 yr)
(n=21)
Group 4 (≥70 yr)
(n=17)
p-value
Metachronous gastric adenoma
No. of patients2676
Histologic type0.759
Tubular adenoma, low grade2 (100)5 (83.3)5 (71.4)4 (66.7)
Tubular adenoma, high grade01 (16.7)2 (28.6)2 (33.3)
Metachronous gastric cancer
No. of patients061411
Histologic typeNA0.477
Differentiated6 (100)11 (78.6)9 (81.8)
Undifferentiated03 (21.4)2 (18.2)
Tumor sizeNA0.149
<20 mm6 (100)9 (64.3)6 (54.5)
≥20 mm05 (35.7)5 (45.5)
Depth of tumor invasionNA0.969
Mucosa4 (66.7)11 (78.6)8 (72.7)
SM11 (16.7)1 (7.1)1 (9.1)
SM2 or deeper1 (16.7)2 (14.3)2 (18.2)
Lymphovascular invasionNA1 (16.7)1 (7.1)2 (18.2)0.683
TreatmentNA0.244
ESD6 (100)9 (64.3)8 (72.7)
Surgery05 (35.7)3 (27.3)
R0 resectionNA5 (83.3)14 (100)9 (81.8)0.253

Data are presented as number (%).

EGC, early gastric cancer; SM1, submucosal invasion <500 µm from the muscularis mucosa; SM2, submucosal invasion ≥500 µm from the muscularis mucosa; ESD, endoscopic submucosal dissection; NA, not available.



4. Risk factors of developing MGN after ESD for EGC in patients with H. pylori eradication

In the univariable Cox proportional hazards regression models, the risk of MGN was significantly related to group 3 (HR, 4.66; 95% CI, 1.09 to 19.92; p=0.038) and group 4 (HR, 10.75; 95% CI, 2.45 to 47.12; p=0.002) compared to group 1 as the reference. On the other hand, based on the age at ESD, only group 4’ (HR, 4.16; 95% CI, 1.46 to 11.98; p=0.008) showed significant difference compared to group 1’ as the reference. In addition, moderate to severe mucosal atrophy and intestinal metaplasia, and synchronous gastric neoplasm were identified as significant risk factors (Table 3).

Table 3. Univariable Cox Proportional Hazards Regression Models of Risk Factors for Metachronous Gastric Neoplasm after Endoscopic Resection for EGC

FactorHazard ratio
(95% CI)
p-value
Age at H. pylori eradication
Group 1 (<50 yr)ReferenceReference
Group 2 (50–59 yr)2.69 (0.60–12.01)0.196
Group 3 (60–69 yr)4.66 (1.09–19.92)0.038
Group 4 (≥70 yr)10.75 (2.45–47.12)0.002
Age at ESD
Group 1’ (<50 yr)ReferenceReference
Group 2’ (50–59 yr)1.52 (0.56–4.16)0.411
Group 3’ (60–69 yr)2.12 (0.79–5.72)0.136
Group 4’ (≥70 yr)4.16 (1.46–11.98)0.008
Male sex1.74 (0.82–3.71)0.149
Tumor size (≥20 mm)1.08 (0.58–2.00)0.804
Depth of tumor invasion (submucosa)1.34 (0.60–3.00)0.473
Undifferentiated histology0.83 (0.30–2.33)0.729
Mucosal atrophy (moderate/severe)1.84 (1.01–3.35)0.048
Intestinal metaplasia
(moderate/severe)
1.84 (1.06–3.20)0.030
Pre-existing adenoma1.95 (0.92–4.15)0.083
Synchronous gastric neoplasm
(adenoma/EGC)
1.84 (0.96–3.51)0.064

EGC, early gastric cancer; CI, confidence interval; H. pylori, Helicobacter pylori; ESD, endoscopic submucosal dissection.



In the multivariable Cox analysis for risk factors of developing MGN, the risk of MGN was significantly related to group 3 (HR, 4.40; 95% CI, 1.03 to 18.84; p=0.045) and group 4 (HR, 10.14; 95% CI, 2.31 to 44.57; p=0.002) compared to group 1 as the reference, even after adjusting for the presence of moderate to severe intestinal metaplasia (Table 4). Excluding age at ESD from the multivariable Cox analysis, due to potential correlation with age at H. pylori eradication, yielded consistent results (Supplementary Table 1).

Table 4. Multivariate Cox Proportional Hazards Regression Models of Risk Factors for Metachronous Gastric Neoplasm after Endoscopic Resection for Early Gastric Cancer

Model 1*Model 2
Hazard ratio (95% CI)p-valueHazard ratio (95% CI)p-value
Age at ESD (≥70 yr)0.62 (0.22–1.75)0.370
Male sex1.64 (0.77–3.51)0.2011.71 (0.80–3.64)0.166
Age at H. pylori eradication
Group 1 (<50 yr)ReferenceReferenceReferenceReference
Group 2 (50–59 yr)2.53 (0.57–11.35)0.2252.60 (0.58–11.63)0.212
Group 3 (60–69 yr)4.22 (0.98–18.14)0.0524.40 (1.03–18.84)0.045
Group 4 (≥70 yr)13.88 (2.67–72.27)0.00210.14 (2.31–44.57)0.002
Mucosal atrophy (moderate/severe)1.33 (0.72–2.48)0.362
Intestinal metaplasia (moderate/severe)1.58 (0.89–2.79)0.1151.67 (0.96–2.90)0.069

CI, confidence interval; ESD, endoscopic submucosal dissection; H. pylori, Helicobacter pylori.

*A model that included all significant factors in the univariable analysis; A model that optimized model 1 using the backward step function



5. Additional analysis

In additional analysis, the cumulative incidence of MGN of the study population was calculated including patients with no eradication therapy (n=322) and persistent infection after therapy (n=54), who were initially excluded from the main analysis (Fig. 1). These patients were referred to as group 5 and showed significantly lower 5-year and 10-year incidence of MGN compared to group 4 (p=0.01). However, there was no significant difference in MGN incidence between groups 4 and 5, when only the patients with age at ESD ≥60 years (p=0.06) and those with age at ESD ≥70 years (p=0.373) in group 5 were included (Supplementary Fig. 3).

Furthermore, to rigorously evaluate the impact of H. pylori eradication on the development of MGN, we compared patients who received eradication therapy immediately after ESD and had confirmed eradication at their first 3-month follow-up (n=155) with those in group 5. The eradicated patients showed a significantly lower incidence of MGN compared to those in group 5 (p=0.001) (Supplementary Fig. 4). After age stratification, the eradicated patients with age at ESD <50 years experienced no MGN during the follow-up period. In addition, the eradicated group showed a significantly lower incidence of MGN compared to group 5 for patients with age at ESD 50 to 59 (p=0.036) and 60 to 69 (p=0.039). However, there was no significant difference in MGN incidence between the two groups for patients with age at ESD ≥70 (p=0.991) (Supplementary Fig. 5).

In this long-term follow-up study, we demonstrated that the incidence of MGN increased with age at H. pylori eradication (Fig. 1A). As old age at ESD (≥70 years) is a well-known risk factor for MGN development after endoscopic resection of EGC,6,11,24 we analyzed the incidence of MGN based on age at ESD, alternatively dividing the patients into group n’ (Fig. 1B). In consistence with previous studies, the patients in group 4’ (age at ESD ≥70 years) had a significantly higher MGN incidence compared to the other groups. However, for the patients in groups 1’ to 3’ (age at ESD <70 years), there was no significant difference in the risk of developing MGN among the groups (Table 3, Fig. 2A). Conversely, when these patients were classified according to age at H. pylori eradication, the incidence of MGN significantly increased with the age (Fig. 2B). Therefore, in H. pylori eradicated patients, the age at eradication may be a more significant determinant for the risk of MGN development than the age at ESD, especially in the patients who were younger than 70 years at the time of ESD.

In this study, group 1 (age at H. pylori eradication <50 years) exhibited no difference between the 5-year and 10-year cumulative incidence of MGN, and group 1 had a lower MGN incidence than group 1’ (2.1% vs 5.4%). Moreover, the patients in group 1 did not experience MGC during the median follow-up duration of 93 months (Supplementary Fig. 2). As the age at H. pylori eradication increased from group 1 to 2–4, the difference between the 5-year and 10-year MGN incidence also increased. Furthermore, the lack of significant difference in MGN incidence among groups 3, 4, and 5 (Supplementary Fig. 3) suggests that H. pylori eradication might be less effective in reducing the risk of MGN in patients aged ≥60 years at the time of eradication. A previous retrospective study reported that H. pylori eradication reduced the risk of MGC in patients aged <70 years, but not in those aged ≥70 years.25 Along with this study, we suggest that H. pylori eradication at a younger age may be associated with more improved long-term outcomes after ESD for EGC, in terms of metachronous tumor recurrence.

In our previous study, patients with age at ESD <50 years showed a lower incidence of MGN than that of older patients in the first 5 years following ESD. After this 5-year period, the MGN incidence increased in these patients, suggesting that these patients should receive the same surveillance schedule as older patients.12 However, this study did not differentiate the patients according to the status of H. pylori infection. In the present study, the patients in group 1 presented favorable outcomes even beyond 5 years after ESD. Moreover, group 2 presented no significant difference in the risk of MGN compared to group 1 (Table 3). Based on these findings, it can be reasonable to suggest longer intervals between surveillance endoscopies for patients who underwent H. pylori eradication before age of 60, compared to those who received the eradication at older age. Nonetheless, further studies with a larger sample size are needed to determine the specific follow-up schedule after ESD for these patients.

Intestinal metaplasia, especially in progressed stages, has been known to be a significant precancerous condition for gastric cancer.13,21,26,27 In our study, we demonstrated that the age at H. pylori eradication was an independent risk factor of MGN, even after adjusting for the presence of moderate to severe intestinal metaplasia according to the updated Sydney system. This indicates that H. pylori eradication at an early age may contribute to the prevention of MGN development, regardless of the presence of advanced intestinal metaplasia. One possible explanation is that H. pylori eradication might have prevented the progression of intestinal metaplasia or reduced the severity of advanced intestinal metaplasia, thereby mitigating field cancerization of the stomach. The concept of “point of no return” has been a long-standing concern regarding whether H. pylori eradication actually reduces gastric carcinogenesis,28-31 and several meta-analyses have suggested that patients with intestinal metaplasia do not benefit from H. pylori eradication.32,33 However, a recent randomized trial demonstrated that H. pylori eradication can lead to a decrease in grades of atrophy and intestinal metaplasia, thereby reducing the incidence of MGC in patients who underwent endoscopic resection for EGC.18 In line with this study, our findings support the current understanding in this field.

This study has several limitations. First, the retrospective study design introduced the possibility of selection bias. Second, the relatively small sample size in each group could have limited the statistical power. However, we included consecutive patients under the same indications of ESD in a large-volume hospital, and we analyzed the risk of MGN based on long-term follow-up duration, at least 5 years after ESD. Finally, this study was performed in a country with high incidence of H. pylori infection and thus further research is needed to generalize these findings to regions with different prevalence of the infection.

In conclusion, the risk of developing MGN after ESD for EGC increases with age at H. pylori eradication. The age at H. pylori eradication may be an independent risk factor for MGN, even after adjusting the presence of advanced intestinal metaplasia.

This work was supported by a grant from Liver Research Institute, Seoul National University College of Medicine.

S.J.C. is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

Study concept and design: S.G.K. Data acquisition: S.L. Data analysis and interpretation: S.L. Drafting of the manuscript: S.L. Critical revision of the manuscript for important intellectual content: S.G.K. Statistical analysis: S.L. Obtained funding: S.G.K. Administrative, technical, or material support: S.J.C., H.C., B.K., M.J.O., Y.S.N., J.H.L., J.K. Study supervision: S.G.K. Approval of final manuscript: all authors.

  1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-249.
    Pubmed CrossRef
  2. Kim SG, Park CM, Lee NR, et al. Long-term clinical outcomes of endoscopic submucosal dissection in patients with early gastric cancer: a prospective multicenter cohort study. Gut Liver 2018;12:402-410.
    Pubmed KoreaMed CrossRef
  3. Japanese Gastric Cancer Association. Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition). Gastric Cancer 2023;26:1-25.
    Pubmed KoreaMed CrossRef
  4. Kim SG, Lyu DH, Park CM, et al. Current status of endoscopic submucosal dissection for early gastric cancer in Korea: role and benefits. Korean J Intern Med 2019;34:785-793.
    Pubmed KoreaMed CrossRef
  5. Lee E, Kim SG, Kim B, et al. Metachronous gastric neoplasm beyond 5 years after endoscopic resection for early gastric cancer. Surg Endosc 2023;37:3901-3910.
    Pubmed CrossRef
  6. Ortigão R, Figueirôa G, Frazzoni L, et al. Risk factors for gastric metachronous lesions after endoscopic or surgical resection: a systematic review and meta-analysis. Endoscopy 2022;54:892-901.
    Pubmed CrossRef
  7. Suk S, Seo YJ, Cheung DY, Lee HH, Kim JI, Park SH. The pattern of metachronous recurrence after endoscopic submucosal dissection for gastric adenocarcinoma and dysplasias. Clin Endosc 2023;56:470-478.
    Pubmed KoreaMed CrossRef
  8. Libânio D, Pimentel-Nunes P, Afonso LP, Henrique R, Dinis-Ribeiro M. Long-term outcomes of gastric endoscopic submucosal dissection: focus on metachronous and non-curative resection management. GE Port J Gastroenterol 2017;24:31-39.
    Pubmed KoreaMed CrossRef
  9. Boda T, Ito M, Oka S, et al. Characteristics of metachronous gastric tumors after endoscopic submucosal dissection for gastric intraepithelial neoplasms. Gastroenterol Res Pract 2014;2014:863595.
    Pubmed KoreaMed CrossRef
  10. Lee MW, Kim GH. Metachronous gastric cancer: another hurdle for successful endoscopic treatment for early gastric cancer?. Gut Liver 2020;14:145-147.
    Pubmed KoreaMed CrossRef
  11. Chung CS, Woo HS, Chung JW, et al. Risk factors for metachronous recurrence after endoscopic submucosal dissection of early gastric cancer. J Korean Med Sci 2017;32:421-426.
    Pubmed KoreaMed CrossRef
  12. Yang HJ, Kim SG, Lim JH, et al. Surveillance strategy according to age after endoscopic resection of early gastric cancer. Surg Endosc 2018;32:846-854.
    Pubmed CrossRef
  13. Na YS, Kim SG, Cho SJ. Risk assessment of metachronous gastric cancer development using OLGA and OLGIM systems after endoscopic submucosal dissection for early gastric cancer: a long-term follow-up study. Gastric Cancer 2023;26:298-306.
    Pubmed CrossRef
  14. Yoon H, Kim N, Shin CM, et al. Risk factors for metachronous gastric neoplasms in patients who underwent endoscopic resection of a gastric neoplasm. Gut Liver 2016;10:228-236.
    Pubmed KoreaMed CrossRef
  15. Shin GY, Cho HJ, Park JM, Lim CH, Cho YK, Choi MG. Increased incidence of metachronous gastric neoplasm after endoscopic resection in patients with synchronous gastric neoplasm. BMC Gastroenterol 2020;20:206.
    Pubmed KoreaMed CrossRef
  16. Bang CS, Baik GH, Shin IS, et al. Helicobacter pylori eradication for prevention of metachronous recurrence after endoscopic resection of early gastric cancer. J Korean Med Sci 2015;30:749-756.
    Pubmed KoreaMed CrossRef
  17. Zhao B, Zhang J, Mei D, et al. Does Helicobacter pylori eradication reduce the incidence of metachronous gastric cancer after curative endoscopic resection of early gastric cancer: a systematic review and meta-analysis. J Clin Gastroenterol 2020;54:235-241.
    Pubmed CrossRef
  18. Choi IJ, Kook MC, Kim YI, et al. Helicobacter pylori therapy for the prevention of metachronous gastric cancer. N Engl J Med 2018;378:1085-1095.
    Pubmed CrossRef
  19. Fukase K, Kato M, Kikuchi S, et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomized controlled trial. Lancet 2008;372:392-397.
    Pubmed CrossRef
  20. Choi JM, Kim SG, Choi J, et al. Effects of Helicobacter pylori eradication for metachronous gastric cancer prevention: a randomized controlled trial. Gastrointest Endosc 2018;88:475-485.
    Pubmed CrossRef
  21. Correa P. Helicobacter pylori and gastric carcinogenesis. Am J Surg Pathol 1995;19 Suppl 1:S37-S43.
  22. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011;14:101-112.
    Pubmed CrossRef
  23. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996;20:1161-1181.
    Pubmed CrossRef
  24. Abe S, Oda I, Suzuki H, et al. Long-term surveillance and treatment outcomes of metachronous gastric cancer occurring after curative endoscopic submucosal dissection. Endoscopy 2015;47:1113-1118.
    Pubmed CrossRef
  25. Han SJ, Kim SG, Lim JH, et al. Long-term effects of Helicobacter pylori eradication on metachronous gastric cancer development. Gut Liver 2018;12:133-141.
    Pubmed KoreaMed CrossRef
  26. Huang KK, Ramnarayanan K, Zhu F, et al. Genomic and epigenomic profiling of high-risk intestinal metaplasia reveals molecular determinants of progression to gastric cancer. Cancer Cell 2018;33:137-150.
    Pubmed CrossRef
  27. Shichijo S, Hirata Y, Niikura R, et al. Histologic intestinal metaplasia and endoscopic atrophy are predictors of gastric cancer development after Helicobacter pylori eradication. Gastrointest Endosc 2016;84:618-624.
    Pubmed CrossRef
  28. Wong BC, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 2004;291:187-194.
    Pubmed CrossRef
  29. Leung WK, Lin SR, Ching JY, et al. Factors predicting progression of gastric intestinal metaplasia: results of a randomized trial on Helicobacter pylori eradication. Gut 2004;53:1244-1249.
    Pubmed KoreaMed CrossRef
  30. Watari J, Tomita T, Tozawa K, Oshima T, Fukui H, Miwa H. Preventing metachronous gastric cancer after the endoscopic resection of gastric epithelial neoplasia: roles of Helicobacter pylori eradication and aspirin. Gut Liver 2020;14:281-290.
    Pubmed KoreaMed CrossRef
  31. Choi JM, Kim SG, Yang HJ, et al. Helicobacter pylori eradication can reverse the methylation-associated regulation of miR-200a/b in gastric carcinogenesis. Gut Liver 2020;14:571-580.
    Pubmed KoreaMed CrossRef
  32. Chen HN, Wang Z, Li X, Zhou ZG. Helicobacter pylori eradication cannot reduce the risk of gastric cancer in patients with intestinal metaplasia and dysplasia: evidence from a meta-analysis. Gastric Cancer 2016;19:166-175.
    Pubmed CrossRef
  33. Rokkas T, Rokka A, Portincasa P. A systematic review and meta-analysis of the role of Helicobacter pylori eradication in preventing gastric cancer. Ann Gastroenterol 2017;30:414-423.
    Pubmed KoreaMed CrossRef

Article

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Gut and Liver

Published online March 21, 2024

Copyright © Gut and Liver.

Risk Assessment of Metachronous Gastric Neoplasm after Endoscopic Resection for Early Gastric Cancer According to Age at Helicobacter pylori Eradication

Seunghan Lee , Soo-Jeong Cho , Hyunsoo Chung , Bokyung Kim , Mi Jin Oh , Yun Suk Na , Jun Hee Lee , Jiyoon Kim , Sang Gyun Kim

Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea

Correspondence to:Sang Gyun Kim
ORCID https://orcid.org/0000-0003-1799-9028
E-mail harley1333@hanmail.net

Received: September 25, 2023; Revised: November 14, 2023; Accepted: December 5, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: Helicobacter pylori eradication can reduce the incidence of metachronous gastric neoplasm (MGN) after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). This study evaluated the risk of developing MGN after ESD for EGC based on age at H. pylori eradication.
Methods: Data of patients who underwent curative ESD for EGC with H. pylori infection between 2005 and 2018 were retrospectively analyzed. The patients were allocated to four groups according to age at H. pylori eradication: group 1 (<50 years), group 2 (50–59 years), group 3 (60–69 years), and group 4 (≥70 years).
Results: All patients were followed up for at least 5 years after ESD. The 5-year cumulative incidence of MGN was 2.1%, 7.0%, 8.7%, and 16.7% in groups 1, 2, 3, and 4, respectively (p<0.001), and groups 3 and 4 showed a significant increase in the risk of MGN (hazard ratio [HR], 4.66; 95% confidence interval [CI], 1.09 to 19.92 and HR, 10.75; 95% CI, 2.45 to 47.12). After adjustments for moderate to severe intestinal metaplasia based on the updated Sydney system, groups 3 and 4 remained significantly associated with MGN (HR, 4.40; 95% CI, 1.03 to 18.84 and HR, 10.14; 95% CI, 2.31 to 44.57).
Conclusions: The incidence of MGN after ESD for EGC increased with age at H. pylori eradication. Age at H. pylori eradication ≥60 years was an independent risk factor for MGN, even after adjusting for the presence of advanced intestinal metaplasia.

Keywords: Early gastric cancer, Endoscopic submucosal dissection, Metachronous neoplasm, Helicobacter pylori

INTRODUCTION

Gastric cancer is the fifth most common malignancy worldwide and the fourth leading cause of cancer-related death.1 Recently, endoscopic submucosal dissection (ESD) has emerged as a curative treatment modality for early gastric cancer (EGC), demonstrating favorable long-term clinical outcomes when performed under specific indications.2-4

However, ESD accompanies risk for developing metachronous gastric neoplasm (MGN) in the remaining gastric mucosa after treatment.5 According to a recent meta-analysis for MGN, the pooled 5-year and 10-year cumulative incidence rates of MGN after ESD for EGC were 9.5% and 14.9%, respectively.6 In addition, previous studies have reported annual incidence rates of MGN ranging from 2.4% to 4.7%.7-9 Therefore, the risk of MGN has become a major concern for patients who underwent ESD for EGC.10

To date, previous studies have identified several risk factors of the development of MGN after endoscopic resection for EGC. These risk factors include old age, male sex, atrophic gastritis, intestinal metaplasia, synchronous neoplasm, and persistent Helicobacter pylori infection.11-17 Among these factors, H. pylori infection is the only modifiable factor and a number of studies have investigated the effect of H. pylori eradication on prevention of metachronous recurrence after ESD for EGC. Several randomized controlled trials demonstrated that H. pylori eradication reduced the incidence of metachronous gastric cancer (MGC).18-20 In one study, H. pylori eradication led to improvement in the grade of glandular atrophy and intestinal metaplasia based on the updated Sydney system.18 Considering the association between H. pylori infection and the sequential progression from atrophic gastritis and intestinal metaplasia to adenoma and cancer in the stomach,21 it is plausible to infer that H. pylori eradication at a younger age may potentially be associated with a lower incidence of MGN.

To the best of our knowledge, no previous studies have specifically investigated the effect of age at H. pylori eradication on the incidence of MGN. In this retrospective cohort study, we aimed to assess the risk of developing MGN after ESD for EGC according to the age at H. pylori eradication.

MATERIALS AND METHODS

1. Study population and design

We performed a retrospective study using data from patients who underwent ESD for EGC with H. pylori infection at Seoul National University Hospital between January 2005 and April 2018. Patients with a follow-up period of less than 5 years were excluded from the analysis, and the data up to April 2023 were analyzed. Information on age, sex, endoscopic findings, histology, H. pylori test results, and medication of the study population was collected from electronic medical records. Patients who underwent non-curative ESD were also excluded.

In the main analysis, we included patients who received curative ESD for EGC, had a follow-up duration of at least 5 years, and achieved eradication of H. pylori through antibiotic therapy. Based on the age at which H. pylori eradication was confirmed, the patients were divided into four groups: group 1 (<50 years), group 2 (50–59 years), group 3 (60–69 years), and group 4 (≥70 years). Additionally, the patients were alternatively categorized into four groups according to age at which ESD was performed: group 1’ (<50 years), group 2’ (50–59 years), group 3’ (60–69 years), and group 4’ (≥70 years).

This study was performed according to the Declaration of Helsinki and was approved by the Institutional Review Board of Seoul National University Hospital (IRB number: 2306-099-1438). The requirement to obtain informed consent from the patients was waived due to the retrospective nature of this study.

2. ESD procedure

The indications for ESD included the following conditions: (1) differentiated-type EGC with tumor size ≤2 cm; (2) high-grade dysplasia; or (3) some cases of low-grade dysplasia, depending on tumor size and patient preference.12 Patients underwent endoscopic ultrasonography and abdominal computed tomography to preclude evidence of submucosal invasion and lymph node or distant metastasis before ESD.

All ESD procedures followed a standardized protocol as described in our previous study.12 Initially, indigo-carmine dye was applied to demarcate the area, marking a boundary 5 mm beyond the lesion. Subsequently, a mixed solution containing indigo carmine, diluted epinephrine (1:100,000), and normal saline was injected to lift the submucosal layer. An initial incision was made outside the marked boundary, and submucosal dissection was conducted using an insulation-tipped knife (H260; Olympus Optical, Tokyo, Japan).

For evaluation of H. pylori infection, mucosal atrophy, and intestinal metaplasia, two random biopsy samples were taken from non-tumorous mucosa: one from the lesser curvature of the antrum, and another from the lesser curvature of the body. Furthermore, a rapid urease test was performed using a tissue sample from the antrum to determine the presence of H. pylori infection.

3. Histopathological evaluation

After ESD, resected specimens were prepared into 2-mm thick sections, followed by hematoxylin and eosin staining. Histopathological evaluation was performed according to the 3rd edition of the Japanese classification of gastric carcinoma.22 In cases of mixed-type cancers, the classification was determined by the differentiation status of the tumor components that constituted more than 50% of the cancer. For tumors with synchronous EGC, the lesion with a deeper invasion depth was selected for evaluation.

Curative ESD was defined as an en bloc resection of a lesion with negative lateral and vertical resection margins, within the curative criteria based on the 2021 Japanese gastric cancer treatment guidelines.3 The curative criteria were defined as one of the following: (1) differentiated type cancer of any size, mucosal invasion, without ulceration; (2) differentiated type cancer of size ≤3 cm, mucosal invasion, with ulceration; (3) differentiated type cancer of size ≤3 cm, with submucosal invasion <500 µm from the muscularis mucosa (SM1); or (4) undifferentiated type cancer of size ≤2 cm with mucosal invasion.

Biopsy specimens taken from non-tumorous mucosa were evaluated based on the updated Sydney system.23 Mucosal atrophy and intestinal metaplasia were graded on a scale of four categories: none, mild, moderate, and severe.

4. H. pylori infection

The positive status of H. pylori infection was determined based on positive results from any of the following tests at the time of ESD: rapid urease test, histologic examination of the antrum, or the body. Successful eradication of H. pylori was defined as negative conversion on follow-up with rapid urease test, histologic examination of the antrum, and the body. In cases where there was a discrepancy between follow-up tests, a positive result was adopted.

The first-line eradication therapy consisted of a triple regimen, including omeprazole, clarithromycin, and amoxicillin, taken for 7 days. The second-line therapy consisted of a quadruple regimen comprising rabeprazole, metronidazole, tetracycline, and bismuth, taken for 7 days. If H. pylori infection was detected during the follow-up after confirmed eradication, it was considered a recurrence of the infection.

5. Follow-up after ESD

Patients underwent upper endoscopy at 3, 6, and 12 months after the initial ESD, and then every 12 months thereafter. During these visits, rapid urease tests and random biopsies were performed to monitor the status of H. pylori infection. The follow-up period was defined as the time between the initial ESD and the last endoscopy documented in the medical records. The development of MGN was defined as the detection of cancer or adenoma distant from the site of ESD, at least 1 year after resection. Any lesion diagnosed within 1 year after resection was considered to be a synchronous neoplasm.5

6. Statistical analysis

Categorical variables were expressed as percentages and compared using the chi-square test or Pearson exact test, as appropriate. Continuous variables were described with median and interquartile ranges and compared using the Student t-test, Mann-Whitney U test, one-way analysis of variance, or Kruskal-Wallis test, as indicated. The cumulative incidence of MGN was assessed using the Kaplan-Meier method and compared by applying log-rank test. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using the Cox proportional hazard regression model. p-values below 0.05 were considered statistically significant. All statistical analyses were conducted with R software version 4.2.3 for Windows (R Foundation, Vienna, Austria).

RESULTS

1. Baseline characteristics

A total of 2,310 patients underwent ESD for EGC between January 2005 and April 2018. Among them, 1,178 patients were initially diagnosed as positive H. pylori infection at the time of ESD. Subsequently, 369 patients with follow-up period less than 5 years and 62 patients who underwent non-curative ESD were excluded from the analysis. After applying the information of H. pylori infection, 322 patients who did not receive eradication therapy, 54 patients with persistent infection after eradication therapy, 16 patients with recurrence of the infection during follow-up, and eight patients with no H. pylori evaluation after eradication therapy were further excluded. Finally, a total of 347 patients who achieved successful H. pylori eradiation and had no recurrence during the follow-up period were included in the main analysis (Fig. 1).

Figure 1. Flow diagram of patient enrollment. ESD, endoscopic submucosal dissection; EGC, early gastric cancer; H. pylori, Helicobacter pylori.

According to the age at H. pylori eradication, 47 patients were categorized into group 1, 114 patients into group 2, 126 patients into group 3, and 60 patients into group 4. Alternatively, based on the age at ESD, 56 patients were classified into group 1’, 121 patients into group 2’, 121 patients into group 3’, and 49 patients into group 4’.

In baseline characteristics, there were no significant differences between the groups for sex (p=0.664), H. pylori eradication (p=0.664), tumor location (p=0.441), tumor size (p=0.436), depth of tumor invasion (p=0.839), histologic type (p=0.124), grade of mucosal atrophy (p=0.136), grade of intestinal metaplasia (p=0.082), pre-existing adenoma (p=0.774), synchronous adenoma (p=0.428), and synchronous EGC (p=0.374). The median follow-up durations for groups 1, 2, 3, and 4 were 93.0, 92.5, 90.5, and 77.5 months, respectively (p=0.171) (Table 1).

Table 1 . Baseline Characteristics of the Patients According to Age at Helicobacter pylori Eradication.

CharacteristicGroup (<50 yr) (n=47)Group 2 (50–59 yr) (n=114)Group 3 (60–69 yr) (n=126)Group 4 (≥70 yr) (n=60)p-value
Age at eradication, yr46.0 (43.0–48.0)56.0 (53.0–58.0)65.0 (63.0–68.0)72.0 (71.0–74.5)<0.001
Age at ESD, yr46.0 (42.0–47.5)54.0 (52.0–57.0)64.0 (62.0–67.0)71.0 (70.0–73.0)<0.001
Sex0.664
Male36 (76.6)81 (71.1)98 (77.8)44 (73.3)
Female11 (23.4)33 (28.0)28 (22.2)16 (26.7)
H. pylori eradication0.664
Triple therapy46 (97.9)114 (100)124 (98.4)59 (98.3)
Quadruple therapy1 (2.1)02 (1.6)1 (1.7)
Location0.441
Upper2 (4.3)5 (4.4)5 (4.0)2 (3.3)
Middle22 (36.8)36 (31.6)39 (31.0)16 (26.7)
Lower23 (48.9)73 (64.0)82 (65.1)42 (70.0)
Tumor size0.436
<20 mm35 (74.5)89 (78.1)99 (78.6)41 (68.3)
≥20 mm12 (15.1)25 (21.9)27 (21.4)19 (31.7)
Depth of tumor invasion0.839
Mucosa41 (87.2)102 (89.5)115 (91.3)55 (91.7)
Submucosa6 (12.8)12 (10.5)11 (8.7)5 (8.3)
Histologic type0.124
Differentiated42 (89.4)100 (87.7)120 (95.2)57 (95.0)
Undifferentiated5 (10.6)14 (12.3)6 (4.8)3 (5.0)
Mucosal atrophy0.136
Absent/mild42 (89.4)93 (81.6)94 (74.6)45 (75.0)
Moderate/severe5 (10.6)21 (18.4)32 (25.4)15 (25.0)
Intestinal metaplasia0.082
Absent/mild40 (85.1)83 (72.8)87 (65.1)38 (63.3)
Moderate/severe7 (14.9)31 (27.2)39 (34.9)22 (36.7)
Additional lesion
Pre-existing adenoma3 (6.4)13 (11.4)11 (8.7)6 (10.0)0.774
Synchronous adenoma3 (6.4)14 (12.3)14 (11.1)10 (16.7)0.428
Synchronous EGC1 (2.1)3 (2.6)8 (6.3)4 (6.7)0.374
Follow-up duration, mo93.0 (70.5–133.5)92.5 (70.0–131.0)90.5 (70.0–130.0)77.5 (69.0–113.5)0.171

Data are presented as median (interquartile range) or number (%)..

ESD, endoscopic submucosal dissection; EGC, early gastric cancer..



2. Incidence of MGN according to age at H. pylori eradication

In a total of 347 enrolled patients, the 5-year and 10-year incidences of MGN were 8.6% and 17.1%, respectively. The 5-year incidence of MGN was 2.1%, 7.0%, 8.7%, and 16.7 % in groups 1, 2, 3, and 4, respectively. The 10-year incidence of MGN was 2.1%, 11.7%, 19.9%, and 35.1% in groups 1, 2, 3, and 4, respectively. There was significant difference in the cumulative incidence of MGN between the groups according to age at H. pylori eradication (p<0.001). Based on age at ESD, the 5-year incidence of MGN was 5.4%, 6.6%, 9.1%, and 16.3% in groups 1’, 2’, 3’, and 4’, respectively. The 10-year incidence of MGN was 5.4%, 15.5%, 20.9%, and 25.1%, in groups 1’, 2’, 3’, and 4’, respectively. A significant difference was also observed in the cumulative incidence of MGN between the groups according to age at ESD (p=0.016) (Fig. 2).

Figure 2. Cumulative incidence of metachronous gastric neoplasm (MGN) after endoscopic submucosal dissection (ESD) for early gastric cancer. (A) According to age at Helicobacter pylori eradication. (B) According to age at ESD.

For the patients in groups 1’, 2’, and 3’ whose age at ESD was less than 70 years, there was no significant difference in the cumulative incidence of MGN (p=0.307). However, when these patients were classified based on the age at H. pylori eradication, the cumulative incidence of MGN significantly increased with the age (p=0.013) (Fig. 3).

Figure 3. Cumulative incidence of metachronous gastric neoplasm (MGN) after endoscopic submucosal dissection (ESD) for, early gastric cancer in patients with age at ESD below 70 years. (A) According to age at Helicobacter pylori eradication. (B) According to age at ESD.

When MGN was divided into metachronous gastric adenoma and MGC for further analysis, there was no significant difference in the cumulative incidence of metachronous gastric adenoma between the groups. (p=0.291) (Supplementary Fig. 1). On the other hand, the cumulative incidence of MGC increased with the age at H. pylori eradication, and there was a significant difference between the groups (p=0.013) (Supplementary Fig. 2).

3. Characteristics and treatment outcomes of MGN

During the follow-up period, MGN occurred in 2, 12, 21, and 17 patients for groups 1, 2, 3, and 4, respectively. Among them, MGC was diagnosed in 0, 6, 14, and 11 patients for groups 1, 2, 3, and 4, respectively. No significant difference was observed in the histologic type of metachronous gastric adenoma across the groups (p=0.759). Most of the lesions diagnosed as MGC were of differentiated histology, smaller than 2 cm, confined to mucosa, without lymphovascular invasion, and were subsequently treated with additional ESD. There was no significant difference in histologic type (p=0.477), tumor size (p=0.149), depth of tumor invasion (p=0.969), lymphovascular invasion (p=0.683), treatment strategy (p=0.244), and proportion of R0 resection (p=0.253) for MGC between the groups (Table 2).

Table 2 . Characteristics and Treatment Outcomes of Metachronous Gastric Neoplasm after Endoscopic Resection for EGC.

Metachronous gastric neoplasmGroup 1 (<50 yr)
(n=2)
Group 2 (50–59 yr)
(n=12)
Group 3 (60–69 yr)
(n=21)
Group 4 (≥70 yr)
(n=17)
p-value
Metachronous gastric adenoma
No. of patients2676
Histologic type0.759
Tubular adenoma, low grade2 (100)5 (83.3)5 (71.4)4 (66.7)
Tubular adenoma, high grade01 (16.7)2 (28.6)2 (33.3)
Metachronous gastric cancer
No. of patients061411
Histologic typeNA0.477
Differentiated6 (100)11 (78.6)9 (81.8)
Undifferentiated03 (21.4)2 (18.2)
Tumor sizeNA0.149
<20 mm6 (100)9 (64.3)6 (54.5)
≥20 mm05 (35.7)5 (45.5)
Depth of tumor invasionNA0.969
Mucosa4 (66.7)11 (78.6)8 (72.7)
SM11 (16.7)1 (7.1)1 (9.1)
SM2 or deeper1 (16.7)2 (14.3)2 (18.2)
Lymphovascular invasionNA1 (16.7)1 (7.1)2 (18.2)0.683
TreatmentNA0.244
ESD6 (100)9 (64.3)8 (72.7)
Surgery05 (35.7)3 (27.3)
R0 resectionNA5 (83.3)14 (100)9 (81.8)0.253

Data are presented as number (%)..

EGC, early gastric cancer; SM1, submucosal invasion <500 µm from the muscularis mucosa; SM2, submucosal invasion ≥500 µm from the muscularis mucosa; ESD, endoscopic submucosal dissection; NA, not available..



4. Risk factors of developing MGN after ESD for EGC in patients with H. pylori eradication

In the univariable Cox proportional hazards regression models, the risk of MGN was significantly related to group 3 (HR, 4.66; 95% CI, 1.09 to 19.92; p=0.038) and group 4 (HR, 10.75; 95% CI, 2.45 to 47.12; p=0.002) compared to group 1 as the reference. On the other hand, based on the age at ESD, only group 4’ (HR, 4.16; 95% CI, 1.46 to 11.98; p=0.008) showed significant difference compared to group 1’ as the reference. In addition, moderate to severe mucosal atrophy and intestinal metaplasia, and synchronous gastric neoplasm were identified as significant risk factors (Table 3).

Table 3 . Univariable Cox Proportional Hazards Regression Models of Risk Factors for Metachronous Gastric Neoplasm after Endoscopic Resection for EGC.

FactorHazard ratio
(95% CI)
p-value
Age at H. pylori eradication
Group 1 (<50 yr)ReferenceReference
Group 2 (50–59 yr)2.69 (0.60–12.01)0.196
Group 3 (60–69 yr)4.66 (1.09–19.92)0.038
Group 4 (≥70 yr)10.75 (2.45–47.12)0.002
Age at ESD
Group 1’ (<50 yr)ReferenceReference
Group 2’ (50–59 yr)1.52 (0.56–4.16)0.411
Group 3’ (60–69 yr)2.12 (0.79–5.72)0.136
Group 4’ (≥70 yr)4.16 (1.46–11.98)0.008
Male sex1.74 (0.82–3.71)0.149
Tumor size (≥20 mm)1.08 (0.58–2.00)0.804
Depth of tumor invasion (submucosa)1.34 (0.60–3.00)0.473
Undifferentiated histology0.83 (0.30–2.33)0.729
Mucosal atrophy (moderate/severe)1.84 (1.01–3.35)0.048
Intestinal metaplasia
(moderate/severe)
1.84 (1.06–3.20)0.030
Pre-existing adenoma1.95 (0.92–4.15)0.083
Synchronous gastric neoplasm
(adenoma/EGC)
1.84 (0.96–3.51)0.064

EGC, early gastric cancer; CI, confidence interval; H. pylori, Helicobacter pylori; ESD, endoscopic submucosal dissection..



In the multivariable Cox analysis for risk factors of developing MGN, the risk of MGN was significantly related to group 3 (HR, 4.40; 95% CI, 1.03 to 18.84; p=0.045) and group 4 (HR, 10.14; 95% CI, 2.31 to 44.57; p=0.002) compared to group 1 as the reference, even after adjusting for the presence of moderate to severe intestinal metaplasia (Table 4). Excluding age at ESD from the multivariable Cox analysis, due to potential correlation with age at H. pylori eradication, yielded consistent results (Supplementary Table 1).

Table 4 . Multivariate Cox Proportional Hazards Regression Models of Risk Factors for Metachronous Gastric Neoplasm after Endoscopic Resection for Early Gastric Cancer.

Model 1*Model 2
Hazard ratio (95% CI)p-valueHazard ratio (95% CI)p-value
Age at ESD (≥70 yr)0.62 (0.22–1.75)0.370
Male sex1.64 (0.77–3.51)0.2011.71 (0.80–3.64)0.166
Age at H. pylori eradication
Group 1 (<50 yr)ReferenceReferenceReferenceReference
Group 2 (50–59 yr)2.53 (0.57–11.35)0.2252.60 (0.58–11.63)0.212
Group 3 (60–69 yr)4.22 (0.98–18.14)0.0524.40 (1.03–18.84)0.045
Group 4 (≥70 yr)13.88 (2.67–72.27)0.00210.14 (2.31–44.57)0.002
Mucosal atrophy (moderate/severe)1.33 (0.72–2.48)0.362
Intestinal metaplasia (moderate/severe)1.58 (0.89–2.79)0.1151.67 (0.96–2.90)0.069

CI, confidence interval; ESD, endoscopic submucosal dissection; H. pylori, Helicobacter pylori..

*A model that included all significant factors in the univariable analysis; A model that optimized model 1 using the backward step function.



5. Additional analysis

In additional analysis, the cumulative incidence of MGN of the study population was calculated including patients with no eradication therapy (n=322) and persistent infection after therapy (n=54), who were initially excluded from the main analysis (Fig. 1). These patients were referred to as group 5 and showed significantly lower 5-year and 10-year incidence of MGN compared to group 4 (p=0.01). However, there was no significant difference in MGN incidence between groups 4 and 5, when only the patients with age at ESD ≥60 years (p=0.06) and those with age at ESD ≥70 years (p=0.373) in group 5 were included (Supplementary Fig. 3).

Furthermore, to rigorously evaluate the impact of H. pylori eradication on the development of MGN, we compared patients who received eradication therapy immediately after ESD and had confirmed eradication at their first 3-month follow-up (n=155) with those in group 5. The eradicated patients showed a significantly lower incidence of MGN compared to those in group 5 (p=0.001) (Supplementary Fig. 4). After age stratification, the eradicated patients with age at ESD <50 years experienced no MGN during the follow-up period. In addition, the eradicated group showed a significantly lower incidence of MGN compared to group 5 for patients with age at ESD 50 to 59 (p=0.036) and 60 to 69 (p=0.039). However, there was no significant difference in MGN incidence between the two groups for patients with age at ESD ≥70 (p=0.991) (Supplementary Fig. 5).

DISCUSSION

In this long-term follow-up study, we demonstrated that the incidence of MGN increased with age at H. pylori eradication (Fig. 1A). As old age at ESD (≥70 years) is a well-known risk factor for MGN development after endoscopic resection of EGC,6,11,24 we analyzed the incidence of MGN based on age at ESD, alternatively dividing the patients into group n’ (Fig. 1B). In consistence with previous studies, the patients in group 4’ (age at ESD ≥70 years) had a significantly higher MGN incidence compared to the other groups. However, for the patients in groups 1’ to 3’ (age at ESD <70 years), there was no significant difference in the risk of developing MGN among the groups (Table 3, Fig. 2A). Conversely, when these patients were classified according to age at H. pylori eradication, the incidence of MGN significantly increased with the age (Fig. 2B). Therefore, in H. pylori eradicated patients, the age at eradication may be a more significant determinant for the risk of MGN development than the age at ESD, especially in the patients who were younger than 70 years at the time of ESD.

In this study, group 1 (age at H. pylori eradication <50 years) exhibited no difference between the 5-year and 10-year cumulative incidence of MGN, and group 1 had a lower MGN incidence than group 1’ (2.1% vs 5.4%). Moreover, the patients in group 1 did not experience MGC during the median follow-up duration of 93 months (Supplementary Fig. 2). As the age at H. pylori eradication increased from group 1 to 2–4, the difference between the 5-year and 10-year MGN incidence also increased. Furthermore, the lack of significant difference in MGN incidence among groups 3, 4, and 5 (Supplementary Fig. 3) suggests that H. pylori eradication might be less effective in reducing the risk of MGN in patients aged ≥60 years at the time of eradication. A previous retrospective study reported that H. pylori eradication reduced the risk of MGC in patients aged <70 years, but not in those aged ≥70 years.25 Along with this study, we suggest that H. pylori eradication at a younger age may be associated with more improved long-term outcomes after ESD for EGC, in terms of metachronous tumor recurrence.

In our previous study, patients with age at ESD <50 years showed a lower incidence of MGN than that of older patients in the first 5 years following ESD. After this 5-year period, the MGN incidence increased in these patients, suggesting that these patients should receive the same surveillance schedule as older patients.12 However, this study did not differentiate the patients according to the status of H. pylori infection. In the present study, the patients in group 1 presented favorable outcomes even beyond 5 years after ESD. Moreover, group 2 presented no significant difference in the risk of MGN compared to group 1 (Table 3). Based on these findings, it can be reasonable to suggest longer intervals between surveillance endoscopies for patients who underwent H. pylori eradication before age of 60, compared to those who received the eradication at older age. Nonetheless, further studies with a larger sample size are needed to determine the specific follow-up schedule after ESD for these patients.

Intestinal metaplasia, especially in progressed stages, has been known to be a significant precancerous condition for gastric cancer.13,21,26,27 In our study, we demonstrated that the age at H. pylori eradication was an independent risk factor of MGN, even after adjusting for the presence of moderate to severe intestinal metaplasia according to the updated Sydney system. This indicates that H. pylori eradication at an early age may contribute to the prevention of MGN development, regardless of the presence of advanced intestinal metaplasia. One possible explanation is that H. pylori eradication might have prevented the progression of intestinal metaplasia or reduced the severity of advanced intestinal metaplasia, thereby mitigating field cancerization of the stomach. The concept of “point of no return” has been a long-standing concern regarding whether H. pylori eradication actually reduces gastric carcinogenesis,28-31 and several meta-analyses have suggested that patients with intestinal metaplasia do not benefit from H. pylori eradication.32,33 However, a recent randomized trial demonstrated that H. pylori eradication can lead to a decrease in grades of atrophy and intestinal metaplasia, thereby reducing the incidence of MGC in patients who underwent endoscopic resection for EGC.18 In line with this study, our findings support the current understanding in this field.

This study has several limitations. First, the retrospective study design introduced the possibility of selection bias. Second, the relatively small sample size in each group could have limited the statistical power. However, we included consecutive patients under the same indications of ESD in a large-volume hospital, and we analyzed the risk of MGN based on long-term follow-up duration, at least 5 years after ESD. Finally, this study was performed in a country with high incidence of H. pylori infection and thus further research is needed to generalize these findings to regions with different prevalence of the infection.

In conclusion, the risk of developing MGN after ESD for EGC increases with age at H. pylori eradication. The age at H. pylori eradication may be an independent risk factor for MGN, even after adjusting the presence of advanced intestinal metaplasia.

ACKNOWLEDGEMENTS

This work was supported by a grant from Liver Research Institute, Seoul National University College of Medicine.

CONFLICTS OF INTEREST

S.J.C. is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

AUTHOR CONTRIBUTIONS

Study concept and design: S.G.K. Data acquisition: S.L. Data analysis and interpretation: S.L. Drafting of the manuscript: S.L. Critical revision of the manuscript for important intellectual content: S.G.K. Statistical analysis: S.L. Obtained funding: S.G.K. Administrative, technical, or material support: S.J.C., H.C., B.K., M.J.O., Y.S.N., J.H.L., J.K. Study supervision: S.G.K. Approval of final manuscript: all authors.

SUPPLEMENTARY MATERIALS

Supplementary materials can be accessed at https://doi.org/10.5009/gnl230383.

Fig 1.

Figure 1.Flow diagram of patient enrollment. ESD, endoscopic submucosal dissection; EGC, early gastric cancer; H. pylori, Helicobacter pylori.
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Fig 2.

Figure 2.Cumulative incidence of metachronous gastric neoplasm (MGN) after endoscopic submucosal dissection (ESD) for early gastric cancer. (A) According to age at Helicobacter pylori eradication. (B) According to age at ESD.
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Fig 3.

Figure 3.Cumulative incidence of metachronous gastric neoplasm (MGN) after endoscopic submucosal dissection (ESD) for, early gastric cancer in patients with age at ESD below 70 years. (A) According to age at Helicobacter pylori eradication. (B) According to age at ESD.
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Table 1 Baseline Characteristics of the Patients According to Age at Helicobacter pylori Eradication

CharacteristicGroup (<50 yr) (n=47)Group 2 (50–59 yr) (n=114)Group 3 (60–69 yr) (n=126)Group 4 (≥70 yr) (n=60)p-value
Age at eradication, yr46.0 (43.0–48.0)56.0 (53.0–58.0)65.0 (63.0–68.0)72.0 (71.0–74.5)<0.001
Age at ESD, yr46.0 (42.0–47.5)54.0 (52.0–57.0)64.0 (62.0–67.0)71.0 (70.0–73.0)<0.001
Sex0.664
Male36 (76.6)81 (71.1)98 (77.8)44 (73.3)
Female11 (23.4)33 (28.0)28 (22.2)16 (26.7)
H. pylori eradication0.664
Triple therapy46 (97.9)114 (100)124 (98.4)59 (98.3)
Quadruple therapy1 (2.1)02 (1.6)1 (1.7)
Location0.441
Upper2 (4.3)5 (4.4)5 (4.0)2 (3.3)
Middle22 (36.8)36 (31.6)39 (31.0)16 (26.7)
Lower23 (48.9)73 (64.0)82 (65.1)42 (70.0)
Tumor size0.436
<20 mm35 (74.5)89 (78.1)99 (78.6)41 (68.3)
≥20 mm12 (15.1)25 (21.9)27 (21.4)19 (31.7)
Depth of tumor invasion0.839
Mucosa41 (87.2)102 (89.5)115 (91.3)55 (91.7)
Submucosa6 (12.8)12 (10.5)11 (8.7)5 (8.3)
Histologic type0.124
Differentiated42 (89.4)100 (87.7)120 (95.2)57 (95.0)
Undifferentiated5 (10.6)14 (12.3)6 (4.8)3 (5.0)
Mucosal atrophy0.136
Absent/mild42 (89.4)93 (81.6)94 (74.6)45 (75.0)
Moderate/severe5 (10.6)21 (18.4)32 (25.4)15 (25.0)
Intestinal metaplasia0.082
Absent/mild40 (85.1)83 (72.8)87 (65.1)38 (63.3)
Moderate/severe7 (14.9)31 (27.2)39 (34.9)22 (36.7)
Additional lesion
Pre-existing adenoma3 (6.4)13 (11.4)11 (8.7)6 (10.0)0.774
Synchronous adenoma3 (6.4)14 (12.3)14 (11.1)10 (16.7)0.428
Synchronous EGC1 (2.1)3 (2.6)8 (6.3)4 (6.7)0.374
Follow-up duration, mo93.0 (70.5–133.5)92.5 (70.0–131.0)90.5 (70.0–130.0)77.5 (69.0–113.5)0.171

Data are presented as median (interquartile range) or number (%).

ESD, endoscopic submucosal dissection; EGC, early gastric cancer.


Table 2 Characteristics and Treatment Outcomes of Metachronous Gastric Neoplasm after Endoscopic Resection for EGC

Metachronous gastric neoplasmGroup 1 (<50 yr)
(n=2)
Group 2 (50–59 yr)
(n=12)
Group 3 (60–69 yr)
(n=21)
Group 4 (≥70 yr)
(n=17)
p-value
Metachronous gastric adenoma
No. of patients2676
Histologic type0.759
Tubular adenoma, low grade2 (100)5 (83.3)5 (71.4)4 (66.7)
Tubular adenoma, high grade01 (16.7)2 (28.6)2 (33.3)
Metachronous gastric cancer
No. of patients061411
Histologic typeNA0.477
Differentiated6 (100)11 (78.6)9 (81.8)
Undifferentiated03 (21.4)2 (18.2)
Tumor sizeNA0.149
<20 mm6 (100)9 (64.3)6 (54.5)
≥20 mm05 (35.7)5 (45.5)
Depth of tumor invasionNA0.969
Mucosa4 (66.7)11 (78.6)8 (72.7)
SM11 (16.7)1 (7.1)1 (9.1)
SM2 or deeper1 (16.7)2 (14.3)2 (18.2)
Lymphovascular invasionNA1 (16.7)1 (7.1)2 (18.2)0.683
TreatmentNA0.244
ESD6 (100)9 (64.3)8 (72.7)
Surgery05 (35.7)3 (27.3)
R0 resectionNA5 (83.3)14 (100)9 (81.8)0.253

Data are presented as number (%).

EGC, early gastric cancer; SM1, submucosal invasion <500 µm from the muscularis mucosa; SM2, submucosal invasion ≥500 µm from the muscularis mucosa; ESD, endoscopic submucosal dissection; NA, not available.


Table 3 Univariable Cox Proportional Hazards Regression Models of Risk Factors for Metachronous Gastric Neoplasm after Endoscopic Resection for EGC

FactorHazard ratio
(95% CI)
p-value
Age at H. pylori eradication
Group 1 (<50 yr)ReferenceReference
Group 2 (50–59 yr)2.69 (0.60–12.01)0.196
Group 3 (60–69 yr)4.66 (1.09–19.92)0.038
Group 4 (≥70 yr)10.75 (2.45–47.12)0.002
Age at ESD
Group 1’ (<50 yr)ReferenceReference
Group 2’ (50–59 yr)1.52 (0.56–4.16)0.411
Group 3’ (60–69 yr)2.12 (0.79–5.72)0.136
Group 4’ (≥70 yr)4.16 (1.46–11.98)0.008
Male sex1.74 (0.82–3.71)0.149
Tumor size (≥20 mm)1.08 (0.58–2.00)0.804
Depth of tumor invasion (submucosa)1.34 (0.60–3.00)0.473
Undifferentiated histology0.83 (0.30–2.33)0.729
Mucosal atrophy (moderate/severe)1.84 (1.01–3.35)0.048
Intestinal metaplasia
(moderate/severe)
1.84 (1.06–3.20)0.030
Pre-existing adenoma1.95 (0.92–4.15)0.083
Synchronous gastric neoplasm
(adenoma/EGC)
1.84 (0.96–3.51)0.064

EGC, early gastric cancer; CI, confidence interval; H. pylori, Helicobacter pylori; ESD, endoscopic submucosal dissection.


Table 4 Multivariate Cox Proportional Hazards Regression Models of Risk Factors for Metachronous Gastric Neoplasm after Endoscopic Resection for Early Gastric Cancer

Model 1*Model 2
Hazard ratio (95% CI)p-valueHazard ratio (95% CI)p-value
Age at ESD (≥70 yr)0.62 (0.22–1.75)0.370
Male sex1.64 (0.77–3.51)0.2011.71 (0.80–3.64)0.166
Age at H. pylori eradication
Group 1 (<50 yr)ReferenceReferenceReferenceReference
Group 2 (50–59 yr)2.53 (0.57–11.35)0.2252.60 (0.58–11.63)0.212
Group 3 (60–69 yr)4.22 (0.98–18.14)0.0524.40 (1.03–18.84)0.045
Group 4 (≥70 yr)13.88 (2.67–72.27)0.00210.14 (2.31–44.57)0.002
Mucosal atrophy (moderate/severe)1.33 (0.72–2.48)0.362
Intestinal metaplasia (moderate/severe)1.58 (0.89–2.79)0.1151.67 (0.96–2.90)0.069

CI, confidence interval; ESD, endoscopic submucosal dissection; H. pylori, Helicobacter pylori.

*A model that included all significant factors in the univariable analysis; A model that optimized model 1 using the backward step function


References

  1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-249.
    Pubmed CrossRef
  2. Kim SG, Park CM, Lee NR, et al. Long-term clinical outcomes of endoscopic submucosal dissection in patients with early gastric cancer: a prospective multicenter cohort study. Gut Liver 2018;12:402-410.
    Pubmed KoreaMed CrossRef
  3. Japanese Gastric Cancer Association. Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition). Gastric Cancer 2023;26:1-25.
    Pubmed KoreaMed CrossRef
  4. Kim SG, Lyu DH, Park CM, et al. Current status of endoscopic submucosal dissection for early gastric cancer in Korea: role and benefits. Korean J Intern Med 2019;34:785-793.
    Pubmed KoreaMed CrossRef
  5. Lee E, Kim SG, Kim B, et al. Metachronous gastric neoplasm beyond 5 years after endoscopic resection for early gastric cancer. Surg Endosc 2023;37:3901-3910.
    Pubmed CrossRef
  6. Ortigão R, Figueirôa G, Frazzoni L, et al. Risk factors for gastric metachronous lesions after endoscopic or surgical resection: a systematic review and meta-analysis. Endoscopy 2022;54:892-901.
    Pubmed CrossRef
  7. Suk S, Seo YJ, Cheung DY, Lee HH, Kim JI, Park SH. The pattern of metachronous recurrence after endoscopic submucosal dissection for gastric adenocarcinoma and dysplasias. Clin Endosc 2023;56:470-478.
    Pubmed KoreaMed CrossRef
  8. Libânio D, Pimentel-Nunes P, Afonso LP, Henrique R, Dinis-Ribeiro M. Long-term outcomes of gastric endoscopic submucosal dissection: focus on metachronous and non-curative resection management. GE Port J Gastroenterol 2017;24:31-39.
    Pubmed KoreaMed CrossRef
  9. Boda T, Ito M, Oka S, et al. Characteristics of metachronous gastric tumors after endoscopic submucosal dissection for gastric intraepithelial neoplasms. Gastroenterol Res Pract 2014;2014:863595.
    Pubmed KoreaMed CrossRef
  10. Lee MW, Kim GH. Metachronous gastric cancer: another hurdle for successful endoscopic treatment for early gastric cancer?. Gut Liver 2020;14:145-147.
    Pubmed KoreaMed CrossRef
  11. Chung CS, Woo HS, Chung JW, et al. Risk factors for metachronous recurrence after endoscopic submucosal dissection of early gastric cancer. J Korean Med Sci 2017;32:421-426.
    Pubmed KoreaMed CrossRef
  12. Yang HJ, Kim SG, Lim JH, et al. Surveillance strategy according to age after endoscopic resection of early gastric cancer. Surg Endosc 2018;32:846-854.
    Pubmed CrossRef
  13. Na YS, Kim SG, Cho SJ. Risk assessment of metachronous gastric cancer development using OLGA and OLGIM systems after endoscopic submucosal dissection for early gastric cancer: a long-term follow-up study. Gastric Cancer 2023;26:298-306.
    Pubmed CrossRef
  14. Yoon H, Kim N, Shin CM, et al. Risk factors for metachronous gastric neoplasms in patients who underwent endoscopic resection of a gastric neoplasm. Gut Liver 2016;10:228-236.
    Pubmed KoreaMed CrossRef
  15. Shin GY, Cho HJ, Park JM, Lim CH, Cho YK, Choi MG. Increased incidence of metachronous gastric neoplasm after endoscopic resection in patients with synchronous gastric neoplasm. BMC Gastroenterol 2020;20:206.
    Pubmed KoreaMed CrossRef
  16. Bang CS, Baik GH, Shin IS, et al. Helicobacter pylori eradication for prevention of metachronous recurrence after endoscopic resection of early gastric cancer. J Korean Med Sci 2015;30:749-756.
    Pubmed KoreaMed CrossRef
  17. Zhao B, Zhang J, Mei D, et al. Does Helicobacter pylori eradication reduce the incidence of metachronous gastric cancer after curative endoscopic resection of early gastric cancer: a systematic review and meta-analysis. J Clin Gastroenterol 2020;54:235-241.
    Pubmed CrossRef
  18. Choi IJ, Kook MC, Kim YI, et al. Helicobacter pylori therapy for the prevention of metachronous gastric cancer. N Engl J Med 2018;378:1085-1095.
    Pubmed CrossRef
  19. Fukase K, Kato M, Kikuchi S, et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomized controlled trial. Lancet 2008;372:392-397.
    Pubmed CrossRef
  20. Choi JM, Kim SG, Choi J, et al. Effects of Helicobacter pylori eradication for metachronous gastric cancer prevention: a randomized controlled trial. Gastrointest Endosc 2018;88:475-485.
    Pubmed CrossRef
  21. Correa P. Helicobacter pylori and gastric carcinogenesis. Am J Surg Pathol 1995;19 Suppl 1:S37-S43.
  22. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011;14:101-112.
    Pubmed CrossRef
  23. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996;20:1161-1181.
    Pubmed CrossRef
  24. Abe S, Oda I, Suzuki H, et al. Long-term surveillance and treatment outcomes of metachronous gastric cancer occurring after curative endoscopic submucosal dissection. Endoscopy 2015;47:1113-1118.
    Pubmed CrossRef
  25. Han SJ, Kim SG, Lim JH, et al. Long-term effects of Helicobacter pylori eradication on metachronous gastric cancer development. Gut Liver 2018;12:133-141.
    Pubmed KoreaMed CrossRef
  26. Huang KK, Ramnarayanan K, Zhu F, et al. Genomic and epigenomic profiling of high-risk intestinal metaplasia reveals molecular determinants of progression to gastric cancer. Cancer Cell 2018;33:137-150.
    Pubmed CrossRef
  27. Shichijo S, Hirata Y, Niikura R, et al. Histologic intestinal metaplasia and endoscopic atrophy are predictors of gastric cancer development after Helicobacter pylori eradication. Gastrointest Endosc 2016;84:618-624.
    Pubmed CrossRef
  28. Wong BC, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 2004;291:187-194.
    Pubmed CrossRef
  29. Leung WK, Lin SR, Ching JY, et al. Factors predicting progression of gastric intestinal metaplasia: results of a randomized trial on Helicobacter pylori eradication. Gut 2004;53:1244-1249.
    Pubmed KoreaMed CrossRef
  30. Watari J, Tomita T, Tozawa K, Oshima T, Fukui H, Miwa H. Preventing metachronous gastric cancer after the endoscopic resection of gastric epithelial neoplasia: roles of Helicobacter pylori eradication and aspirin. Gut Liver 2020;14:281-290.
    Pubmed KoreaMed CrossRef
  31. Choi JM, Kim SG, Yang HJ, et al. Helicobacter pylori eradication can reverse the methylation-associated regulation of miR-200a/b in gastric carcinogenesis. Gut Liver 2020;14:571-580.
    Pubmed KoreaMed CrossRef
  32. Chen HN, Wang Z, Li X, Zhou ZG. Helicobacter pylori eradication cannot reduce the risk of gastric cancer in patients with intestinal metaplasia and dysplasia: evidence from a meta-analysis. Gastric Cancer 2016;19:166-175.
    Pubmed CrossRef
  33. Rokkas T, Rokka A, Portincasa P. A systematic review and meta-analysis of the role of Helicobacter pylori eradication in preventing gastric cancer. Ann Gastroenterol 2017;30:414-423.
    Pubmed KoreaMed CrossRef
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March, 2024

pISSN 1976-2283
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