Early detection of gastric cancer after Helicobacter pylori eradication due to endoscopic surveillance

Abstract Background Helicobacter pylori eradication therapy is commonly performed to reduce the incidence of gastric cancer. However, gastric cancer is occasionally discovered even after successful eradication therapy. Therefore, we examined the prognosis of gastric cancer patients, diagnosed after successful H. pylori eradication therapy. Materials and Methods All‐cause death rates and gastric cancer‐specific death rates in gastric cancer patients who received successful H. pylori eradication treatment was tracked and compared to rates in patients who did not receive successful eradication therapy. Results In total, 160 gastric cancer patients were followed‐up for up to 11.7 years (mean 3.5 years). Among them, 53 gastric cancer patients received successful H. pylori eradication therapy prior to gastric cancer diagnosis. During the follow‐up period, 11 all‐cause deaths occurred. In the successful eradication group, the proportion of patients with cancer stage I was higher. The proportions of patients who received curative endoscopic therapy and endoscopic examination in the 2 years prior to gastric cancer diagnosis were also higher in the successful eradication group. Kaplan–Meier analysis of all‐cause death and gastric cancer‐specific death revealed a lower death rate in patients in the successful eradication group (P = .0139, and P = .0396, respectively, log‐rank test). The multivariate analysis showed that endoscopy within 2 years before cancer diagnosis is associated with stage I cancer. Conclusions Possible early discovery of gastric cancer after H. pylori eradication due to regular endoscopic surveillance may contribute to better prognosis of patients with gastric cancer.


| INTRODUC TI ON
Helicobacter pylori infection is one of the most common triggers of gastric cancer, and gastric cancer is the major cause of cancer deaths. [1][2][3][4] Gastric cancers are the third leading cause of cancer mortality and advanced disease carries a dismal prognosis with a 5-year overall survival rate of less than 5%. 5,6 Surgery and endoscopic resection at an early stage is still the only chance for cure. 7,8 Although it has been reported that H. pylori eradication therapy reduces the incidence of gastric cancer and is widely conducted to prevent gastric carcinogenesis, gastric cancers are still diagnosed in patients who received successful eradication therapy. [9][10][11][12][13] Thus, endoscopic surveillance of gastric cancers after H. pylori eradication is expected to be a beneficial approach for detection.
The endoscopic and histological features of gastric cancers after eradication have been investigated vigorously. [14][15][16] To the best of our knowledge, research on gastric cancer deaths after successful H. pylori eradication therapy is insufficient. Therefore, we examined the prognosis of gastric cancer diagnosed after successful H. pylori eradication therapy.

| Patients
Gastric cancer patients diagnosed at Toyoshima Endoscopy Clinic were analysed retrospectively using an endoscopic database and clinical charts. Esophagogastroduodenoscopy was performed by certificated endoscopists. The patients underwent esophagogastroduodenoscopy either for screening, for a previous history of esophagogastroduodenal disease, present symptoms or abnormal findings on barium meal examination. Biopsy specimens were taken from lesions suspected to be gastric cancer, and the final diagnosis of gastric cancer was based on pathology results. Gastric cancers were classified pathologically as either intestinal or diffuse type according to Lauren's classification. 17

| Clinicopathological assessment
Clinicopathological findings, including the interval since H. pylori eradication, interval since last endoscopy, age, sex, body mass index (BMI), past history of cancer (other than gastric cancer), first degree family history of gastric cancer, 12  The interval since last endoscopy was defined as the interval between the endoscopy during which the gastric cancer was detected and the previous endoscopy.

| H. pylori infection status
Helicobacter pylori infection was confirmed when any one of the following tests was positive; 13 19 We removed groups (3) and (4) from the analysis comparing the effect of H. pylori eradication.

| Statistical analysis
All statistical analyses were performed using JMP10 software (SAS Institute, Cary, NC, USA). Welch's t test was used to compare the means of continuous variables. Comparisons of nominal variables were performed using the χ 2 test or Fisher's exact test, as appropriate. The incidence of all-cause death was evaluated using the Kaplan-Meier method, and the statistical significance of the differences was evaluated by log-rank test. All-cause death was the primary endpoint, and data were censored at the final visit.
Additional endpoint was gastric cancer death. Odds ratios (OR) with 95% confidence intervals (CI) were used as a measure of association and were adjusted using unconditional logistic regression models.
A two-sided P -value of <.05 was considered to indicate statistical significance.

| Baseline characteristics of 160 gastric cancer patients
The baseline characteristics of the gastric cancer patients are pro-  20 We also excluded the 12 patients in the H. pylori spontaneous eradication group (no H. pylori infection patients without history of eradication therapy with atrophic gastritis). 21,22 As shown in Table 2 Figure 1B. A significant between-group difference was also found using a log-rank test (P = .0396).

| Associated factors of gastric cancer stage
We conducted a multivariate analysis of the 142 patients (89 in the persistent infection group and 53 in the successful eradication therapy group) shown in Table 2 Table 3, endoscopy within 2 years is associated with stage I. The other factors did not statistically affect the cancer stage.

| D ISCUSS I ON
We examined the prognosis of gastric cancer patients diagnosed after successful H. pylori eradication therapy and found that these gastric cancer patients showed better prognosis than the gastric cancer patients who did not undergo successful eradication therapy.
In this study, 86.8% of gastric cancers diagnosed after successful eradication therapy were the intestinal type (Table 2), and it was more frequent than the diffuse type. This is consistent with past reports. 10,13,23 Our study revealed that gastric cancer patients diagnosed after successful eradication therapy showed early stage cancer at diagnosis and high a proportion of them received curative endoscopic therapy ( Table 2). Decreased Prostate Stem Cell Antigen (PSCA) expression has been documented in gastric cancer 24 and we recently showed that H. pylori eradication therapy resulted in increased PSCA expression. 25 The other molecular biological effects of H. pylori eradication treatment on stomach cancer carcinogenesis and progression, which could not be evaluated in this research, have been vigorously investigated. [26][27][28] Researchers have also reported that after H. pylori eradication, gastric atrophy decreases gradually and significantly. 29,30 Although the inhibitory effect on the development of gastric cancer following H. pylori eradication, which alters the biological characteristics and surrounding environment of the gastric cancer (as described above), is expected to improve prognosis, the present study failed to show this. Instead, we showed that patients who received successful H. pylori eradication therapy tended to undergo endoscopy in the 2 years prior to gastric cancer diagnosis ( Table 2) and "endoscopy within 2 years before cancer diagnosis" contributed to early diagnosis of gastric cancer (Table 3). Representative guidelines recommend H. pylori eradication to reduce the gastric cancer incidence, and regular endoscopic surveillance for early detection and early treatment. 31,32 We believe our results support the important role of endoscopic surveillance after eradication therapy.
There were limitations to our study. First, the study participants were from a single outpatient endoscopic clinic. Future large-scale research is needed. Second, we could not distinguish whether the gastric cancers diagnosed after eradication had occurred after eradication or existed before the eradication. Third, patients did not randomly receive H. pylori eradication therapy, and thus, there were background differences in the patients who received therapy and those who did not, such as the interval between endoscopic examinations. We are planning to conduct a further analysis that involves a greater number of cases and matches the backgrounds of the eradication group and natural history group as closely as possible.

| CON CLUS ION
In conclusion, we found that patients with gastric cancer, diagnosed after successful H. pylori eradication therapy, had a low mortality rate. Although the mortality rate was significantly decreased in the successful H. pylori eradication therapy group, the "endoscopy within 2 years before cancer diagnosis" was a confounding factor.
That periodic endoscopy was associated with eradication treatment suggest that it may also lead to a reduction in the mortality rate and is therefore recommended.

ACK N OWLED G EM ENTS
The authors thank the gastroenterologists who performed the endoscopic procedures at Toyoshima Endoscopy Clinic (Tokyo, Japan).
We are grateful to Mr. Yamakawa and Mr. Sugita for their arrangement of the database.

D I S CLOS U R E S O F I NTE R E S T S
The authors have no competing interests.