Impact of perioperative Helicobacter pylori eradication therapy on long-term survival after distal gastrectomy for gastric cancer

Abstract

BACKGROUND

Persistent Helicobacter pylori (H. pylori) infection is associated with adverse outcomes after gastrectomy for gastric cancer.

AIM

To evaluate the association of perioperative H. pylori eradication therapy with longterm survival in patients undergoing distal gastrectomy for gastric cancer.

METHODS

This retrospective cohort study involved H. pylori-positive patients who underwent distal gastrectomy with D2 lymphadenectomy for gastric adenocarcinoma at our hospital from January 2016 to January 2021. The patients were divided into a perioperative eradication group and a non-eradication group depending on whether they received a 14-day bismuth-containing quadruple regimen. Key measurements included H. pylori status at 6 months, nutritional/inflammatory parameters at 12 months, remnant gastric lesions at 1 year, adjuvant chemotherapy completion, and long-term oncologic outcomes, including 5-year overall survival (OS) and disease-free survival (DFS).

RESULTS

Among the 271 eligible patients (143 non-eradication and 128 eradication), the eradication success rate was 91.41% in the eradication group. Compared with the non-eradication group, the eradication group was associated with significantly higher 5-year OS (91.41% vs 80.42%, P = 0.010) and 5-year DFS (85.94% vs 72.73%, P = 0.008) and lower rates of metachronous gastric cancer (1.56% vs 7.69%, P = 0.018) and gastric cancer-specific death (6.25% vs 15.38%, P = 0.017). Multivariate Cox regression analysis adjusting for age, sex, pathological tumor-node-metastasis stage, differentiation, and lymphovascular invasion revealed that perioperative eradication remained independently associated with improved OS (hazard ratio = 0.551, P = 0.036) and DFS (hazard ratio = 0.604, P = 0.043).

CONCLUSION

In this retrospective cohort, perioperative H. pylori eradication therapy was independently associated with improved long-term survival and reduced risk of metachronous gastric cancer in patients who underwent distal gastrectomy for gastric cancer.

Key Words: Helicobacter pylori; Gastrectomy; Stomach neoplasms; Perioperative care; Disease-free survival

Core Tip: This retrospective cohort study evaluated whether perioperative Helicobacter pylori (H. pylori) eradication therapy is associated with improved long-term outcomes in H. pylori-positive patients after distal gastrectomy for gastric cancer. Eradication therapy was independently associated with higher 5-year overall survival and disease-free survival, lower metachronous gastric cancer risk, better nutritional recovery, less advanced remnant gastric atrophy, and improved chemotherapy tolerance. These findings suggest that perioperative H. pylori eradication may be a valuable adjunct to comprehensive postoperative management.

INTRODUCTION

Gastric cancer remains one of the leading causes of cancer-related mortality worldwide and has a particularly high incidence in East Asian populations[1]. Despite advances in surgical techniques and perioperative management, the prognosis for patients with locally advanced gastric cancer is still suboptimal, with 5-year survival rates ranging from 30% to 60% after curative resection[2,3]. Helicobacter pylori (H. pylori) is a class I carcinogen and plays a well-established etiological role in non-cardia gastric adenocarcinoma. Persistent H. pylori infection induces chronic gastritis, which progresses through atrophic gastritis and intestinal metaplasia to dysplasia and eventually to carcinoma, a cascade known as Correa’s pathway[4,5]. Beyond its role in carcinogenesis, H. pylori infection may also influence postoperative outcomes in patients who underwent gastrectomy[6].

After distal gastrectomy, the remnant gastric mucosa is exposed to altered luminal environments, including duodenogastric reflux, reduced gastric acidity, and bacterial overgrowth[7]. Combined with persistent H. pylori infection, these changes can promote ongoing inflammation, accelerate gastric atrophy and intestinal metaplasia progression, and increase the risk of metachronous gastric cancer in the remnant stomach[8,9]. Moreover, H. pylori-associated chronic inflammation may impair nutritional recovery and systemic immune function, potentially affecting tolerance to adjuvant chemotherapy and long-term survival[10,11]. Whether H. pylori eradication in the perioperative period can modify these adverse processes remains unclear.

Observational studies suggested that H. pylori eradication after gastrectomy reduces the incidence of metachronous gastric cancer and improves remnant gastritis. For instance, Kim et al[12] recently demonstrated that H. pylori eradication reduced the risk of metachronous gastric neoplasia by restoring immune function in the gastric mucosa, as evidenced by increased CD4+ T-cell infiltration and enhanced local cytokine responses. In a large retrospective cohort, Zhao et al[6] reported that anti-H. pylori treatment after radical gastrectomy significantly reduced gastric cancer recurrence risk, highlighting the potential survival benefit of its eradication in the postoperative setting. Nonetheless, evidence regarding its impact on long-term survival and adjuvant chemotherapy completion is limited and inconsistent. Previous studies primarily focused on endoscopic findings or short-term outcomes, while only few systematically evaluated the association of perioperative eradication with overall survival (OS), disease-free survival (DFS), and surrogate endpoints such as nutritional status, inflammatory markers, and chemotherapy adherence[13]. Furthermore, the optimal timing for eradication, whether before surgery or after resumption of oral intake, has not been established, and the safety of initiating eradication therapy close to surgery has emerged as a concern.

This retrospective cohort study aimed to investigate the association of perioperative H. pylori eradication therapy with long-term survival, metachronous gastric cancer risk, postoperative nutritional and inflammatory status, and adjuvant chemotherapy completion in patients who underwent distal gastrectomy for gastric cancer.

MATERIALS AND METHODS

Subject selection

Patients: This study retrospectively analyzed H. pylori-positive patients who underwent distal gastrectomy for gastric cancer at our hospital from January 2016 to January 2021. The patients were divided into two groups depending on whether they received perioperative eradication therapy: Non-eradication group (n = 143) and eradication group (n = 128). Group assignment was determined based on real-world clinical practice. Patients with confirmed H. pylori infection who were deemed suitable for eradication therapy based on renal and hepatic function, absence of contraindications to the regimen (e.g., penicillin or bismuth allergy), and the attending physician’s perioperative risk assessment were offered the perioperative eradication protocol. Patients who declined eradication therapy or had contraindications to any component of the regimen were assigned to the non-eradication group.

The inclusion criteria were as follows: (1) Histopathologically confirmed gastric adenocarcinoma; (2) Standard distal gastrectomy with D2 lymphadenectomy achieving R0 resection; (3) Preoperative confirmation of H. pylori infection by histology, rapid urease test, or ¹³C-urea breath test; (4) Receipt of anti-H. pylori treatment during the perioperative period (defined as starting 7 days before surgery or upon resumption of oral intake after surgery) in the eradication group and nonreceipt of anti-H. pylori treatment in the non-eradication group; and (5) Available complete clinical and follow-up data (completed 5-year follow-up or died within the follow-up period).

The exclusion criteria were as follows: (1) Preoperative neoadjuvant chemotherapy or radiotherapy; (2) Gastric stump cancer or recurrent cancer; (3) Concomitant other organ malignancies; (4) Perioperative death or death within 30 days postoperatively; (5) Absence of postoperative H. pylori reevaluation within 6 months; and (6) Severe hepatic or renal insufficiency or coagulation disorders. Owing to the inclusion criterion requiring complete clinical and follow-up data, no patients with missing data or loss to follow-up were included in this study. Accordingly, all analyses were performed on complete cases without the need for imputation.

Ethical statement: This study followed the principles of the Declaration of Helsinki and was approved by the Ethics Committee of our hospital. As a retrospective analysis of anonymized medical records, informed consent was waived. All patient data were deidentified to ensure privacy, and strict confidentiality measures were implemented throughout the study.

Treatment measures

Surgical management: All patients underwent laparoscopic or open distal subtotal gastrectomy by the same gastric cancer specialty team, ensuring D2 lymph node dissection. Laparoscopic procedures were performed using a high-definition laparoscopic system. Digestive tract reconstruction was performed using Billroth I, Billroth II, or Roux-en-Y anastomosis according to tumor location and surgeon preference.

Perioperative H. pylori eradication regimen: Patients in the eradication group received a bismuth-containing quadruple regimen starting from 7 days before surgery or upon resumption of oral intake after surgery for a total of 14 days. The regimen consisted of 20 mg rabeprazole twice daily, 220 mg bismuth potassium citrate twice daily, 1.0 g amoxicillin twice daily, and 500 mg clarithromycin twice daily. For patients with a penicillin allergy, amoxicillin was replaced with 400 mg metronidazole three times daily. The non-eradication group did not receive any anti-H. pylori therapy.

Adjuvant therapy: According to their postoperative pathological staging (American Joint Committee on Cancer 8^th edition), patients with stage II or III disease were recommended to receive adjuvant chemotherapy, commonly XELOX (capecitabine + oxaliplatin) or SOX (S-1 + oxaliplatin) for 6-8 planned cycles. Dose modifications or delays due to adverse events were recorded in detail.

Data collection and measurement methods

Data were extracted from the electronic medical record system using a predefined form, followed by independent confirmation by two investigators.

Baseline characteristics: Baseline characteristics included age, sex, body mass index, comorbidity (Charlson Comorbidity Index), preoperative H. pylori detection method and results, tumor characteristics (location, size, differentiation, Lauren classification, tumor-node-metastasis stage, and lymphovascular invasion), and surgical details (reconstruction type, operative time, and blood loss).

Postoperative H. pylori reevaluation: At 6 months postoperatively, gastroscopic biopsies were obtained from the remnant stomach and anastomotic site using an electronic gastroscope. H. pylori infection was assessed by histological examination with Warthin-Starry silver staining and immunohistochemistry, combined with a rapid urease test. H. pylori infection status was defined as follows: Negative results on both histology and the rapid urease test were classified as negative, whereas a positive result on either test was classified as positive (high-sensitivity rule).

Short-term postoperative outcomes: Short-term postoperative outcomes included complications within 30 days (Clavien-Dindo classification) and postoperative hospital stay.

Nutritional and inflammatory indicators: Nutritional and inflammatory indicators, including body weight, serum albumin, and hemoglobin and the neutrophil-to-lymphocyte ratio (NLR), were assessed at 12 months postoperatively. Baseline body weight was defined as the measurement obtained closest to the day of surgery within 1 week before surgery. Albumin and hemoglobin levels were measured using an automated biochemical analyzer, and peripheral blood neutrophil and lymphocyte counts were obtained using an automated hematology analyzer to calculate the NLR.

Assessment of remnant gastric lesions: At 1 year postoperatively, gastroscopy was performed using an electronic gastroscope to evaluate the remnant gastric mucosa. Gastric atrophy was evaluated in accordance with the Kimura-Takemoto classification and quantified as an atrophy score: 0 = none, 1 = mild (closed-type C-1/C-2), 2 = moderate (closed-type C-3/open-type O-1), and 3 = severe (open-type O-2/O-3). Intestinal metaplasia was scored using the updated Sydney system: 0 = none, 1 = mild, 2 = moderate, and 3 = marked. Remnant gastritis severity was graded endoscopically as absent, mild, moderate, or severe depending on the presence of mucosal hyperemia, edema, and erosion. Bile reflux was graded endoscopically as absent, mild, moderate, or severe according to the amount of bile observed in the remnant stomach.

Adjuvant chemotherapy completion: Adjuvant chemotherapy completion was analyzed in patients who initiated at least one cycle of adjuvant chemotherapy. Data on chemotherapy start time, relative dose intensity (RDI), delay (defined as > 7 days beyond the planned interval), dose reduction (defined as ≥ 15% reduction from the standard dose), number of completed cycles, planned cycle completion, and discontinuation due to adverse events were collected.

Follow-up and survival evaluation: Follow-up examinations including chest and abdominal computed tomography were performed to assess recurrence and metastasis. OS was defined as the time from surgery to death from any cause or last follow-up. DFS was defined as the time from surgery to first recurrence, metastasis, death from any cause, or last follow-up. Recurrence was classified as local, regional, or distant. Metachronous gastric cancer was defined as a new primary adenocarcinoma arising in the remnant stomach or other parts of the stomach and confirmed by histopathology.

Outcomes

Primary outcome measures were 5-year OS and DFS rates. Secondary outcome measures were perioperative eradication success rate and spontaneous clearance rate at 6 months postoperatively; postoperative complication rate and proportion of severe complications (≥ Clavien-Dindo grade III); postoperative nutritional and inflammatory status, including changes in body weight, albumin, hemoglobin, and NLR at 1 year; adjuvant chemotherapy tolerability, including chemotherapy delay rate, dose reduction rate, and mean number of completed cycles; improvement in remnant gastric lesions, including atrophy score, intestinal metaplasia score, and bile reflux rate at 1 year postoperatively; and cumulative incidence of metachronous gastric cancer with a maximum follow-up of 5 years.

Statistical analysis

SPSS 29.0 was used for data analysis. Categorical variables were presented as n (%) and compared using χ² test or Fisher’s exact test. The Shapiro-Wilk method was used to test the normality of continuous variables; normally distributed data were expressed as mean ± SD and compared using independent samples t-test. Multivariate Cox proportional hazards regression models were constructed to identify independent prognostic factors for OS and DFS. Results were expressed as hazard ratios (HRs) with 95% confidence intervals. All tests were two-sided, and P < 0.05 was considered statistically significant.

RESULTS

Baseline demographic characteristics

Baseline demographic characteristics were comparable between the non-eradication group (n = 143) and eradication group (n = 128), with no significant differences in age (P = 0.119), sex (P = 0.163), body mass index (P = 0.275), Charlson Comorbidity Index (P = 0.310), smoking history (P = 0.222), or alcohol history (P = 0.177) (Table 1).

Table 1 Comparison of baseline demographic characteristics between the two groups, n (%)/mean ± SD.

Parameters	Non-eradication group (n = 143)	Eradication group (n = 128)	t/χ2	P value
Age (years)	59.41 ± 6.84	58.24 ± 6.15	1.565	0.119
Sex			1.948	0.163
Male	105 (73.43)	84 (65.63)
Female	38 (26.57)	44 (34.38)
BMI (kg/m2)	23.02 ± 2.91	22.68 ± 2.53	1.094	0.275
Charlson Comorbidity Index	2.11 ± 0.68	2.04 ± 0.62	1.018	0.310
Smoking history	56 (39.16)	41 (32.03)	1.494	0.222
Alcohol history	50 (34.97)	35 (27.34)	1.822	0.177

BMI: Body mass index.

Tumor pathological characteristics

There were no significant differences in tumor size (P = 0.432), location (P = 0.790), differentiation (P = 0.268), Lauren classification (P = 0.719), pathological tumor-node-metastasis (pTNM) stage (P = 0.501), or lymphovascular invasion (P = 0.453) between the two groups, confirming comparable baseline tumor pathology (Table 2).

Table 2 Comparison of tumor pathological characteristics between the two groups, n (%).

Parameters	Non-eradication group (n = 143)	Eradication group (n = 128)	t/χ2	P value
Tumor size (cm), mean ± SD	4.38 ± 1.44	4.52 ± 1.48	0.787	0.432
Tumor location			0.472	0.790
Antrum	108 (75.52)	92 (71.88)
Gastric angle	23 (16.08)	24 (18.75)
Lower body	12 (8.39)	12 (9.38)
Differentiation			1.226	0.268
Well/moderate	80 (55.94)	63 (49.22)
Poor	63 (44.06)	65 (50.78)
Lauren classification			0.659	0.719
Intestinal	76 (53.15)	68 (53.13)
Diffuse	40 (27.97)	40 (31.25)
Mixed	27 (18.88)	20 (15.63)
pTNM stage			1.383	0.501
I	37 (25.87)	38 (29.69)
II	47 (32.87)	46 (35.94)
III	59 (41.26)	44 (34.38)
Lymphovascular invasion	52 (36.36)	41 (32.03)	0.562	0.453

pTNM: Pathological tumor-node-metastasis.

Surgical parameters

No significant differences in surgical approach (P = 0.813), reconstruction type (P = 0.478), number of lymph nodes harvested (P = 0.132), or postoperative hospital stay (P = 0.069) were found between the two groups. These findings indicate comparable surgical management, thus ensuring that subsequent survival comparisons can be attributed to eradication rather than surgical variations (Table 3).

Table 3 Comparison of surgical parameters between the two groups, n (%)/mean ± SD.

Parameters	Non-eradication group (n = 143)	Eradication group (n = 128)	t/χ2	P value
Surgical approach			0.056	0.813
Laparoscopic	98 (68.53)	86 (67.19)
Open	45 (31.47)	42 (32.81)
Reconstruction type			1.478	0.478
B-I	64 (44.76)	48 (37.50)
B-II	52 (36.36)	52 (40.63)
R-Y	27 (18.88)	28 (21.88)
Number of lymph nodes harvested	31.48 ± 6.52	32.58 ± 5.98	1.511	0.132
Postoperative hospital stay (days)	11.16 ± 3.24	10.52 ± 2.88	1.829	0.069

B-I: Billroth I reconstruction; B-II: Billroth II reconstruction; R-Y: Roux-en-Y reconstruction.

H. pylori eradication and postoperative H. pylori status

All patients in the eradication group completed the prescribed regimen, with an eradication success rate of 91.41% (Table 4). At 6 months postoperatively, the proportion of H. pylori-negative patients was significantly higher in the eradication group than in the noneradication group (P < 0.001; χ² = 142.668). Spontaneous clearance occurred in 18.88% of the noneradication group (P < 0.001; χ² = 26.842).

Table 4 Comparison of perioperative Helicobacter pylori eradication and postoperative Helicobacter pylori status, n (%).

Parameters	Non-eradication group (n = 143)	Eradication group (n = 128)	χ2	P value
Completed eradication regimen	-	128 (100.00)	271.000	< 0.001
Eradication successful	-	117 (91.41)	230.017	< 0.001
Helicobacter pylori status at 6 months postop			142.668	< 0.001
Negative	27 (18.88)	117 (91.41)
Positive	116 (81.12)	11 (8.59)
Spontaneous clearance	27 (18.88)	-	26.842	< 0.001

Postoperative 30-day complications

The overall complication rates were 20.28% in the non-eradication group and 15.63% in the eradication group (P = 0.320). No significant differences were observed between the two groups in rates of severe complications (Clavien-Dindo ≥ III, P = 0.347), anastomotic leakage (P = 0.536), intra-abdominal infection (P = 0.375), wound infection (P = 0.324), or delayed gastric emptying (P = 0.806), indicating that perioperative eradication therapy does not increase the risk of early postoperative adverse events (Table 5).

Table 5 Comparison of 30-day postoperative complications between the two groups, n (%).

Parameters	Non-eradication group (n = 143)	Eradication group (n = 128)	χ2	P value
Overall complications	29 (20.28)	20 (15.63)	0.988	0.320
Clavien-Dindo ≥ grade III	12 (8.39)	7 (5.47)	0.885	0.347
Anastomotic leakage	5 (3.50)	2 (1.56)	0.382	0.536
Intra-abdominal infection	9 (6.29)	5 (3.91)	0.786	0.375
Wound infection	8 (5.59)	4 (3.13)	0.973	0.324
Delayed gastric emptying	10 (6.99)	8 (6.25)	0.060	0.806

Clavien-Dindo: Clavien-Dindo Classification of Surgical Complications.

Postoperative nutritional and inflammatory status

At 12 months postoperatively, the eradication group demonstrated significantly less body weight loss (P = 0.004; t = 2.896), higher albumin (P = 0.002; t = 3.114) and hemoglobin (P = 0.016; t = 2.430) levels, and a lower NLR (P = 0.004; t = 2.886) than the non-eradication group. In contrast, the preoperative levels of these parameters were similar between the groups (all P > 0.05), confirming comparable baseline nutritional and inflammatory statuses (Figure 1).

Figure 1 Comparison of postoperative nutritional and inflammatory status between the two groups. A: Body weight loss (%); B: Albumin (g/L); C: Hemoglobin (g/L); D: Neutrophil-to-lymphocyte ratio. ^aP < 0.05; ^bP < 0.01. NLR: Neutrophil-to-lymphocyte ratio; Preop: Preoperative; Postop: Postoperative.

Remnant gastric lesions at 1 year postoperatively

At 1 year postoperatively, the eradication group showed significantly lower atrophy scores (P < 0.001; t = 7.077) and intestinal metaplasia scores (P < 0.001; t = 8.045) compared with the non-eradication group. Although bile reflux grades were similar between the groups (P = 0.938), remnant gastritis severity was significantly reduced (P = 0.046; χ² = 7.978) and anastomotic ulcer incidence was lower (P = 0.018; χ² = 5.619, Table 6) in the eradication group.

Table 6 Comparison of remnant gastric lesions at 1 year postoperatively, n (%)/mean ± SD.

Parameters	Non-eradication group (n = 143)	Eradication group (n = 128)	t/χ2	P value
Atrophy score (0-3)	1.86 ± 0.60	1.44 ± 0.48	7.077	< 0.001
Intestinal metaplasia score (0-3)	1.67 ± 0.56	1.26 ± 0.42	8.045	< 0.001
Bile reflux grade			0.409	0.938
Absent	98 (68.53)	92 (71.88)
Mild	30 (20.98)	24 (18.75)
Moderate	12 (8.39)	10 (7.81)
Severe	3 (2.10)	2 (1.56)
Remnant gastritis severity			7.978	0.046
Absent	28 (19.58)	38 (29.69)
Mild	64 (44.76)	62 (48.44)
Moderate	36 (25.17)	22 (17.19)
Severe	15 (10.49)	6 (4.69)
Anastomotic ulcer	15 (10.49)	4 (3.13)	5.619	0.018

Completion of adjuvant chemotherapy

Among patients with stage II/III gastric cancer who received adjuvant chemotherapy (non-eradication: n = 105; eradication: n = 90), chemotherapy regimen selection was similar between the groups (P = 0.853). However, the eradication group showed significantly fewer chemotherapy delays (P = 0.043; χ² = 4.103), dose reductions (P = 0.031; χ² = 4.645), and discontinuations due to adverse events (P = 0.044; χ² = 4.067) compared with the non-eradication group. The number of completed cycles (P = 0.005; t = 2.832), RDI (P = 0.002; t = 3.165) and proportion of planned cycle completion (P = 0.004; χ² = 8.205) were all significantly higher in the eradication group (Table 7). These results indicate that perioperative H. pylori eradication therapy is associated with improved adherence to and completion of adjuvant chemotherapy regimens among patients with stage II/III gastric cancer following distal gastrectomy (Table 7).

Table 7 Comparison of adjuvant chemotherapy completion (stage II/III patients), n (%)/mean ± SD.

Parameters	Non-eradication group (n = 143)	Eradication group (n = 128)	t/χ2	P value
Chemotherapy regimen			0.319	0.853
XELOX	59 (56.19)	48 (53.33)
SOX	38 (36.19)	36 (40.00)
Other	8 (7.62)	6 (6.67)
Chemotherapy delay	29 (28.71)	14 (15.56)	4.103	0.043
Dose reduction	24 (23.76)	10 (11.11)	4.645	0.031
Completed cycles	5.68 ± 1.48	6.22 ± 1.16	2.832	0.005
Relative dose intensity (%)	85.28 ± 10.86	89.54 ± 7.88	3.165	0.002
Planned cycle completion	67 (66.34)	74 (82.22)	8.205	0.004
Discontinuation due to adverse events	20 (19.80)	8 (8.89)	4.067	0.044

XELOX: Capecitabine plus oxaliplatin; SOX: S-1 plus oxaliplatin.

Long-term oncologic outcomes

The 5-year OS rate (P = 0.010; χ² = 6.618) and DFS rate (P = 0.008; χ² = 7.097) were significantly higher in the eradication group than in the non-eradication group. Metachronous gastric cancer occurred less frequently (P = 0.018; χ² = 5.557) and gastric cancer-specific death was lower (P = 0.017; χ² = 5.725; Table 8) in the eradication group.

Table 8 Comparison of long-term oncologic outcomes between the two groups, n (%).

Parameters	Non-eradication group (n = 143)	Eradication group (n = 128)	χ2	P value
5-year OS rate (%)	80.42	91.41	6.618	0.010
All-cause death	28 (19.58)	11 (8.59)
5-year DFS rate (%)	72.73	85.94	7.097	0.008
Recurrence or metastasis	39 (27.27)	18 (14.06)
Local recurrence	14 (9.79)	6 (4.69)
Regional recurrence	10 (6.99)	5 (3.91)
Distant metastasis	15 (10.49)	7 (5.47)
Metachronous gastric cancer	11 (7.69)	2 (1.56)	5.557	0.018
Gastric cancer-specific death	22 (15.38)	8 (6.25)	5.725	0.017

OS: Overall survival; DFS: Disease-free survival.

Multivariate Cox regression analysis of prognostic factors

In the multivariate Cox regression analysis, perioperative H. pylori eradication remained an independent significant predictor of improved OS (HR = 0.551, P = 0.036; Wald χ² = 4.405) and DFS (HR = 0.604, P = 0.043; Wald χ² = 4.113) after adjustment for age, sex, pTNM stage, differentiation, and lymphovascular invasion. pTNM stage III was the only other significant predictor, and it was associated with poor OS (HR = 2.347, P = 0.007) and DFS (HR = 2.287, P = 0.003). Other variables, including age, sex, differentiation, and lymphovascular invasion, did not reach statistical significance (all P > 0.05; Table 9).

Table 9 Multivariate Cox regression analysis of factors associated with overall survival and disease-free survival.

Variable	β	SE	Wald χ2	P value	HR	95%CI
OS
Eradication (yes vs no)	-0.598	0.285	4.405	0.036	0.551	0.310-0.964
Age (per year)	0.032	0.018	3.160	0.075	1.036	0.993-1.075
Sex (male vs female)	0.128	0.248	0.267	0.606	1.143	0.701-1.853
pTNM stage (III vs I-II)	0.852	0.314	7.361	0.007	2.347	1.274-4.340
Differentiation (poor vs well/moderate)	0.318	0.242	1.728	0.189	1.375	0.863-2.211
Lymphovascular invasion (yes vs no)	0.452	0.256	3.117	0.078	1.571	0.955-2.592
DFS
Eradication (yes vs no)	-0.511	0.252	4.113	0.043	0.604	0.362-0.984
Age (per year)	0.018	0.017	1.121	0.290	1.025	0.996-1.050
Sex (male vs female)	0.146	0.228	0.410	0.522	1.166	0.741-1.813
pTNM stage (III vs I-II)	0.824	0.278	8.787	0.003	2.287	1.327-3.931
Differentiation (poor vs well/moderate)	0.262	0.218	1.444	0.230	1.306	0.859-1.992
Lymphovascular invasion (yes vs no)	0.378	0.234	2.610	0.106	1.462	0.926-2.315

β: Regression coefficient; HR: Hazard ratio; CI: Confidence interval; OS: Overall survival; DFS: Disease-free survival; pTNM: Pathological tumor-node-metastasis.

DISCUSSION

In this retrospective cohort study of H. pylori-positive patients undergoing distal gastrectomy for gastric cancer, perioperative eradication therapy was associated with a range of favorable outcomes, including improved nutritional and inflammatory recovery, remnant gastric mucosal condition, tolerance to adjuvant chemotherapy, and superior long-term survival with a low incidence of metachronous gastric cancer. These associations were preserved after adjustment for major confounders, suggesting that perioperative eradication may play an adjunctive role in postoperative management.

The eradication regimen achieved a high success rate of over 90%, which is comparable with the reported efficacy of bismuth-containing quadruple therapy in Asian populations[14,15]. In the non-eradication group, nearly onefifth of patients showed spontaneous H. pylori clearance at 6 months. This phenomenon was observed after gastrectomy, possibly due to the altered gastric environment of reduced acid secretion, duodenogastric reflux, and bile acids, which may suppress H. pylori colonization[16]. However, the spontaneous clearance rate was substantially lower than the eradication rate, indicating that active intervention is more reliable in clearing the infection[17].

From a mechanistic perspective, chronic H. pylori infection sustains a pro-inflammatory milieu by activating nuclear factor-kappa B and signal transducer and activator of transcription 3 signaling to drive interleukin-6 and tumor necrosis factor-alpha expression and contributes to an immunosuppressive tumor microenvironment by recruiting myeloid-derived suppressor cells and regulatory T cells[4,5]. Eradication attenuates this inflammatory burden, restores local immune competence, and may reduce the risk of metachronous carcinogenesis[12]. Furthermore, H. pylori-induced inflammation may downregulate drug-metabolizing enzymes and transporters, potentially compromising the efficacy and increasing the toxicity of chemotherapeutic agents such as oxaliplatin and capecitabine[18,19]. By eliminating the infection, eradication therapy may enhance tolerance of and clinical response to adjuvant chemotherapy.

The patients who received perioperative eradication had less body weight loss, higher albumin and hemoglobin levels, and a lower NLR 1 year after surgery compared with the non-eradication group. In contrast, the preoperative values were similar between the groups. These findings suggest an association between H. pylori eradication and improved postoperative nutritional and systemic inflammatory status[20,21]. Chronic H. pylori infection is known to induce a proinflammatory state, elevate circulating cytokines such as interleukin-6 and tumor necrosis factor-alpha, and increase resting energy expenditure. Persistent infection after gastrectomy may therefore exacerbate postoperative catabolism and impair protein synthesis. Eradication possibly reduces this chronic inflammatory burden, facilitating nutritional recovery and preserving lean body mass[22]. Improved hemoglobin levels may reflect enhanced iron absorption after the resolution of H. pylori-induced atrophic gastritis, as the bacterium interferes with iron metabolism[23]. Low NLR, a surrogate marker of systemic inflammation, further supports the notion that eradication attenuates persistent low-grade inflammation.

At 1 year postoperatively, the eradication group showed lower atrophy and intestinal metaplasia scores, less severe remnant gastritis, and a lower frequency of anastomotic ulcer compared with the non-eradication group. There was no difference in bile reflux, indicating that the observed benefits are not confounded by differential reflux exposure[24]. Bile reflux is primarily determined by the reconstruction method, which was comparable between the groups. The improvement in precancerous lesions - atrophy and intestinal metaplasia - is consistent with the well-established concept that H. pylori eradication can halt or reverse these changes in the unoperated stomach[25]. In the remnant stomach, the added insult of duodenogastric reflux may accelerate carcinogenesis; however, our data suggest that eradication still provides a protective effect. The low rate of anastomotic ulceration may be explained by the reduced mucosal inflammation and improved epithelial integrity after infection clearance[26].

Among the patients with stage II/III gastric cancer who received adjuvant chemotherapy, those in the eradication group had fewer chemotherapy delays, fewer dose reductions, a higher number of completed cycles, greater RDI, and a higher rate of planned cycle completion compared with the non-eradication group. Discontinuation due to adverse events was also less frequent in the eradication group. These differences are clinically important because poor adherence to adjuvant chemotherapy compromises survival from gastric cancer. The mechanisms possibly involve nutritional and inflammatory improvements. Enhanced nutritional reserve (high albumin, less weight loss) and low systemic inflammation (low NLR) may help patients tolerate myelosuppression, gastrointestinal toxicity, and fatigue[27]. Moreover, H. pylori eradication can reduce the risk of chemotherapy-induced gastritis and ulceration, thereby minimizing interruptions. Our findings align with studies showing that H. pylori eradication before chemotherapy in patients with gastric cancer reduces the incidence of severe neutropenia and adverse gastrointestinal events[18,19].

The most striking associations were seen in longterm oncologic outcomes. The eradication group had higher 5-year OS and DFS rates, fewer recurrences or metastases, and lower rates of gastric cancer-specific death compared with the non-eradication group[28]. Metachronous gastric cancer in the remnant stomach was markedly less frequent in the eradication group. This phenomenon is biologically plausible: Chronic H. pylori infection drives persistent inflammation, oxidative stress, and epithelial proliferation, creating a field defect that predisposes the tissue to new primary cancers[29,30]. Eradication reduces this field effect, as reflected by improved atrophy and intestinal metaplasia scores. Several large, randomized trials in the unoperated stomach demonstrated that H. pylori eradication reduces the incidence of metachronous gastric cancer after the endoscopic resection of early gastric cancer[31]. Our study extended this evidence to the postgastrectomy setting, where the remnant mucosa is at particularly high risk because of bile reflux and bacterial overgrowth.

After adjustment for age, sex, pTNM stage, differentiation, and lymphovascular invasion, multivariate Cox regression analysis confirmed that perioperative eradication was independently associated with improved OS and DFS. The HRs were approximately 0.55 for OS and 0.60 for DFS, indicating a clinically meaningful magnitude of association. pTNM stage III remained the strongest adverse prognostic factor.

This study has several limitations. First, the retrospective design precludes causal inference; the observed associations may be influenced by unmeasured confounders, such as socioeconomic status, dietary habits, or adherence to other lifestyle measures. Second, the non-eradication group was not a placebo-controlled cohort, and the decision to offer eradication was not randomized, thus introducing potential selection bias. However, baseline characteristics and surgical parameters were well balanced. Third, the study was conducted at a single center, limiting generalizability. Fourth, H. pylori status was assessed only at baseline and 6 months postoperatively; long-term persistence or reinfection was not monitored. Fifth, the eradication regimen was not blinded, and the patients in the non-eradication group may have received informal antiH. pylori treatment outside the protocol, though we attempted to exclude such cases. Future prospective randomized controlled trials are necessary to confirm whether perioperative H. pylori eradication causally improves survival and chemotherapy tolerance. In addition, studies should investigate the optimal timing of eradication (preoperative vs postoperative) and the cost-effectiveness of routine perioperative testing and treatment. Longer follow-up beyond 5 years would also help assess the durability of the benefit in preventing metachronous cancers. Mechanistic studies examining changes in the gastric microbiome, local immune response, and systemic cytokine profiles after eradication would provide deeper insights. Until then, our findings support perioperative H. pylori eradication as a potentially beneficial component of comprehensive care for H. pylori-positive patients with gastric cancer undergoing distal gastrectomy.

CONCLUSION

In this retrospective cohort study of H. pylori-positive patients undergoing distal gastrectomy for gastric cancer, perioperative eradication therapy was independently associated with higher 5-year OS and DFS, a lower incidence of metachronous gastric cancer, and reduced gastric cancerspecific mortality. Patients receiving eradication therapy also showed enhanced nutritional and inflammatory recovery at 1 year, less advanced remnant gastric atrophy and intestinal metaplasia, and improved tolerance to adjuvant chemotherapy. These associations persisted after the adjustment for major prognostic factors. While the retrospective design precludes causal conclusions, the consistency of findings across multiple clinically relevant endpoints suggests that perioperative H. pylori eradication may represent a valuable component of multimodal management in this population. Prospective randomized trials are warranted to confirm these observations and establish the optimal timing and long-term benefits of eradication in the perioperative setting.