Efficacy and safety of Huazhuojiedu decoction for gastric precancerous lesions after endoscopic submucosal dissection

Abstract

BACKGROUND

Gastric precancerous lesions, including mucosal atrophy, intestinal metaplasia, and intraepithelial neoplasia, may persist after endoscopic submucosal dissection (ESD) for early gastric cancer, contributing to an annual incidence of metachronous gastric cancer of approximately 2%-3%. Established lesions are poorly reversible with conventional therapies, including Helicobacter pylori eradication and proton pump inhibitors. Huazhuojiedu decoction (HJD), a traditional Chinese medicine (TCM) formula traditionally used to clear heat, resolve turbidity, and detoxify, has potential anti-inflammatory and antitumor effects and warrants systematic clinical evaluation in patients after ESD.

AIM

To evaluate the efficacy and safety of HJD in combination with conventional Western medical therapy for gastric precancerous lesions after ESD for early gastric cancer.

METHODS

This retrospective study included 236 patients with gastric precancerous lesions who underwent ESD for early gastric cancer at the Third Affiliated Hospital of Beijing University of Chinese Medicine between January 2020 and January 2026. Patients were classified according to treatment regimen into an observation group (n = 119) and a control group (n = 117). The control group received a proton pump inhibitor plus with gastric mucosal protective agents, whereas the observation group received HJD in addition to the control regimen. Outcomes included histopathologic response, overall clinical efficacy, TCM syndrome scores, gastric function markers, such as pepsinogen I, pepsinogen II, the pepsinogen I/II ratio, and gastrin-17, serum inflammatory factors [interleukin (IL) 6, IL-8 and tumor necrosis factor-α], gastrointestinal quality-of-life index scores, and adverse events. The development of metachronous gastric cancer and progression of precancerous lesions were also assessed during follow-up.

RESULTS

Histological reversal and improvement rates were significantly higher in the observation group than in the control group (21.0% vs 10.3% and 42.0% vs 29.1%, respectively; both P < 0.05), as was the overall clinical response rate (63.0% vs 39.3%, P < 0.05). Histopathological and TCM syndrome scores and serum inflammatory markers (IL-6, IL-8 and tumor necrosis factor-α) were significantly lower in the observation group, whereas gastric function indices (pepsinogen I, the pepsinogen I/II ratio, and gastrin-17) and gastrointestinal quality-of-life index scores were significantly higher (all P < 0.05). The cumulative incidence of metachronous gastric cancer was lower in the observation group than in the control group (1.7% vs 5.4%), as was the rate of precancerous lesion progression (7.8% vs 18.8%). Cox regression analysis identified HJD treatment as an independent protective factor (hazard ratio = 0.385, P = 0.015).

CONCLUSION

In this retrospective clinical study, HJD combined with conventional Western medical therapy was associated with histopathological improvement of gastric precancerous lesions after ESD for early gastric cancer, alleviation of clinical symptoms, improved gastric function and quality of life, and reduced systemic inflammation. HJD treatment was also associated with lower risks of metachronous gastric cancer and progression of precancerous lesions.

Key Words: Huazhuojiedu decoction; Early gastric cancer; Endoscopic submucosal dissection; Gastric precancerous lesions; Integrated traditional and Western Medicine

Core Tip: Huazhuojiedu decoction combined with conventional Western therapy significantly improves histopathological outcomes in patients with gastric precancerous lesions after endoscopic submucosal dissection. This study demonstrates enhanced reversal and improvement rates, enhanced gastric function (pepsinogen I, pepsinogen I/II ratio, gastrin-17), and reduced inflammatory cytokines (interleukin-6, interleukin-8, tumour necrosis factor-α). Importantly, combination therapy is associated with a lower incidence of metachronous gastric cancer and reduced progression of precancerous lesions during follow-up. These findings suggest that Huazhuojiedu decoction may exert protective effects through anti-inflammatory and multi-target regulatory mechanisms, offering a promising integrative strategy for post-endoscopic submucosal dissection management, although further randomized controlled trials are required for confirmation.

INTRODUCTION

Gastric cancer is the second most common malignant tumor of the digestive system worldwide, and its incidence and mortality remain among the highest of all malignancies in China[1]. Due to rapid advances in digestive endoscopy technology, endoscopic submucosal dissection (ESD) has emerged as the gold standard for treating early gastric cancer. It has several benefits, including low trauma, short recovery period, complete lesion resection and precise pathology evaluation[2]. However, although ESD can completely remove focal cancerous lesions, it does not reverse the underlying pathological changes in the surrounding gastric mucosa. Gastric mucosal atrophy, intestinal metaplasia, and intraepithelial neoplasia are key precancerous lesions in the progression to gastric cancer and are common in patients with early gastric cancer[2,3]. The annual incidence of metachronous gastric cancer after ESD is approximately 2%-3%, with a 5-year cumulative incidence of 10%-15%, substantially higher than that in the general population[4]. Therefore, effective treatment of residual precancerous lesions after ESD and reduction of the risk of metachronous gastric cancer remain important clinical challenges.

Current Western medical treatments for gastric precancerous lesions are limited and primarily include Helicobacter pylori (H. pylori) eradication, proton pump inhibitors, and gastric mucosal protective agents. However, the ability of these interventions to reverse established gastric mucosal atrophy, intestinal metaplasia, and intraepithelial neoplasia remains unclear[5]. Recently, traditional Chinese medicine (TCM) has shown potential benefits in the treatment of gastric precancerous lesions. According to TCM theory, these lesions fall within the categories of “gastric stuffiness” and “stomach pain”, with an underlying pathogenesis characterized by spleen-stomach deficiency, accumulation of dampness and turbidity, and interaction between toxin and blood stasis. Accordingly, treatment principles include strengthening the spleen, resolving turbidity, detoxifying, and dissipating masses[6]. Recent pharmacological studies suggest that many Chinese medicines traditionally used to clear heat, detoxify, resolve turbidity, and eliminate stasis may exert anti-inflammatory and antioxidant effects, regulate apoptosis and cell proliferation, and inhibit epithelial-mesenchymal transition[6]. Through these multiple targets and pathways, such therapies may influence the process of gastric mucosal carcinogenesis[7].

Huazhuojiedu decoction (HJD) is derived from the classic formula “Ganluxiaodu Dan” and incorporates the TCM principles of clearing heat and dampness, resolving turbidity, and detoxifying. Long-term clinical use has suggested potential efficacy in the treatment of gastric precancerous lesions. Related qi-tonifying, detoxifying, and stasis-resolving formulas have also been reported to inhibit the progression of gastric precancerous lesions by suppressing NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis[8]. Based on their traditional medicinal properties, the components of HJD are described as follows: Artemisia capillaris (Yinchen) clears damp-heat and promotes gallbladder function; Scutellaria baicalensis and Coptis chinensis clear heat and toxins and dry dampness; Hedyotis diffusa (Hedyotis), Scutellaria barbata (Banzhilian), and Lobelia chinensis (Banbianlian), clear heat and toxins, activate blood, and dissipate masses; Agastache rugosa (Huoxiang) and Eupatorium fortunei (Peilan) aromatically resolve turbidity, invigorate the spleen, and harmonize the stomach; Sophora flavescens (Kushen) clears heat and dries dampness; and Gynostemma pentaphyllum (Jiaogulan) tonifies qi and strengthens the spleen[9]. Previous studies have suggested that HJD can suppress gastric mucosal inflammation and regulate the balance between proliferation and apoptosis of gastric epithelial cells, indicating potential antitumor effects[10]. However, the clinical efficiency of HJD for precancerous lesions after ESD has not been systemically evaluated. Unlike previous studies, which have focused primarily on chronic atrophic gastritis without prior endoscopic resection, the present study specifically examines patients after ESD, a clinically important and understudied population at increased risk of metachronous gastric cancer. Therefore, this retrospective study analyzed clinical data from patients with early gastric cancer patients who underwent ESD at the Third Affiliated Hospital of Beijing University of Chinese Medicine. We evaluated the efficacy and safety of HJD combined with conventional Western medical therapy for residual gastric precancerous lesions after ESD, with the aim of providing evidence to inform its further clinical use[11].

MATERIALS AND METHODS

Study design

This retrospective clinical study identified patients who underwent ESD for pathologically confirmed gastric precancerous lesions and early gastric cancer at the Third Affiliated Hospital of Beijing University of Chinese Medicine between January 2020 and January 2026. Patients were categorized into the observation group (HJD plus conventional treatment) or the control group (conventional treatment alone) based on the treatment regimen received during routine clinical care, which was determined by patient preference, TCM constitution assessment, and clinician judgement. No randomization was performed, which is a limitation of the study. Patients with high-grade intraepithelial neoplasia (HGIN) in both groups underwent enhanced surveillance with gastroscopic re-examination every 6 months in accordance with contemporary recommendations. The study was approved by the hospital's Medical Ethics Committee; informed consent was waived because of the retrospective use of anonymized medical records.

Study subjects

Inclusion criteria: (1) Age 18-75 years; (2) Diagnosis of early gastric cancer or carcinoma in situ, with successful completion of ESD; (3) Residual precancerous lesions after R0 resection, including atrophic gastritis with intestinal metaplasia and/or low-grade intraepithelial neoplasia; (4) H. pylori-positive patients received bismuth-containing quadruple eradication therapy, with eradication confirmed by a negative ¹³C-urea breath test; (5) Follow-up ≥ 12 months; and (6) Complete clinical data and good treatment compliance.

Exclusion criteria: Positive resection margins or vascular invasion; concomitant malignancy; renal failure, hepatic dysfunction, cardiac insufficiency, or alanine/aspartate aminotransferase levels exceeding twice the upper limit of normal; diabetes mellitus; autoimmune diseases requiring immunosuppressive therapy; pregnancy or lactation; history of allergy to the study medications; psychiatric disorders; or concurrent participation in other clinical trials.

A total of 236 patients were enrolled: 119 in the observation group and 117 in the control group.

Treatment methods

The control group received rabeprazole sodium 20 mg twice daily for 8 weeks, followed by 20 mg once daily for the remainder of the 6-month treatment period, and aluminum magnesium carbonate 1.0 g three times daily for 6 months. Patients also underwent regular follow-up and gastroscopic monitoring.

The observation group received the above treatment plus HJD (Yinchen 15 g, Huangqin 12 g, Baihuasheshecao 15 g, Banlangen 15 g, Banbianlian 15 g, Huoxiang 9 g, Banzhilian 15 g, Kushen 10 g, Huanglian 12 g, Jiaogulan 15 g). The herbs were prepared using an automatic decoction machine, yielding 400 mL/dose, which was divided into two 200-mL bags. Patients took the decoction warm twice daily, 30 minutes after meals, for 6 months (two 3-month courses), concurrently with conventional Western medical treatment.

Data collection

General information: Data on demographic characteristics (sex, age, and body mass index), lifestyle factors (smoking and alcohol consumption), medical history (diabetes and hypertension), pre-ESD pathological stage, type and location of residual precancerous lesions, H. pylori status, and pre-treatment TCM syndrome scores were collected.

Primary outcome measures: Gastroscopic re-examination and pathological biopsy were performed before treatment and at 6 months. Histopathological scoring followed the Updated Sydney System: Atrophy and intestinal metaplasia were each scored from 0 to 3 (none to severe), and intraepithelial neoplasia was scored as 0, 2, or 4 (none, low grade, or high grade, respectively). The total score ranged from 0 to 10, with higher scores indicating more severe lesions.

Secondary outcome measures: (1) Clinical efficacy based on changes in histopathological scores; (2) TCM syndrome scores (0-36 points, 12 items across 8 dimensions), assessed at baseline and at 3 and 6 months; (3) Gastric function, assessed by serum pepsinogen I (PGI), the pepsinogen I/II ratio (PGR), and gastrin-17 (G-17) measured by enzyme-linked immunosorbent assay before and after treatment; (4) Inflammatory markers, including serum interleukin (IL) 6, IL-8, and tumor necrosis factor α (TNF-α), measured by enzyme-linked immunosorbent assay; (5) Quality of life, assessed using the Gastrointestinal Quality-of-Life Index (GIQLI) (0-144 points, 36 items across 5 dimensions) before and after treatment; and (6) Safety, assessed through ongoing monitoring of adverse events, liver and kidney function, and blood counts.

Follow-up protocol

Gastroscopy with biopsy was performed at the completion of treatment and annually thereafter. Follow-up ended in January 2026 at death or loss to follow-up. Metachronous gastric cancer was defined as a new gastric cancer occurring ≥ 12 months after ESD at a site distinct from the original lesion, or within 12 months if located ≤ 2 cm from the original lesion. Progression of precancerous lesions was defined as worsening of atrophy or intestinal metaplasia by ≥ 1 grade or progression from low-grade intraepithelial neoplasia to high-grade intraepithelial neoplasia (HGIN).

Efficacy evaluation criteria

Histopathological outcomes: (1) Reversal: Resolution of neoplasia or a ≥ 2)-point reduction in histopathological score; (2) Improvement: HGIN regressed to low-grade intraepithelial neoplasia or the histopathological score decreased by 1 point; (3) Stable: Change in histopathological score < 1 point; and (4) Progression: Histopathological score increased by ≥ 1 or new neoplasia developed.

Clinical efficacy: (1) Strong effect: Histopathological score decreased by ≥ 70%; (2) Effective: Score decreased by 30% to < 70%); (3) Ineffective: Score decreased by < 30%; and (4) Progression: Score increased. The overall effective rate was calculated as (marked effect + effective)/total × 100%. TCM syndrome efficacy was classified as clinical cure (≥ 95% reduction in score); marked effect (70% to < 95% reduction), effective (30% to < 70% reduction), or ineffective (< 30% reduction).

Statistical analysis

SPSS 26.0 was used for statistical analysis. Normally distributed continuous variables were presented as mean ± SD and compared using the t-test; non-normally distributed variables were presented as M (Q1, Q3) and compared using the Mann-Whitney U or Wilcoxon test, as appropriate. Categorical variables were compared using the χ² test or Fisher’s exact test. Repeated-measures analysis of variance, with Greenhouse-Geisser correction for violations of sphericity and Bonferroni post-hoc adjustment as appropriate, was used for comparisons across multiple time points. Event incidence was analyzed using Kaplan-Meier curves and log-rank tests, and independent risk factors for precancerous lesion events were identified using Cox regression. All tests were two-sided, and P < 0.05 was considered statistically significant.

RESULTS

Baseline characteristics of the two groups

Overall, 236 patients were included, with 119 in the observation group and 117 in the control group. There were no statistically significant differences between the groups in sex, age, body mass index, smoking or drinking history, history of diabetes or hypertension, pre-ESD pathological stage, degree of differentiation (Table 1), type or location of residual precancerous lesions, or H. pylori infection and eradication status (all P > 0.05), indicating that the groups were comparable at baseline.

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

Variable	Observation (n = 119)	Control (n = 117)	χ2/t/Z	P value
Gender - male	71 (59.7)	67 (57.3)	0.186	0.666
Gender - female	48 (40.3)	50 (42.7)	-	-
Age (years)	58.34 ± 8.72	57.86 ± 9.15	0.412	0.681
BMI (kg/m2)	23.18 ± 2.86	23.42 ± 2.91	-0.639	0.523
Smoking history	42 (35.3)	38 (32.5)	0.204	0.651
Drinking history	35 (29.4)	31 (26.5)	0.249	0.618
Diabetes history	18 (15.1)	15 (12.8)	0.260	0.610
Hypertension history	32 (26.9)	29 (24.8)	0.137	0.711
Staging - carcinoma in situ	98 (82.4)	95 (81.2)	0.089	0.766
Staging - intramucosal carcinoma	21 (17.6)	22 (18.8)	-	-
Differentiation - well-moderate	103 (86.6)	99 (84.6)	0.324	0.569
Differentiation - poorly differentiated	16 (13.4)	18 (15.4)	-	-
Atrophic gastritis	119 (100.0)	117 (100.0)	-	-
Intestinal metaplasia	108 (90.8)	104 (88.9)	0.225	0.635
LGIN	45 (37.8)	42 (35.9)	0.093	0.760
HGIN	12 (10.1)	14 (12.0)	0.212	0.645
Location - antrum	52 (43.7)	54 (46.2)	0.892	0.827
Location - body	35 (29.4)	31 (26.5)	-	-
Location - angle	23 (19.3)	24 (20.5)	-	-
Location - cardia	9 (7.6)	8 (6.8)	-	-
H. pylori infection	68 (57.1)	64 (54.7)	0.141	0.707
Pre-treatment TCM score	18.52 ± 5.36	18.21 ± 5.48	0.439	0.661

BMI: Body mass index; LGIN: Low-grade intraepithelial neoplasia; HGIN: High-grade intraepithelial neoplasia; TCM: Traditional Chinese medicine; H. pylori: Helicobacter pylori.

Comparison of histopathological efficacy between the two groups

After treatment, the histopathological reversal, improvement, stable, and progression rates in the observation group were 21.0% (25/119), 42.0% (50/119), 31.1% (37/119) and 5.9% (7/119), respectively. In the control group, the corresponding rates were 10.3% (12/117), 29.1% (34/117), 47.0% (55/117), and 13.7% (16/117), respectively. Histopathological outcomes were significantly better in the observation group than in the control group (Z = -3.284, P < 0.001; Table 2).

Table 2 Comparison of histopathological efficacy between two groups, n (%).

Group	n	Reversal	Improvement	Stable	Progression
Observation	119	25 (21.0)	50 (42.0)	37 (31.1)	7 (5.9)
Control	117	12 (10.3)	34 (29.1)	55 (47.0)	16 (13.7)
Z/P value	-	Z = -3.284	P = 0.001	-	-

Clinical efficacy of the two groups

After treatment, the overall clinical effective rate was 63.0% (75/119) in the observation group, significantly higher than the 39.3% (46/117) observed in the control group (Z = -3.412, P < 0.001; Table 3).

Table 3 Comparison of clinical efficacy between the two groups, n (%).

Group	n	Marked	Effective	Ineffective	Progression	Total effective rate
Observation	119	28 (23.5)	47 (39.5)	37 (31.1)	7 (5.9)	75 (63.0)
Control	117	14 (12.0)	32 (27.4)	55 (47.0)	16 (13.7)	46 (39.3)
Z/P value	-	-	Z = -3.412	P < 0.001	-	-

Histopathological scores before and after treatment in the two groups

Before treatment, there were no significant differences between the two groups in atrophy, intestinal metaplasia, intraepithelial neoplasia, or total histopathological scores (P > 0.05). After treatment, all histopathological scores decreased significantly from baseline in both groups (P < 0.05). The atrophy, intestinal metaplasia, intraepithelial neoplasia, and total histopathological scores were also significantly lower in the observation group than in the control group after treatment (P < 0.05; Table 4).

Table 4 Comparison of histopathological scores before and after treatment, mean ± SD.

Group	Time	Atrophy	Intestinal metaplasia	Intraepithelial neoplasia	Total
Observation (n = 119)	Before	2.15 ± 0.68	1.89 ± 0.72	1.18 ± 1.24	5.22 ± 1.86
	After	1.52 ± 0.71a	1.28 ± 0.69a	0.54 ± 0.82a	3.34 ± 1.58a
Control (n = 117)	Before	2.11 ± 0.65	1.85 ± 0.74	1.22 ± 1.28	5.18 ± 1.92
	After	1.82 ± 0.69a	1.58 ± 0.72a	0.86 ± 1.05a	4.26 ± 1.74a
t/P value (after)	-	-3.297/0.001	-3.275/0.001	-2.622/0.009	-4.269/< 0.001

^aP < 0.05 vs pre-treatment within the same group.

TCM syndrome scores in the two groups

Repeated-measures analysis of variance was used. Mauchly’s test indicated a violation of sphericity; therefore, the Greenhouse-Geisser correction was applied. There were significant effects of time (F = 156.328, P < 0.001) and group (F = 18.634, P < 0.001), as well as a significant time × group interaction (F = 15.872, P < 0.001). Before treatment, TCM syndrome scores did not differ significantly between the two groups (P > 0.05). At 3 months and at the end of treatment, scores were significantly lower than baseline in both groups and were significantly lower in the observation group than in the control group (all P < 0.017). Bonferroni correction was applied to post-hoc pairwise comparisons (adjusted significance level α’ = 0.05/3 ≈ 0.017). In both groups, TCM syndrome scores at the end of treatment were also significantly lower than those at 3 months (P < 0.017; Table 5).

Table 5 Comparison of traditional Chinese medicine syndrome scores between the two groups, mean ± SD.

Group	n	Before	3 months	Completion
Observation	119	18.52 ± 5.36	11.86 ± 4.28a,b	7.24 ± 3.56 a,b,c
Control	117	18.21 ± 5.48	14.35 ± 4.86a	10.82 ± 4.15a,c
t/P value	-	0.439/0.661	-4.189/< 0.001	-7.139/< 0.001

^aP < 0.017 vs pre-treatment.

^bP < 0.017 vs control.

^cP < 0.017 vs 3 months.

TCM syndrome efficacy in the two groups

After treatment, the overall effective rate for TCM syndromes was 85.7% (102/119) in the observation group, significantly higher than the 65.0% (76/117) observed in the control group (Z = -3.658, P < 0.001; Table 6).

Table 6 Comparison of traditional Chinese medicine syndrome efficacy between two groups, n (%).

Group	n	Cure	Marked	Effective	Ineffective	Total effective rate
Observation	119	15 (12.6)	45 (37.8)	42 (35.3)	17 (14.3)	102 (85.7)
Control	117	6 (5.1)	28 (23.9)	42 (35.9)	41 (35.0)	76 (65.0)
Z/P value	-	-	-	Z = -3.658	P < 0.001	-

Comparison of gastric function indicators before and after treatment

Before treatment, serum PGI, PGII, PGR and G-17 levels did not differ significantly between the two groups (P > 0.05). After treatment, both groups showed significantly increased serum PGI, PGR and G-17 levels and decreased PGII levels compared with baseline (P < 0.05). Serum PGI, PGR, and G-17 levels were significantly higher in the observation group than in the control group (P < 0.05), whereas PGII levels were lower in the observation group, although the between-group difference was not statistically significant (P > 0.05; Table 7).

Table 7 Comparison of gastric function indicators, mean ± SD.

Group	Time	PGI (μg/L)	PGII (μg/L)	PGR	G-17 (pmol/L)
Observation (n = 119)	Before	68.52 ± 18.34	15.86 ± 5.42	4.32 ± 1.38	5.86 ± 2.34
	After	82.76 ± 19.85a	13.24 ± 4.56a	6.25 ± 1.82a	8.34 ± 2.86a
Control (n = 117)	Before	67.86 ± 17.92	15.62 ± 5.28	4.34 ± 1.42	5.72 ± 2.28
	After	75.42 ± 18.68a	14.28 ± 4.82a	5.28 ± 1.65a	7.12 ± 2.64a
t/P value (after)		3.012/0.003	-1.718/0.087	4.326/< 0.001	3.426/< 0.001

^aP < 0.05 vs pre-treatment within the same group.

PGI: Pepsinogen I; PGII: Pepsinogen II; PGR: Pepsinogen I/II ratio.

Comparison of inflammatory factor levels before and after treatment

Before treatment, serum IL-6, IL-8 and TNF-α levels did not differ significantly between the two groups (P > 0.05). After treatment, levels of all three inflammatory markers were significantly lower than baseline in both groups before treatment (P < 0.05) and were significantly lower in the observation group than in the control group (P < 0.05, Table 8).

Table 8 Comparison of inflammatory factor levels, mean ± SD.

Group	Time	IL-6 (pg/mL)	IL-8 (pg/mL)	TNF-α (pg/mL)
Observation (n = 119)	Before	28.56 ± 8.72	42.35 ± 12.68	35.82 ± 10.45
	After	18.92 ± 6.54a	28.64 ± 9.86a	24.18 ± 8.26a
Control (n = 117)	Before	29.12 ± 8.45	43.12 ± 12.34	36.24 ± 10.18
	After	23.45 ± 7.82a	35.28 ± 10.92a	29.86 ± 9.12a
t/P value (after)		-4.836/< 0.001	-4.920/< 0.001	-5.032/< 0.001

^aP < 0.05 vs pre-treatment within the same group.

IL: Interleukin; TNF-α: Tumor necrosis factor-α.

Quality of life scores before and after treatment

Before treatment, there were no significant differences in GIQLI dimension or total scores between the two groups (P > 0.05). After treatment, GIQLI dimension and total scores increased significantly from baseline in both groups (P < 0.05). Scores for gastrointestinal symptoms, physical function, emotional status, social function, and overall quality of life were significantly higher in the observation group than in the control group (P < 0.05). However, there was no significant between-group difference in the treatment-effect dimension score (P > 0.05; Table 9).

Table 9 Comparison of gastrointestinal quality-of-life index score scores before and after treatment, mean ± SD.

Group	Time	GI symptoms	Physical	Emotional	Social	Treat	Total
Observation (n = 119)	Before	42.56 ± 8.34	18.24 ± 4.52	12.86 ± 3.28	7.52 ± 2.15	5.24 ± 1.56	86.42 ± 15.62
	After	58.72 ± 9.18a	24.35 ± 4.86a	17.24 ± 3.45a	10.18 ± 2.34a	6.85 ± 1.42a	117.34 ± 16.85a
Control (n = 117)	Before	42.18 ± 8.56	18.12 ± 4.68	12.72 ± 3.35	7.45 ± 2.22	5.18 ± 1.62	85.65 ± 16.24
	After	51.45 ± 8.86a	21.56 ± 4.72a	15.18 ± 3.52a	8.86 ± 2.28a	6.52 ± 1.48a	103.57 ± 16.42a
t (after)		6.204	4.505	4.571	4.418	1.756	6.385
P value (after)		< 0.001	< 0.001	< 0.001	< 0.001	0.080	< 0.001

^aP < 0.05 vs pre-treatment within the same group.

GI: Gastrointestinal.

Metachronous gastric cancer and progression of precancerous lesions during follow-up

As of January 2026, the median follow-up duration for the 236 patients was 36 months (range, 12-72 months). Eight patients were lost to follow-up (3 in the observation group and 5 in the control group), corresponding to an overall loss-to-follow-up rate of 3.4%. During follow-up, 2 patients (1.7%) developed metachronous gastric cancer and 9 (7.8%) experienced progression of precancerous lesions in the observation group, compared with 6 (5.4%) and 21 (18.8%), respectively, in the control group. Kaplan-Meier analysis showed a significantly lower cumulative incidence of metachronous gastric cancer in the observation group (log-rank χ² = 4.125, P = 0.042). The cumulative incidence of precancerous lesion progression was also significantly lower in the observation group than in the control group (log-rank χ² = 6.852, P = 0.009; Table 10).

Table 10 Metachronous gastric cancer and precancerous lesion progression, n (%).

Group	n	Metachronous GC	χ2/P value	PL progression	χ2/P value
Observation	116	2 (1.7)	4.125/0.042	9 (7.8)	6.852/0.009
Control	112	6 (5.4)	-	21 (18.8)	-

n denotes patients with complete follow-up (observation 116, control 112) after excluding 8 Losses to follow-up.

GC: Gastric cancer; PL: Precancerous lesion.

Cox regression analysis of factors associated with precancerous lesion progression

Variables with P < 0.10 in univariate analysis were included in the multivariate Cox proportional hazards regression model, with precancerous lesion progression as the dependent variable. HGIN [hazard ratio (HR) = 3.286, 95% confidence interval (CI): 1.524-7.086, P = 0.002] and a total pathological score ≥ 6 (HR = 2.458, 95%CI: 1.182-5.112, P = 0.016) were identified as independent risk factors for progression. HJD treatment was associated with a lower risk of precancerous lesion progression (HR = 0.385, 95%CI: 0.178-0.832, P = 0.015; Table 11).

Table 11 Cox regression analysis of factors affecting precancerous lesion progression.

Variable	Univariate HR (95%CI)	Univariate P	Multivariate HR (95%CI)	Multivariate P
Age (≥ 65 vs < 65)	1.682 (0.886-3.194)	0.112	-	-
Gender (male vs female)	1.124 (0.568-2.224)	0.736	-	-
BMI (≥ 24 vs < 24)	0.892 (0.456-1.745)	0.738	-	-
Smoking (yes vs no)	1.524 (0.792-2.932)	0.208	-	-
Drinking (yes vs no)	1.436 (0.724-2.848)	0.302	-	-
Diabetes (yes vs no)	1.386 (0.624-3.078)	0.422	-	-
Hypertension (yes vs no)	1.245 (0.612-2.534)	0.546	-	-
Poorly differentiation (yes vs no)	1.724 (0.786-3.782)	0.174	-	-
HGIN (yes vs no)	3.856 (1.892-7.862)	< 0.001	3.286 (1.524-7.086)	0.002
Score ≥ 6 (yes vs no)	2.724 (1.386-5.352)	0.004	2.458 (1.182-5.112)	0.016
Cardia (yes vs no)	1.856 (0.824-4.182)	0.135	-	-
HJD treatment (yes vs no)	0.362 (0.172-0.762)	0.007	0.385 (0.178-0.832)	0.015

HR: Hazard ratio; BMI: Body mass index; HGIN: High-grade intraepithelial neoplasia; HJD: Huazhuojiedu decoction.

Safety evaluation

The adverse event rate during treatment was 12.6% (15/119) in the observation group and 9.4% (11/117) in the control group, with no significant difference between the groups (χ² = 0.612, P = 0.434). Adverse events in the observation group included mild diarrhea (5 cases), nausea (4 cases), abdominal pain (3 cases), rash (2 cases), and mild liver function abnormality (alanine aminotransferase elevation < 2 times upper limit of normal, 1 case). In the control group, adverse events included nausea (4 cases), diarrhea (3 cases), abdominal pain (2 cases), and constipation (2 cases). All adverse events were mild and resolved spontaneously or with symptomatic treatment without affecting treatment. No serious adverse events occurred. After treatment, liver and kidney function indices (alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine) and complete blood count parameters (white blood cell, red blood cell, hemoglobin, and platelet count) remained within normal ranges in both groups, with no significant difference between the groups (P > 0.05; Table 12).

Table 12 Comparison of adverse reactions between two groups, n (%).

Adverse reaction	Observation (n = 119)	Control (n = 117)
Nausea	4 (3.4)	4 (3.4)
Diarrhea	5 (4.2)	3 (2.6)
Abdominal pain	3 (2.5)	2 (1.7)
Constipation	0 (0.0)	2 (1.7)
Rash	2 (1.7)	0 (0.0)
Mild liver function abnormality	1 (0.8)	0 (0.0)
Total	15 (12.6)	11 (9.4)
χ2/P value	0.612	0.434

DISCUSSION

Although ESD can achieve complete resection of local lesions in patients with early gastric cancer, it does not alter the underlying pathological state of the surrounding gastric mucosa. Residual atrophic gastritis, intestinal metaplasia and intraepithelial neoplasia remain important risk factors for metachronous gastric cancer[12]. Studies have reported a 5-year incidence of metachronous gastric cancer of 10%-15% after ESD, considerably higher than that in the general population[13]. Therefore, active management of residual precancerous lesions after ESD is clinically important for reducing the risk of metachronous gastric cancer.

In this retrospective clinical study, histopathological outcomes were more favorable in the observation group than in the control group. The rates of pathological reversal and improvement were 21.0% and 42.0%, respectively, and the overall clinical effective rate was 63.0%, all significantly higher than those in the control group (P < 0.05). These findings are consistent with recent studies of TCM interventions for gastric precancerous lesions[14]. Current Western medical treatment options are limited and primarily include H. pylori eradication, acid suppression, and gastric mucosal protection[14], with limited ability to reverse established atrophy or intestinal metaplasia[15]. In the control group, the rate of pathological improvement was 39.4%, while the progression rate was 13.7%, suggesting that conventional Western medical treatment alone may have limited efficacy in reversing precancerous lesions.

According to TCM theory, gastric precancerous lesions fall within the category of “gastric stuffiness,” with a pathogenesis rooted in spleen-stomach deficiency and characterized by the accumulation of dampness and turbidity and the interaction of toxin and blood stasis[16]. HJD was formulated according to this pathogenic framework. In the formula, Artemisia capillaris clears damp-heat; Scutellaria baicalensis (Chinese skullcap) and Coptis chinensis are bitter-cold herbs used to dry dampness and clear toxins; Hedyotis diffusa and Scutellaria barbata clear heat and toxins and disperse masses; Agastache rugosa and Eupatorium fortunei aromatically resolve turbidity and invigorate the spleen; and Gynostemma pentaphyllum supplements qi and supports healthy qi. Modern pharmacological studies have shown that baicalin, a component of Scutellaria baicalensis, can inhibit gastric mucosal inflammatory responses and regulate apoptosis[17]. Hedyotis diffusa may exert antitumor effects against gastric cancer through activation of endoplasmic reticulum stress and modulation of metabolic pathways[18], while Scutellaria barbata extracts have been reported to inhibit gastric cancer cell proliferation and induce apoptosis[19]. Together, these components may act synergistically through multiple targets and pathways involved in gastric mucosal carcinogenesis.

The present study showed that serum PGI, PGR and G-17 levels were significantly higher in the observation group than in the control group after treatment. PGI is primarily secreted bv chief cells of the gastric fundic glands, and reduced PGI levels are an important marker of gastric mucosal atrophy, while a lower PGR is associated with more severe atrophy[20]. G-17 is secreted by antral G cells and is also reduced in patients with atrophic gastritis[21]. The increases in these markers suggest that HJD may gastric mucosal repair and improve gastric secretion function. In addition, serum IL-6, IL-8 and TNF-α levels were significantly lower in the observation group than in the control group, suggesting an anti-inflammatory effect of HJD. Chronic inflammation is an important driver of gastric mucosal carcinogenesis, as persistent inflammatory stimulation can damage gastric epithelial cell DNA and promote abnormal proliferation[22]. HJD may therefore help inhibit the progression from chronic inflammation to gastric carcinogenesis by reducing inflammatory signaling[23].

Regarding symptom improvement, the overall effective rate for TCM syndromes was 85.7% in the observation group, and the total GIQLI score was significantly higher than that in the control group. Patients with gastric precancerous lesions commonly experience gastrointestinal symptoms, including abdominal distention, loss of appetite, and belching, which can substantially impair quality of life[24]. These findings suggest that HJD may help alleviate clinical symptoms and improve quality of life, which, according to TCM theory, may be related to its effects of aromatically resolving turbidity, strengthening the spleen, and harmonizing the stomach[25].

The follow-up results showed that the incidence of metachronous gastric cancer was 1.7% and the rate of precancerous lesion progression rate was 7.8% in the observation group, both significantly lower than those in the control group. Cox regression analysis identified HJD treatment as an independent protective factor against precancerous lesion progression (HR = 0.385). These findings are consistent with long-term follow-up studies of related TCM formulas for gastric precancerous lesions[26]. HGIN and a total pathological score ≥ 6 were identified as independent risk factors for progression[27], suggesting that patients with these high-risk features may benefit from more intensive postoperative surveillance and intervention.

In terms of safety, adverse event rates were similar between the two groups. Adverse events in the observation group were primarily mild gastrointestinal symptoms, and no serious adverse events occurred. In addition, no clinically significant abnormalities in liver or kidney function or complete blood counts were observed during treatment[28], suggesting that HJD was generally safe and well-tolerated.

This study has several limitations. First, as a single-center retrospective study with non-randomized treatment allocation, it is subject to potential selection bias, and the generalizability of the findings may be limited. Second, the relatively short follow-up period limits assessment of metachronous gastric cancer, and longer-term follow-up is needed. Finally, the mechanisms underlying the potential effects of HJD could not be directly investigated in this study and require further evaluation in basic and translational studies.

CONCLUSION

In summary, this retrospective study suggests that HJD combined with conventional Western medical treatment was associated with improved histopathological outcomes in patients with gastric precancerous lesions after ESD for early gastric cancer, as well as relief of clinical symptoms, improved gastric function, reduced inflammatory marker levels, and better quality of life. HJD treatment was also associated with lower risks of metachronous gastric cancer and precancerous lesion progression, with an acceptable safety profile. These findings provide preliminary clinical evidence supporting an integrated traditional Chinese and Western medicine approach to managing gastric precancerous lesions after ESD. However, prospective, multi-center, large-scale randomized controlled trials are needed to confirm these findings.