Efficacy and safety of sequential hyperthermic intraperitoneal chemotherapy following surgery for pathological T staging 4 gastric cancer

Abstract

BACKGROUND

Peritoneal metastasis influences prognosis and quality of life in patients with gastric cancer. The efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) as postoperative adjuvant therapy for advanced gastric cancer remains unclear.

AIM

To evaluate the efficacy and safety of HIPEC plus postoperative adjuvant chemotherapy (AC) for locally advanced gastric cancer.

METHODS

We analyzed 225 patients with gastric cancer who underwent radical surgery, categorized by those receiving HIPEC plus AC (HIPEC + AC group) and those receiving AC alone (AC group). Treatments were administered every other day, for a total of one to three sessions. Overall survival, disease-free survival (DFS), disease-free interval, peritoneal metastasis-free interval, and safety outcomes were compared between the groups. Survival analysis was performed using Kaplan-Meier curves with log-rank tests for group comparisons.

RESULTS

In total, 225 patients with non-metastatic pathological T staging 4 gastric adenocarcinoma were included (HIPEC + AC group, n = 96; AC group, n = 129). Propensity score matching balanced between-group baseline characteristics. The incidence of treatment-related adverse reactions did not differ significantly between groups. With median follow-up durations of 68.00 months (HIPEC + AC group) and 56.00 months (AC group), the HIPEC + AC group demonstrated better 3-year DFS (69.0% vs 50.0%) and longer disease-free interval and peritoneal metastasis-free interval. Three-year overall survival did not differ significantly (74.0% vs 65.0%). The median survival was 50 months in the AC group, but remained unreached in the HIPEC + AC group (cumulative survival > 50%).

CONCLUSION

HIPEC plus postoperative AC improves DFS and reduces peritoneal metastasis risk in non-metastatic pathological T staging 4 gastric adenocarcinoma without increasing adverse events, confirming its safety and efficacy in preventing recurrence and dissemination.

Key Words: Hyperthermic intraperitoneal chemotherapy; Gastric cancer; Prognosis; Overall survival; Disease-free survival; Disease-free interval; Peritoneal metastasis-free interval

Core Tip: The efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) as a postoperative adjuvant therapy for locally advanced gastric cancer remains unclear. This study analyzed 225 patients with nonmetastatic pathological T staging 4 gastric adenocarcinoma and found that HIPEC plus adjuvant chemotherapy significantly improved disease-free survival and reduced the risk of peritoneal metastasis without additional adverse reactions in non-metastatic pathological T staging 4 gastric adenocarcinoma. These results establish HIPEC as a safe and effective adjuvant therapy for preventing postoperative recurrence and peritoneal dissemination.

INTRODUCTION

Gastric cancer is the fifth most prevalent malignancy worldwide and a leading cause of cancer-related mortality, accounting for 4.8% of all cancer cases and 6.8% of cancer-related deaths. This disease has particularly high incidence rates in East Asian regions, including China and Japan[1]. Peritoneal metastasis is a frequent and aggressive progression pathway in gastric cancer and is associated with dismal clinical outcomes. Current evidence suggests that 10%-21% of patients with gastric cancer develop peritoneal metastases, with median survival typically limited to 4-6 months[2,3]. These metastases not only drastically shorten patient survival but also frequently cause debilitating complications, including ascites, intestinal obstruction, and cachexia, severely compromising the quality of life. The effective prevention of peritoneal metastasis following radical gastric cancer surgery represents a critical therapeutic challenge.

Conventional systemic chemotherapy has limited efficacy in preventing or treating peritoneal metastases because the peritoneum-plasma barrier restricts drug penetration, often resulting in poor outcomes in patients with gastric cancer[4,5]. Hyperthermic intraperitoneal chemotherapy (HIPEC) delivers temperature-controlled chemotherapeutic agents directly into the abdominal cavity, increasing local drug concentrations and enhancing cytotoxic effects. As part of multimodal therapy, HIPEC has demonstrated clinical utility in managing peritoneal carcinomatosis and is increasingly incorporated into multicenter treatment protocols[6]. When administered after tumor resection, HIPEC augments chemotherapeutic cytotoxicity and improves the overall treatment efficacy[7]. In patients with established peritoneal cancer, the combination of HIPEC and cytoreductive surgery may allow some patients to achieve long-term survival[8]. HIPEC is also under investigation as a prophylactic intervention to prevent the peritoneal seeding of gastrointestinal cancers[9]. A 2021 study reported that prophylactic HIPEC after curative colon cancer resection may reduce peritoneal recurrence and improve disease-free survival (DFS)[10]. Additional research supports its potential in preventing postoperative peritoneal recurrence in gastric cancer[11]; however, large-scale randomized trials validating long-term efficacy and safety remain necessary. The clinical benefits of HIPEC vary owing to patient heterogeneity and tumor biology, with not all individuals experiencing significant improvements[12]. A 2019 systematic review of 11 studies comparing prophylactic HIPEC combined with surgery to surgery alone for gastric cancer suggested that HIPEC reduces peritoneal recurrence and improves survival outcomes while demonstrating safety and feasibility[13]. However, the included studies were characterized by methodological heterogeneity and partial obsolescence. Consequently, no international consensus has been reached regarding the role of HIPEC in the management of resectable gastric cancers[14].

To assess the efficacy and safety of HIPEC combined with curative gastrectomy, we retrospectively reviewed the medical records of patients with locally advanced gastric cancer [pathological stage T4a-b/N0-3/non-metastatic (M0)] treated by a single surgical team at our institution. We compared the postoperative outcomes between patients receiving HIPEC plus adjuvant chemotherapy (AC) and those who received AC alone, focusing on median survival, overall survival (OS), DFS, disease-free interval (DFI), peritoneal metastasis-free interval (PMFI) and treatment-related adverse reactions.

MATERIALS AND METHODS

Patient selection

This study analyzed patients with M0 pathological T staging (pT) 4 stage gastric adenocarcinoma who underwent curative gastrectomy between March 2017 and September 2021. Based on historical treatment records, eligible patients were stratified into two groups: (1) The HIPEC + AC group received HIPEC combined with standard AC; and (2) The AC group received standard AC alone (Figure 1). Our retrospective protocol complied with the ethical principles of the Declaration of Helsinki and was approved by the Institutional Review Board of our hospital (No. 2025 LWB196).

Figure 1 Flow chart illustrating decision about different treatment. AC: Adjuvant chemotherapy; HIPEC: Hyperthermic intraperitoneal chemotherapy; pT4: Pathological T staging.

Patients were included if they met the following criteria: (1) Pathological diagnosis of locally advanced gastric cancer (T4a-b, N0-3, M0); (2) Treatment with radical gastrectomy; and (3) Postoperative administration of AC alone or in combination with HIPEC.

The exclusion criteria were as follows: (1) Preoperative diagnosis of peritoneal or distant metastases; (2) Received preoperative chemoradiotherapy or other experimental therapies; (3) Contraindications to HIPEC or systemic chemotherapeutic agents; (4) Concurrent or prior malignancy within 5 years; and (5) Absence of postoperative adjuvant therapy.

Patient treatment

Two patient cohorts underwent radical gastrectomy prior to treatment. Following the Japanese Gastric Cancer Treatment Guidelines[15], the surgeons performed either total gastrectomy or distal gastrectomy with concomitant D2 Lymphadenectomy. Digestive tract reconstruction involved a Roux-en-Y esophagojejunostomy (or gastrojejunostomy) with Braun's anastomosis, when applicable.

The HIPEC + AC group underwent abdominal puncture tube placement 3-4 weeks postoperatively, connecting the infusion tube to the precise intraperitoneal hyperthermic perfusion treatment system (HGGZ-102intraperitoneal hyperthermic perfusion treatment machine), which continuously and stably injected and drained the abdominal cavity. The treatment was conducted at 43 ± 0.1 °C with a perfusion rate of 400-600 mL/minute. Each session lasted 60-90 minutes and used 5 L of perfusate. The chemotherapeutic agents added to the perfusate were either docetaxel (80 mg) or 5-fluorouracil (1 g), dissolved in the 5 L solution. Treatments were administered every other day, for a total of one to three sessions[16]. When patients maintained adequate physical condition and tolerance, standard chemotherapy was commenced 48 hours after HIPEC completion. By contrast, chemotherapy was initiated 3-4 weeks postoperatively in the AC group. Both groups received postoperative gastric cancer chemotherapy following the NCCN guidelines[17], primarily using5-fluorouracil-based regimens, including FOLFOX, SOX, or XELOX.

Effect indicators

Median survival time was the time point at which the cumulative survival probability reached 50%. OS was defined as the time interval from treatment initiation to death from any cause. DFS was the duration from treatment commencement to first recurrence or death from any cause (whichever occurred first). DFI was measured from the date of surgery or treatment initiation until the first documented recurrence or metastasis. PMFI was measured from the date of surgery or treatment initiation until the first documented peritoneal metastasis, based on either imaging or histological evidence. Treatment-related adverse events were recorded. Tumor marker levels were assessed before and 1 month after treatment.

Adverse events monitored during HIPEC therapy included intra-abdominal infection, hemorrhage, intestinal obstruction, bowel perforation, abdominal pain, nausea and vomiting, diarrhea, poor appetite, and fatigue.

Systemic chemotherapeutic toxicities included hematological effects such as myelosuppression (neutropenia, thrombocytopenia, and anemia) and hepatorenal dysfunction, including elevated alanine or aspartate aminotransferase and creatinine levels.

Statistical analysis

All statistical analyses were performed using Statistical Package for the Social Sciences 25.0 (IBM Corp., Armonk, NY, United States). Continuous variables, expressed as mean ± SD, were compared using Student's t-test, while the Mann-Whitney U test was used to analyze non-normally distributed data. Categorical variables were expressed as percentages and compared using χ² tests or Fisher's exact tests as appropriate. Survival analysis was performed using Kaplan-Meier curves with log-rank tests for group comparisons. Statistical significance was defined as P < 0.05.

RESULTS

Patient characteristics

After the exclusion criteria were applied, 225 patients with complete datasets were included, comprising 96 patients in the HIPEC + AC group and 129 patients in the AC group. A comparative analysis of the clinicopathological characteristics (Table 1) revealed statistically significant differences between the groups before propensity score matching (PSM) for age, tumor location, and pathological N staging (P < 0.05). No significant differences were found in sex, differentiation grade, or pT (P ≥ 0.05) (Table 1).

Table 1 General patient characteristics, n (%)/mean ± SD/mean (interquartile range).

Characteristic	Before PSM				After PSM
	HIPEC + AC group (n = 96)	AC group (n = 129)	P value	SMD	HIPEC + AC group (n = 80)	AC group (n = 80)	P value	SMD
Sex			0.060				0.587
Male	75 (78.12)	86 (66.67)		-0.243	61 (76.25)	58 (72.50)		-0.084
Female	21 (21.88)	43 (33.33)		0.243	19 (23.75)	22 (27.50)		0.084
Age	60.00 (53.00, 67.25)	65.00 (58.00, 71.00)	< 0.001	0.479	61.50 (55.00, 69.00)	65.00 (55.75, 70.00)	0.299	0.126
Body mass index	21.63 ± 3.21	21.89 ± 3.21	0.550	0.081	21.76 ± 3.22	22.08 ± 3.34	0.546	0.094
Tumor location			0.022				0.884
Upper	27 (28.12)	60 (46.51)		0.369	25 (31.25)	29 (36.25)		0.104
Middle	23 (23.96)	20 (15.50)		-0.234	19 (23.75)	16 (20.00)		-0.094
Lower	45 (46.88)	46 (35.66)		-0.234	35 (43.75)	34 (42.50)		-0.025
Anastomotic site	1 (1.04)	3 (2.33)		0.085	1 (1.25)	1 (1.25)		0.000
Tumor differentiation			0.793				0.668
High-grade	78 (81.25)	103 (79.84)		-0.035	66 (82.50)	68 (85.00)		0.070
Low-grade	18 (18.75)	26 (20.16)		0.035	14 (17.50)	12 (15.00)		-0.070
Pathological T staging			0.897				0.755
T4a	89 (92.71)	119 (92.25)		-0.017	74 (92.50)	75 (93.75)		0.052
T4b	7 (7.29)	10 (7.75)		0.017	6 (7.50)	5 (6.25)		-0.052
Pathological N staging			0.038				0.598
N0	9 (9.38)	25 (19.38)		0.253	9 (11.25)	7 (8.75)		-0.088
N+	87 (90.62)	104 (80.62)		-0.253	71 (88.75)	73 (91.25)		0.088

AC: Adjuvant chemotherapy; HIPEC: Hyperthermic intraperitoneal chemotherapy; PSM: Propensity score matching; SMD: Standardized mean difference.

Based on the clinical and pathological data described above, we performed 1:1 PSM, yielding 80 precisely matched pairs. After matching, the two patient groups showed no statistically significant differences in clinical or pathological characteristics (Table 1).

Chemotherapy regimens and treatment-related adverse reactions

The HIPEC perfusate contained docetaxel 80 mg (83 patients) or 5-fluorouracil 1 g (13 patients). All AC regimens were fluorouracil-based and administered in combination with platinum-based agents (40 patients in the HIPEC + AC group vs 64 patients in the AC group), taxanes (22 patients in the HIPEC + AC group vs 50 patients in the AC group), platinum-taxane combinations (26 patients in the HIPEC + AC group vs 6 patients in the AC group), or camptothecins (8 patients in the HIPEC + AC group vs 9 in the AC group) (Table 2).

Table 2 Chemotherapy agents for hyperthermic intraperitoneal chemotherapy and adjuvant chemotherapy regimen, n (%).

	HIPEC + AC group (n = 96)	AC group (n = 129)
Chemotherapy agents for HIPEC
Docetaxel	83 (86.46)	-
5-fluorouracil	13 (13.54)	-
AC regimen
Platinum-based agents	40 (41.67)	64 (49.61)
Taxanes	22 (22.92)	50 (38.76)
Platinum-taxane combinations	26 (27.08)	6 (4.65)
Camptothecins	8 (8.33)	9 (6.98)

AC: Adjuvant chemotherapy; HIPEC: Hyperthermic intraperitoneal chemotherapy.

The safety analysis revealed comparable rates of myelosuppression (before PSM: 28.13% vs 34.11%, P = 0.339; after PSM: 30.00% vs 37.50%, P = 0.316) and liver function abnormalities (before PSM: 11.46% vs 12.40%, P = 0.829; after PSM: 12.50% vs 12.50%, P = 1.000) between the HIPEC + AC and AC groups. Renal function abnormalities occurred in one patient in the AC group but were absent in the HIPEC + AC cohort (Table 3).

Table 3 Adverse treatment reaction, n (%).

	Before PSM				After PSM
	HIPEC + AC group	AC group	χ2	P value	HIPEC + AC group	AC group	χ2	P value
Myelosuppression			0.912	0.339			1.006	0.316
Yes	27 (28.13)	44 (34.11)			24 (30.00)	30 (37.50)
No	69 (71.88)	85 (65.89)			56 (70.00)	50 (62.50)
Liver function abnormalities			0.047	0.829			0.000	1.000
Yes	11 (11.46)	16 (12.40)			10 (12.50)	10 (12.50)
No	85 (88.54)	113 (87.60)			70 (87.50)	70 (87.50)

AC: Adjuvant chemotherapy; HIPEC: Hyperthermic intraperitoneal chemotherapy; PSM: Propensity score matching.

Intra-abdominal infection developed in five patients (5.21%) in the HIPEC + AC group, while one patient (1.04%) experienced intra-abdominal hemorrhage. Five patients (5.21%) reported abdominal pain, and 23 (23.96%) experienced nausea and vomiting. Three patients (3.13%) presented with diarrhea, 3 (3.13%) reported poor appetite and fatigue, and 3 (3.13%) developed intestinal obstruction. No bowel perforations resulted from the peritoneal catheter placement (Table 4).

Table 4 Adverse treatment reaction to hyperthermic intraperitoneal chemotherapy.

	Number	Percentage (%)
Intra-abdominal infection	5	5.21
Intra-abdominal hemorrhage	1	1.04
Abdominal pain	5	5.21
Nausea and vomiting	23	23.96
Diarrhea	3	3.13
Poor appetite and fatigue	3	3.13
Intestinal obstruction	3	3.13

Survival analysis

After PSM, the AC group showed a median follow-up period of 56.00 ± 4.61 months, while the HIPEC + AC group exhibited a longer follow-up duration of 68.00 ± 4.99 months. At the final follow-up, the HIPEC + AC group maintained a cumulative survival rate above 50%, with the median survival time remaining unreached, whereas the AC group demonstrated a median survival of 50 months.

Prior to PSM, the HIPEC + AC group exhibited higher OS rates than the AC group at 1 year (95.00% vs 91.00%), 2 years (82.00% vs 78.00%), and 3 years (74.00% vs 65.00%), although these differences were not statistically significant [hazard ratio (HR) = 0.755, 95%CI: 0.502-1.136, P = 0.174; Supplementary Figure 1A]. DFS was significantly longer in the HIPEC + AC group at 1 year (91.00% vs 79.00%), 2 years (72.00% vs 62.00%), and 3 years (68.00% vs 51.00%) than in the AC group (HR = 0.681, 95%CI: 0.467-0.994, P = 0.043; Supplementary Figure 1B). DFI was significantly longer in the HIPEC + AC cohort than in the AC controls (HR = 0.652, 95%CI: 0.423-1.003, P = 0.048; Supplementary Figure 1C). Similarly, PMFI demonstrated a statistically significant prolongation following HIPEC + AC treatment (HR = 0.540, 95%CI: 0.318-0.919, P = 0.020; Supplementary Figure 1D).

Following PSM, the HIPEC + AC group demonstrated higher OS rates than the AC group at 1 year (94.00% vs 89.00%), 2 years (80.00% vs 75.00%), and 3 years (74.00% vs 65.00%), although this difference was not statistically significant (HR = 0.727, 95%CI: 0.450-1.173, P = 0.187; Figure 2A). DFS was significantly longer in the HIPEC + AC group at all time points: 1 year (90.00% vs 75.00%), 2 years (73.00% vs 59.00%), and 3 years (69.00% vs 50.00%), with statistically significant differences (HR = 0.632, 95%CI: 0.047-0.981, P = 0.037; Figure 2B). DFI was also markedly extended in the HIPEC + AC group compared with that in the controls (HR = 0.524, 95%CI: 0.316-0.869, P = 0.010; Figure 2C). Similarly, the PMFI showed a statistically significant prolongation following HIPEC + AC treatment (HR = 0.428, 95%CI: 0.234-00.782, P = 0.004; Figure 2D).

Figure 2 Overall survival, disease-free survival, disease-free interval, and peritoneal metastases-free interval in the hyperthermic intraperitoneal chemotherapy + adjuvant chemotherapy and adjuvant chemotherapy groups after propensity score matching. A: Overall survival; B: Disease-free survival; C: Disease-free interval; D: Peritoneal metastases-free interval. AC: Adjuvant chemotherapy; HIPEC: Hyperthermic intraperitoneal chemotherapy; HR: Hazard ratio.

To further evaluate the efficacy of HIPEC in the context of different systemic chemotherapy regimens, we conducted two subgroup analyses. First, in patients who received the potent "platinum-taxane combination regimen", the HIPEC + AC group demonstrated significantly superior OS, DFS, DFI, and PMFI vs the AC group (Supplementary Figure 2). Second, in the subgroup of patients who received the most commonly used SOX (tegafur, gimeracil, and oxaliplatin) or XELOX (capecitabine and oxaliplatin) regimens, the HIPEC + AC group also showed consistent trends toward better outcomes in terms of OS, DFS, DFI, and PMFI (Supplementary Figure 3). The differences in the latter subgroup did not reach statistical significance, potentially due to the limited sample size; nevertheless, both analyses consistently suggested that HIPEC provided an additional survival benefit when combined with systemic chemotherapy, regardless of the regimen intensity.

Patterns of recurrence and metastasis

At the final follow-up, the recurrence patterns in the HIPEC + AC group included peritoneal metastasis (n = 20; 20.83%), local recurrence (n = 11; 10.46%), and distant metastasis (n = 19; 19.79%) (Supplementary Figure 4A). Correspondingly, patients in the AC group developed peritoneal metastases (n = 43, 33.33%), local recurrence (n = 19, 14.73%), and distant metastases (n = 29, 27.13%) (Supplementary Figure 4B). The peritoneal metastasis rate was significantly lower in the HIPEC + AC group than in the AC group (20.83% vs 33.33%, P = 0.039).

Following PSM, the HIPEC + AC group exhibited recurrence patterns consisting of peritoneal metastasis (n = 16, 20.00%), local recurrence (n = 9, 11.25%), and distant metastasis (n = 14, 17.50%) (Figure 3A). The AC group exhibited peritoneal metastasis (n = 31, 38.75%), local recurrence (n = 11, 13.75%), and distant metastasis (n = 22, 27.50%) (Figure 3B). Peritoneal metastasis rates were significantly lower in the HIPEC + AC group than in the AC group (20.00% vs 38.75%, P = 0.009).

Figure 3 Patterns of recurrence and metastasis after propensity score matching. A: Hyperthermic intraperitoneal chemotherapy + adjuvant chemotherapy group; B: Adjuvant chemotherapy group. AC: Adjuvant chemotherapy; HIPEC: Hyperthermic intraperitoneal chemotherapy.

DISCUSSION

This retrospective study evaluated patients with locally advanced gastric cancer (T4a-b, N0-3, M0) and compared postoperative HIPEC combined with AC with AC alone. The HIPEC + AC group demonstrated significantly prolonged DFS, DFI, and PMFI, along with lower peritoneal metastasis rates and greater reduction in tumor markers, compared with the AC group. No significant intergroup differences were observed in treatment-related adverse reactions. These findings suggest that combining HIPEC with AC improves disease control without substantially increasing toxicity.

HIPEC has emerged as a novel locoregional therapeutic approach, garnering increasing attention in recent clinical trials. A growing body of international evidence[18] demonstrates that combining HIPEC with standard systemic chemotherapy significantly improves the survival outcomes of patients with peritoneal metastatic disease. For instance, a large-scale multicenter randomized controlled trial confirmed that integrating HIPEC with postoperative systemic chemotherapy significantly prolonged DFS and OS compared with systemic chemotherapy alone[19]. Nevertheless, standardized treatment protocols for HIPEC remain undefined, and its clinical benefits in patients with resectable gastric cancer currently lack an international consensus.

HIPEC demonstrates an acceptable safety profile as adjuvant therapy for gastric cancer, with studies reporting no significant increase in adverse reactions[20-23]. These findings support its clinical application and facilitate further research. Currently, most HIPEC implementation methods involve intraoperative placement of perfusion catheters and intraoperative or early postoperative intraperitoneal hyperthermic chemotherapy. However, given patients' compromised postoperative status and the high complication rates reported in many studies[24], we instead perform ultrasound-guided catheter placement 3-4 weeks postoperatively, when patients exhibit better physical recovery and treatment tolerance. This approach aligns with the concept of postoperative application explored by Zhu et al[25], who employed a similar regimen and reported a favorable safety profile. However, the method we use also has certain drawbacks, such as the possibility that the catheter placement may not reach deeper locations, and some patients may not be able to fully immerse the chemotherapeutic drugs in the entire peritoneal cavity owing to postoperative adhesions. To address these issues, we employ abdominal massage and frequent positional changes during perfusion to enhance drug distribution and peritoneal contact[26]. Our study found comparable rates of myelosuppression (30.00% vs 37.50%) and liver function abnormalities (12.50% vs 12.50%) between the HIPEC + AC and AC groups (P ≥ 0.05), consistent with previous reports that HIPEC does not exacerbate hematologic or hepatic toxicity. While HIPEC treatment led to occasional complications such as intra-abdominal hemorrhage, intra-abdominal infection, and intestinal obstruction, these events remained infrequent and manageable, aligning with prior findings[27]. Notably, no peritoneal puncture-related intestinal perforation was observed, further supporting the safety of HIPEC.

HIPEC has demonstrated survival benefits in multiple clinical studies[28-30]. Desiderio et al's meta-analysis[9] of 11 randomized and 21 non-randomized controlled trials (2520 patients) revealed significantly improved 3-year [relative risk (RR) = 0.71, 95%CI: 0.53-0.96, P = 0.03] and 5-year (RR = 0.82, 95%CI: 0.70-0.96, P = 0.01) OS rates compared with those in controls. In 2020, Xie et al[31] prospectively analyzed 113 patients with locally advanced gastric cancer and compared AC alone with AC combined with prophylactic HIPEC after curative gastrectomy. The control group showed 1-year and 3-year DFS rates of 91.9% and 60.4%, respectively, whereas the HIPEC group showed rates of 92.1% and 63.0%, respectively (P = 0.037). OS rates reached 95.2% and 66.3% in controls compared with 96.1% and 68.6% in the HIPEC group at 1 year and 3 years, respectively (P = 0.044), suggesting that postoperative HIPEC decreases peritoneal metastasis and improves survival in these patients. However, some studies reported no significant improvement in recurrence-free survival (84.8% vs 88.2%; P = 0.986)[22] or OS (41.1% vs 34.5%; P = 0.118)[32] with HIPEC.

In this study, OS did not differ significantly between the HIPEC + AC and AC groups, with P values of 0.174 and 0.187 before and after PSM (both P > 0.05). This finding may be due to several factors. OS depends on multiple determinants, such as intra-abdominal disease control, distant metastasis progression, patient heterogeneity, performance status, and postoperative management[33-35]. The progression of PM also varies substantially according to tumor biology and individual patient characteristics. Although the HIPEC + AC regimen demonstrated superior local control and suppression of peritoneal metastasis, these benefits may have been offset by competing survival determinants, potentially explaining the absence of significant OS improvement.

The significant improvement in DFS and DFI represents a pivotal finding of this study. Before and after PSM, the HIPEC + AC group consistently showed better DFS and DFI outcomes than the AC group, aligning with existing evidence[32,36,37]. These results suggest that HIPEC substantially delays disease recurrence or progression. By delivering high-concentration chemotherapeutic agents directly into the peritoneal cavity, HIPEC eradicates free cancer cells and micro metastases, thereby reducing the risk of local recurrence[38,39]. The synergistic effect of hyperthermia potentiates chemotherapeutic efficacy through enhanced drug penetration and cytotoxicity within the abdominal cavity, ultimately prolonging DFS. Consequently, the observed advantages in DFS and DFI are attributable to the capacity of HIPEC for effective intraperitoneal tumor control.

Peritoneal metastasis in gastric cancer confers a poor prognosis, and systemic chemotherapy provides limited survival benefits. HIPEC may serve as an adjuvant therapy postoperatively to enhance survival rates and reduce peritoneal metastasis[8]. A meta-analysis confirmed the efficacy of HIPEC in preventing peritoneal metastasis (RR = 0.63, 95%CI: 0.45-0.88, P < 0.01)[9]; a 2020 prospective study reported 11 peritoneal recurrences with conventional chemotherapy compared with only 2 with HIPEC (P = 0.020)[31]. In this study, the PMFI emerged as one of the most significantly improved endpoints in the HIPEC + AC group. PSM minimized confounding variables, facilitating precise assessment of the effect of HIPEC on metastasis rates. The HIPEC + AC group exhibited consistently lower peritoneal metastasis rates than the AC group across all timepoints, demonstrating the therapeutic efficacy of HIPEC. Extended follow-up revealed sustained low metastasis rates in the HIPEC + AC group, suggesting durable prophylactic effects. As an adjuvant prophylactic modality following curative surgery, HIPEC effectively reduced peritoneal recurrence, a finding concordant with that of multiple studies[25]. The pronounced advantage of HIPEC in peritoneal control suggests a potential benefit for distinct patient subsets, particularly those at high risk of peritoneal metastasis.

The significant improvements in DFS, DFI, and PMFI demonstrates the efficacy of HIPEC in delaying recurrence and preventing peritoneal dissemination. When considering the OS data, the observed HR before and after PSM (0.755 and 0.727, respectively) consistently favored the HIPEC + AC group, with absolute improvements in the 3-year OS rates (74.0% vs 65.0%). While this difference did not cross the threshold of statistical significance within the limits of our study, the OS endpoint is influenced by a broader and more complex set of factors that extend beyond the initial management of intra-abdominal disease. The biological aggression of the primary tumor, pattern and management of distant metastases, and efficacy of subsequent lines of therapy after recurrence can modulate the ultimate survival outcome. Furthermore, in a cohort of patients with a median age > 60 years, competing risks from non-cancer-related mortality may also attenuate the observable OS difference. Therefore, the pronounced benefits in disease control and prevention of peritoneal recurrence establish HIPEC as a highly valuable adjuvant strategy, warranting further validation in larger prospective cohorts with extended follow-up.

Another significant finding of this study stems from the subgroup analyses. The results indicated that HIPEC provided an additional survival benefit, whether it was combined with the potent "platinum-taxane combination regimen" (being statistically significant) or the commonly used SOX/XELOX regimens (showing clear positive trends). This strongly suggests that the survival improvement associated with HIPEC is independent of the intensity of concomitant systemic chemotherapy and is likely attributable to its intrinsic efficacy in controlling intraperitoneal microscopic disease. The lack of statistical significance in the SOX/XELOX subgroup underscores the need for validation of its efficacy in larger cohorts receiving specific chemotherapy regimens.

This study has several limitations. First, its retrospective design may introduce unknown confounding factors, and the non-randomized controlled approach could lead to patient selection bias. However, strict PSM was implemented to minimize these effects and strengthen the validity of the conclusions. Second, this was a single-center study with a relatively small sample size. However, all patients were drawn from the same treatment cohort and received standardized surgical and adjuvant therapies, minimizing variations in survival outcomes attributable to treatment heterogeneity. Extended follow-up duration and large-scale multicenter randomized controlled trials are warranted to validate these findings and optimize therapeutic strategies for patients with gastric cancer.

CONCLUSION

For patients with locally advanced gastric cancer (stage T4a-b/N0-3/M0), the combination of postoperative HIPEC and conventional AC may prolong DFS and prevent peritoneal metastasis without significantly increasing the incidence of treatment-related adverse reactions. This regimen provides a clinically meaningful value in the management of gastric cancer.