Corresponding author: Professor Wang Pengyuan

Wang Pengyuan Li Nan Chen Shanwen

Department of Gastrointestinal Surgery, Peking University First Hospital

Citation: Wang Pengyuan, Li Nan, Chen Shanwen. Current status and future prospects of hyperthermic intraperitoneal chemotherapy in the treatment of gastric cancer [J]. Chinese Journal of General Surgery, 2026, 41(4): 319-323. DOI: 10.3760/cma.j.cn 113855-20251224-00686.

[Abstract] Peritoneal metastasis in gastric cancer is a critical factor affecting patient prognosis. Approximately 10%–30% of patients at initial diagnosis and more than half of those with advanced gastric cancer after surgery develop peritoneal metastases. Untreated patients have a median survival of only 3–6 months, and the 5-year survival rate is less than 2%. Hyperthermic intraperitoneal chemotherapy (HIPEC) combines chemotherapy with warmed irrigation fluid delivered continuously at a constant temperature into the peritoneal cavity, achieving triple synergistic effects: chemotherapy, hyperthermia, and mechanical lavage. The elevated temperature (42–43°C) activates heat shock proteins, enhances drug penetration and DNA binding, and overcomes the blood–peritoneum barrier while slowing drug metabolism, thereby maintaining high concentrations of cytotoxic agents in the peritoneal space for an extended duration. Simultaneously, continuous infusion of large volumes effectively removes free cancer cells and surgical debris through mechanical flushing. Clinical studies have demonstrated the definitive efficacy of HIPEC in treating ovarian cancer, peritoneal mesothelioma, and pseudomyxoma peritonei. It also shows significant value in the prevention and treatment of peritoneal metastases from gastric cancer, transitioning from empirical use toward standardized therapeutic strategies and emerging as a potential core technological approach to improve patient outcomes.

[Keywords] Gastric neoplasms; Chemotherapy, neoplasm, regional perfusion; Neoplasm metastasis

Funding Project: National Natural Science Foundation of China Special Project (T2541067)

Peritoneal metastasis is one of the most common sites of metastasis in gastric cancer. Approximately 10% to 30% of patients with newly diagnosed gastric cancer already have peritoneal metastases, and more than 50% of patients with T3 or T4 disease develop peritoneal metastases after surgery. ^[1] Without effective multimodal therapy, patients with peritoneal metastases from gastric cancer have a very poor prognosis, with a median survival of only 3 to 6 months and a 5-year survival rate of less than 2%; most patients die within a short period due to rapid tumor progression and complications. ^[2-4] Hyperthermic intraperitoneal chemotherapy (HIPEC), a technique for treating primary peritoneal tumors or peritoneal metastases, is now widely used in clinical practice. It involves mixing commonly used chemotherapeutic agents with a large volume of irrigation fluid, heating the mixture with specialized equipment, and continuously infusing it into the patient’s peritoneal cavity at a constant temperature. This approach combines pharmacologic chemotherapy, hyperthermia, and mechanical lavage to eliminate occult or established tumor cells within the abdominal cavity. ^[5] Currently, HIPEC can be used to treat ovarian cancer, peritoneal mesothelioma, pseudomyxoma peritonei, and colorectal cancer, among others. ^[6] Moreover, the therapeutic efficacy is considerable. As HIPEC has been successfully applied to treat peritoneal metastases from tumors, an increasing number of researchers both domestically and internationally have begun focusing on studies investigating the use of HIPEC to prevent peritoneal metastasis in gastric cancer.

The advantage of HIPEC lies in its ability to bypass the blood-peritoneum barrier while slowing the metabolism of chemotherapeutic agents, thereby significantly increasing intraperitoneal drug concentrations. The thermal component of HIPEC not only activates heat-shock proteins to promote tumor cell apoptosis but also enhances the permeability of chemotherapeutic drugs, dilates vessels around the tumor, alters tumor cell membrane permeability, and strengthens the binding affinity of chemotherapeutics to DNA and cellular macromolecules, thus augmenting their cytotoxicity. Furthermore, elevated temperatures increase the depth of drug penetration into tumor tissue, far surpassing the effects of chemotherapy alone. Continuous (60–120 minutes) infusion of large volumes of perfusate effectively removes free tissue debris and potentially disseminated cancer cells from the peritoneal cavity through mechanical action, ensuring a clean surgical field and reducing the likelihood of residual tumor. ^[7-8] Numerous clinical studies have demonstrated that HIPEC is an effective treatment for peritoneal metastases from various cancers, including gastric cancer. Moreover, it is increasingly recognized as a promising new approach for preventing peritoneal implantation and metastasis in gastric cancer.

I. Current Status of HIPEC Application in the Treatment of Peritoneal Implant Metastases from Gastric Cancer

The core of the application lies in whether the patient’s oncological benefits outweigh the risks of surgery; when the peritoneal cancer index (PCI) is <15 or there are resectable liver metastases and malignant ascites, aggressive attempts should be made to use HIPEC therapy to improve the tumor’s biological behavior. ^[9] HIPEC combined with cytoreductive surgery (CRS) for the treatment of peritoneal implantations from gastric cancer is currently a major focus of research. A prospective observational study published in South Korea in 2018 further confirmed that the efficacy of HIPEC is closely related to the tumor burden of peritoneal implantations in gastric cancer; patients with PCI scores of ≤10, 11–20, and 21–39 had median overall survival (OS) times of 26, 16, and 12 months, respectively. PCI grade and the extent of cytoreduction were identified as key prognostic predictors. ^[9] . A 2019 French CYTO-CHIP propensity score analysis study demonstrated that, for patients with peritoneal metastases from gastric cancer achieving complete cytoreduction, CRS plus HIPEC confers a survival benefit compared with CRS alone, particularly in the subgroup with a PCI of 0, where OS reached 22.8 months versus only 12.9 months in the control group. ^[10] A 2023 meta-analysis from the United Kingdom indicated that HIPEC can improve 3- and 5-year survival rates and reduce peritoneal recurrence rates in patients with advanced gastric cancer, without significantly increasing the incidence of complications. ^[11] . A phase II/III randomized controlled trial, GASTRIPEC-I, published in Germany in 2024, showed that although CRS plus HIPEC did not improve overall survival in patients with peritoneally implanted gastric cancer (14.9 months vs. 14.9 months), it significantly prolonged progression-free survival (7.1 months vs. 3.5 months) and distant metastasis–free survival. ^[12] A 2024 study published by Nanfang Hospital in China showed that among patients with peritoneal implantation metastases from gastric cancer undergoing HIPEC, using a PCI score of 6 as the cutoff, the median overall survival was 29 months in the low-PCI group and 11 months in the high-PCI group, while the median progression-free survival was 23 months and 10 months, respectively, suggesting that a higher PCI score portends a poorer prognosis. ^[13] 。

At the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Professor Zhu Zhenggang’s team from Ruijin Hospital reported the results of the DRAGON-01 study. The study evaluated the efficacy and safety of intraperitoneal plus intravenous paclitaxel combined with S-1 (NIPS group) versus intravenous paclitaxel combined with S-1 (PS group) in patients with gastric cancer and peritoneal metastases. The findings showed that, compared with intravenous paclitaxel plus S-1, the combination of intraperitoneal and intravenous paclitaxel plus S-1 significantly improved overall survival in these patients, with manageable toxicity. ^[14] These findings demonstrate that the benefits of HIPEC are undeniable; it does indeed confer a survival advantage, prolonging patients’ survival, and importantly, it does not increase the incidence of complications. HIPEC is more effective in patients with lower PCI scores, yet it also yields favorable outcomes in those with higher PCI scores.

II. Current Status of the Application of HIPEC for Preventing Peritoneal Implant Metastasis After Gastric Cancer Surgery

The mechanisms underlying peritoneal implantation metastasis in gastric cancer have not yet been fully elucidated. Currently, the “seed and soil” hypothesis is widely accepted in the scientific community, proposing that metastasis occurs in several steps: (1) shedding and migration of tumor cells; (2) adhesion to and invasion at the metastatic site; and (3) angiogenesis and proliferation. ^[15] The prerequisite for peritoneal implantation is the presence of intraperitoneal free cancer cells (IFCCs). The two main sources of IFCCs are tumor invasion through the serosa and surgery-related iatrogenic factors. These include gastric cancer penetrating the serosa when invading and infiltrating normal tissues, thereby generating free cancer cells in the peritoneal cavity under surgical compression, as well as lymph node dissection performed when lymphatic vessels are involved or intraoperative bleeding following vascular involvement by the tumor. Based on this theory, procedures such as lymph node dissection during gastrectomy may induce the dissemination of tumor cells into the peritoneal cavity. Therefore, concurrent or early HIPEC after gastric cancer surgery can be employed to eliminate IFCCs, thereby reducing postoperative peritoneal metastasis in patients with gastric cancer and improving overall survival rates in those with advanced disease.

A study conducted at Peking University People’s Hospital consecutively enrolled 119 gastric cancer patients who underwent surgery in the Department of Gastrointestinal Surgery between July 2014 and March 2016. At three time points—immediately after laparotomy, immediately after surgical manipulation, and 3 hours after peritoneal irrigation—the peritoneal cavity was irrigated with 300–400 mL of normal saline, and the lavage fluid was collected. IFCCs were detected using conventional cytology by centrifugation, membrane filtration cytology, immunocytochemistry, and RT‑PCR. The results showed that gastric cancer patients positive for IFCCs had poorer short-term outcomes than those negative; surgical manipulation increased the risk of IFCC shedding; and peritoneal irrigation performed after surgical manipulation reduced the number of IFCCs. ^[16] Therefore, the key to preventing peritoneal metastasis in gastric cancer lies in minimizing the generation of IFCCs during tumor resection or lymph node dissection, while simultaneously using HIPEC to reduce the number and density of IFCCs, thereby maximizing prevention of peritoneal metastatic cancer. A retrospective analysis published in 2020 by Tianjin Medical University examined patients who underwent HIPEC treatment (paclitaxel 175 mg/m²... ² Eighty patients with stage IIIb gastric cancer who underwent HIPEC (temperature 43°C, duration 60 minutes, three sessions) were compared with 90 patients with stage IIIb gastric cancer who underwent surgery alone during the same period. Based on whether HIPEC was administered postoperatively, patients were divided into an HIPEC group (study group) and a surgery-alone group (control group). The median survival in the HIPEC group was 54 months, versus 38 months in the control group. The results indicate that surgery combined with HIPEC is safe and feasible, improves the 5-year survival rate in patients with signet-ring cell carcinoma and advanced gastric cancer of Borrmann type III or IV, prolongs survival, and does not increase the incidence of postoperative complications. ^[17] . A prospective phase III multicenter randomized controlled study published in Spain in 2023 randomly assigned patients with peritoneal metastases from gastric cancer to receive CRS plus HIPEC (study group, 89 patients, 30 mg/m within 60 minutes ² ) or simple cytoreductive surgery (control group, 95 patients). Compared with surgery alone, the study group had a 3-year regional control rate of 97.6%, which was significantly higher than the control group’s 87.6% ( P <0.05) ^[18] Overall, numerous domestic and international studies to date indicate that prophylactic HIPEC can reduce the incidence of peritoneal metastasis in advanced gastric cancer and effectively improve patients’ overall prognosis.

III. Selection of Chemotherapeutic Agents for HIPEC in Gastric Cancer and Research Advances

HIPEC monotherapy has limited efficacy; although combination therapy can improve outcomes, it also increases the risk of adverse reactions. Therefore, striking a balance between efficacy and safety is a key consideration in selecting drugs for HIPEC. In clinical practice, drug selection should be guided by commonly used agents for intravenous chemotherapy of the primary tumor, the patient’s prior sensitive medications or results of drug-sensitivity testing, while prioritizing agents with high tumor tissue penetration, large molecular weight, low peritoneal absorption rate, synergistic effects with thermal treatment, minimal peritoneal irritation, and proven antitumor activity. ^[19] 。

Cisplatin inhibits cell proliferation by binding to DNA and forming Pt/DNA adducts that disrupt DNA structure. Moreover, cisplatin can induce the generation of reactive oxygen species (ROS), leading to tumor cell death. The concentration of cisplatin and the duration of its exposure are positively correlated with the level of ROS produced, thereby influencing its cytotoxic effect on cancer cells. ^[20-21] Paclitaxel stabilizes microtubules and blocks mitosis, while also inducing apoptosis, modulating immunity, and inhibiting tumor migration. Its microtubule-targeting mechanism differs from that of conventional DNA-damaging chemotherapeutics; it demonstrates significant efficacy in breast cancer, ovarian cancer, non–small cell lung cancer, and other malignancies, making it a first-line chemotherapeutic agent. It is now also widely incorporated into HIPEC regimens for advanced gastric cancer. ^[22] Paclitaxel is used in HIPEC primarily in two core regimens: single-agent HIPEC and combination HIPEC. Single-agent paclitaxel HIPEC for peritoneal metastases from gastric cancer is safe and feasible, effectively controls ascites, and is associated with manageable adverse events such as neutropenia. ^[23-24] . Paclitaxel combined with cisplatin or oxaliplatin has also demonstrated good efficacy. ^[25] Mitomycin C has been used in HIPEC for gastric cancer since 1988, and this drug has been widely employed in both conventional chemotherapy and HIPEC for an extended period. Mitomycin C exerts its anticancer effects by inducing cross-linking between DNA strands, thereby disrupting DNA replication and transcription and ultimately inhibiting the division and proliferation of cancer cells. ^[26] Mitomycin monotherapy is generally used for pseudomyxoma peritonei and locally advanced colorectal cancer to reduce recurrence and improve prognosis. Combination therapy often pairs it with platinum agents, achieving synergistic effects; this regimen is suitable for peritoneal metastases from gastric and colorectal cancers, offering particular advantages in high-risk patients or during palliative care. ^[27] 。

A single-center study in China found that using paclitaxel (40 mg/m ² ) The treatment regimen of HIPEC sequential intraperitoneal–intravenous infusion combined with S-1 can significantly improve the R in patients with peritoneal metastasis from gastric cancer. ₀ Surgical conversion rate ^[28] . The Dutch PERISCOPE I study, on the other hand, clearly demonstrated that oxaliplatin (460 mg/m ² ) in combination with docetaxel (50 mg/m ² ) Recommended HIPEC dose for Phase II clinical trials ^[29] A Bayesian network meta-analysis conducted in China included 11 randomized controlled trials involving a total of 1,092 patients. The results confirmed that both single-agent and combination regimens containing cisplatin, mitomycin C, and other drugs could improve overall survival (OS) in patients. Among these, cisplatin-based regimens were superior to other regimens in terms of OS improvement and overall disease recurrence control. ^[30] Furthermore, a 10-year single-center study conducted abroad validated the therapeutic efficacy of CRS combined with HIPEC and intraoperative radiotherapy. The study commonly employed regimens such as cisplatin in combination with mitomycin C. The results indicated that this multimodal treatment strategy significantly prolonged patients’ overall survival (OS) and disease-free survival (DFS) without increasing morbidity or mortality. ^[31] 。

In the development of new drugs and combination therapies for HIPEC, domestic researchers have engineered a novel nanoassembly composed of gambogic acid and metformin, enabling HIPEC to be used in the treatment of orthotopic colorectal and ovarian cancers. Hyperthermia can trigger immunogenic cell death in cancer cells, leading to the release of damage-associated molecular patterns and thereby enhancing the immunogenicity of the tumor microenvironment. Gambogic acid is an effective inhibitor of heat shock proteins, increasing cancer cells’ sensitivity to heat-induced cell death. Moreover, gambogic acid itself is a chemotherapeutic agent that can efficiently induce apoptosis in cancer cells and amplify heat‑induced immunogenic cell death. Metformin effectively degrades the tumor extracellular matrix, promoting deep penetration of nanoparticles into tumor tissue and facilitating the infiltration of cytotoxic T lymphocytes. Importantly, the synergistic combination of gambogic acid and metformin during HIPEC elicits a robust antitumor immune response in vivo. This integrated strategy offers a promising therapeutic avenue for the treatment of advanced abdominopelvic malignancies. ^[32] 。

Overall, commonly used drugs for HIPEC include cisplatin, oxaliplatin, mitomycin C, fluorouracil, paclitaxel, and docetaxel; in clinical practice, melphalan can be used as an alternative for patients allergic to cisplatin. The nanoengineered assemblies developed above have demonstrated promising application potential and hold promise for treating patients with advanced gastric cancer. Currently, there are differences in efficacy among single-agent regimens and combination therapies using various conventional chemotherapeutic agents, yet systematic studies on drug administration remain lacking; therefore, future research should focus on standardizing drug combinations and dosing.

IV. Conclusion

The 2025 NCCN Guidelines for Gastric Cancer recommend that HIPEC should only be performed after multidisciplinary discussion, and all patients being considered for HIPEC should undergo pretreatment evaluation, including chest, abdominal, and pelvic CT scans for tumor staging, diagnostic laparoscopy with collection of lavage fluid for PCI assessment, and consideration of PET scanning to rule out distant metastases. For certain patients with advanced gastric cancer and a PCI score ≤10, HIPEC combined with CRS is an option; for some patients with a PCI >10, the use of HIPEC in clinical trials may be considered. ^[33] Overall, although HIPEC research remains somewhat fragmented, it can play a beneficial role in treating peritoneal metastases from advanced gastric cancer, potentially improving patients’ 5-year survival rate, disease-free survival, or other clinical outcomes. Current NCCN guidelines recommend that, at experienced centers, HIPEC be administered early postoperatively in gastric cancer patients with risk factors for peritoneal implantation metastases to prevent such spread; moreover, numerous domestic and international studies have confirmed that HIPEC can effectively prevent peritoneal metastasis in patients with advanced gastric cancer. ^[34] 。

Finally, it is worth noting that in the era of cancer immunotherapy, although HIPEC has potential immune-activating effects and has demonstrated some clinical value in reducing peritoneal metastasis from gastric cancer, its standardized combination with immunotherapy for gastric cancer still lacks robust support from high-quality, prospective clinical trials. Currently, no systematic studies have clarified the optimal timing, administration sequence, treatment duration, or safety profile of combining these two approaches in the management of advanced gastric cancer. Therefore, within a multidisciplinary collaborative framework, it is urgently necessary to systematically advance research on HIPEC’s modulation of the tumor immune microenvironment across three dimensions: mechanistic, clinical, and translational. At the mechanistic level, single-cell multi-omics and spatial transcriptomics should be leveraged to dynamically map the immune microenvironment of peritoneal metastatic lesions before and after HIPEC intervention, determining whether and how HIPEC can convert “cold tumors” into “hot tumors” by inducing immunogenic cell death, reshaping antigen-presenting networks, and depleting suppressive immune cells, thereby providing a theoretical foundation for combination therapy. At the clinical level, prospective randomized controlled trials should be designed targeting high-risk populations—such as those with Borrmann type IV, Lauren diffuse histology, or positive preoperative peritoneal free cancer cells—using “HIPEC combined with immune checkpoint inhibitors” as the intervention node, with a focus on addressing key issues including the optimal timing of intervention, coordination of drug administration schedules, and perioperative safety boundaries. At the translational level, dynamic efficacy-prediction systems based on liquid biopsy biomarkers—including circulating tumor DNA, ascitic exosomes, and peripheral blood cytokine profiles—should be actively explored, facilitating a transition of combination regimens from empiric use under fixed protocols toward a precision medicine paradigm guided by biomarkers. Only through this triple-driven approach—deep mechanistic investigation, evidence-based development, and practical translation—can HIPEC combined with immunotherapy break free from the confines of case reports and retrospective analyses and truly become a robust standard treatment option within comprehensive therapeutic strategies for advanced gastric cancer, particularly for patients at high risk of peritoneal metastasis.

Conflicts of Interest: All authors declare that no conflicts of interest exist.

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