Advances and challenges in the application of prophylactic hyperthermic intraperitoneal chemotherapy for gastric cancer

Gastric cancer is the fifth most common malignant tumor worldwide and the third leading cause of cancer-related deaths, posing a serious threat to global public health. Despite notable advancements in surgical techniques, systemic chemotherapy, targeted therapy, and immunotherapy in recent years, the overall prognosis for patients with locally advanced gastric cancer (AGC) remains suboptimal, primarily due to the high propensity for local and distant metastasis. Peritoneal metastasis (PM), in particular, has become one of the most formidable clinical challenges owing to its high incidence, inherent resistance to systemic chemotherapy, and extremely poor prognosis. To address this challenge, Prophylactic Hyperthermic Intraperitoneal Chemotherapy (P-HIPEC) has emerged as a focal point of research. This therapeutic modality aims to eradicate microscopic residual tumors and free cancer cells in the abdominal cavity following radical gastrectomy, thereby effectively reducing the risk of peritoneal metastasis and improving long-term patient survival. This review systematically examines the latest research progress of P-HIPEC in the treatment of gastric cancer, provides an in-depth analysis of its mechanism of action, indications, criteria for patient and drug selection, evidence of clinical efficacy, safety controversies, and challenges in standardization. It also looks forward to future research directions in this field, with the aim of providing a valuable reference for clinical practice and academic research.

1 Introduction

Gastric cancer constitutes a major global health burden and is the fifth most common malignant tumor and the third leading cause of cancer-related mortality worldwide (1). Despite multimodal advancements in surgical techniques, systemic chemotherapy, targeted therapy, and immunotherapy, the prognosis for patients with locally advanced gastric cancer (AGC) remains suboptimal (2). This is primarily attributed to a high rate of recurrence, with peritoneal metastasis (PM) emerging as a particularly challenging and frequent mode of treatment failure (3). The development of PM is associated with an inferior prognosis, as conventional systemic chemotherapy offers limited efficacy due to the restrictive nature of the plasma-peritoneal barrier (4). In response to this critical unmet need, Prophylactic Hyperthermic Intraperitoneal Chemotherapy (P-HIPEC) has been developed as a targeted locoregional strategy designed to eradicate residual microscopic disease and free-floating cancer cells within the peritoneal cavity (5).

This review aims to provide a comprehensive and systematic overview of the current research landscape of P-HIPEC for gastric cancer. Beyond merely compiling existing data, we critically evaluate how these findings directly translate to clinical decision-making, particularly in the era of modern systemic chemotherapy (e.g., FLOT regimen). We specifically address the heterogeneity in HIPEC protocols and provide actionable recommendations to aid oncology specialists in optimizing patient selection.

2 Gastric cancer and peritoneal metastasis

Peritoneal metastasis is one of the most common and detrimental forms of distant spread in advanced GC, and it is a primary cause of treatment failure and patient mortality.

2.1 Epidemiology

The peritoneum is one of the most common sites of metastasis after curative surgery for advanced gastric cancer, serving as the initial site of metastasis in approximately 40% to 60% of patients. For T3 and T4 stage gastric cancer, the incidence of peritoneal metastasis after radical surgery exceeds 50% (6). Once overt peritoneal metastasis occurs, the prognosis is extremely poor, with the median survival time dropping to 3 to 6 months and a 5-year survival rate of nearly 0% (7). Microscopic metastatic lesions and free cancer cells (FCCs) in the abdominal cavity are difficult to detect with conventional imaging techniques in the early stages. Furthermore, traditional systemic intravenous chemotherapy is largely ineffective because the peritoneal-plasma barrier prevents drugs from reaching therapeutic concentrations within the peritoneal cavity.

2.2 Molecular pathogenesis

Peritoneal metastasis is a highly ordered, multi-step biological process governed by the “seed and soil” theory (Figure 1) (8). It begins with the detachment of cancer cells from the primary tumor, a process facilitated by Epithelial-Mesenchymal Transition (EMT). During EMT, downregulation of E-cadherin and activation of transcription factors (e.g., Snail, Twist, ZEB) confer migratory properties to gastric cancer cells (9–11). Once exfoliated, free cancer cells (FCCs) survive in the peritoneal cavity by aggregating into spheroids to resist anoikis and navigate toward the peritoneum via chemokine axes, such as CXCL12/CXCR4 (12, 13). Adhesion involves the interaction between cancer cells and the mesothelium. Tumor-derived TGF-β1 induces mesothelial-to-mesenchymal transition in peritoneal cells, exposing the basement membrane (14). Adhesion molecules such as integrin α3β1, CD44, and PCDHB9 then anchor cancer cells to the submesothelial matrix (15–17). Finally, tumor cells secrete matrix metalloproteinases (MMPs) to degrade the extracellular matrix and Vascular Endothelial Growth Factor (VEGF) to induce angiogenesis, establishing macroscopc nodules (17, 18).

Figure 1

Figure 1. Process of peritoneal metastasis in gastric cancer. Conceptual cascade of peritoneal metastasis in gastric cancer and the perioperative window targeted by prophylactic HIPEC. Tumor serosal involvement facilitates exfoliation of free cancer cells (FCCs) into the peritoneal cavity, followed by survival, adhesion to injured/inflamed mesothelium, invasion, and outgrowth into macroscopic implants. P-HIPEC is delivered at curative-intent surgery to eradicate FCCs and microscopic disease before implantation becomes established. FCCs, free cancer cells; GC, gastric cancer; HIPEC, hyperthermic intraperitoneal chemotherapy; PM, peritoneal metastasis.

The existence of the plasma-peritoneal barrier makes it difficult for traditional systemic intravenous chemotherapy to achieve effective cytotoxic concentrations within the peritoneal cavity. Therefore, the development of local therapeutic strategies that act directly on the peritoneum has become an urgent need.

3 Mechanism of action of HIPEC

At least one inflow catheter and one to two outflow catheters are positioned intraperitoneally, along with temperature probes placed in different abdominal quadrants. The perfusion device is primed with isotonic carrier solution and gradually heated until both the perfusion circuit and intraperitoneal cavity temperatures stabilize within the range of 41–43°C. Chemotherapeutic agents are then administered based on the patient’s body surface area or a predetermined protocol. A suitable perfusion flow rate is set, commonly between 0.8 and 1.5 L/min, adjusted according to device characteristics and intraperitoneal capacity, and the chemotherapy is circulated for a duration of 60–90 minutes. Throughout the perfusion, patient positioning is periodically adjusted and gentle abdominal manipulation is performed to facilitate uniform distribution of the therapeutic solution. Continuous monitoring of inflow and outflow temperatures, as well as multipoint intraperitoneal temperatures, is conducted to maintain the desired therapeutic range. Upon completion, the peritoneal cavity is thoroughly rinsed with warmed saline, residual perfusate is collected and properly disposed of according to standard guidelines, drainage tubes may be retained as clinically indicated, and surgical closure is performed (Figure 2).

Figure 2

Figure 2. Schematic of hyperthermic intraperitoneal chemotherapy (HIPEC). Schematic overview of intraoperative HIPEC delivery. Representative elements include inflow/outflow catheter placement, perfusion circuit with heating/exchanger, target intraperitoneal temperature monitoring, and differences between open (Coliseum) and closed techniques. HIPEC, hyperthermic intraperitoneal chemotherapy.

The clinical efficacy of prophylactic HIPEC stems from the synergistic effects of multiple actions, including hyperthermia (HT), high-dose regional chemotherapy, mechanical flushing, and immunomodulation. This technology is designed to completely eradicate the residual microscopic tumor burden within the peritoneal cavity.

3.1 Hyperthermia

Hyperthermia is the core element that distinguishes HIPEC from normothermic intraperitoneal chemotherapy (NIPEC), and it possesses multi-level anti-tumor effects. ① Direct cytotoxicity: Numerous experiments have confirmed that tumor cells are significantly more sensitive to heat than normal tissue cells due to their disorganized vascular structure, poor blood supply, and acidic microenvironment (19, 20). Continuous exposure to a temperature of 43°C for 1 hour can cause irreversible damage to tumor cells, leading to apoptosis or necrosis, whereas normal tissue cells can tolerate temperatures up to 47°C. Thermal effects can directly damage the cell membrane and organelles (such as lysosomes and mitochondria) of cancer cells and interfere with their energy metabolism(Figure 3) (21). ② Enhancement of chemotherapeutic drug efficacy: There is a synergistic effect between hyperthermia and chemotherapy drugs. High temperatures increase the fluidity and permeability of the tumor cell membrane, promoting more effective entry of chemotherapy drugs into the cancer cells. Additionally, hyperthermia can alter blood perfusion in tumor tissues, increasing drug accumulation. Critically, hyperthermia can interfere with the self-repair capabilities of tumor cells at the molecular level (22–24). ③ Inhibition of DNA Damage Repair (DDR): Many chemotherapy drugs (e.g., platinum agents, mitomycin C) kill cancer cells by causing DNA damage. However, cancer cells possess a complex DNA Damage Repair (DDR) system to counteract this damage (25). Research shows that hyperthermia can effectively inhibit DDR, making cancer cells more vulnerable to chemotherapeutic attack: (i) Inhibition of Homologous Recombination (HR) repair: HR is a key pathway for repairing DNA double-strand breaks (DSBs) (26). Hyperthermia has been shown to promote the degradation of the key repair protein BRCA2, thereby significantly inhibiting the activity of the HR pathway (27) (Figure 4). (ii) Functional PARP inhibition: A recent groundbreaking study revealed a deeper synergistic mechanism of hyperthermia. Poly(ADP-ribose) polymerase 1 (PARP1) is a key sensor and signaling molecule in DDR. When chemotherapy drugs cause DNA damage, PARP1 is activated (28). PARP1 catalyzes a modification called PARylation to recruit repair proteins and pause the cell cycle, allowing time for DNA repair. The study found that hyperthermia at 42°C can efficiently inhibit the enzymatic activity of PARP1, with an effect comparable to that of pharmacological PARP inhibitors (PARPi) (29). By inhibiting PARP1, hyperthermia prevents the normal replication fork slowing and repair processes after DNA damage, leading to a dramatic increase in replication stress under continuous chemotherapy. This results in the formation of a large number of irreparable, lethal DSBs, thereby greatly enhancing the cytotoxic effect of chemotherapy. This finding provides a solid theoretical basis for prioritizing DNA-damaging agents in HIPEC regimens (Figure 4).

Figure 3

Figure 3. Direct cytotoxic effects of hyperthermia (41-43°C) on tumor cells. Clinically relevant effects of hyperthermia combined with intraperitoneal chemotherapy. Hyperthermia increases local cytotoxicity, improves peritoneal surface drug penetration, and can impair DNA damage repair, thereby sensitizing tumor cells to chemotherapy. The magnitude of effect depends on protocol parameters (temperature stability, exposure duration, and drug regimen). DDR, DNA damage repair; HIPEC, hyperthermic intraperitoneal chemotherapy.

Figure 4

Figure 4. Hyperthermia-induced HR and PARP inhibition. Proposed interaction between hyperthermia-induced impairment of homologous recombination and PARP inhibition as a rationale for future combination strategies. Hyperthermia may transiently reduce homologous recombination capacity, potentially creating a vulnerability that could be exploited by PARP inhibitors in selected contexts. HR, homologous recombination; PARP, poly(ADP-ribose) polymerase.

3.2 Pharmacokinetics

The cornerstone of HIPEC’s theoretical basis lies in its unique pharmacokinetic advantage: utilizing and overcoming the plasma-peritoneal barrier. This semipermeable membrane structure hinders the absorption of large-molecule, hydrophilic chemotherapy drugs from the peritoneal cavity into the systemic circulation (30). Consequently, direct intraperitoneal administration can achieve extremely high drug concentrations within the peritoneal cavity—potentially tens of times higher than those achievable with safe systemic administration—while systemic drug exposure and toxic side effects remain relatively low (31–33). This high-concentration local chemotherapy environment is crucial for eradicating free cancer cells and micrometastases in the abdominal cavity, as it can overcome the relative resistance of tumor cells to conventional doses of chemotherapy. However, this advantage is accompanied by an inherent limitation: the penetration depth of most chemotherapy drugs into peritoneal tissue is very limited, typically only 2–5 mm (24). This fact underscores why HIPEC must be combined with thorough surgical intervention. The core principle established by pioneers like Sugarbaker is that any visible tumor nodule larger than this penetration depth must be removed through cytoreductive surgery (CRS). The role of HIPEC is to treat the “residual” disease that is not visible to the naked eye. Without thorough CRS as a prerequisite, the efficacy of HIPEC is greatly diminished (30).

3.3 Mechanical flushing and immunomodulation

① Physical removal: During the HIPEC procedure, a large volume (typically 4–6 liters) of perfusate circulates at high speed within the peritoneal cavity. This continuous mechanical flushing physically removes and dilutes suspended and unattached FCCs, reducing the probability of their implantation (30). ② Immune activation effect: Hyperthermia itself is a stressor that can induce tumor cells to express Heat Shock Proteins (HSPs). When released extracellularly, these HSPs can act as a “danger signal,” recognized and captured by antigen-presenting cells such as Dendritic Cells (DCs). This promotes DC maturation and enhances their ability to present tumor-associated antigens, ultimately activating a specific T-cell immune response against the tumor and producing a long-term anti-tumor effect (34).

4 Indications and patient selection for P-HIPEC

P-HIPEC is not suitable for all gastric cancer patients; strict patient selection is a prerequisite for ensuring its efficacy and safety. The core principle for applying P-HIPEC is for patient subgroups who have no macroscopic peritoneal metastasis (Peritoneal Carcinomatosis Index, PCI = 0) but are judged to have a high risk of peritoneal metastasis based on clinicopathological features (3). Based on multiple clinical studies, systematic reviews, and expert consensus, the currently recognized high-risk factors for peritoneal metastasis in gastric cancer include: ① T stage: Tumor invasion to the subserosa (pT3) or perforation of the serosa (pT4a) is the most important criterion for selecting patients for P-HIPEC (35). Notably, tumor invasion into adjacent structures (pT4b) represents the highest risk for exfoliation and is considered a strong indication for P-HIPEC in many protocols (36). ② N stage: Positive lymph node metastasis (N+) is also a recognized high-risk factor, indicating a stronger invasive and metastatic capacity of the tumor. ③ Peritoneal Cytology: In the absence of macroscopic peritoneal nodules (P0), the detection of cancer cells in peritoneal washings (CY1) is a sign of extremely poor prognosis, with a 5-year survival rate comparable to that of patients with macroscopic metastases. Therefore, a CY1 status is considered by many scholars as an indication for prophylactic or early therapeutic HIPEC (37). It is noteworthy, however, that some strictly defined clinical trials, aiming to assess purely prophylactic effects, have excluded CY1 patients, considering them to have M1 stage metastasis (37, 38). This ambiguity in the definition and stratification of CY1 patients is a significant reason why results from different studies are difficult to compare directly. ④ Histological type: Specific histological types are closely related to the risk of peritoneal metastasis. According to the Lauren classification, diffuse-type gastric cancer is more prone to peritoneal dissemination than intestinal-type. Patients histologically diagnosed with signet ring cell carcinoma also have a significantly increased risk of peritoneal metastasis (39). ⑤ Other high-risk factors: Borrmann type IV (linitis plastica), tumor perforation or intraoperative rupture, and lymphovascular invasion are also considered high-risk markers for peritoneal metastasis (40). Furthermore, the “Expert Consensus on the Clinical Application of Hyperthermic Intraperitoneal Chemotherapy Technology (2016 Edition)” from China and its subsequent updates provide clear guidance for the clinical application of P-HIPEC (41). The consensus details the above high-risk factors as indications and specifies contraindications, including: ① Absolute contraindications: Confirmed distant organ metastases (e.g., liver, lung, bone), extensive retroperitoneal lymph node metastasis. ② Relative contraindications: Poor general condition of the patient (e.g., ECOG score >1 or KPS score <70), advanced age (usually >75 years) or very young age (<20 years), severe dysfunction of vital organs such as the heart, lungs, liver, or kidneys, rendering the patient unable to tolerate prolonged surgery and chemotherapy.

Patient selection for P-HIPEC is a process of comprehensive evaluation by a multidisciplinary team (MDT), which requires combining findings from preoperative imaging, endoscopic ultrasound, pathology, and intraoperative exploration, and conducting a thorough assessment of the patient’s risks and potential benefits.

While the “Expert Consensus on the Clinical Application of Hyperthermic Intraperitoneal Chemotherapy Technology” from China provides clear guidance, international perspectives vary. The PSOGI (Peritoneal Surface Oncology Group International) and recent European guidelines also advocate for P-HIPEC in high-risk groups, particularly T4 tumors, though criteria regarding CY1 status remain a subject of ongoing standardization (42–44).

5 Drug and regimen selection for P-HIPEC

The development of a P-HIPEC regimen involves multiple aspects, including the choice of chemotherapeutic agents, setting of technical parameters, and timing of implementation. However, there is currently no globally unified, standardized protocol in this field. The significant variations in regimens used by different research centers are a major cause of heterogeneity in study results. The selection of drugs for HIPEC should follow several basic principles: ① Efficacy against gastric cancer cells: The drug itself must be cytotoxic to gastric cancer. ② Hyperthermic sensitization effect: The drug’s anti-tumor activity should be enhanced at high temperatures. ③ Pharmacokinetic advantages: The drug should have characteristics such as a large molecular weight, good water solubility, and low absorption from the peritoneum, allowing it to be confined within the peritoneal cavity. ④ Good safety profile: The drug should have low peritoneal irritability and be unlikely to cause severe chemical peritonitis or intestinal adhesions.

The drugs more commonly used in clinical practice are: ① Mitomycin C (MMC): As an alkylating agent, MMC is one of the oldest and most widely used drugs in the history of HIPEC. It has a large molecular weight and a clear hyperthermic sensitization effect. Many early key studies used MMC monotherapy for P-HIPEC (45). ② Platinum Agents: Cisplatin (CDDP) and Oxaliplatin have become mainstream choices in modern HIPEC regimens due to their potent DNA cross-linking damage and proven significant hyperthermic sensitization effects. These drugs can be used alone or in combination with other agents (46). For example, the ongoing large-scale European Phase III clinical trial (GASTRICHIP) uses oxaliplatin (47). ③ Taxanes: Paclitaxel (PTX) and Docetaxel (DOC) are also used in HIPEC research due to their unique anti-tumor mechanisms and favorable intraperitoneal pharmacokinetic properties. These drugs can also be combined with platinum agents to achieve a stronger synergistic effect (48, 49). ④ Combination regimens: To further improve efficacy, some research centers have begun to explore combination drug regimens, such as cisplatin combined with docetaxel (49), or more complex three-drug combinations (e.g., MMC+CDDP+5-FU). However, the safety and efficacy of these combination regimens still require confirmation from more high-quality clinical trials.

In addition to drug selection, the specific technical parameters of HIPEC also vary: ① Perfusion technique: This is mainly divided into the open (Coliseum technique) and closed methods. The open technique is performed under direct vision, which theoretically allows for more uniform drug distribution but has disadvantages such as aerosolization of chemotherapy drugs, increased exposure risk for the surgical team, and rapid heat loss. The closed technique is performed after closing the abdominal wall, offering higher safety but potentially leading to uneven drug distribution. ② Temperature: Most study protocols set the target intraperitoneal temperature at 42-43°C, a range that balances the therapeutic effect of hyperthermia with the risk of tissue damage. ③ Duration: The perfusion duration is typically 60 to 90 minutes, with the specific time depending on the properties of the selected drug and the study protocol design. ④ Timing: The vast majority of P-HIPEC procedures are performed as a single session after the completion of radical gastrectomy, either before or after gastrointestinal reconstruction. However, a few studies are exploring a model of early postoperative (e.g., 1–2 days post-op) fractionated perfusion through a pre-placed catheter, the pros and cons of which are yet to be determined. The following table summarizes the P-HIPEC regimens used in some key clinical trials to visually demonstrate their diversity (Table 1).

Table 1

Table 1. Prophylactic HIPEC regimens in key clinical trials.

This heterogeneity in regimens is a major challenge facing research in the P-HIPEC field. It directly affects the comparability of results from different studies and hinders the formation of unified clinical practice guidelines. Future research urgently needs to determine the optimal combination of drugs, dosages, and technical parameters through well-designed head-to-head comparative trials.

6 Clinical efficacy analysis of P-HIPEC

The clinical efficacy of P-HIPEC is primarily measured by its impact on peritoneal metastasis rate, disease-free survival (DFS), and overall survival (OS). Existing evidence shows varying degrees of consistency and controversy across these different endpoints.

To improve transparency and avoid mixing fundamentally different intents, we now clearly distinguish prophylactic HIPEC (P-HIPEC; high-risk P0 disease at curative gastrectomy) from therapeutic CRS+HIPEC (macroscopic peritoneal carcinomatosis/metastasis) and anchor each PM/DFS/OS statement to specific RCTs and the most recent meta-analyses. In the prophylactic setting, randomized-trial meta-analyses consistently suggest reduced peritoneal failure: Sun et al. reported fewer peritoneal dissemination events (RR 0.69, 95% CI 0.52–0.93) and fewer peritoneal recurrence-related deaths (RR 0.45, 95% CI 0.27–0.82), but with substantial heterogeneity for the latter endpoint (I²=62%), highlighting the impact of patient selection, regimens, and technique. In the same analysis, OS showed low heterogeneity (I²=0%) (52). Method-specific pooling further supports regimen/technique dependence: Huang et al. reported a favorable 5-year recurrence signal for intraoperative hyperthermic IPC (HIIC) (RR 0.47, 95% CI 0.39–0.56) with moderate heterogeneity (I²=39%), and Yan et al. demonstrated that heterogeneity differs by IPC category (e.g., NIIC I²=48.9% vs HIIC I²=27.7%), arguing against a single “one-size-fits-all” pooled conclusion (53).

In contrast, the therapeutic setting should be reported separately: the phase III RCT by Yang et al. in gastric cancer peritoneal carcinomatosis showed improved median survival with CRS+HIPEC versus CRS alone (11.0 vs 6.5 months; p=0.046), underscoring that established PM populations and outcomes are not directly comparable to prophylaxis (54). Finally, we explicitly note that much prophylactic randomized evidence is derived from Asian, largely pre-FLOT eras, limiting Western generalizability; ongoing European phase III programs (e.g., GASTRICHIP and PREVENT) are designed to test P-HIPEC within contemporary staging and perioperative chemotherapy frameworks and will be critical to clarify external validity.

6.1 Peritoneal metastasis rate

P-HIPEC has demonstrated its most definitive clinical benefit in reducing the risk of peritoneal metastasis. The vast majority of evidence, from early retrospective studies to recent randomized controlled trials (RCTs) and meta-analyses, consistently indicates that the addition of P-HIPEC to surgery or surgery combined with systemic chemotherapy significantly reduces the incidence of postoperative peritoneal metastasis. Multiple meta-analyses report odds ratios (OR) concentrated in the range of 0.22 to 0.24, which means P-HIPEC can reduce the risk of peritoneal metastasis by approximately 75% to 78%, a clinically significant finding (52, 53, 55, 56). This result strongly supports the theoretical basis of P-HIPEC as a locoregional preventive measure.

6.2 Disease-free survival

Given its effectiveness in controlling peritoneal metastasis, the improvement in disease-free survival with P-HIPEC has also been widely confirmed. Multiple studies, including some high-quality propensity score matching (PSM) analyses and meta-analyses, have reported that DFS is significantly better in the P-HIPEC group compared to the control group. For instance, a recent retrospective study using PSM analysis found that the median DFS in the P-HIPEC group was 49.9 months, compared to only 26.9 months in the control group, with a hazard ratio (HR) of 0.569 (p=0.013), a statistically significant difference (6). This indicates that P-HIPEC not only prevents metastasis at a specific site but also effectively prolongs the time from surgery to the first recurrence.

6.3 Overall survival

Whether P-HIPEC improves overall survival remains the central and unresolved controversy. The literature can be interpreted in two contrasting directions: (1) Evidence suggesting an OS benefit: Several meta-analyses—largely driven by Asian cohorts and older systemic-therapy eras—report improved short- and long-term OS metrics for patients receiving P-HIPEC compared with surgery alone. These findings form much of the rationale for continued investigation and selective adoption in high-risk settings (57, 58). (2) Evidence showing no clear OS benefit (or uncertainty): Other analyses, including more recent studies and those incorporating Western practice patterns or more rigorous designs, have not consistently demonstrated an OS advantage (59). This inconsistency suggests that the efficacy of P-HIPEC may be highly context-dependent. The controversy over OS benefit may have multiple complex underlying reasons: ① Intrinsic heterogeneity of studies: Different studies have huge variations in patient selection criteria, quality of surgery, HIPEC regimens, and perioperative systemic chemotherapy regimens (3). Many early studies (from 20–30 years ago) were conducted before the popularization of modern high-efficiency systemic chemotherapy regimens (such as the FLOT regimen). The baseline prognosis of the control groups in these studies was inherently poorer, which may have exaggerated the relative survival benefit of P-HIPEC. ② Geographical and population differences: The vast majority of evidence currently comes from Asian countries, especially Japan, China, and South Korea (3). Considering the potential differences between Eastern and Western populations in the etiology, molecular subtypes, biological behavior of gastric cancer, and response to treatment, it has always been questioned whether the results from Asian studies can be directly extrapolated to Western populations. This is a major reason for initiating large-scale European clinical trials like GASTRICHIP—to validate its efficacy in a Western population. ③ Shift in metastasis patterns and impact of subsequent treatments: As a local therapy, P-HIPEC’s main role is to eradicate micrometastases in the peritoneal cavity to effectively prevent peritoneal metastasis. However, this treatment is powerless against pre-existing micrometastases in distant organs (such as the liver, lungs, and distant lymph nodes). Therefore, P-HIPEC may only modify the metastatic pattern by reducing peritoneal dissemination, while patients may ultimately still succumb to distant metastases. Furthermore, with advances in cancer treatment, even if a patient relapses, effective second- and third-line systemic treatments (including new chemotherapy drugs, targeted therapies, and immunotherapies) may prolong the post-recurrence survival time, thereby diluting or masking the direct impact of P-HIPEC on initial OS. The table below summarizes the efficacy data from some key RCTs and meta-analyses to visually present the current evidence and points of controversy in this field (Table 2).

Table 2

Table 2. Efficacy results from key randomized controlled trials and meta-analyses of prophylactic HIPEC.

The value of P-HIPEC in controlling locoregional recurrence has been largely confirmed, but whether this can be translated into an ultimate survival benefit in the context of modern systemic therapy remains an unresolved core issue. Future large-scale, high-quality, and standardized RCTs are needed to provide a definitive answer.

7 Safety and complications of P-HIPEC

When considering the widespread application of a prophylactic treatment to a high-risk population, its safety is a consideration of equal importance to its efficacy. Historically, concerns about HIPEC potentially causing severe postoperative complications were a major obstacle to its widespread adoption. However, with the maturation of the technique and accumulation of experience, modern studies indicate that in skilled and experienced medical centers, the safety of P-HIPEC is acceptable.

7.1 Overall morbidity and mortality

Multiple studies and meta-analyses have shown that, compared to patients undergoing radical gastrectomy alone, the addition of P-HIPEC does not significantly increase the overall rate of severe postoperative complications (defined as Clavien-Dindo grade ≥ III) or surgery-related mortality. For example, an interim safety analysis of the ongoing PREVENT trial reported similar rates of serious adverse events (SAEs) in the HIPEC and control groups (35% and 30%, respectively), indicating that the addition of HIPEC did not introduce extra risk (50). This suggests that with strict patient selection and standardized procedures, P-HIPEC can be safely integrated into radical gastrectomy for gastric cancer.

7.2 Analysis of specific complications

Although the overall risk of complications is not significantly increased, P-HIPEC is associated with a higher incidence of certain specific toxic side effects related to chemotherapy drugs. ① Renal impairment: This is the most frequently reported and most significantly different specific complication of P-HIPEC. Multiple meta-analyses have consistently found that the incidence of postoperative renal insufficiency or acute kidney injury is significantly higher in the HIPEC group than in the control group, with ORs ranging from 2.44 to 3.94 (57, 58). This nephrotoxicity is mainly related to the intraperitoneal chemotherapy drugs used, especially drugs like cisplatin, which are metabolized by the kidneys and have known nephrotoxic effects (55). Therefore, strict preoperative assessment of renal function and active perioperative renal protective measures, such as hydration, are crucial for preventing such complications. ② Hematological toxicity: Neutropenia, thrombocytopenia, and anemia are common systemic toxicities caused by chemotherapy drugs entering the bloodstream. Although these complications occur after HIPEC, most meta-analyses have not found a statistically significant difference in the overall incidence of severe hematological toxicity between the HIPEC and control groups. This indicates that due to the peritoneal-plasma barrier, systemic absorption of intraperitoneally administered drugs is limited, and the resulting bone marrow suppression is mostly mild, manageable, and reversible. Studies have also pointed out that mitomycin C is an independent risk factor for severe hematological toxicity (62). ③ Gastrointestinal complications: (i) Anastomotic leak: This is a major concern for gastrointestinal surgeons. Early views suggested that hyperthermia and chemotherapy drugs might impair anastomotic healing. However, a large body of modern research data shows that because P-HIPEC does not involve extensive peritoneal stripping and cytoreductive surgery (CRS), the trauma to the intestine is relatively small, and thus the addition of HIPEC does not significantly increase the risk of anastomotic leak (63). This finding is important for promoting the application of P-HIPEC. (ii) Intestinal obstruction: The incidence of postoperative intestinal obstruction is usually not significantly different between the HIPEC and control groups (58). ④ Other complications: Some studies have reported a slight increase in pulmonary complications (such as pneumonia, pleural effusion) in the HIPEC group (one meta-analysis reported an OR of 6.03) (57), but this is not a consistent finding. As for complications like infection and fever, reports vary among studies, with some even suggesting that HIPEC may reduce the incidence of postoperative fever.

The safety of P-HIPEC is within an acceptable range. Its risks are mainly concentrated on foreseeable and manageable chemotherapy-related toxicities (especially nephrotoxicity), rather than unpredictable catastrophic surgical events. This requires the establishment of a multidisciplinary collaborative management model in clinical practice, with refined risk assessment and perioperative monitoring of patients.

8 Limitations and controversies of existing research

Although research on P-HIPEC in the treatment of gastric cancer has progressed, the current body of evidence still has numerous limitations and controversies. These issues are key to understanding the current clinical status and future direction of this technology.

8.1 Heterogeneity of evidence

This is the most fundamental and core challenge for P-HIPEC. The existing evidence, especially the primary studies on which meta-analyses rely, exhibits immense heterogeneity on multiple levels, which severely affects the reliability and generalizability of the conclusions. ① Varied study designs: There are significant differences among studies in patient inclusion criteria (e.g., stratification of CY1), choice of HIPEC drugs (MMC, cisplatin, oxaliplatin, etc.), technical protocols (temperature, duration, open/closed), surgical techniques (extent of D1/D2 lymph node dissection), and perioperative systemic chemotherapy regimens (3). The clinical significance of pooled effect sizes (such as OR or HR) obtained by simply mathematically combining the results of these disparately designed studies is necessarily questionable. ② Wide time span of studies: Many of the early key studies included in meta-analyses (such as the pioneering work by Koga et al.) were completed in the 1980s and 1990s (64). In that era, the standardization of gastric cancer surgery, the level of perioperative management, and the effectiveness of systemic chemotherapy were far inferior to today’s standards. In particular, highly effective perioperative chemotherapy regimens like FLOT were not available. Therefore, the prognostic baseline of the control groups in these studies (usually surgery alone) was much poorer than that of control groups under modern standards, which may have exaggerated the relative survival benefit of P-HIPEC.

8.2 Geographical limitation of evidence

The vast majority of high-quality evidence supporting the effectiveness of P-HIPEC comes from Asian countries, particularly China, Japan, and South Korea (3). This pronounced geographical bias raises a critical question: can the positive results observed in Asian populations be directly applied to Western populations? There may be differences between Eastern and Western populations in the epidemiological characteristics, main pathological types, molecular subtype profiles (e.g., proportions of EBV-associated, MSI-H, GS, CIN), and response to chemotherapy for gastric cancer. Therefore, using Asian experience as the basis for global guidelines is highly controversial in the absence of evidence from large, prospective RCTs in Western populations. This is also the core rationale driving European trials such as GASTRICHIP (3). In addition, differences in perioperative standards (extent of lymphadenectomy, perioperative chemotherapy uptake, and postoperative surveillance) may modify both baseline peritoneal recurrence risk and the absolute benefit achievable with P-HIPEC. Therefore, subgroup reporting by region/era and chemotherapy backbone (FLOT-era vs non-FLOT-era) should be prioritized, and conclusions derived from predominantly Eastern, pre-FLOT datasets should be framed as hypothesis-generating for contemporary Western practice.

8.3 Uncertainty of overall survival benefit

As mentioned above, the uncertainty surrounding overall survival benefits remains the central point of contention. Current studies have shifted from simply comparing the efficacy of HIPEC versus surgery alone to exploring whether prophylactic HIPEC can provide additional survival benefits when combined with modern, highly effective perioperative systemic chemotherapy regimens (such as FLOT). Many oncologists remain skeptical, arguing that the local control effects of prophylactic HIPEC may be overshadowed or weakened by the potent systemic effects of contemporary chemotherapy. Addressing this issue is a primary objective of clinical trials such as PREVENT.

8.4 Lack of technical standardization and long-term quality of life data

Currently, there is no globally recognized, standardized technical operating procedure for P-HIPEC. The optimal chemotherapy drugs, the most appropriate drug dosages, the ideal perfusion temperature and duration, and the pros and cons of open versus closed techniques are all without definitive conclusions. This “kaleidoscopic” clinical practice not only makes it difficult to compare study results but also poses significant obstacles to the dissemination and quality control of the technology. Furthermore, most studies focus on survival and recurrence rates as endpoints, while high-quality data on the long-term impact of P-HIPEC on patients’ Quality of Life (QoL) are relatively scarce. This is an important gap that future research needs to address.

From a patient-centered perspective, future trials should incorporate validated patient-reported outcome measures (PROMs) alongside oncologic endpoints to clarify the net clinical benefit of P-HIPEC. A pragmatic framework would include (i) early postoperative recovery domains (pain, bowel function, fatigue), (ii) longer-term gastrointestinal function and nutritional status, and (iii) global quality of life at standardized timepoints (e.g., baseline, 3, 6, 12 months, then annually). Reporting PROM completion rates and minimally important differences will be essential to interpret whether reduced peritoneal recurrence translates into meaningful survivorship benefit.

8.5 Practical standardization checklist

To improve interpretability and enable cross-study comparison, future reports of P-HIPEC in gastric cancer should, at minimum, specify:

1. Intended setting: prophylactic (P0/CY0) vs early-therapeutic (P0/CY1) vs macroscopic PM (therapeutic CRS/HIPEC).

2. Baseline systemic regimen: perioperative chemotherapy details (e.g., FLOT vs non-FLOT), number of cycles, and compliance.

3. Surgical quality: extent of gastrectomy, lymphadenectomy (D1/D2), R0/R1, and standardized postoperative care.

4. HIPEC technique: open vs closed, perfusion system, target intraperitoneal temperature (range and monitoring sites), flow rate, and duration with rationale.

5. Drug regimen: agent(s), dose calculation (mg/m² vs fixed), carrier solution, timing relative to anastomosis, and any nephroprotection strategy (for cisplatin).

6. Safety definitions: complication grading (e.g., Clavien–Dindo), toxicity criteria (e.g., CTCAE), and explicit definitions for renal/pulmonary events.

7. Outcomes: peritoneal recurrence, DFS, OS, and patient-reported outcomes (when available), with prespecified follow-up schedules.

9 Future prospects

Facing the current controversies and shortcomings, P-HIPEC is at a critical crossroads. Future development will focus on clarifying its precise role in the modern multidisciplinary comprehensive treatment of gastric cancer through high-quality clinical trial evidence, technological innovation, and precision strategies.

A series of rigorously designed, large-scale Phase III RCTs are currently underway. Their results are expected to answer many of the long-standing controversies in the field and may guide future clinical practice guidelines. ① GASTRICHIP (NCT01882933): This French-led, multicenter European RCT aims to directly validate the efficacy of Asian experience in a Western population. The trial randomly compares the efficacy of oxaliplatin HIPEC versus no HIPEC after D2 radical surgery, with 5-year OS as the primary endpoint. Its results will be persuasive (47). ② PREVENT (FLOT9, NCT04447352): This German-led RCT specifically targets patients with diffuse-type gastric cancer, who have the highest risk of peritoneal metastasis. In the context of the current optimal perioperative FLOT chemotherapy, it compares the efficacy of surgery combined with cisplatin HIPEC versus surgery alone, with DFS as the primary endpoint. The design of this trial addresses the question of the additional value of P-HIPEC on top of the most potent modern systemic therapy (50). ③ CHIMERA (NCT04597294): This Polish-led RCT has made a bold innovation in treatment timing. It explores a unique treatment model of neoadjuvant (preoperative) laparoscopic HIPEC combined with perioperative FLOT. The theoretical basis is that by using minimally invasive laparoscopic HIPEC to clear micrometastases in the peritoneal cavity before systemic chemotherapy and radical surgery, it may be possible to block the metastatic process earlier (51). The designs of these trials are distinctive, exploring the value of P-HIPEC from different dimensions such as population, chemotherapy background, drug selection, and treatment timing. Even if their final results differ, they will greatly enrich our understanding of P-HIPEC and promote its application from a “one-size-fits-all” approach to a more refined and individualized one.

New technologies are beginning to be applied in the clinic: ① New drug delivery systems: To overcome the disadvantage of uneven drug distribution in traditional closed-method HIPEC, new technologies are emerging. For example, “Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)” uses laparoscopy to aerosolize chemotherapy drugs, utilizing pressure to distribute them evenly over the peritoneal surface. Additionally, some new HIPEC systems generate turbulence by injecting CO2 gas into the peritoneal cavity to improve the distribution of liquid drugs (65). ② Integration of minimally invasive techniques: Combining the precise operation and minimally invasive advantages of “Robotic Surgery” with HIPEC is expected to further reduce surgical trauma and postoperative complications while ensuring oncological radicality, thereby accelerating patient recovery (66). ③ New drugs and combination therapies: Future research will no longer be limited to traditional chemotherapy drugs but may explore the application of novel drugs in HIPEC. Even more anticipated is the combination of HIPEC, an efficient local therapy, with systemic targeted therapies or immune checkpoint inhibitors to achieve a three-dimensional attack on both local micro-lesions and systemic micrometastases.

At the level of patient selection, the future goal is to achieve true individualized treatment, providing P-HIPEC to patients most likely to benefit while avoiding unnecessary treatment for non-responsive or high-risk patients. Future research will focus on finding reliable molecular biomarkers that can predict the risk of peritoneal metastasis and the efficacy of P-HIPEC. These biomarkers may be derived from tumor tissue (e.g., specific gene mutations, EMT-related gene expression profiles), peritoneal washings, or by detecting circulating tumor DNA (ctDNA) or specific molecules in exosomes (e.g., miRNAs) in peripheral blood through liquid biopsy techniques (67). This would allow for the precise identification of the best candidates for P-HIPEC preoperatively or intraoperatively.

P-HIPEC should not be regarded as an independent treatment modality but should be integrated into the entire perioperative multidisciplinary treatment system for gastric cancer. Future research needs to further optimize the integration model of P-HIPEC with modern systemic chemotherapy regimens (such as FLOT), including the optimal timing and sequence of administration, to maximize their synergistic anti-tumor effects and minimize the risk of overlapping toxicities (50, 51).

9.1 Clinical practice implications

1. Who may benefit most: Patients with non-metastatic but high-risk disease (e.g., serosal involvement pT4a, bulky nodal disease, diffuse/mixed Lauren type) undergoing high-quality curative gastrectomy with appropriate perioperative systemic therapy.

2. Where evidence is strongest: Consistent reduction in peritoneal recurrence and improvement in disease-free survival in many studies, predominantly from Asian cohorts and pre-FLOT eras.

3. Where evidence is uncertain: Overall survival benefit remains inconsistent across meta-analyses and populations; generalizability to Western/FLOT-era practice is not yet definitive.

4. Key risks to discuss: Drug-specific toxicities (notably cisplatin-associated acute kidney injury), perioperative morbidity, and the impact of protocol variability (drug/dose/temperature/duration, open vs closed technique).

5. MDT discussion points: Intended setting (P0/CY0 prophylaxis vs P0/CY1 early-therapeutic), expected absolute recurrence risk, institutional HIPEC expertise/quality assurance, patient comorbidity/renal reserve, and availability of clinical trials.

10 Conclusion

Prophylactic Hyperthermic Intraperitoneal Chemotherapy (P-HIPEC), as a local therapeutic strategy aimed at reducing the risk of peritoneal metastasis after radical gastrectomy for gastric cancer, has had its value in controlling locoregional disease well-affirmed. A substantial body of evidence clearly indicates that for high-risk gastric cancer patients, intraoperative P-HIPEC can significantly reduce the risk of postoperative peritoneal metastasis and effectively prolong disease-free survival, which forms its most solid basis for clinical application. However, despite its significant effect in preventing metastasis, whether it can ultimately translate into an improvement in overall survival remains the biggest controversy in the field. The conflict in existing evidence mainly stems from the high heterogeneity of studies, the geographical limitation of evidence (mainly from Asia), and the potential confounding effect of modern high-efficiency systemic chemotherapy regimens on overall patient survival. In terms of safety, P-HIPEC is considered acceptable in experienced multidisciplinary treatment centers. It does not significantly increase the risk of severe surgery-related complications such as anastomotic leak, but its specific renal toxicity is a definite risk that requires high vigilance and management. The future direction for P-HIPEC lies in precision, standardization, and integration. The focus of the academic community has shifted from “whether it is effective” to “for whom it is effective” and “how to be most effective.” The results of large-scale Phase III clinical trials, represented by GASTRICHIP and PREVENT, will provide higher-quality evidence for the application of P-HIPEC in the context of modern therapy. Exploring new biomarkers to achieve individualized screening and deeply integrating it with systemic treatments such as targeted and immune therapies will be the core driving force for advancing the field. The value of P-HIPEC is not as a universal standard treatment, but as an indispensable part of individualized, multidisciplinary comprehensive therapy, offering a significant opportunity for carefully selected high-risk patients to reduce their risk of metastasis and improve their prognosis.

Author contributions

ML: Writing – original draft. XS: Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by Kunshan First People’s Hospital-Key Project of the Medical and Health Science and Technology Innovation Special Program (Grant No. KSKFQYLWS2023002).

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Abbreviations

AGC, advanced gastric cancer; AKI, acute kidney injury; CY1, positive peritoneal cytology without macroscopic peritoneal metastasis; DFS, disease-free survival; FCCs, free cancer cells; HIPEC, hyperthermic intraperitoneal chemotherapy; MDT, multidisciplinary team; NIPEC, normothermic intraperitoneal chemotherapy; OS, overall survival; P-HIPEC, prophylactic hyperthermic intraperitoneal chemotherapy; PM, peritoneal metastasis.

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, and Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin. (2018) 68:394–424. doi: 10.3322/caac.21492

PubMed Abstract | Crossref Full Text | Google Scholar

2. Joshi SS and Badgwell BD. Current treatment and recent progress in gastric cancer. CA: A Cancer J Clin. (2021) 71:264–79. doi: 10.3322/caac.21657

PubMed Abstract | Crossref Full Text | Google Scholar

3. Brenkman HJF, Päeva M, van Hillegersberg R, Ruurda JP, and Haj Mohammad N. Prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) for gastric cancer-A systematic review. J Clin Med. (2019) 8:1685. doi: 10.3390/jcm8101685

PubMed Abstract | Crossref Full Text | Google Scholar

4. Li AY, Sedighim S, Tajik F, Khan AM, Radhakrishnan VK, Dayyani F, et al. Regional therapy approaches for gastric cancer with limited peritoneal disease. J Gastrointestinal Cancer. (2024) 55:534–48. doi: 10.1007/s12029-023-00994-5

PubMed Abstract | Crossref Full Text | Google Scholar

5. Khan H and Johnston FM. Current role for cytoreduction and HIPEC for gastric cancer with peritoneal disease. J Surg Oncol. (2022) 125:1176–82. doi: 10.1002/jso.26894

PubMed Abstract | Crossref Full Text | Google Scholar

6. Gong Z, Zhou L, He Y, Zhou J, and Deng Y. Huang Z. (2025). Efficacy analysis of prophylactic hyperthermic intraperitoneal chemotherapy in patients with locally advanced gastric cancer: a retrospective study. Front Oncol. 14:1503045. doi: 10.3389/fonc.2024.1503045

PubMed Abstract | Crossref Full Text | Google Scholar

7. Gill RS, Al-Adra DP, Nagendran J, Campbell S, Shi X, and Haase E. Treatment of gastric cancer with peritoneal carcinomatosis by cytoreductive surgery and HIPEC: a systematic review of survival, mortality, and morbidity. J Surg Oncol. (2011) 104:692–8. doi: 10.1002/jso.22017

PubMed Abstract | Crossref Full Text | Google Scholar

8. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. (1889) 133:571–3. doi: 10.1016/S0140-6736(00)49915-0

Crossref Full Text | Google Scholar

9. Huang L, Wu R-L, and Xu A-M. Epithelial-mesenchymal transition in gastric cancer. Am J Trans Res. (2015) 7:2141–58.

Google Scholar

10. Peng Z, Wang C-X, Fang E-H, Wang G-B, and Tong Q. Role of epithelial-mesenchymal transition in gastric cancer initiation and progression. World J Gastroenterol. (2014) 20:5403–10. doi: 10.3748/wjg.v20.i18.5403

PubMed Abstract | Crossref Full Text | Google Scholar

11. Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, et al. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol. (2002) 161:1881–91. doi: 10.1016/S0002-9440(10)64464-1

PubMed Abstract | Crossref Full Text | Google Scholar

12. Chen K, Chen J, Jin X, Huang Y, Su Q, and Chen L. Exosome-mediated peritoneal dissemination in gastric cancer and its clinical applications. Biomed Rep. (2018) 8:503–9. doi: 10.3892/br.2018.1088

PubMed Abstract | Crossref Full Text | Google Scholar

13. Sun F, Feng M, and Guan W. Mechanisms of peritoneal dissemination in gastric cancer. Oncol Lett. (2017) 14:6991–8. doi: 10.3892/ol.2017.7149

PubMed Abstract | Crossref Full Text | Google Scholar

14. Saito H, Fushida S, Harada S, Miyashita T, Oyama K, Yamaguchi T, et al. Importance of human peritoneal mesothelial cells in the progression, fibrosis, and control of gastric cancer: inhibition of growth and fibrosis by tranilast. Gastric Cancer. (2018) 21:55–67. doi: 10.1007/s10120-017-0726-5

PubMed Abstract | Crossref Full Text | Google Scholar

15. Takatsuki H, Komatsu S, Sano R, Takada Y, and Tsuji T. Adhesion of gastric carcinoma cells to peritoneum mediated by alpha3beta1 integrin (VLA-3). Cancer Res. (2004) 64:6065–70. doi: 10.1158/0008-5472.CAN-04-0321

PubMed Abstract | Crossref Full Text | Google Scholar

16. Nishimura S, Chung YS, Yashiro M, Inoue T, and Sowa M. CD44H plays an important role in peritoneal dissemination of scirrhous gastric cancer cells. Japanese J Cancer Res. (1996) 87:1235–44. doi: 10.1111/j.1349-7006.1996.tb03138.x

PubMed Abstract | Crossref Full Text | Google Scholar

17. Mukai S, Oue N, Oshima T, Imai T, Sekino Y, Honma R, et al. Overexpression of PCDHB9 promotes peritoneal metastasis and correlates with poor prognosis in patients with gastric cancer. J Pathol. (2017) 243:100–10. doi: 10.1002/path.4931

PubMed Abstract | Crossref Full Text | Google Scholar

18. Kanda M and Kodera Y. Molecular mechanisms of peritoneal dissemination in gastric cancer. World J Gastroenterol. (2016) 22:6829–40. doi: 10.3748/wjg.v22.i30.6829

PubMed Abstract | Crossref Full Text | Google Scholar

19. Hegyi G, Szigeti GP, and Szász A. Hyperthermia versus oncothermia: Cellular effects in complementary cancer therapy. Evidence-Based Complementary and. Altern Med. (2013) 2013:672873. doi: 10.1155/2013/672873

PubMed Abstract | Crossref Full Text | Google Scholar

20. Amin M, Anvari M, and Rezaei M. Hyperthermia and temperature-sensitive nanomaterials for cancer therapy. Pharmaceutics. (2020) 12:1007. doi: 10.3390/pharmaceutics12111007

PubMed Abstract | Crossref Full Text | Google Scholar

21. Hildebrandt B, Wust P, Ahlers O, Dieing A, Sreenivasa G, Kerner T, et al. The cellular and molecular basis of hyperthermia. Crit Rev oncology/hematology. (2002) 43:33–56. doi: 10.1016/s1040-8428(01)00179-2

PubMed Abstract | Crossref Full Text | Google Scholar

22. Solanki SL, Mukherjee S, Agarwal V, Thota RS, Balakrishnan K, Shah SB, et al. Society of Onco-Anaesthesia and Perioperative Care consensus guidelines for perioperative management of patients for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Indian J Anaesth. (2019) 63:972–87. doi: 10.4103/ija.IJA_765_19

PubMed Abstract | Crossref Full Text | Google Scholar

23. Bhandoria G, Solanki SL, Bhavsar M, Balakrishnan K, Bapuji C, Bhorkar N, et al. Enhanced recovery after surgery (ERAS) in cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC): a cross-sectional survey. Pleura Peritoneum. (2021) 6:99–111. doi: 10.1515/pp-2021-0117

PubMed Abstract | Crossref Full Text | Google Scholar

24. Glehen O, Mohamed F, and Gilly FN. Peritoneal carcinomatosis from digestive tract cancer: new management by cytoreductive surgery and intraperitoneal chemohyperthermia. Lancet Oncol. (2004) 5:219–28. doi: 10.1016/S1470-2045(04)01425-1

PubMed Abstract | Crossref Full Text | Google Scholar

25. Jurkovicova D, Neophytou CM, Gašparović AČ., and Gonçalves AC. DNA damage response in cancer therapy and resistance: challenges and opportunities. Int J Mol Sci. (2022) 23:14672. doi: 10.3390/ijms232314672

PubMed Abstract | Crossref Full Text | Google Scholar

26. Ihara M, Takeshita S, Okaichi K, Okumura Y, and Ohnishi T. Heat exposure enhances radiosensitivity by depressing DNA-PK kinase activity during double strand break repair. Int J Hyperthermia. (2014) 30:102–9. doi: 10.3109/02656736.2014.887793

PubMed Abstract | Crossref Full Text | Google Scholar

27. Krawczyk PM, Eppink B, Essers J, Stap J, Rodermond H, Odijk H, et al. Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition. Proc Natl Acad Sci U S A. (2011) 108:9851–6. doi: 10.1073/pnas.1101053108

PubMed Abstract | Crossref Full Text | Google Scholar

28. Osawa T, Davies D, and Hartley J. Mechanism of cell death resulting from DNA interstrand cross-linking in mammalian cells. Cell Death Dis. (2011) 2:e187. doi: 10.1038/cddis.2011.70

PubMed Abstract | Crossref Full Text | Google Scholar

29. Schaaf L, Schwab M, Ulmer C, Heine S, Mürdter TE, Schmid JO, et al. Hyperthermia synergizes with chemotherapy by inhibiting PARP1-dependent DNA replication arrest. Cancer Res. (2016) 76:2868–75. doi: 10.1158/0008-5472.CAN-15-2908

PubMed Abstract | Crossref Full Text | Google Scholar

30. Jacquet P and Sugarbaker PH. Peritoneal-plasma barrier. Cancer Treat Res. (1996) 82:53–63. doi: 10.1007/978-1-4613-1247-5_4

PubMed Abstract | Crossref Full Text | Google Scholar

31. Dedrick RL and Flessner MF. Pharmacokinetic problems in peritoneal drug administration: tissue penetration and surface exposure. J Natl Cancer Institute. (1997) 89:480–7. doi: 10.1093/jnci/89.7.480

PubMed Abstract | Crossref Full Text | Google Scholar

32. de Bree E, Michelakis D, Stamatiou D, Romanos J, and Zoras O. Pharmacological principles of intraperitoneal and bidirectional chemotherapy. Pleura Peritoneum. (2017) 2:47–62. doi: 10.1515/pp-2017-0010

PubMed Abstract | Crossref Full Text | Google Scholar

33. Lemoine L, Sugarbaker P, and Van der Speeten K. Drugs, doses, and durations of intraperitoneal chemotherapy: standardising HIPEC and EPIC for colorectal, appendiceal, gastric, ovarian peritoneal surface Malignancies and peritoneal mesothelioma. Int J Hyperthermia. (2017) 33:582–92. doi: 10.1080/02656736.2017.1291999

PubMed Abstract | Crossref Full Text | Google Scholar

34. Srivastava P. Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol. (2002) 2:185–94. doi: 10.4143/crt.201

Crossref Full Text | Google Scholar

35. Kwon OK, Chung HY, and Yu W. Early postoperative intraperitoneal chemotherapy for macroscopically serosa-invading gastric cancer patients. Cancer Res Treat. (2014) 46:270–9. doi: 10.4143/crt.2014.46.3.270

PubMed Abstract | Crossref Full Text | Google Scholar

36. Kang Y, Wang F, Zu H, Yang Z, and Xue Y. A new subclassification of pT4 gastric cancers according to the width of serosal invasion. PloS One. (2013) 8:e68042. doi: 10.1371/journal.pone.0068042

PubMed Abstract | Crossref Full Text | Google Scholar

37. Kwon SJ. Evaluation of the 7th UICC TNM staging system of gastric cancer. J Gastric Cancer. (2011) 11:78–85. doi: 10.5230/jgc.2011.11.2.78

PubMed Abstract | Crossref Full Text | Google Scholar

38. Bentrem D, Wilton A, Mazumdar M, Brennan M, and Coit D. The value of peritoneal cytology as a preoperative predictor in patients with gastric carcinoma undergoing a curative resection. Ann Surg Oncol. (2005) 12:347–53. doi: 10.1245/ASO.2005.03.065

PubMed Abstract | Crossref Full Text | Google Scholar

39. Riihimäki M, Hemminki A, Sundquist K, Sundquist J, and Hemminki K. Metastatic spread in patients with gastric cancer. Oncotarget. (2016) 7:52307–16. doi: 10.18632/oncotarget.10740

PubMed Abstract | Crossref Full Text | Google Scholar

40. Thomassen I, van Gestel YR, van Ramshorst B, Luyer MD, Bosscha K, Nienhuijs SW, et al. Peritoneal carcinomatosis of gastric origin: a population-based study on incidence, survival and risk factors. Int J Cancer. (2014) 134:622–8. doi: 10.1002/ijc.28373

PubMed Abstract | Crossref Full Text | Google Scholar

41. Expert Cooperative Group for the Clinical Application of Hyperthermic Intraperitoneal Chemotherapy. Expert consensus on the clinical application of hyperthermic intraperitoneal chemotherapy technology (2016 edition). Chin J Gastrointestinal Surg. (2016) 19:121–5. doi: 10.3760/cma.j.issn.1671-0274.2016.02.001

Crossref Full Text | Google Scholar

42. Chinese Society of Clinical Oncology (CSCO) Peritoneal Tumor Committee and Guangdong Anti-Cancer Association Hyperthermia Committee. Expert consensus on the clinical application of hyperthermic intraperitoneal chemotherapy technology (2019 edition). Natl Med J China. (2020) 100:89–96. doi: 10.3760/cma.j.issn.0376-2491.2020.02.003

Crossref Full Text | Google Scholar

43. Kusamura S, Bhatt A, van der Speeten K, Kepenekian V, Hübner M, Eveno C, et al. Review of 2022 PSOGI/RENAPE consensus on HIPEC. J Surg Oncol. (2024) 130:1290–8. doi: 10.1002/jso.27885

PubMed Abstract | Crossref Full Text | Google Scholar

44. Valletti M, Eshmuminov D, Gnecco N, Gutschow CA, Schneider PM, and Lehmann K. Gastric cancer with positive peritoneal cytology: Survival benefit after induction chemotherapy and conversion to negative peritoneal cytology. World J Surg Oncol. (2021) 19:181. doi: 10.1186/s12957-021-02351-x

PubMed Abstract | Crossref Full Text | Google Scholar

45. Koga S, Hamazoe R, Maeta M, Shimizu N, Murakami A, and Wakatsuki T. Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous hyperthermic peritoneal perfusion with mitomycin C. Cancer. (1988) 61:232–7. doi: 10.1002/1097-0142(19880115)61:2<232::AID-CNCR2820610205>3.0.CO;2-U

Crossref Full Text | Google Scholar

46. Wiedemann GJ, Robins HI, Gutsche S, Mentzel M, Deeken M, Katschinski DM, et al. Ifosfamide, carboplatin and etoposide (ICE) combined with 41.8 degrees C whole body hyperthermia in patients with refractory sarcoma. Eur J Cancer. (1996) 32A:888–92. doi: 10.1016/0959-8049(95)00622-2

PubMed Abstract | Crossref Full Text | Google Scholar

47. Glehen O, Passot G, Villeneuve L, Vaudoyer D, Bin-Dorel S, Boschetti G, et al. GASTRICHIP: D2 resection and hyperthermic intraperitoneal chemotherapy in locally advanced gastric carcinoma: a randomized and multicenter phase III study. BMC Cancer. (2014) 14:183. doi: 10.1186/1471-2407-14-183

PubMed Abstract | Crossref Full Text | Google Scholar

48. Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, et al. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. J Clin Oncol. (2018) 36:1922–9. doi: 10.1200/JCO.2018.77.8613

PubMed Abstract | Crossref Full Text | Google Scholar

49. Yonemura Y, Canbay E, Li Y, Coccolini F, Glehen O, Sugarbaker PH, et al. A comprehensive treatment for peritoneal metastases from gastric cancer with curative intent. Eur J Surg Oncol. (2016) 42:1123–31. doi: 10.1016/j.ejso.2016.03.016

PubMed Abstract | Crossref Full Text | Google Scholar

50. Götze TO, Piso P, Lorenzen S, Bankstahl US, Pauligk C, Elshafei M, et al. Preventive HIPEC in combination with perioperative FLOT versus FLOT alone for resectable diffuse type gastric and gastroesophageal junction type II/III adenocarcinoma - the phase III “PREVENT”- (FLOT9) trial of the AIO/CAOGI/ACO. BMC Cancer. (2021) 21:1158. doi: 10.1186/s12885-021-08872-8

PubMed Abstract | Crossref Full Text | Google Scholar

51. ClinicalTrials.gov. A randomized, multicenter clinical trial comparing the combination of perioperative FLOT4 chemotherapy and preoperative laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) plus gastrectomy to perioperative FLOT4 chemotherapy and gastrectomy alone in patients with advanced gastric cancer at high risk of peritoneal recurrence. (2024). Identifier: NCT04597294.

Google Scholar

52. Sun J, Song Y, Wang Z, Gao P, Chen X, Xu Y, et al. Benefits of hyperthermic intraperitoneal chemotherapy for patients with serosal invasion in gastric cancer: a meta-analysis of the randomized controlled trials. BMC Cancer. (2012) 12:526. doi: 10.1186/1471-2407-12-526

PubMed Abstract | Crossref Full Text | Google Scholar

53. Huang JY, Xu YY, Sun Z, Zhu Z, Song YX, Guo PT, et al. Comparison different methods of intraoperative and intraperitoneal chemotherapy for patients with gastric cancer: a meta-analysis. Asian Pac J Cancer Prev. (2012) 13:4379–85. doi: 10.7314/apjcp.2012.13.9.4379

PubMed Abstract | Crossref Full Text | Google Scholar

54. Yang XJ, Huang CQ, Suo T, Mei LJ, Yang GL, Cheng FL, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol. (2011) 18:1575–81. doi: 10.1245/s10434-011-1631-5

PubMed Abstract | Crossref Full Text | Google Scholar

55. Mi DH, Li Z, Yang KH, Cao N, Lethaby A, Tian JH, et al. Surgery combined with intraoperative hyperthermic intraperitoneal chemotherapy (IHIC) for gastric cancer: a systematic review and meta-analysis of randomised controlled trials. Int J Hyperthermia. (2013) 29:156–67. doi: 10.3109/02656736.2013.768359

PubMed Abstract | Crossref Full Text | Google Scholar

56. Yan TD, Black D, Sugarbaker PH, Zhu J, Yonemura Y, Petrou G, et al. A systematic review and meta-analysis of the randomized controlled trials on adjuvant intraperitoneal chemotherapy for resectable gastric cancer. Ann Surg Oncol. (2007) 14:2702–13. doi: 10.1245/s10434-007-9487-4

PubMed Abstract | Crossref Full Text | Google Scholar

57. Zhuang X, He Y, and Ma W. Prophylactic hyperthermic intraperitoneal chemotherapy may benefit the long-term survival of patients after radical gastric cancer surgery. Sci Rep. (2022) 12:2583. doi: 10.1038/s41598-022-06417-y

PubMed Abstract | Crossref Full Text | Google Scholar

58. Patel M, Arora A, Mukherjee D, and Mukherjee S. Effect of hyperthermic intraperitoneal chemotherapy on survival and recurrence rates in advanced gastric cancer: a systematic review and meta-analysis. Int J Surg. (2023) 109:2435–50. doi: 10.1097/JS9.0000000000000457

PubMed Abstract | Crossref Full Text | Google Scholar

59. Xie TY, Wu D, Li S, Qiu ZY, Song QY, Guan D, et al. Role of prophylactic hyperthermic intraperitoneal chemotherapy in patients with locally advanced gastric cancer. World J Gastrointest Oncol. (2020) 12:782–90. doi: 10.4251/wjgo.v12.i7.782

PubMed Abstract | Crossref Full Text | Google Scholar

60. Chen Y, Zhou Y, Xiong H, Wei Z, Zhang D, and Li S. Exploring the efficacy of hyperthermic intraperitoneal perfusion chemotherapy in gastric cancer: meta-analysis based on randomized controlled trials. Ann Surg Oncol. (2025) 32:240–8. doi: 10.1245/s10434-024-16298-2

PubMed Abstract | Crossref Full Text | Google Scholar

61. Jian C, Mou H, Zhang Y, Fan Q, and Ou Y. Survival and complications of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in patients with intra-abdominal Malignancies: A meta-analysis of randomized controlled trials. Front Pharmacol. (2023) 14:1094834. doi: 10.3389/fphar.2023.1094834

PubMed Abstract | Crossref Full Text | Google Scholar

62. Karimi M, Shirsalimi N, and Sedighi E. Challenges following CRS and HIPEC surgery in cancer patients with peritoneal metastasis: a comprehensive review of clinical outcomes. Front Surg. (2024) 11:1498529. doi: 10.3389/fsurg.2024.1498529

PubMed Abstract | Crossref Full Text | Google Scholar

63. Dominic JL, Kannan A, Tara A, Hakim Mohammed AR, Win M, Khorochkov A, et al. Prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) for the prevention and control of peritoneal metastasis in patients with gastrointestinal Malignancies: a systematic review of randomized controlled trials. EXCLI J. (2021) 20:1328–45. doi: 10.17179/excli2021-4108

PubMed Abstract | Crossref Full Text | Google Scholar

64. Kunte AR, Parray AM, Bhandare MS, and Solanki SL. Role of prophylactic HIPEC in non-metastatic, serosa-invasive gastric cancer: a literature review. Pleura Peritoneum. (2022) 7:103–15. doi: 10.1515/pp-2022-0104

PubMed Abstract | Crossref Full Text | Google Scholar

65. Di Giorgio A, Gerardi C, Abatini C, Melotti G, Bonavina L, Torri V, et al. Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery for gastric carcinoma at high risk of peritoneal carcinomatosis: short and long-term outcomes (GOETH STUDY)-a collaborative randomized controlled trial by ACOI, FONDAZIONE AIOM, SIC, SICE, and SICO. Trials. (2022) 23:969. doi: 10.1186/s13063-022-06880-y

PubMed Abstract | Crossref Full Text | Google Scholar

66. Ortega J, Orfanelli T, Levine E, and Konstantinidis IT. The robotic future of minimally invasive cytoreduction and hyperthermic intraperitoneal chemotherapy for peritoneal surface Malignancies. Chin Clin Oncol. (2023) 12:16. doi: 10.21037/cco-22-118

PubMed Abstract | Crossref Full Text | Google Scholar

67. Sun Z, Yang S, Zhou Q, Wang G, Song J, Li Z, et al. Emerging role of exosome-derived long non-coding RNAs in tumor microenvironment. Mol Cancer. (2018) 17:82. doi: 10.1186/s12943-018-0831-z

PubMed Abstract | Crossref Full Text | Google Scholar