Prophylactic hyperthermic intraperitoneal chemotherapy for gastric cancer: Current evidence, persistent uncertainties, and future perspectives

Abstract

Peritoneal metastases remain a major cause of treatment failure and poor prognosis in locally advanced gastric cancer, with a substantial proportion of patients harboring occult peritoneal metastases undetectable by imaging and many developing peritoneal recurrences as the first site of relapse after curative resection. While cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has gained traction for established peritoneal metastases, the clinical role of prophylactic HIPEC in gastric cancer without established peritoneal metastases remains unsettled. Meta-analyses and recent trials offer conflicting evidence: Some demonstrate meaningful reductions in peritoneal recurrence alongside improved overall and disease-free survival, whereas others show no discernible survival advantage or recurrence benefit. Although prophylactic HIPEC for gastric cancer appears generally safe and does not materially increase overall severe complication rates, it carries distinct risks that demand vigilant monitoring, including renal impairment, pulmonary dysfunction, and hematologic toxicity. Patient selection is paramount, with serosal invasion, nodal burden, diffuse type histology, and positive peritoneal cytology emerging as key determinants of potential benefit in this gastric cancer population. Persistent heterogeneity in treatment protocols, spanning drug selection, timing, and perfusion parameters, further clouds consensus regarding the optimal application of prophylactic HIPEC in gastric cancer. Emerging technologies and synergistic combinations with novel systemic therapies provide new directions for optimizing the therapeutic effect of prophylactic HIPEC. This opinion review summarizes the current clinical evidence, existing controversies, and future research perspectives of prophylactic HIPEC in locally advanced gastric cancer, aiming to provide valuable insights for clinical practice and further research.

Key Words: Gastric cancer; Prophylactic hyperthermic intraperitoneal chemotherapy; Peritoneal recurrence; Patient selection; Safety; Prognosis

Core Tip: Prophylactic hyperthermic intraperitoneal chemotherapy aims to eliminate occult free cancer cells following curative gastrectomy for locally advanced gastric cancer, thereby reducing peritoneal recurrence. While meta-analyses suggest potential improvements in survival and peritoneal control, conflicting trial results and persistent protocol heterogeneity preclude definitive recommendations. Although prophylactic hyperthermic intraperitoneal chemotherapy appears generally safe, it carries distinct risks that demand vigilant monitoring, including renal impairment, pulmonary dysfunction, and hematologic toxicity. Optimal patient selection, guided by serosal invasion, nodal burden, diffuse histology, and positive peritoneal cytology, remains paramount. Ongoing trials and novel combinatorial strategies may help clarify its therapeutic role.

INTRODUCTION

Peritoneal metastases is one of the most common forms of distant spread in locally advanced gastric cancer (LAGC) and a major cause of treatment failure and mortality. In LAGC, the prevalence of occult peritoneal metastases undetectable by imaging is up to 52%[1]. Moreover, 40%-60% of LAGC patients after curative resection developing peritoneal metastases as the first site of recurrence[2]. Nearly 20% of patients with LAGC still develop peritoneal metastases after curative surgery and systemic chemotherapy[3]. Once overt peritoneal metastasis develops, median survival time drops to 3-6 months, and the 5-year survival rate is less than 2%[4]. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been developed as a promising treatment strategy for LAGC patients with peritoneal metastases[5]. CRS removes all visible tumors and the primary cancer and HIPEC uses heated drugs to kill any remaining microscopic cancer cells.

Prophylactic HIPEC is one of the distinct clinical applications of intraperitoneal chemotherapy, alongside therapeutic HIPEC for established peritoneal metastases[6]. It is defined as intraperitoneal chemotherapy administered after curative gastrectomy in patients without established peritoneal metastases, aiming to eradicate occult free cancer cells and reduce the risk of peritoneal recurrence[7,8]. In 1988, Koga et al[9] provided the first clinical evidence for the feasibility and safety of continuous hyperthermic peritoneal perfusion with mitomycin C in preventing peritoneal recurrence after gastric cancer surgery, establishing an early foundation for prophylactic HIPEC. In a randomized controlled study, Hamazoe et al[10] confirmed that prophylactic HIPEC significantly reduced peritoneal recurrence and improved overall survival (OS) in gastric cancer patients. Fujimoto et al[11] further showed that intraperitoneal hyperthermic chemoperfusion could lower peritoneal recurrence rates and extend survival in advanced gastric cancer, adding real-world support to the emerging approach.

Latest meta-analyses of randomized and non-randomized studies have also reported favorable survival and recurrence outcomes with therapeutic HIPEC for gastric cancer with peritoneal metastases[8,12]. However, while therapeutic HIPEC has become a standard option for gastric cancer with overt peritoneal metastases[13,14], whether to perform prophylactic HIPEC in LAGC patients without evidence of peritoneal metastases remains controversial. Based on this background, we discuss the landscape of conflicting survival evidence, the generally favorable safety profile, the pivotal role of patient selection, the pressing need for treatment protocol standardization, and the emerging frontier of technologies and synergistic combinations beyond conventional HIPEC (Figure 1).

Figure 1 Prophylactic hyperthermic intraperitoneal chemotherapy in gastric cancer: A schematic overview. This figure summarizes the core components of prophylactic hyperthermic intraperitoneal chemotherapy in gastric cancer, including conflicting survival evidence, favorable safety profile, patient selection, treatment protocol standardization, and emerging technologies and synergistic combinations beyond conventional hyperthermic intraperitoneal chemotherapy. HIPEC: Hyperthermic intraperitoneal chemotherapy.

SURVIVAL BENEFIT: A LANDSCAPE OF CONFLICTING EVIDENCE

Multiple systematic reviews and meta-analyses in the last two years have consistently indicated that prophylactic HIPEC reduces peritoneal recurrence and improves survival outcomes in patients with LAGC (Table 1). Based on a review by Diamantis et al[8] encompassing 14 randomized controlled trials (1383 patients) and 16 non-randomized studies (1647 patients), prophylactic HIPEC demonstrates efficacy in improving both OS and disease-free survival (DFS) among patients with gastric cancer at high risk of peritoneal metastases. Nevertheless, the findings of these meta-analyses warrant further confirmation, given the considerable heterogeneity across studies and the suboptimal quality of the included trials. According to a systematic review by D’Acapito et al[15] of 13 prospective studies (eight therapeutic HIPEC, five prophylactic HIPEC), CRS-HIPEC achieved a median OS of 11-24.9 months vs 4-6 months with systemic therapy alone in therapeutic settings, while prophylactic HIPEC significantly reduced peritoneal recurrence, particularly in T4 tumors. According to a recent systematic review and meta-analysis by Zhang et al[16] of nine randomized controlled trials (1021 patients), HIPEC significantly reduces peritoneal metastasis [odds ratio (OR) = 0.24] and distant metastasis (OR = 0.45), prolongs 3-year OS (OR = 1.48) and DFS (OR = 1.92).

Table 1 Summary of recent systematic reviews and meta-analyses on prophylactic hyperthermic intraperitoneal chemotherapy in gastric cancer.

Ref.	Study type	Inclusion period	Included studies	Sample size (HIPEC/control)
Stefano et al[7], 2024	Systematic review and meta-analysis	1988-2022	16 RCTs (14 prophylactic + 2 therapeutic)	1641
Diamantis et al[8], 2025	Systematic Review	1988-2021	14 RCTs + 16 nonRCTs (all prophylactic)	RCTs: 1383 (627/756); non-RCTs: 1647 (609/1038)
Chen et al[12], 2025	Meta-analysis	2004-2022	12 RCTs (5 therapeutic + 7 prophylactic)	1181 (540/641)
D’Acapito et al[15], 2025	Systematic Review	2010-2024	13 prospective studies (8 therapeutic + 5 prophylactic)	985 [prophylactic: 644 (331/313)]
Zhang et al[16], 2026	Systematic review and meta-analysis	Until April 2025	9 RCTs (all prophylactic)	1021 (487/534)

HIPEC: Hyperthermic intraperitoneal chemotherapy; RCTs: Randomized controlled trials.

Recent evidence from both retrospective and prospective studies remains conflicting as to whether prophylactic HIPEC confers a survival advantage in LAGC. In a cohort of 225 patients with non-metastatic pT4 gastric cancer, Lian et al[17] demonstrated that prophylactic HIPEC reduced peritoneal recurrence rates (20.00% vs 38.83%, P = 0.009) and improved 3-year DFS (69.0% vs 50.0%, P = 0.037) compared with adjuvant chemotherapy alone, with comparable safety profiles. However, a phase II trial by Fan et al[18] (n = 50) found that adding cisplatin-based prophylactic HIPEC to radical gastrectomy and adjuvant chemotherapy failed to significantly improve 5-year OS (75.8% vs 88.2%, P = 0.300) and 5-year recurrence-free survival (75.8% vs 88.2%, P = 0.344) and decrease peritoneal recurrence rate (9.09% vs 11.76%, P = 0.765). Multivariate analysis confirmed that only pT stage was significantly associated with prognosis, but HIPEC was not an independent prognostic factor.

Collectively, these findings challenge the routine use of prophylactic HIPEC and highlight considerable variability in its current clinical application. This variability may originate from differences in how responsive patient subsets are selected, temporal bias and methodological confounders[19]. Currently, several ongoing well-designed, large-scale phase III randomized clinical trials are expected to provide conclusive evidence that may help settle the current controversies (Table 2).

Table 2 Ongoing phase III randomized controlled trials of prophylactic hyperthermic intraperitoneal chemotherapy for gastric cancer.

Trial name	Registration number	Eligible population	Intervention	Primary endpoint	Estimated completion	Region
D2 resection and HIPEC in locally advanced gastric carcinoma (GASTRICHIP)	NCT01882933	Locally advanced gastric cancer (T3/T4/N+ or positive peritoneal cytology)	D2 gastrectomy ± HIPEC (oxaliplatin)	OS	May 2026	France
Efficacy of HIPEC in the treatment of locally advanced gastric cancer after radical gastrectomy with D2 (EHTLAGCRGD2)	NCT02356276	Locally advanced gastric cancer (cT3/T4, Nx, M0)	Surgery + systemic chemotherapy ± repeated paclitaxel HIPEC	5-year OS	January 2022	China
Prophylactic surgery plus HIPEC with CO2 in patients affected by gastric carcinoma (GOETH study)	NCT03917173	High-risk gastric cancer (T3/T4/N+ or positive peritoneal cytology)	Radical gastrectomy ± HIPEC with CO2 (mitomycin C + cisplatin)	DFS	June 2025	Italy
HIPEC + FLOT vs FLOT alone in patients with gastric cancer and GEJ (PREVENT)	NCT04447352	Resectable locally advanced gastric/gastroesophageal junction cancer (≥ cT3 any N)	Perioperative FLOT ± prophylactic HIPEC	PFS/DFS	May 2027	Germany
Laparoscopic gastrectomy with D2 lymphadenectomy combined with HIPEC or not	NCT05871099	Patients with locally advanced gastric cancer undergoing laparoscopic D2 radical gastrectomy	Laparoscopic (robotic) D2 surgery + HIPEC (2 times) + systemic ± prophylactic HIPEC	5-year RFS	December 2030	China

HIPEC: Hyperthermic intraperitoneal chemotherapy; OS: Overall survival; DFS: Disease-free survival; PFS: Progression-free survival; RFS: Recurrence-free survival; GEJ: Gastroesophageal junction.

SAFETY PROFILE: GENERALLY FAVORABLE WITH CURRENT EVIDENCE

While prophylactic HIPEC is technically safe and does not significantly elevate the aggregate risk of severe postoperative morbidity or procedure-related mortality, as corroborated by multiple systematic reviews and meta-analyses, it is nonetheless associated with prolonged recovery and the introduction of distinct chemotherapy-related toxicities[7,19-21]. According to a propensity score matching analysis focusing on elderly patients with LAGC, the addition of prophylactic HIPEC to radical surgery did not result in a significant increase in postoperative complications or duration of hospitalization compared to surgery alone[22].

However, although the overall risk of complications is not significantly elevated, HIPEC is associated with a higher incidence of certain specific toxic side effects[23]. Renal injury is a frequent complication in patients undergoing CRS/HIPEC, a phenomenon due to a multifactorial interplay of increased intra-abdominal pressure, heat stress, and drug toxicity[24]. Notably, renal impairment stands as the most consistently documented risk directly attributable to HIPEC, a phenomenon largely driven by the systemic absorption of nephrotoxic agents like cisplatin[25]. A meta-analysis of six randomized controlled trials suggests that HIPEC is associated with an elevated risk of postoperative renal dysfunction (OR = 3.94)[26]. Pulmonary complications following prophylactic HIPEC appear to arise from a multifactorial interplay, wherein the systemic inflammatory response of gastrectomy is compounded by the procedure-specific insults of hyperthermia and chemotherapy-induced diaphragmatic irritation. A meta-analysis of 22 studies (including 12 randomized controlled trials, encompassing a total of 2097 patients)[27] indicated that prophylactic HIPEC may be associated with a high risk of renal dysfunction (OR = 2.44) and pulmonary dysfunction (OR = 6.03).

Hematologic toxicity associated with prophylactic HIPEC is largely attributable to the systemic absorption of intraperitoneal chemotherapeutic agents. A retrospective study of T4 gastric cancer reported that postoperative platelet counts were significantly lower in patients receiving lobaplatin-based prophylactic HIPEC compared with controls (P < 0.05), although no increase in hemorrhagic events was observed[28]. In a large-sample analysis of 449 patients with gastrointestinal malignancies, the incidence of thrombocytopenia was higher in the HIPEC group than in the surgery-alone group (7.7% vs 2.9%, P = 0.046), and the rate of postoperative hemoglobin decline was markedly elevated in the HIPEC cohort relative to surgical controls (49.0% vs 25.7%, P < 0.01)[29]. These findings underscore the necessity of routine hematologic surveillance during the course of prophylactic HIPEC.

In contrast, gastrointestinal sequelae such as anastomotic leakage and bowel obstruction, while intuitively concerning given the combination of hyperthermia and high-dose chemotherapy on healing tissues, do not appear to be statistically increased in the prophylactic setting[30]. Consequently, while the addition of HIPEC does not appear to broadly escalate the surgical complication burden, the management paradigm for these patients must incorporate proactive strategies for renal preservation and respiratory surveillance.

PATIENT SELECTION: THE KEY TO OPTIMIZING INDICATIONS

The core controversy surrounding the clinical utility of HIPEC lies in the lack of precise patient selection. Several well-established risk factors are known to drive peritoneal recurrence of gastric cancer, including how deeply the tumor has invaded, whether regional lymph nodes are involved, the specific histological type, and findings from peritoneal cytology[31]. Such high-risk patients constitute the primary target population for prophylactic HIPEC.

Serosal invasion, reflecting an advanced T stage in gastric cancer, largely dictates the rationale for prophylactic HIPEC[32]. From a biological perspective, serosal penetration fundamentally alters the disease trajectory by creating a direct conduit for tumor cells to shed into the abdominal cavity, a necessary precursor to peritoneal spread. While T stage defines the anatomical risk of peritoneal exposure, the extent of lymphatic involvement provides an equally critical dimension in stratifying patients for this locoregional therapy. Ikeguchi et al[33] reported that the survival benefit of CRS/HIPEC depends largely on lymph node status. No survival gain was observed in node-negative patients (5-year survival: 65% vs 68%). A paradoxical outcome occurred in those with > 10 positive nodes, where HIPEC was linked to worse survival (10% vs 29%). The greatest benefit appeared in patients with 1-9 metastatic nodes (66% vs 44%). Thus, HIPEC appears to benefit only patients with a moderate burden of nodal metastasis. This observation underscores the hypothesis that prophylactic HIPEC is a locoregional strategy best employed before systemic micrometastatic burden becomes overwhelming and untreatable by local means alone. This is consistent with known prognostic factors for CRS/HIPEC, where lymph node metastasis is an independent negative predictor (hazard ratio = 3.53, P = 0.005)[34]. Therefore, serosal invasion and lymph node burden are the key determinants of the effectiveness of prophylactic HIPEC.

Lauren classification also serves as a critical determinant in selecting suitable candidates for prophylactic HIPEC. The peritoneal recurrence rate for diffuse-type gastric cancer ranges from 60% to 70%, whereas the corresponding figure for intestinal-type disease is only 20% to 30%[35,36]. At the molecular level, diffuse-type gastric carcinoma cells exhibit downregulation of E-cadherin expression and activation of epithelial-mesenchymal transition, endowing them with heightened invasiveness and a greater propensity for intraperitoneal shedding[37]. Currently, the phase III PREVENT (FLOT9) trial, a multicenter, randomized, controlled, open-label study, specifically targets patients with resectable diffuse or mixed type gastric cancer, aiming to evaluate perioperative FLOT chemotherapy with vs without prophylactic HIPEC[38]. Consequently, histologic classification should also be regarded as a key consideration in patient selection for prophylactic HIPEC among those with LAGC.

Positive peritoneal cytology (CY+) represents a robust predictor of peritoneal recurrence[39]. The presence of CY+ signifies that free intraperitoneal cancer cells are already present even in the absence of macroscopically visible peritoneal implants, thereby establishing the subclinical foundation for subsequent peritoneal dissemination[40]. Viewed through the temporal lens of peritoneal carcinomatosis, CY+ may be regarded as a precursor stage to overt peritoneal metastasis. Therefore, intervention with prophylactic HIPEC holds the potential to disrupt the implantation of free cancer cells and abort the formation of micrometastatic deposits[41], thereby improving long-term oncologic outcomes.

Selecting patients for prophylactic HIPEC requires a multidisciplinary team (MDT) to weigh individual risks and potential benefits by integrating preoperative and intraoperative findings. Future clinical studies should shift focus from whether to use HIPEC to which patients to select, including but not limited to adopting artificial intelligence risk models, so as to optimize patient selection and maximize treatment benefit in those most likely to respond.

TREATMENT PROTOCOLS: THE CASE FOR STANDARDIZATION

HIPEC can directly act on free tumor cells within the abdominal cavity. It utilizes the synergistic effect of hyperthermia to enhance the cytotoxicity of chemotherapeutic agents and increase the sensitivity of tumor tissues to these drugs[42]. Simultaneously, through continuous circulatory perfusion, HIPEC exerts a mechanical flushing effect on free cancer cells and microscopic peritoneal metastatic lesions within the abdominal cavity, thereby helping to eliminate residual cancer cells and micro-metastases[43]. Furthermore, the hyperthermic effect of HIPEC can induce protein denaturation in tumor cells by activating heat shock proteins, which subsequently triggers an anti-tumor response from the immune system and inhibits angiogenesis[44]. Several factors go into designing a prophylactic HIPEC regimen, including drug choice, timing, and technical parameters[45]. Previous studies have often employed disparate technical protocols, and this lack of a standardized treatment regimen has been a primary source of controversy regarding the efficacy of prophylactic HIPEC.

Clinically, several drugs are more commonly used: Mitomycin C, which has a high molecular weight and a pronounced hyperthermia-sensitizing effect; cisplatin and oxaliplatin, which are known for their potent DNA crosslinking damage and well-documented hyperthermia-enhanced activity; and paclitaxel and docetaxel, which offer a unique antitumor mechanism and favorable intraperitoneal pharmacokinetic properties[46]. In a systematic review and Bayesian network meta-analysis, Wang et al[47] found that the cisplatin regimen was superior to other regimens in terms of OS and overall disease recurrence, achieving a balance between efficacy and safety. According to earlier reports, precision HIPEC could use pharmacogenomic profiling to find predictive biomarkers, detect genetic signs of drug sensitivity or resistance, identify patients who would benefit from a specific regimen, and improve outcome prediction[48]. To further enhance therapeutic efficacy and mitigate adverse effects, several centers have begun to explore alternative drug combination regimens for HIPEC. Meanwhile, given the distinct renal safety concerns with cisplatin in the prophylactic setting where patients are also recovering from gastrectomy, we opine that non-nephrotoxic agents like mitomycin C or oxaliplatin may represent a more prudent first-line investigational choice in future trial designs.

Beyond drug choice, HIPEC procedures also differ in technical details. HIPEC perfusion methods generally divide into the open coliseum technique, first described by Sugarbaker, and the closed technique[49,50]. The open approach, done with the abdomen exposed, may help distribute drugs more evenly. The closed approach, performed after suturing the abdominal wall, is thought to be safer. The optimal timing for prophylactic HIPEC remains undefined. Current strategies include intraoperative/immediate postoperative delivery vs delayed administration. Gong et al[51] reported no significant differences in OS, DFS, complications, or recurrence patterns between early (day of surgery to postoperative day 2) and late (postoperative day 3 or later) HIPEC. Nonetheless, early administration is generally preferred to minimize peritoneal metastases during the waiting period, though final timing should be tailored to the recovery and tolerance of each patient. Clinically, perfusion temperature is routinely maintained at 41-43 °C for 60-90 minutes to balance adequate drug-tumor contact time and reduced systemic toxicity. The choice of temperature range must balance the therapeutic benefits of hyperthermia, which enhances chemotherapy cytotoxicity, against the risks of tissue damage and systemic hyperthermia-related complications[52]. The duration of perfusion depends more on the properties of the drugs used.

Although different studies offered valuable clinical evidence to inform the design of HIPEC technical parameters and chemotherapy combinations, the clinical implementation of HIPEC remains highly dependent on institutional practice preferences and international consensus[53,54]. Therefore, prospective multicenter clinical trials are urgently needed to optimize and standardize HIPEC technical protocols.

BEYOND HIPEC: EMERGING TECHNOLOGIES AND SYNERGISTIC COMBINATIONS

To overcome the disadvantage of uneven drug distribution associated with conventional closedtechnique HIPEC, novel drug delivery technologies are emerging. For example, pressurized intraperitoneal aerosol chemotherapy uses a laparoscopic approach to aerosolize chemotherapeutic agents, enabling uniform distribution across the peritoneal surface under pressure[55-58]. In addition, some newer HIPEC systems generate turbulence by insufflating carbon dioxide gas into the peritoneal cavity to improve the distribution of liquid drugs[59]. Meanwhile, combining the precision and minimally invasive advantages of robotic surgery with HIPEC holds promise for further reducing surgical trauma and postoperative complications, ensuring oncologic radicality, and accelerating patient recovery[60]. Furthermore, optimizing HIPEC within a multimodal therapeutic paradigm requires exploring synergistic combinatorial or sequential strategies with novel systemic therapies (e.g., claudin 18.2-targeted agents[61] and immune checkpoint inhibitors[62,63]) to determine optimal treatment sequences for patients. Ultimately, the seamless integration of HIPEC into the comprehensive management continuum of gastric cancer, supported by enhanced MDT collaboration, will facilitate individualized and more effective treatment strategies.

CONCLUSION

Prophylactic HIPEC holds potential value in reducing peritoneal recurrence and improving survival outcomes for high-risk LAGC patients, but its routine clinical application remains controversial due to conflicting evidence from clinical studies. The key to optimizing its efficacy lies in precise patient selection, which should integrate multiple risk factors including serosal invasion, lymph node metastasis burden, Lauren classification, and peritoneal cytology to identify patients most likely to benefit. Although prophylactic HIPEC is generally safe, proactive monitoring and intervention for specific toxicities (e.g., renal, pulmonary, hematologic) are essential to ensure patient safety. The lack of standardized treatment protocols remains a major obstacle, and large-scale, well-designed phase III randomized controlled trials are urgently needed to clarify optimal drug regimens, timing, and technical parameters. Additionally, the integration of emerging technologies (such as pressurized intraperitoneal aerosol chemotherapy) and synergistic combinations with novel systemic therapies may further enhance the therapeutic effect of prophylactic HIPEC. In the future, under the guidance of MDT collaboration, individualized treatment strategies based on precise patient stratification and standardized protocols will be the main direction to maximize the clinical value of prophylactic HIPEC in LAGC.