Good Doctor·Hyperthermic Perfusion | Literature Brief Review | Current Clinical Applications and Future Prospects of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in the Treatment of Advanced Ovarian Cancer

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01. The Past: Establishment of the Theoretical Foundation and Early Exploration (1980s–2010)

The Therapeutic Dilemma of Peritoneal Metastasis

Ovarian cancer is the leading cause of cancer‑related mortality among malignant neoplasms of the female reproductive system. The disease has an insidious onset, and approximately 75% of patients are already at an advanced stage at the time of initial diagnosis, often with extensive peritoneal dissemination throughout the pelvic and abdominal cavities. Despite continuous refinements in cytoreductive surgery and advances in systemic chemotherapy and maintenance therapy, peritoneal metastasis and recurrence remain central challenges in clinical practice—both the primary cause of treatment failure and a critical bottleneck limiting long‑term survival [1,2].

Peritoneal metastases typically exhibit a diffuse, superficial, millet‑grain‑like distribution. Following intravenous administration, chemotherapeutic agents struggle to achieve effective therapeutic concentrations within the peritoneal and pelvic cavities for two main reasons: first, the peritoneal–plasma barrier restricts the transmembrane transport of drugs from the bloodstream to the peritoneal surface; second, the metastatic lesions themselves are characterized by impaired microcirculatory perfusion, interstitial fibrosis, and elevated interstitial hydrostatic pressure, further diminishing the drugs’ tissue penetration [2,3]. It is precisely on the basis of these barriers that regional hyperthermic intraperitoneal chemotherapy has been deemed both theoretically sound and clinically necessary.

The theoretical basis of HIPEC

Hyperthermic intraperitoneal chemotherapy (HIPEC) leverages precise temperature control, continuous perfusion, and adequate abdominal cavity distension to combine local hyperthermia with intra‑abdominal and pelvic chemotherapy, thereby eradicating residual microscopic lesions and free cancer cells within the peritoneal and pelvic cavities [2,3]. Hyperthermia itself exerts direct cytotoxic effects: tumor cells sustain irreversible damage after exposure to 43°C for one hour, whereas normal visceral tissues can tolerate 45°C for the same duration. Moreover, thermal conditions of 42–43°C enhance chemosensitivity, increase tumor vascular permeability, and facilitate deeper drug penetration into tissues. HIPEC not only markedly elevates local drug concentrations and tissue penetration depth but also reduces systemic drug exposure and associated toxicities [2,3]. Clinically, following maximal cytoreductive surgery (CRS)—defined as CC‑0/1—a platinum‑based chemotherapy regimen is commonly employed, with an infusion duration typically set at 60 minutes [3]. In addition, the combination of hyperthermia and chemotherapy can induce immunogenic cell death (ICD), triggering an antitumor immune response. Together, these mechanisms underpin the therapeutic rationale for HIPEC in the management of malignant peritoneal tumors.

Early Clinical Exploration

In 1980, Spratt et al. first applied HIPEC to patients with peritoneal pseudomyxoma, providing preliminary evidence of its safety and feasibility [5]. Since then, this technique has gradually expanded into the field of gynecologic oncology. Around 1999, clinical reports began to emerge on the use of hyperthermic therapy in combination with surgery for ovarian cancer. In China, gynecologic oncology experts formulated the first “Expert Consensus on the Clinical Application of Intraperitoneal Hyperthermic Perfusion Chemotherapy for Gynecologic Malignancies” in 2017, which was revised and republished as the second edition in 2019 [6], thereby establishing a relatively systematic set of guidelines for HIPEC in the country. In addition, academic societies in the United States, Australia, France, and across Europe have also successively issued their own consensus statements and management protocols.

Early prospective studies have demonstrated that HIPEC is safe and feasible in the treatment of gynecologic malignancies. In 2003, Verwaal et al. conducted a landmark randomized controlled trial in patients with peritoneal metastases from colorectal cancer, providing an important benchmark for the clinical value of HIPEC in intra-abdominal malignancies [7]. However, high‑level evidence in the field of ovarian cancer was not firmly established until the publication of the OVHIPEC‑1 study in 2018 [8].

02. Current Status: Key Clinical Studies and Evidence Hierarchy (2018–Present)

Interval Cytoreductive Surgery Combined with HIPEC: The Highest Level of Evidence

Interval debulking surgery (IDS) combined with HIPEC represents the clinical setting with the strongest evidence and the highest level of guideline recommendation. IDS is performed when patients have a high tumor burden and are not suitable for immediate primary cytoreductive surgery (PCS); it involves neoadjuvant chemotherapy (NACT) followed by CRS. Neoadjuvant chemotherapy can reduce peritoneal tumor burden and increase the rate of maximal cytoreduction, thereby enabling HIPEC to more effectively eradicate microscopic residual foci and free cancer cells.

OVHIPEC‑1 (NCT00426257) represents the highest‑level multicenter, randomized controlled evidence to date. Preliminary results published in the New England Journal of Medicine in 2018 showed that, among patients with stage III ovarian cancer who completed neoadjuvant chemotherapy and underwent satisfactory IDS, the addition of cisplatin HIPEC (100 mg/m² administered in three segments, at 40°C for 90 minutes via open‑cavity perfusion) extended median progression‑free survival (PFS) by 3.5 months compared with IDS alone (14.3 months vs. 10.7 months; HR 0.63; 95% CI 0.48–0.83), and median overall survival (OS) by 11.8 months (44.9 months vs. 33.3 months; HR 0.70; 95% CI 0.53–0.92). No significant differences were observed between the two groups in terms of adverse events or quality‑of‑life scores [8]. Ten‑year follow‑up data released in 2023 further confirmed these benefits, demonstrating that the survival advantage conferred by HIPEC is sustained and even more pronounced [9]. Accordingly, this regimen has now been designated by the NCCN Guidelines as a treatment option to be considered during interval debulking surgery (Category 1 evidence) [10].

The K-HIPEC study (NCT01091636) reached a similar conclusion. A randomized controlled trial published in 2022 enrolled 184 patients with FIGO stage III–IV disease who had undergone satisfactory CRS. In the overall population, there were no significant differences between the HIPEC group and the control group in median progression-free survival (mPFS; 19.8 months vs. 18.8 months) or median overall survival (mOS; 69.5 months vs. 61.3 months) (P > 0.05). However, prespecified subgroup analyses revealed that among the 77 patients who received IDS—43 of whom underwent HIPEC and 34 who did not—the IDS plus HIPEC regimen (cisplatin 75 mg/m², 41.5°C, 90 min, closed-loop) resulted in mPFS and mOS that were 2.0 months longer (17.4 months vs. 15.4 months) and 13.6 months longer (61.8 months vs. 48.2 months), respectively, compared with the IDS-alone group; both differences were statistically significant (P = 0.04) [11].

It is worth noting that the OVHIPEC‑1, K‑HIPEC, and KGOG‑3042 studies all demonstrated nearly identical reductions in recurrence risk among patients with intra‑disseminated disease (IDS), suggesting that differences in patient ethnicity and treatment regimen did not diminish the survival benefits of cisplatin‑based HIPEC [9, 11, 12]. Furthermore, a meta‑analysis by Filis et al. [13] confirmed that combining IDS with HIPEC significantly improves patient survival.

Primary cytoreductive surgery combined with HIPEC: Evidence remains controversial.

The use of HIPEC in primary cytoreductive surgery (PCS) remains controversial, with evidence levels lower than those of IDS. Subgroup analyses of K‑HIPEC within the PCS setting have failed to demonstrate a survival benefit. Similarly, Lim et al. [11] found no improvement in progression-free survival (PFS) or overall survival (OS) in the overall population, with suggestive benefits observed only in the IDS subgroup [11]. A multicenter retrospective study conducted in China, however, suggested that HIPEC could reduce mortality risk by 36% (HR = 0.64; 95% CI, 0.50–0.82; P < 0.001) [14]. A meta-analysis by Huo et al. [15] also indicated that combining PCS with HIPEC may improve long-term survival, though considerable heterogeneity was noted across studies. The ongoing domestic HIPEC‑03 trial (NCT03373058) holds promise for providing higher‑level evidence regarding the value of post‑PCS HIPEC. Moving forward, it will be essential to progressively standardize key variables—including the quality of cytoreduction, preoperative CT‑based peritoneal cancer index (CT‑PCI), chemotherapy regimens, temperature and duration, and infusion pathways—in order to identify the patient populations that truly derive clinical benefit [1, 2, 16].

Recurrent Ovarian Cancer: An Evidence-Based Exploration Amidst Controversy

In recurrent ovarian cancer, whether secondary cytoreductive surgery combined with HIPEC confers clinical benefit remains inconclusive, and rigorous patient selection is critical to determining treatment success.

CHIPOR (NCT01376752) is currently the phase III trial with the highest level of evidence in this field. In 2024, The Lancet Oncology reported that among patients with platinum-sensitive recurrent ovarian cancer, the addition of cisplatin HIPEC to secondary cytoreductive surgery significantly reduced the risk of death, extending median overall survival from 45.8 months to 54.3 months. Additionally, peritoneal progression-free survival was prolonged from 12.2 months to 13.1 months.

However, the subsequently published HORSE (MITO‑18) trial failed to replicate this finding. Results from that study, published in the Journal of Clinical Oncology in 2025, showed that among patients with platinum‑sensitive recurrent ovarian cancer, HIPEC did not confer a progression‑free survival (PFS) benefit; the median PFS was 25 months versus 23 months in the two groups (HR = 1.02, P = 0.91). These two studies, which reached opposite conclusions, highlight the lack of a unified consensus regarding screening criteria, surgical completeness, and perfusion protocols—issues that lie at the heart of the ongoing controversy. Earlier, a phase II randomized controlled trial by Spiliotis et al. [19] also suggested that, in recurrent patients—particularly those who were platinum‑sensitive—combined HIPEC could prolong survival (median OS: 26.7 months vs. 13.4 months); however, that study reported overall survival rather than median survival, and its sample size and design were relatively limited.

Overall, current evidence suggests that recurrent patients who are platinum-sensitive, have peritoneal disease confined to the abdomen, are likely to achieve R0/R1 resection, and have adequate organ reserve are more likely to benefit from HIPEC [1,3,20]. PFS benefits are more readily observed in the IDS population, possibly because this group tends to receive relatively standardized preoperative chemotherapy regimens and uses consistent criteria for assessing tumor burden and resectability; by contrast, the recurrent population is highly heterogeneous, and pooled effect estimates often lean toward neutrality or even a negative trend. Recent studies also indicate that HIPEC may alter the pattern of recurrence—rendering diffuse micrometastases more localized, delaying the time to recurrence, and making recurrences more detectable on imaging, thus facilitating retreatment—but such changes do not always translate into direct improvements in PFS or OS [1,3,16,19]. As for whether patients who recur after HIPEC can undergo repeat HIPEC, no prospective evidence currently supports this approach [20]. Tonello et al. [21], after conducting a systematic review of 28 global guidelines related to “HIPEC and ovarian cancer,” found that 22 (80%) do not recommend routine use of HIPEC in recurrent ovarian cancer.

Platinum‑resistant/refractory ovarian cancer and the elderly population

Patients with platinum‑resistant or refractory disease often present with a high peritoneal tumor burden, a complex treatment history, and impaired organ function, leading to a markedly increased risk of HIPEC‑related complications. Moreover, the existing high‑level evidence does not address this patient population, and routine use is therefore not recommended in clinical practice. At present, HIPEC in this setting is limited to investigational applications—such as managing ascites, alleviating symptoms, or serving as part of conversion therapy—and must be administered only after rigorous patient selection and with informed consent [1,2].

Advanced age alone is not an absolute contraindication to HIPEC; the key determinants are organ function and physical performance status. Several studies have shown that, in elderly patients, the rates of complications, acute kidney injury, and length of hospital stay following CRS plus HIPEC do not differ significantly from those in younger cohorts. However, patients aged 70 years or older derive less survival benefit than those aged 65–69 years [22]. Compared with chronological age, geriatric comorbidity assessment (CGA), frailty index, nutritional status, and comorbidity scores provide stronger predictive power for both complications and prognosis [23].

Rare pathological subtypes and molecular stratification

Current evidence on HIPEC is predominantly focused on high-grade serous carcinoma; rare subtypes such as clear cell carcinoma, mucinous carcinoma, and endometrioid carcinoma are underrepresented, making it difficult to draw robust conclusions. There is an urgent need for subtype‑specific studies [1,16]. A multicenter cohort study by Mercier et al. [24] demonstrated that HIPEC is feasible for uncommon types of ovarian malignancies with peritoneal dissemination—including mucinous carcinoma, sex cord–stromal tumors, germ cell tumors, and small cell carcinoma—and may improve outcomes.

Molecular stratification is increasingly emerging as a key approach in precision screening. Subgroup analyses from the OVHIPEC study indicate that BRCA wild‑type patients derive particularly substantial benefits from HIPEC, suggesting that HIPEC may be especially valuable for this subgroup [25]. Further stratification by homologous recombination deficiency (HRD) status revealed that HRD‑positive tumors without pathogenic BRCA1/2 mutations experienced the most pronounced clinical benefit [26].

03. Perioperative Safety and Complication Management

The safety of HIPEC is closely linked to the chemotherapy regimen. The most characteristic toxic effect is nephrotoxicity; a prior history of platinum‑based drug exposure, intraoperative thermal stress, and inadequate fluid management can all synergistically increase the risk of renal injury. Prolonged hospitalization or delays in subsequent chemotherapy may adversely affect patients’ long-term outcomes. When using cisplatin, concomitant use of other nephrotoxic agents should be avoided, and renal protective measures such as sodium thiosulfate should be implemented when necessary [27].

In recent years, perioperative fluid management has shifted from empirical fluid replacement to a risk‑stratified approach that, prior to surgery, assesses renal reserve, concomitant medications, and past exposure to nephrotoxins; during surgery, it maintains urine output above 100 mL/h while dynamically monitoring electrolytes; and postoperatively, it triggers tiered interventions based on changes in serum creatinine, thereby establishing end-to-end management [2,3]. Existing risk models can reliably predict acute kidney injury and other severe complications in patients undergoing CRS combined with HIPEC, providing a quantitative basis for preoperative communication and dose‑adjustment decisions [28,29].

Following HIPEC, structural remodeling of the retroperitoneum may occur, with intra-abdominal adhesions and delayed‑onset small bowel obstruction being relatively common long‑term sequelae. Rehospitalization due to obstruction can adversely affect overall survival [30,31]. In very rare cases, patients may develop encapsulating peritoneal sclerosis, characterized on imaging and during surgery by intestinal segments encased in a thickened fibrous membrane, with pathology showing fibrous tissue proliferation accompanied by inflammatory infiltration [32]. For patients with obstruction who fail conservative management after HIPEC and in whom tumor recurrence has been ruled out, clinicians should heighten their awareness of this complication and consider surgical release or peritoneal stripping as appropriate.

Furthermore, among elderly patients, those with more advanced disease stages, or those who underwent PCI, delayed initiation of adjuvant chemotherapy due to postoperative complications is relatively common, which may adversely affect overall survival (OS) [33]. However, evidence also suggests that delaying the start of adjuvant chemotherapy beyond 42 days does not significantly shorten progression-free survival (PFS) or OS, implying that commencing chemotherapy after six weeks does not necessarily lead to a marked deterioration in outcomes; this issue, nonetheless, requires validation through higher-quality studies [33, 34].

04. Technological Heterogeneity and Standardization

There are marked differences among centers regarding drug selection, dosing, perfusion temperature, duration of perfusion, and surgical approach in HIPEC. This technical heterogeneity directly affects treatment efficacy, reproducibility, safety, and the cross‑study comparability of results, and has become a major barrier to the standardized adoption of this technique. In China, the “Expert Consensus on the Clinical Application of Hyperthermic Intraperitoneal Chemotherapy for Gynecologic Malignancies (2019)” recommends a cisplatin dose not exceeding 80 mg/m² [6]. Moreover, factors that truly determine the penetration of the drug into the peritoneal surface and superficial tissues also include key hemodynamic parameters such as temperature stability, perfusion flow rate, volume of irrigation fluid, circulation pathway, and intra‑abdominal pressure [2,11]. This point is particularly important, because HIPEC is by no means as simple as “infusing chemotherapy drugs into the abdominal cavity.” Its therapeutic outcome depends on the interplay of temperature, drug concentration, treatment duration, uniformity of distribution, and depth of tissue penetration.

05. The Future: Integration of Precision and New Technologies

Precision Medicine and Molecular Biomarkers

Dellinger et al. observed that patients undergoing platinum-based HIPEC exhibited characteristic alterations in the transcriptome and immune phenotype, with RNA‑seq–based changes induced by local hyperthermia combined with chemotherapy being reproducible [35]. A paired‑sample study using carboplatin as the perfusate likewise demonstrated that tumor and normal tissues follow distinct trajectories of post‑treatment transcriptomic remodeling, providing a foundation for developing predictive models that balance efficacy and toxicity [36].

A more clinically actionable strategy is the integrated modeling of clinical and biological variables: incorporating clinical parameters such as PCI scores, R0/R1 resection status, chemotherapy regimens and exposure metrics, and renal functional reserve into a unified framework alongside molecular signatures—including immune infiltration patterns, DNA damage response, and cellular stress pathways—detected in tissue and peritoneal fluid [35,36]. In the future, identifying patients who will benefit from HIPEC will no longer rely on single biomarkers but will increasingly shift toward multidimensional predictive models grounded in molecular profiling and the tumor microenvironment.

Minimally Invasive Techniques and Image Guidance

Another important direction in the evolution of HIPEC technology is minimally invasive intraperitoneal hyperthermic perfusion combined with image-guided, precision monitoring. This approach offers distinct advantages, including reduced surgical trauma, improved control over temperature and drug distribution, and a shorter postoperative recovery period [37, 38]. Imaging plays a pivotal role throughout the entire process—preoperatively for assessing tumor burden and determining resectability, and postoperatively for identifying complications and monitoring recurrence patterns. A systematic review published in Radiographics has laid the groundwork for developing an imaging‑omics framework specifically tailored to HIPEC [39]. Deep learning–based quantitative models derived from CT scans can serve as objective tools for preoperative risk stratification, helping to minimize intercenter assessment bias [40].

Quality Control in Big Data and Artificial Intelligence

Big data technologies can integrate multi-dimensional, end-to-end data from HIPEC procedures, enabling quantitative analysis of quality-control metrics and the discovery of underlying patterns. Meanwhile, artificial intelligence can leverage multi-omics data to build predictive models that monitor treatment in real time, flag potential risks, and optimize patient-specific parameters, thereby shifting quality-control approaches from experience‑driven to data‑informed [28, 29, 41]. Preliminary efforts have already succeeded in identifying high-risk patients within retrospective cohorts; however, widespread clinical implementation still requires multicenter external validation. Moving forward, it will be essential to overcome barriers to multicenter data sharing, enhance the external validity and generalizability of AI models, and incorporate precision‑oriented information such as molecular biomarkers and microenvironmental characteristics, ultimately fostering deep integration among big data, artificial intelligence, and precision medicine [42].

06. Conclusion

Looking back, peritoneal metastasis was once an insurmountable hurdle in the treatment of ovarian cancer, and the theoretical foundations and early exploratory studies of HIPEC paved the way for subsequent breakthroughs. Today, IDS combined with HIPEC is the only treatment approach supported by high‑level evidence that can confer long‑term survival benefits to carefully selected patients with advanced ovarian cancer [9,13]; studies such as OVHIPEC‑1 and K‑HIPEC have already led to its inclusion in clinical guidelines. However, its application in primary cytoreductive surgery (PCS) and in recurrent ovarian cancer remains controversial, with the extent of benefit hinging critically on meticulous patient selection, the completeness of debulking, and the effective management of perioperative complications.

The future of advanced ovarian cancer treatment is not simply “more HIPEC”; rather, it entails a progression toward: more precise patient selection, more complete cytoreduction, more standardized HIPEC procedures, biologically stratified guidance, dynamic molecular‑level monitoring, and early intervention for residual or recurrent lesions. IDS/PCS plus HIPEC will continue to serve as the cornerstone of curative therapy for appropriately selected patients with advanced ovarian cancer, while major advances will stem from integrating treatment strategies that are more precise, safer, and increasingly biologically individualized—approaches that can be progressively quantified at the molecular level.

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