Ovarian cancer is the most lethal gynecologic malignancy and accounts for the highest mortality among gynecological cancers in developed countries [1]. Despite advances in diagnostic methods and treatment strategies, the overall 5-year survival rate remains low (approximately 30–40 %), mainly due to late-stage diagnosis [1]. The disease often presents with vague and nonspecific symptoms, leading to delayed detection and extensive peritoneal spread at diagnosis [1].

Surgery is a key component in the management of ovarian cancer, both at initial presentation and, in selected cases, at recurrence [[2], [3], [4]]. For newly diagnosed patients, standard treatment includes cytoreductive surgery (CRS) combined with platinum-based chemotherapy (with or without maintenance therapy) [1,2]. The prognostic value of complete cytoreduction (defined as no visible residual disease (CC-0 resection)) is well established [1]. In a pooled analysis of three randomized trials, Du Bois et al. showed that complete tumor resection is the strongest predictor of overall survival, with median overall survival exceeding 60 months in patients undergoing CC-0 resection [2]. In the recurrent setting, the role of surgery is more controversial. The DESKTOP trials by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) have provided evidence to guide patient selection for secondary cytoreductive surgery. The DESKTOP I study introduced the AGO score (a predictive model based on performance status, absence of ascites, and complete resection during primary surgery) to identify patients most likely to benefit from secondary cytoreductive surgery [3]. DESKTOP III later confirmed a survival benefit when complete resection was achieved, with a median overall survival of 53.7 months in the surgical group versus 46 months in the non-surgical group [4].

Hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a promising adjunct to CRS, especially in patients with newly diagnosed or recurrent ovarian cancer [[5], [6], [7], [8], [9], [10], [11], [12]]. HIPEC involves the intraoperative delivery of heated chemotherapy directly into the peritoneal cavity after surgical debulking. The elevated temperature enhances drug penetration and cytotoxicity while exerting direct thermal damage to tumor cells. By targeting microscopic residual disease, HIPEC aims to lower recurrence risk and improve long-term outcomes, with potentially reduced systemic toxicity [[5], [6], [7], [8], [9], [10], [11], [12]].

While the role of HIPEC in newly diagnosed ovarian cancer is still under investigation, its use in recurrent disease remains debated due to mixed results from clinical studies. This review evaluates current evidence on HIPEC in primary and interval debulking surgeries as well as in recurrence. We critically analyze its therapeutic potential, limitations, and the challenges in incorporating HIPEC into standard clinical practice.

HIPEC has gained growing attention in the treatment of ovarian cancer. The aim of this systematic review is to collect data from randomized trials testing the value of HIPEC in subjects with advanced/recurrent ovarian cancer. The review followed the suggestions from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [13]. Data were extracted from randomized controlled trials (RCT). The search was comprehensive, using several databases from each database's earliest inception to 30 June 2025. PubMed (MEDLINE), Embase, CENTRAL, Scopus, and Web of Science databases, as well as ClinicalTrials.gov were systematically searched and supplemented by secondary screening of the references of all studies included. We searched for abstracts and conference proceedings as well. Two (GB, GV) authors independently screened records retrieved through the search strategy from titles and abstracts. Potentially relevant studies were acquired in full text and assessed for final inclusion independently by two authors. Any disagreement was discussed with the other authors.

The database search identified 1065 records. Based on study eligibility criteria, seven studies were included for the quantitative synthesis. Fig. 1 shows the PRISMA flow chart. Notably, HIPEC has been studied in combination with primary debulking surgery, interval debulking following neoadjuvant chemotherapy, and secondary cytoreductive surgery, administered either before or after systemic therapy. We found studies reporting data on HIPEC at the time of primary debulking surgery (n = 2) [7,11], interval debulking surgery (n = 4) [5,7,11,12], and secondary cytoreductive surgery (n = 4) [[8], [9], [10], [11]]. Data of 1252 patients with ovarian cancer were examined: 630 and 622 having surgery plus HIPEC and surgery alone, respectively. Table 1 summarizes evidence in across various clinical settings [[5], [6], [7], [8], [9], [10], [11], [12]].

In treatment-naïve patients with advanced ovarian cancer, emerging retrospective evidence suggests that HIPEC following CRS may confer a significant survival benefit [[14], [15], [16]]. In a retrospective multicenter study conducted in China, Lei et al. evaluated 584 patients with FIGO stage III disease and reported a median overall survival of 49.8 months in patients undergoing primary debulking surgery with HIPEC, compared to 34.0 months in those treated with surgery alone [14]. Similarly, Karanikas et al., in a retrospective analysis, reported 5- and 10-year overall survival rates of 69.6 % and 64.2 %, respectively, in patients treated with CRS plus HIPEC (n = 79), compared to 40.8 % and 35.0 % in the CRS-alone group (n = 72). The adjusted hazard ratio (aHR) for all-cause mortality in the HIPEC group was 0.33 (95 % CI: 0.17–0.63, p = 0.001). Additionally, both disease-specific survival and disease-free survival were significantly improved, with aHRs of 0.25 (p = 0.003) and 0.54 (p = 0.041), respectively [15]. Conversely, subgroup analysis from the Korean randomized trial (NCT01091636) failed to demonstrate a survival benefit from HIPEC in the primary debulking surgery setting [7]. These results underscore the need for further prospective, adequately powered studies to definitively assess the therapeutic value of HIPEC at the time of primary debulking surgery. To date, HIPEC at the time of primary debulking surgery, should be offered only in the context of clinical trials.

The role of hyperthermic HIPEC in interval debulking surgery has been validated by several phase III trials. In 2018, van Driel et al. demonstrated the efficacy of HIPEC in a randomized trial comparing IDS plus HIPEC versus IDS alone in patients with advanced ovarian cancer [5]. The study reported a median PFS of 14.2 months in the HIPEC group compared to 10.7 months in the control group (HR: 0.66; 95 % CI: 0.50–0.87; p = 0.03), and a median overall survival of 45.7 versus 33.9 months, respectively (HR: 0.67; 95 % CI: 0.48–0.95; p = 0.02). Updated results from the OVHIPEC-1 trial confirmed the long-term survival benefit of HIPEC in patients with FIGO stage III epithelial ovarian cancer undergoing IDS [6]. However, limitations of the study (including the relatively small sample size (245 patients), a modest absolute difference in events (n = 15), and a limited number of deaths (n = 8)) warrant cautious interpretation [5,6].

The findings were further supported by the KOV-HIPEC-01 trial (NCT01091636), in which Lim et al. reported a median progression-free survival of 17.4 months in the HIPEC group versus 15.4 months in the control group, and median overall survival of 61.8 versus 48.2 months, respectively (n = 92 per arm) [7]. However, it is important to highlight that the study was not powered to assess the role of HIPEC in patients undergoing IDS. Moreover, enrollment into the trial was not stratified by type of surgery, stage, BRCA status, or homologous recombination deficiency, potentially introducing biases in the interpretation of the results.

The study also demonstrated the cost-effectiveness of HIPEC, with an incremental cost-effectiveness ratio (ICER) within acceptable thresholds for advanced oncologic therapies, highlighting both the clinical and economic value of the approach [17]. In a Phase II trial, Batista et al. investigated a short-course HIPEC regimen during IDS. Despite the limited sample size (n = 15), the study suggested that abbreviated HIPEC protocols may be feasible and potentially effective for selected patients [18].

Accumulating evidence supports the use of HIPEC during IDS following neoadjuvant chemotherapy. The intraperitoneal administration of heated chemotherapy allows for high locoregional drug concentrations, enhancing cytotoxic effects while minimizing systemic exposure. Nevertheless, optimal patient selection remains paramount; favorable factors include ECOG performance status 0–1 and the ability to achieve CC-0 or CC-1 cytoreduction [[5], [6], [7]]. Table 2 shows an example of HIPEC application during IDS. Ongoing research is focused on refining treatment parameters, evaluating predictive biomarkers such as BRCA mutation status and homologous recombination deficiency (HRD), and assessing long-term quality-of-life outcomes. A secondary analysis of the OVHIPEC trial suggested that patients with HRD/BRCA wild-type tumors derived greater benefit from HIPEC compared to those with BRCA-mutated or non-HRD tumors [19]. However, this evidence remains preliminary. Further prospective studies are needed to define the molecular and clinical profiles most likely to benefit from HIPEC and to guide its integration into personalized treatment strategies.

Recurrent ovarian cancer remains a significant clinical challenge due to its high relapse rates following initial treatment. HIPEC has been investigated as an adjunct to secondary cytoreductive surgery in this setting, providing localized chemotherapy delivery potentiated by hyperthermia [[8], [9], [10]]. While some studies have suggested survival benefits of HIPEC in recurrent ovarian cancer, its role remains controversial due to conflicting results from clinical trials.

Several investigations have focused on the survival advantage of HIPEC in platinum-sensitive recurrent disease, a subgroup more likely to benefit from surgery. Spiliotis et al. conducted a randomized controlled trial comparing secondary cytoreductive surgery alone (n = 60) to secondary cytoreductive surgery plus HIPEC (n = 60), reporting a significant improvement in overall survival for the HIPEC group, with median overall survival of 26.7 months versus 13.4 months in the secondary cytoreductive surgery-only group (p = 0.006) [10]. The study emphasized the potential benefit of HIPEC, particularly in patients with limited disease burden and platinum-sensitive recurrence [10]. Conversely, the HORSE trial (NCT01539785), led by Fagotti et al., did not demonstrate a significant overall survival benefit with HIPEC [8]. This multicenter randomized phase III trial enrolled patients with platinum-sensitive recurrent ovarian cancer and evaluated the addition of cisplatin-based HIPEC to secondary cytoreductive surgery, finding no statistically significant difference in overall survival between groups [8]. Key factors potentially explaining these results include patient selection and suboptimal cytoreduction in some cases, which may have compromised HIPEC efficacy, as the procedure's success heavily depends on achieving minimal residual disease. In contrast, the CHIPOR trial (NCT01376752) yielded promising results. This phase III randomized study in platinum-sensitive recurrent ovarian cancer showed a significant overall survival improvement in patients treated with chemotherapy plus secondary cytoreductive surgery and HIPEC compared to chemotherapy plus secondary cytoreductive surgery alone. The CHIPOR trial included patients having 6 cycles of chemotherapy (with or without bevacizumab) plus cytoreductive surgery. Patients with macroscopically complete tumor resection (CC0 or CC1) were then randomly assigned to receive HIPEC (1-h infusion of cisplatin 75 mg/m2 in 2 L/m2 of serum at 41 ± 1 °C) or no HIPEC. After surgery, patients received standard-of-care maintenance therapy at the investigator's discretion. The study enrolled 415 patients (207 HIPEC, 208 no HIPEC). Specifically, the 5-year overall survival rate was 50 % in the HIPEC group versus 36 % in the control group (p = 0.03), underscoring the importance of optimal cytoreduction and stringent patient selection [9]. Unlike the HORSE trial, CHIPOR included patients who received and responded to chemotherapy before surgery, similar to the interval debulking surgery setting, which likely contributed to the differing outcomes [8,9,20].

Beyond these pivotal trials, other studies have highlighted considerable heterogeneity in HIPEC protocols, including variations in drug selection, perfusion temperature, and duration [[21], [22], [23], [24]]. Ansaloni et al. reviewed these discrepancies, noting cisplatin as the preferred agent for its intraperitoneal penetration and cytotoxicity, although carboplatin and paclitaxel have also been used with varying success. The optimal temperature remains debated, with most protocols targeting 41–42 °C to maximize efficacy while minimizing toxicity [23]. Zivanovic et al. further demonstrated that achieving CC-0 cytoreduction prior to HIPEC is crucial, as residual macroscopic disease significantly reduces HIPEC's survival benefit due to limited chemotherapy penetration [24]. These findings reinforce the necessity of surgical expertise and meticulous patient selection to optimize outcomes. The conflicting results from trials such as HORSE and CHIPOR highlight several challenges in applying HIPEC for recurrent ovarian cancer [8,9]. First, no data support the role of HIPEC in patients receiving surgery and HIPEC followed by chemotherapy [8,24]. The influence of preoperative chemotherapy on tumor biology and its role in identifying patients who may benefit from HIPEC warrants further investigation. Second, the variability in HIPEC protocols complicates cross-study comparisons and interpretation. Finally, achieving optimal cytoreduction remains a fundamental prerequisite for successful HIPEC, underscoring the need for experienced surgical teams and strict patient selection criteria.