Efficacy and safety of hyperthermic intraperitoneal intraoperative chemotherapy plus surgery in advanced ovarian cancer patients

Abstract

Objective

This study aimed to evaluate the efficacy and safety of hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC) in patients with advanced ovarian cancer.

Methods

A total of 200 patients with advanced ovarian cancer were enrolled in this retrospective study and randomly allocated to two groups (research registry number: 11353). On the first day after abdominal closure, routine treatment was performed in the non-HIPEC group, whereas HIPEC was performed in the HIPEC group. The surgical outcomes, overall survival, progression-free survival, side effects, and quality of life of patients were compared between the two groups, and the risk factors for overall survival and progression-free survival were analyzed.

Results

The basic information of the patients showed no significant difference between the two groups (p > 0.05). There was no significant difference in the time from surgery to first flatus, postoperative hospital stay, abdominal pain, bleeding, leakage, or other blood indices between the two groups (p > 0.05); however, the symptoms of ileus and pelvic abscess appeared more frequently in the non-HIPEC group (p < 0.05). HIPEC, tumor size, N stage, T stage, and vascular invasion were significant indicators, while HIPEC, tumor size, vascular invasion, N stage, and T stage were independent prognostic factors. The 3-year survival rate of the HIPEC group (42%) was higher than that of the non-HIPEC group (21%) (p < 0.001). The progression-free survival curve of the HIPEC group was superior to that of the non-HIPEC group (p < 0.001), and the recurrence rate of the HIPEC group (25%) was lower than that of the non-HIPEC group (49%) (p < 0.001).

Conclusions

HIPEC can reduce the possibility of perioperative complications such as intestinal obstruction and pelvic abscess, and the overall survival and progression-free survival curves were better in the HIPEC group.

Keywords

Advanced ovarian cancer hyperthermic intraperitoneal intraoperative chemotherapy overall survival progression-free survival recurrence

Introduction

Ovarian cancer is one of the most common reproductive system tumors. Due to the lack of specific clinical symptoms in the early stages of ovarian cancer and limited screening methods, 60%–70% of the cases are diagnosed at an advanced stage, during which the treatment efficacy is poor.¹ Therefore, although the incidence rate of ovarian cancer is lower than those of cervical cancer and endometrial cancer, it shows the highest mortality rate among gynecological cancers, making it a serious disease threatening women’s health.² In the comprehensive management system for advanced ovarian cancer, surgery is the cornerstone of treatment and holds an irreplaceable position. The current goal of ovarian cancer treatment is to maintain a longer progression-free survival (PFS) and overall survival (OS) while improving the patient’s quality of life.^3,4 After resection, one of the major challenges is the peritoneal dissemination and recurrence of ovarian cancer, making the removal of residual tumor cells essential. Despite chemotherapy, the prognosis of these patients remains poor.^5–7

In recent years, hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC) has received increasing attention. A study revealed that HIPEC can improve prognosis and help eradicate peritoneal free cancer cells in ovarian cancer patients.⁸ HIPEC refers to a treatment technique that prevents and treats peritoneal cancer and malignant ascites. It involves heating a chemotherapeutic drug–containing infusion solution to the treatment temperature, infusing it into the abdominal cavity of cancer patients, and maintaining circulation for a certain period.⁹ Research has shown that HIPEC has unique therapeutic effects on various malignant tumors and ascites in the abdominal cavity.^10–12 However, only a few studies have explored the outcome of HIPEC after staging surgery for ovarian cancer. In this study, we evaluated the efficacy and safety of HIPEC in patients with advanced ovarian cancer to enhance their clinical benefits and improve treatment outcomes.

Materials and methods

Patients

This study was retrospectively registered at the Research Registry https://www.researchregistry.com/: registration number 11353. The study population comprised advanced ovarian cancer patients with clinically T3 or T4 and M0 disease according to magnetic resonance imaging (MRI) and abdominal ultrasound. The seventh edition of the American Joint Committee on Cancer staging manual was used to determine the tumor, node, and metastasis stage. Each patient signed the informed consent, and this study was approved by the institutional review board of Zhongnan Hospital of Wuhan University. This study was conducted in accordance with the 1975 Declaration of Helsinki, as revised in 2024. The reporting of this study conforms to the Consolidated Standards of Reporting Trials (CONSORT) statements.¹³

Inclusion and exclusion criteria

Patients were enrolled according to the predefined inclusion and exclusion criteria.

The inclusion criteria included the following: (a) confirmed ovarian cancer with T3/4; (b) deemed suitable to undergo primary cytoreductive surgery (PCS) based on preoperative evaluation; (c) patients with informed understanding of this study; and (d) patients available for follow-up.

The exclusion criteria included the following: (a) ovarian cancer accompanied with malignant tumors in other parts of the body and (b) patients who had received prior radiation therapy or chemotherapy before surgery.

Procedure

Patients were randomized to the HIPEC group or non-HIPEC (NHIPEC) group in a 1:1 ratio, according to the new CONSORT 2025 statement.

The NHIPEC group received symptomatic treatment and fluid replacement within 1 week after surgery.

Both groups underwent PCS. In the HIPEC group, within 24 h after closing the abdomen, thermal perfusion chemotherapy was performed using a body cavity thermal perfusion therapy machine. A solution of 3000 mL of 0.9% sodium chloride containing 60 mg of cisplatin (National Medical Products Administration H20030675, 20 mL: 20 mg) was infused into the abdominal cavity at a flow rate of 500 mL/min and maintained at 43°C. Each infusion was retained for 90 min, after which the solution was slowly drained. This procedure was repeated every other day, for a total of three times, and the patient’s vital signs were closely monitored during the infusion process. The remaining treatment methods are the same as those of the NHIPEC group. Two weeks after PCS, both groups received 6–8 courses of routine systemic intravenous chemotherapy (paclitaxel + cisplatin).

Observation indicators

Baseline data

The baseline data included age, tumor size, pathological type, differentiated grade, International Federation of Gynecology and Obstetrics (FIGO) staging, lymph node metastasis, carbohydrate antigen-125 (CA125) level, and blood indices (neutrophil count, lymphocyte count, neutrophil–lymphocyte ratio (NLR), and platelet count).

Treatment effect and safety after surgery

The postoperative hospital stay (days); blood indices; and incidences of abdominal pain, bleeding, and leakage were compared between the two groups of patients.

OS and PFS of patients

OS is defined as the time from the date of initial surgery until death or end of follow-up. PFS is defined as the time from the date of initial surgery until tumor recurrence or end of follow-up. Diagnosis of recurrence was made via abdominal ultrasound, MRI, and pathology tests. Recurrence and survival status were recorded through telephone follow-up, with a cutoff date of 30 June 2024.

Statistical analysis

SPSS version 26.0 and GraphPad Prism software were used. The data were expressed as percentages (%) and mean ± SD. Comparisons of measurement data were performed using the unpaired Student’s t-test, whereas the categorical data were analyzed using the chi-square test or rank-sum test. Survival analysis was conducted using the Kaplan–Meier method, and the log-rank test was used to compare the statistical differences between survival curves. p < 0.05 was considered to indicate a statistically significant difference.

Results

Baseline characteristics

The baseline characteristics of the 200 ovarian cancer patients are shown in Table 1. There was no significant difference in baseline information between the HIPEC and NHIPEC groups (p > 0.05).

Table 1.

Baseline characteristics of the patients.

Variables	NHIPEC, n = 100	HIPEC, n = 100	p value
Age (years)	63.89 ± 7.41	63.66 ± 6.90	0.84
Pathological type			0.81
Epithelial tumor	35	38
Germ cell tumor	35	36
Sex cord stromal tumor	30	20
Differentiated grade			0.64
High	2	5
Middle	56	58
Low	42	37
T stage			0.78
T3	53	55
T4	47	45
N stage			0.94
N0	10	11
N1	32	35
N2	35	31
N3	23	23
Tumor size (cm)	8.58 ± 1.58	8.57 ± 1.45	0.48
CA125 level (g/L)	399.10 ± 43.58	398.66 ± 47.66	0.72
Neutrophil count (10⁹/L)	3.07 ± 0.66	3.056 ± 0.67	0.70
Lymphocyte count (10⁹/L)	1.71 ± 0.65	1.72 ± 0.65	0.95
NLR	3.08 ± 0.59	3.06 ± 0.59	0.87
Platelet count (10⁹/L)	240.45 ± 49.75	239.79 ± 51.79	0.94

HIPEC: hyperthermic intraperitoneal intraoperative chemotherapy; NHIPEC: nonhyperthermic intraperitoneal intraoperative chemotherapy; NLR: neutrophil–lymphocyte ratio; CA125: carbohydrate antigen-125.

Treatment effect after surgery

Table 2 presents the results of surgery. No significant differences were observed between the two groups (p > 0.05) in terms of postoperative hospital stay, abdominal pain, bleeding, leakage, and blood indices. However, the HIPEC group had a lower incidence of symptoms such as intestinal obstruction and pelvic abscess (p < 0.05) than the NHIPEC group.

Table 2.

Outcomes after surgery.

Variables	NHIPEC, n = 100	HIPEC, n = 100	p value
Type of surgery			0.78
Total	55	57
Distal	45	43
Postoperative hospital stay (days)	13.04 ± 1.50	13.32 ± 1.48	0.81
Abdominal pain	13/100	10/100	0.51
Ileus	19/100	5/100	0.002
Abdominal abscess	16/100	3/100	0.002
Leakage	6/100	4/100	0.77
Bleeding	7/100	5/100	0.55
Neutrophil count (10⁹/L)	8.93 ± 0.84	9.02 ± 0.95	0.62
Lymphocyte count (10⁹/L)	3.07 ± 0.54	3.51 ± 0.69	0.56
NLR	12.85 ± 1.90	12.89 ± 1.85	0.52
Platelet count (10⁹/L)	175.48 ± 46.75	175.21 ± 48.30	0.73

HIPEC: hyperthermic intraperitoneal intraoperative chemotherapy; NHIPEC: nonhyperthermic intraperitoneal intraoperative chemotherapy; NLR: neutrophil–lymphocyte ratio.

OS of patients

The risk factors for OS are shown in Table 3. The results showed that HIPEC, tumor size, N stage, T stage, differentiated grade, and vascular invasion were significant indicators. Multivariate analysis further revealed that HIPEC, tumor size, vascular invasion, N stage, and T stage were independent prognostic factors (Table 4). The survival curve (Figure 1) revealed that the prognosis of the HIPEC group was significantly better than that of the NHIPEC group (p < 0.001). The 3-year survival rate of the HIPEC group (42%) was higher than that of the NHIPEC group (21%).

Table 3.

Univariate analysis of overall survival.

Variables	β	HR (95%CI)	p value
Age (years)	0.024	1.355 (0.834–1.766)	0.162
HIPEC/non-HIPEC	−0.883	0.371 (0.119–0.835)	0.000
Tumor size	0.292	2.267 (1.398–2.878)	0.000
Type of surgery	0.169	1.106 (0.558–2.254)	0.751
Tumor location	0.073	0.928 (0.679–1.255)	0.651
Differentiated grade	0.471	0.616 (0.352–1.069)	0.035
T stage	1.352	3.689 (1.013–5.131)	0.031
N stage	0.535	1.707 (1.239–2.276)	0.000
Vascular invasion	−0.815	0.592 (0.221–0.875)	0.000

CI: confidence interval; HIPEC: hyperthermic intraperitoneal intraoperative chemotherapy; HR: hazard ratio; NHIPEC: nonhyperthermic intraperitoneal intraoperative chemotherapy.

Table 4.

Multivariate analysis of overall survival.

Variables	β	HR (95%CI)	p value
HIPEC/non-HIPEC	−0.812	0.411 (0.110–0.812)	0.000
Tumor size	0.128	1.255 (1.332–2.523)	0.000
Differentiated grade	0.321	0.616 (0.252–1.069)	0.055
T stage	1.229	2.692 (1.012–3.391)	0.023
N stage	0.312	1.502 (1.128–2.386)	0.011
Vascular invasion	−0.525	0.523 (0.232–1.253)	0.016

CI: confidence interval; HIPEC: hyperthermic intraperitoneal intraoperative chemotherapy; HR: hazard ratio; NHIPEC: nonhyperthermic intraperitoneal intraoperative chemotherapy.

Figure 1.

Kaplan–Meier curves of overall survival in the NHIPEC and HIPEC groups. NHIPEC: nonhyperthermic intraperitoneal intraoperative chemotherapy; HIPEC: hyperthermic intraperitoneal intraoperative chemotherapy.

PFS of patients

The risk factors for PFS included HIPEC, tumor size, T stage, N stage, and vascular invasion (Table 5). HIPEC and tumor size were independent risk factors (Table 6). The PFS curve of the HIPEC group was superior to that of the NHIPEC group (p < 0.005) (Figure 2), and the 1-year recurrence rate of the HIPEC group (25%) was lower than that of the NHIPEC group (49%).

Table 5.

Univariate analysis of PFS.

Variables	β	HR (95%CI)	p value
Age (years)	0.036	1.326 (0.823–1.795)	0.201
HIPEC/non-HIPEC	−0.765	0.332 (0.113–0.822)	0.000
Tumor size	0.512	1.130 (0.335–1.992)	0.000
Type of surgery	0.173	1.013 (0.569–2.032)	0.551
Tumor location	0.065	0.833 (0.535–1.033)	0.362
Differentiated grade	0.452	0.623 (0.301–1.053)	0.063
T stage	1.022	2.633 (1.005–4.132)	0.026
N stage	0.632	1.413 (1.012–2.036)	0.000
Vascular invasion	−0.813	0.392 (0.101–0.853)	0.000

CI: confidence interval; HIPEC: hyperthermic intraperitoneal intraoperative chemotherapy; HR: hazard ratio; NHIPEC: non-hyperthermic intraperitoneal intraoperative chemotherapy; PFS: progression-free survival.

Table 6.

Multivariate analysis of PFS.

Variables	β	HR (95%CI)	p value
HIPEC/non-HIPEC	−0.615	0.352 (0.112–0.693)	0.0012
Tumor size	0.202	2.015 (1.702–3.103)	0.0025
T stage	1.039	2.372 (1.012–3.392)	0.062
N stage	0.312	1.502 (0.615–2.036)	0.058
Vascular invasion	−0.325	0.401 (0.112–1.023)	0.073

CI: confidence interval; HIPEC: hyperthermic intraperitoneal intraoperative chemotherapy; HR: hazard ratio; NHIPEC: nonhyperthermic intraperitoneal intraoperative chemotherapy; PFS: progression-free survival.

Figure 2.

Kaplan–Meier curves of progression-free survival in the NHIPEC and HIPEC groups. NHIPEC: nonhyperthermic intraperitoneal intraoperative chemotherapy; HIPEC: hyperthermic intraperitoneal intraoperative chemotherapy.

Discussion

Ovarian cancer is the most lethal malignant tumor among female reproductive system tumors, with 75% of the patients presenting at advanced stages, accompanied with extensive abdominal implantation.¹⁴ PCS combined with intravenous chemotherapy is the standard treatment mode for advanced ovarian cancer; however, 70% of the patients still experience recurrence after surgery, mainly in the abdominal cavity, which can lead to serious complications such as intestinal obstruction and malignant ascites, with an extremely poor prognosis.¹⁵ Therefore, to improve the patient survival rate and reduce recurrence, intraperitoneal chemotherapy is gradually being used in clinical practice. In the clinical treatment of advanced intraperitoneal malignant tumors, intraperitoneal hyperthermia chemotherapy has been widely used.¹⁶

HIPEC provides precise temperature control and circulating perfusion on the basis of abdominal chemotherapy.¹⁷ Its mechanism of action combines the pharmacological activity of intraperitoneal chemotherapy and the effect of hyperthermia, thereby enhancing the cytotoxic and osmotic effects of chemotherapeutic drugs and effectively clearing free cancer cells and small lesions in the abdominal cavity.¹⁸ HIPEC can induce tumor cell degeneration and necrosis by infusing therapeutic drugs at 43°C through a thermal killing effect, and the continuous circulation of thermal infusion can have a mechanical flushing effect on free tumor cells, thereby clearing small metastases and residual lesions in the abdominal cavity.^19,20 In addition, intraperitoneal hyperthermic infusion can regulate the proportion of drugs in the abdominal cavity and blood in the peritoneal plasma barrier, which is beneficial for increasing drug concentration in the pelvic and abdominal cavity to prolong the antitumor effect.²¹ HIPEC is administered directly via the abdominal cavity, and the concentration of chemotherapeutic drugs in the abdominal cavity is 20–1000 times higher than the plasma level.²² It can increase the chance of contact between chemotherapeutic drugs and tumor cells to maximize the killing of peritoneal tumor cells and reduce postoperative tumor metastasis. Chemotherapeutic drugs can be absorbed from the peritoneum and enter the systemic circulation through the peritoneal lymphatic stomata; conversely, chemotherapeutic drugs can also be absorbed into the portal vein through the peritoneal visceral layer covering the liver, spleen, stomach, small intestine, colon, and mesentery to prevent and treat intra-abdominal micrometastasis.^23,24 After primary tumor resection, the proliferation kinetics of residual cancer cells changed 24 h later, the residual G0 phase cancer cells entered the proliferation phase, and the proliferation rate slowed down after 3 days.¹¹ After 1 week, it returned to preoperative levels; early HIPEC treatment after PCS surgery can effectively inhibit tumor cell metastasis and achieve better therapeutic effects.²⁵

HIPEC was first reported for the treatment of peritoneal metastasis in gastrointestinal tumors.²⁶ As the clinical symptoms of advanced ovarian cancer were similar to those of gastrointestinal tumors, such as widespread implantation in the abdominal cavity and malignant ascites, further research on the application of HIPEC in the treatment of ovarian cancer has been promoted.^27,28 In a prospective randomized controlled study evaluating the efficacy of HIPEC in patients with advanced ovarian cancer, compared with PCS patients who did not receive HIPEC, stage III ovarian cancer patients who received HIPEC had a longer recurrence-free survival and median survival that were extended by 3.6 months (hazard ratio (HR): 0.66, 95% confidence interval (CI): 0.50–0.87, p = 0.003) and 11.8 months (HR: 0.67, 95% CI: 0.48–0.94, p = 0.02), respectively.¹ Our study is a retrospective real-world study, and the results show that compared with the NHIPEC group, the PFS and OS of ovarian cancer patients in the HIPEC group were significantly improved, the 3-year survival rate of the HIPEC group (42%) was higher than that of the NHIPEC group (21%), and the postoperative recurrence rate was significantly reduced (p < 0.05). It can be considered that HIPEC is one of the important factors affecting the surgical prognosis of advanced ovarian cancer. Unlike previous studies, the cisplatin dosage in HIPEC was 60–80 mg/m² (100–110 mg).²⁹ However, this study has certain limitations, as it is a single-center retrospective study with a relatively small sample size. Further prospective randomized controlled trials are needed to confirm this result.

The 3-year recurrence rate of ovarian cancer patients is approximately 70% after the initial treatment with surgery and chemotherapy, and some patients even experience recurrence within 1 year after the end of treatment.³⁰ Ovarian cancer recurrence is a complex process involving multiple factors, and the main reasons for recurrence are incomplete surgery, nonstandard chemotherapy, and genetic inheritance.²⁹ However, most advanced ovarian cancer cells already metastasize widely, and even with tumor reduction surgery and subsequent intensive treatment, the probability of recurrence is still high.³¹ Research has shown that the combination of cytoreductive surgery and HIPEC treatment significantly improves survival rates and recurrence rates for patients with gynecological malignancies originating from peritoneal tumors.³² A study found that patients with ovarian cancer and diffuse peritoneal metastasis who underwent cytoreductive surgery combined with HIPEC treatment had an average survival period of 30 ± 6 months, a 5-year survival rate of 54%, and a median survival period of 24 months. Research has shown that the combination of tumor cell reduction surgery and postoperative HIPEC can help inhibit angiogenesis in ovarian cancer, enhance cellular immune function, improve patient survival rate, and reduce recurrence.^33,34 The results of this study show that the 3-year survival rate of the HIPEC group (42%) was higher than that of the NHIPEC group (21%), and the 1-year recurrence rate of the HIPEC group (25%) was lower than that of the NHIPEC group (49%), which was consistent with previous research reports.

The related complications of HIPEC application in ovarian cancer mainly include abdominal pain, abdominal infection, anemia, intestinal obstruction, and electrolyte imbalance.^35–37 The results of this study suggest that compared with the NHIPEC group, the HIPEC group has a lower incidence of symptoms such as intestinal obstruction and pelvic abscess (p < 0.05). A large number of recent studies have shown that HIPEC does not increase the probability of complications,^38–41 indicating that HIPEC is a safe and feasible treatment option, and our study also reached the same conclusion.

Currently, research on HIPEC in the field of advanced ovarian cancer includes intermittent tumor cell reduction surgery combined with HIPEC after neoadjuvant chemotherapy, initial tumor reduction surgery combined with HIPEC, and preoperative neoadjuvant HIPEC.^18,42 The above research indicates that HIPEC has significant value in the treatment of advanced ovarian cancer. However, there are differences in perfusion time, frequency, temperature, type, and dosage of chemotherapeutic drugs in different studies.^43,44 The issues that still need to be explored for the clinical treatment of HIPEC include the method of infusion, time and frequency of infusion, temperature range for infusion, degree of thoroughness of perfusion surgery, selection of chemotherapeutic drugs, and their toxic side effects.⁴⁵ Therefore, multi-center, large-scale, standardized randomized controlled trials are still needed to determine the effectiveness and safety of HIPEC in treating ovarian cancer to provide a basis for standardized clinical treatment.

Our research indicates that HIPEC improves treatment efficacy and survival rates, which can reduce the possibility of perioperative complications and recurrence rate, and the OS and PFS curves were better in the HIPEC group. However, our research has some limitations. First, we analyzed only patients with advanced ovarian cancer, which is not representative of all patients. Second, we did not perform a sample size calculation, and the limited number of samples may affect the statistical significance of the results. Third, post-study registration may have introduced bias to our results and is a limitation of this study.

Conclusion

The OS and PFS curves were better in the HIPEC group. The possibility of perioperative complications, including ileus and abdominal abscess, could be reduced by HIPEC. HIPEC can benefit patients with advanced ovarian cancer and would be a promising therapeutic strategy.

Footnotes

Acknowledgments

We would like to thank all members of our research team for their valuable contributions.

Author contributions

Chang Yanan designed and completed this study. Liu Ting, Xu Yaxin, Cao Wei Li, and Chen Hong revised the main work. All authors contributed to the article and approved the submitted version.

Data availability statement

The data can be obtained from the corresponding author.

Declaration of conflicting interests

The authors state that they have no conflicts of interest to declare.

Funding

This research did not receive any financial support.

ORCID iDs

Chang Yanan

Chen Hong

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