Abstract
Background/Aim: Peritoneal carcinomatosis of recurrent endometrial cancer (EC) is a rare clinical entity with dismal prognosis. The purpose of this study was the presentation of the outcomes of patients with peritoneal carcinomatosis from recurrent endometrial cancer treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
Patients and Methods: The files of the patients with recurrent EC and peritoneal carcinomatosis treated with CRS and HIPEC between 2000 and 2024 were retrospectively reviewed. Clinical and histopathological variables were correlated to survival, morbidity, and mortality.
Results: CRS plus HIPEC was performed in 23 female patients, mean age 60.4±7.9 (48-75) years. The mean peritoneal cancer index was 10.6±6 (3-39). Complete or near-complete cytoreduction was possible in 82.6% of patients. The incidence of severe morbidity and hospital mortality was 8.68% and 0%, respectively. Recurrence was recorded in 47% of patients. The overall 5- and 10-year survival was 78%. The completeness of cytoreduction score was identified as the single possible prognostic variable of survival.
Conclusion: Complete cytoreduction combined with HIPEC appears to offer significant survival benefit with low morbidity in patients with recurrent EC and peritoneal carcinomatosis.
Introduction
Patients with recurrent endometrial carcinomas (EC) represent a heterogenous group that varies by histological subtype, previous treatment, time interval to recurrence, disease burden, and anatomic location (1). Peritoneal carcinomatosis is rare, although in recent years increased incidence has been detected in approximately 2% of all recurrences. The pathophysiology of loco-regional recurrence has not been completely clarified (2). The incidence of recurrence in patients with early or advanced stage or even those with a more aggressive subtype varies from 7-15% (1, 3). The loco-regional and distant recurrences are 50%, and 25% respectively. Both distant and loco-regional recurrences are recorded concomitantly in 25% of cases. Most recurrences occur within 2-3 years after initial treatment. Recurrences of the endometrioid sub-type occur in approximately 20% and in non-endometrioid in 50% (1, 4). The life expectancy of patients presenting with peritoneal carcinomatosis from EC is extremely poor, usually with an estimated median survival of less than 12 months (5).
The management of women with primary or recurrent peritoneal dissemination remains heterogeneous. There is no standard treatment strategy for patients with endometrial cancer recurrence. There are very few publications focusing on recurrent endometrial cancer especially in terms of assessment of the feasibility and efficacy of cytoreductive surgery (CRS) alone or in combination with hyperthermic intraperitoneal chemotherapy (HIPEC). Survival benefit in patients with recurrent EC with peritoneal metastasis can be achieved with complete or near-complete cytoreduction. HIPEC has been suggested to provide additional therapeutic benefit (6, 7). However, this data does not establish the independent effect of HIPEC. Therefore, the indication for CRS and HIPEC for peritoneal metastasis from recurrent EC has been an individualized decision so far.
The aim of the study was to present the short- and long-term outcomes in women with peritoneal carcinomatosis of recurrent endometrial cancer treated with CRS and HIPEC. The overall survival (OS), the recurrences, and the pattern of recurrence were the primary end points. Morbidity and mortality were secondary outcomes.
Patients and Methods
The files of the patients who underwent CRS and HIPEC for peritoneal recurrence of endometrial cancer between 2000 and 2024 were retrospectively reviewed. The diagnosis was possible by physical examination, hematologic-biochemical analysis, tumor markers [carcinoembryonic antigen (CEA), cancer antigen-125], and imaging studies [thoracic-abdominal computed tomography (CT) or magnetic resonance imaging (MRI)].
All patients 1) with metachronous peritoneal metastasis from endometrial cancer, 2) of any histologic type of endometrial cancer, 3) age >18 years old, 4) with normal hematological profile, 5) blood urea level <50 mg/dl, 6) creatinine level <1.5 mg/dl, 7) normal hepatic examinations (except for biliary obstruction), and 8) capable to undergo major surgery were included for treatment. In contrast, patients with: 1) distant and unresectable metastatic disease, 2) psychiatric disease or addiction, 3) poor performance status (<50% according to Karnofsky performance scale), 4) previous history of neoplastic disease at risk for recurrence were excluded from treatment. All the operations were performed by the same surgical and anesthesiological team.
The patients’ age, performance status, ASA class, extent of previous surgery, extent of peritoneal dissemination, completeness of cytoreduction, histopathologic subtype, degree of differentiation, and post-operative length of stay were correlated with survival, recurrences, morbidity, and in-hospital mortality. The post-operative complications (within 30 days after surgery) as defined and graded by Clavien-Dindo classification (8, 9) were carefully recorded. All grade IIIb-V complications were considered as severe.
The performance status was assessed using the Karnofsky performance scale (10). The extent of previous surgery was assessed using the Prior Surgical Score (PSS) (11) and the extent of tumor dissemination by the Peritoneal Cancer Index (PCI) (12, 13). The completeness of cytoreduction was assessed after the completion of the operation using the completeness of cytoreduction (CC)-score (13). Complete cytoreduction (CC-0) indicated the operation with no macroscopically visible residual tumor, near complete cytoreduction (CC-1) indicated the operation with macroscopically visible tumor with maximal diameter <2.5 mm, and incomplete cytoreduction (CC-2 and CC-3) indicated the operations that left behind macroscopically visible tumor with maximal diameter >2.5 mm.
Surgery. All patients were treated according to the standard protocol for CRS and HIPEC. A vertical midline incision extending from the xiphoid process to the pubic symphysis was always used for maximal abdominal exposure with the patient placed in the modified lithotomy position. After lysis of the adhesions the extent of disease was assessed by calculating the PCI score. Standard peritonectomy procedures (14, 15) and all required visceral resections were performed in order to achieve complete or near complete cytoreduction. Visceral resections were performed according to the required standard oncological procedures. Para-aortic, para-caval and pelvic lymphadenectomies were performed, if they had not been previously performed. HIPEC was administered after the tumor resection by the open abdominal (Coliseum) technique (15, 16) implemented at 42.5-43°C for 90 min with Cisplatin (50 mg/m2) and Doxorubicin (15 mg/m2). A heater circulator with two roller pumps, one heat exchanger, one reservoir, an extracorporeal system with two inflow and two outflow tubes, and four thermal probes was used for HIPEC (Sun Chip, Gamida Tech, Paris, France). A prime solution of 2-3 l of normal saline or Ringer’s lactate solution was instilled into the abdomen prior to the administration of the cytostatic drugs. As soon as the mean abdominal temperature reached 40°C, the cytostatic drugs were administered in the abdomen. During HIPEC, the patients simultaneously received intravenous ifosphamide (1,300 mg/m2) and mesna (260 mg/m2). Bi-cavitary HIPEC was performed in cases where the diaphragm had been opened during the subdiaphragmatic peritonectomy procedure. The pleural cavities were always drained if subdiaphragmatic peritonectomy procedures were performed.
The reconstruction of the continuity of the gastrointestinal tract was always performed after the completion of HIPEC. A protective stoma was always performed if more than two anastomoses needed to be constructed.
Perioperative management of the patients followed the current guidelines (17, 18). All patients remained in the intensive care unit (ICU) for at least 24 h. The morbidity and in-hospital mortality rates were carefully recorded.
All patients received systemic chemotherapy. The patients were followed up every four months for the first year and every six months thereafter. The re-examination was possible with physical examination, hematological-biochemical examinations, tumor markers (CEA, CA-125) and thoracic-abdominal computed tomography (CT)-scans. The recurrences and the sites of recurrence were recorded and defined as distant or loco-regional. Survival was recorded from the time of initial examination until the date of death or last follow-up appointment. The OS was evaluated from the date of surgery until the date of death or last follow-up.
The study was approved by the Ethical Committee of the Euromedica Kyanous Stavros Hospital of Thessaloniki (No. 64/28-7-2023). All procedures were performed in compliance with relevant laws and institutional guidelines. Privacy rights of human subjects were observed. The manuscript was written following the STROBE recommendations for reporting observational studies (19).
Statistical analysis. The statistical analysis was possible using the SPSS package 17.0 version (IBM Armonk, NY, USA). The proportions of patients with a given characteristic were compared using the chi-squared analysis or Fisher’s exact test. Survival curves were obtained using the Kaplan-Meier method, and the comparison of the curves was performed using the log-rank test. Cox’s regression model and logistic regression analysis were used for multiple analyses. A two-tailed p-value <0.05 was considered statistically significant.
Results
A total of 23 women with metachronous peritoneal carcinomatosis of endometrial cancer were included in the study. Rates of missing data were less than 1% for all variables except for data regarding TNM classification staging and the adjuvant therapy after the first operation where the missing data rates were higher.
The mean age of patients was 60.4±7.9 years (range=48-75 years). Four patients had been treated with adjuvant chemotherapy and radiotherapy and 6 had been treated with adjuvant radiotherapy. The mean PCI was 10.6±6 (range=3-39). Most patients (73.9%) had undergone complex and extensive operations previously for the treatment of the primary tumor. The majority of them (82.56%) underwent complete or near complete cytoreduction and HIPEC. There was no 30-day or in-hospital mortality; however, 8.68% of the patients suffered from severe morbidity. Table I presents patients’ clinical and pathological characteristics. The operative procedures are listed in Table II. No variable was identified to be related to morbidity in univariate analysis (Table III).
Patient characteristics.
Operative procedures.
Univariate analysis of morbidity.
Survival. The overall 5- and 10-year survival was 78% (Figure 1). The ASA stage, the completeness of cytoreduction, and the extent of peritoneal dissemination were found to be related to survival by univariate analysis. Multivariate analysis showed that the completeness of cytoreduction was the single possible prognostic indicator of survival (Table IV). The mean disease-free interval (from the time of the second surgical treatment) was 36±11 (range=24-52 months).
Kaplan-Meier overall survival curve of patients with recurrent endometrial cancer and peritoneal carcinomatosis treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. The estimated 5- and 10-year overall survival was 78%.
Analysis of morbidity.
Follow-up. The mean follow-up time was 17.5 months (range=3-104 months). During follow-up 19 patients (47%) were recorded with recurrence. In seven (30.4%) patients the recurrences were loco-regional, and in 2twopatients (8.7%) were distant (Table I). No variable was identified to be related to recurrence (Table V).
Univariate analysis of recurrence.
Discussion
Patients with recurrent EC represent a heterogenous group that varies in terms of histological subtype, previous adjuvant therapy, time interval to recurrence, and burden and location of disease (1). The literature focused on the management of recurrent EC is retrospective. From the available data only one third of the patients with recurrence underwent secondary radical surgery (1).
EC recurrence may be locoregional, or distant (either abdominal or extra-abdominal) (1). The pathophysiology of loco-regional recurrence is not completely understood particularly in those cases in which the neoplasm has not invaded through the wall of the uterine corpus. The local recurrence at the vaginal stump may be the result of cancer emboli entrapped at the suture line of the vault after exfoliation from the uterine mucosa either spontaneously or most frequently during surgical manipulations. However, the regional or peritoneal recurrence is rather the result of cancer emboli spread through the Fallopian tubes (20).
The appropriate treatment for recurrent EC is not well established and a multidisciplinary approach is necessary (4, 21). There is limited and inconclusive data on surgical treatment. CRS and platinum based systemic chemotherapy is the standard strategy for selected patients with metachronous peritoneal metastasis. A regional (intraperitoneal chemotherapy) treatment has seldomly been used. However, there is a need for improving the outcomes of patients with peritoneal metastasis from recurrent endometrial cancer. Combination of CRS and HIPEC has been proposed, with good results (20).
Complete cytoreduction was significantly associated with improved OS (3). In our cohort we achieved one of the highest reported rates of complete cytoreduction, 78.26%, while it is reported to range 57-95.7% (3, 6, 7, 21, 22). Properly selected patients will be offered significant survival benefit from CRS and HIPEC (7). Patients’ OS in our cohort was 78% at 10 years and is one of the longest OS rates reported so far in the literature. The completeness of cytoreduction was the single identified possible prognostic factor of survival. That was also the only significant variable after CRS in relation to progression free survival and OS in previous studies (23-26). Recent multicenter studies and systematic reviews also indicate the significant impact on survival of secondary complete cytoreduction in recurrent EC (5, 21, 22, 27). The most recently published meta-analysis reported estimated 1-, 2-, and 5-year survival rates of 65%, 37%, and 16%, respectively, for patients with endometrial cancer and peritoneal metastasis treated with CRS. Notably, patients who underwent optimal cytoreduction experienced a median survival time at least twice as long–and in some cases significantly longer–than those with suboptimal cytoreduction (5). The benefit of complete cytoreduction was evident even in patients with IVb EC regardless of the administration of neo-adjuvant or adjuvant chemotherapy and the presence of distant metastases (28). Moreover, even in comparison to other treatment modalities (chemotherapy, radiotherapy, hormonal therapy) CRS for recurrent EC resulted in improved oncologic outcomes and conferred a significant survival benefit (1, 5, 23). Our study demonstrated that CRS for recurrent EC should be considered as part of the standard treatment.
The purpose of cytoreduction is the resection of all or nearly all the macroscopically visible tumor. Microscopic tumor emboli and tumor cells will always remain in the abdominal cavity even after CC-0 surgery. These emboli will progress to large tumors if left untreated. Disease relapse during follow-up can be attributed to this microscopic component that cannot be seen by the surgeon. The administration of HIPEC after CRS may eradicate the microscopic component of the disease as has been shown in other diseases manifested with peritoneal dissemination (5, 29, 30). The administration of HIPEC after CRS facilitates treatment of the microscopic component of the disease through mechanical (continuous flow of the perfusion solution), physical (heat) and pharmacological (cytostatic) pathways (5, 16). Moreover, HIPEC achieves high local concentration while plasma concentration remains low and may destroy the peritoneally confined emboli when they are <0.25 mm in their largest diameter. Cancer nodules implanted at the peritoneal surfaces are not supported by adequate vasculature, which has been partially or totally destroyed by surgical manipulations. In addition, heat modifies the resistance of tumor cells enhancing their chemosensitivity. HIPEC is a targeted treatment strategy, theoretically preventing or delaying the progression of the disease within the peritoneal cavity while limiting systemic side effects (5, 16).
Limited literature exists on the use of HIPEC after CRS in treating peritoneal metastasis from EC. The most recent multicenter study, from PSOGI and BIG RENAPE groups, assessing the therapeutic value of HIPEC in addition to CRS in patients with peritoneal metastasis of endometrial cancer did not show any survival benefit (6). In this study, the use of HIPEC combined with CRS did not significantly affect disease-free survival and OS over CRS alone. Despite a poorer prognosis in case of recurrent disease, the use of HIPEC in women with peritoneal recurrence resulted in survival rates comparable to those of a primary advanced stage managed with optimal CRS. On the contrary, in a previous multicenter study from Spain, the addition of HIPEC after primary or secondary CRS conferred a better 5-year recurrence free survival of 23%, with a 5-year OS rate 40% in patients treated for peritoneal metastasis from EC (31). These results are in accordance with similar results from another multicenter study where in selected patients CRS and HIPEC achieved 5-year OS of 30% and a progression free survival of 15.5% (32). Even though they were well-designed studies with large sample sizes, they were retrospective. Moreover, all the aforementioned studies included patients with peritoneal metastases from both primary and recurrent EC, while the HIPEC protocol was not the same for all patients. On the contrary, our study included only patients with peritoneal metastasis from recurrent EC and the HIPEC protocol was the same for all patients. The last published meta-analysis showed that CRS and HIPEC had a significant survival impact with a 5-year survival rate of 22% (5). The survival benefit was most evident in the first two years after treatment. The optimal HIPEC protocol, in relation to the molecular profiling of the tumor, is an ongoing issue that warrants further investigation (5).
Similarly, in patients with peritoneal sarcomatosis, CRS and HIPEC confer a survival benefit especially in female patients. Although radical surgery with no microscopic residual disease seems to be the only valid therapeutic option for sarcoma diffusion throughout the abdomen the additional benefit of HIPEC remains to be evaluated (33). In addition, in a cohort of peritoneal metastases form rare histologies and uncommon tumor origins, including endometroid carcinoma, treated by complete cytoreduction with HIPEC, long term survival was achieved (34).
Although 47% of our patients had a recurrence after CRS and HIPEC, these recurrences were mainly locoregional. In the literature, there is limited data regarding the sites of recurrences after CRS and HIPEC.
CRS followed by HIPEC is a safe procedure with acceptable morbidity and mortality (3, 6, 7, 23). No mortality is reported in recent studies, while morbidity rates range from 14 to 42%, comprising mainly grade 1 and 2 complications using the Clavien-Dindo classification (21). In our cohort the severe complications were limited and comparable or even fewer in relation to literature reports, while there was no 30-day in-hospital mortality. No relation between morbidity and the factors studied was identified. Although most of the adverse events can be attributed to CRS, it cannot be ruled out that HIPEC increases the morbidity of CRS (7), but in our cohort such relation was not established.
Patient selection for CRS and HIPEC is of utmost importance, both for the best oncologic outcomes and regarding the morbidity and mortality when treating patients with recurrent EC. However, there are no particular criteria regarding patient selection of recurrent EC, and very few publications have proposed criteria (23, 31). Younger patients, acceptable performance status, high possibility of achieving complete cytoreduction, histology, time interval from initial surgery to recurrence and metastasis confined to the abdominal cavity are among them. The patients in our cohort met most of the criteria proposed.
The main strengths of this study are: i) the relatively large patient cohort. Most of the studies (even the multicenter) have small sample sizes, ii) the standardized procedure of the CRS and HIPEC protocol, which was used to treat all of our patients, iii) the focus of the study on the surgical management of the peritoneal metastasis exclusively due to recurrent EC only, and iv) the implementation of HIPEC after CRS as a treatment strategy.
The limitations of the study are i) the retrospective nature of the study with a long study period (24 years), ii) the single-center design, iii) no representation of the other, less common, histologic types of EC, and iv) absence of knowledge regarding the groups of the molecularly heterogenous high-grade endometrioid carcinoma with favorable as well as unfavorable prognosis (35), v) no consideration of the different patterns of endometrial cancer recurrence, involving the abdominal cavity alone or in combination with the pelvis and the vagina, vi) missing data regarding the stage classification of the first operation and the adjuvant therapy of the patients, vii) no calculation of the comprehensive complication index, which represents the true burden of morbidity and complications for each patient, however this was not carried out in any other similar studies either.
Implications for practice and future research. A standard CRS and HIPEC protocol was implemented as a treatment strategy for peritoneal carcinomatosis due to recurrent EC. Well-designed comparative clinical trials are still needed to investigate the therapeutic value of this treatment strategy, to establish the optimal HIPEC protocol and to establish patient selection criteria for optimal management. Moreover, a subgroup analysis of the results of this treatment strategy according to the molecular profile of the tumor would be worthwhile. Current guidelines indicate only cytoreductive surgery in patients with peritoneal carcinomatosis from recurrent EC (36, 37). The combination of HIPEC and immunotherapy should be also investigated.
Conclusion
Complete cytoreduction combined with hyperthermic intraperitoneal chemotherapy appears to offer significant survival benefit with low morbidity in patients with recurrent endometrial cancer and peritoneal carcinomatosis.
Footnotes
Authors’ Contributions
E Lolis: Conceptualization, Writing - original draft; D Kyziridis: Investigation, Validation; A Kalakonas: Data curation, Formal analysis; A Tentes: Project administration, Supervision, Writing - review & editing; All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Funding
This study received no funding.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received May 1, 2025.
- Revision received May 28, 2025.
- Accepted June 9, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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