Journal of Surgery

Introduction

Cytoreductive Surgery (CRS) followed by adjuvant systemic chemotherapy remains the standard of care for epithelial ovarian cancer [1]. Despite an initial favorable response, the majority of patients eventually experience recurrence. The 5-year survival rate remains below 30%, and the median Disease-Free Survival (DFS) is limited to approximately 18 months [2,3]. The introduction of Neoadjuvant Chemotherapy (NACT) has contributed in reducing peritoneal tumor burden, although it has not demonstrated any significant benefit in Overall Survival (OS) [4,5]. In recent years, prospective randomized trials have reported improved survival outcomes when Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is incorporated into interval cytoreduction protocols [6,7]. Since 2018, CRS combined with HIPEC has gained popularity in the United States [8], not only in the setting of recurrent and chemo-resistant disease, but also as upfront treatment in selected patients, with encouraging results [9,10]. Although, its role remains controversial and not yet definitively established, HIPEC has recently been proposed in the international guidelines as an option in the treatment of ovarian cancer [8,11-13]. The most significant prognostic factor of long-term survival is considered the performance of complete cytoreduction [14,15]. However, even with advanced multimodal therapies, recurrence remains common and continues to pose a major clinical challenge. Gadducci et al. reported a recurrence rate of 73% after primary CRS followed by systemic chemotherapy, and 87.1% following interval cytoreduction [16]. Esselen et al. observed a 62.9% recurrence rate after optimal cytoreduction combined with intravenous and intraperitoneal chemotherapy [17]. According to Chambers et al., recurrence rates following interval and recurrent CRS with HIPEC were 55% and 49%, respectively [18], while Munoz-Casares et al. reported rates of 57% and 43% for primary and recurrent disease treated with CRS and HIPEC, respectively [19]. These findings suggest that although intraperitoneal chemotherapy may reduce recurrence, the rate remains high regardless of treatment strategy. Historically, infra-colic omentectomy was considered sufficient for complete cytoreduction. However, undetected microscopic implants in the retained omentum may have contributed to rapid progression postoperatively, mistakenly classified as recurrence. Such cases likely reflect disease progression rather than true recurrence, possibly leading to overestimation of recurrence rates in earlier studies. The objective of the present study is to evaluate the incidence and anatomical distribution of recurrence in patients with epithelial ovarian cancer treated with complete cytoreductive surgery in combination with HIPEC.

Patients and Methods

Patients

The medical records of 239 women with advanced epithelial ovarian cancer who underwent complete Cytoreductive Surgery (CRS) in combination with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) between January 1^st 2003 and December 31^st 2023 were retrieved from a prospectively maintained institutional database. Diagnosis was established by physical examination, hematological and biochemical testing, tumor markers (CEA, CA 19-9, CA-125), thoracic and abdominal imaging (CT or MRI), and cytology or biopsy (either percutaneous or laparoscopic).Eligible patients were those capable of undergoing major surgery, with an ECOG performance status <2, white blood cell count >4000/mL, platelet count >150000/mL, blood urea <50 mg/dL, serum creatinine <1.5 mg/dL, no recent history of pulmonary disease, no signs of cardiomyopathy or electrocardiographic abnormalities, and no active urinary tract infection. All patients were over 18 years of age. Exclusion criteria included history of another malignancy at risk for recurrence (except adequately treated basal cell carcinoma or in-situ cervical cancer), distant unresectable metastases, pregnancy, or high-risk comorbidities involving renal, hepatic, cardiovascular, or pulmonary systems.

Ethical Aspects

A signed consent form, including an authorization statement that medical records can be used for future research, was obtained preoperatively. For the current retrospective, observational study an approval of the Institutional Ethical Committee was not deemed necessary.

Study Outcomes

The primary outcome of the study was recurrence sites. Secondary outcomes were DFS and OS.

Treatment Procedure

All patients underwent laparotomy via a midline incision extending from the xiphoid process to the pubic symphysis. The extent of prior surgery was assessed based on operative reports. Tumor volume was evaluated across the 13 abdominopelvic regions, and the Peritoneal Cancer Index (PCI) was calculated [20]. Standard peritonectomy procedures [21] and multivisceral resections were performed to achieve complete cytoreduction. The Completeness of Cytoreduction (CC) score was documented postoperatively [20]. From the total of 239 patients, 192 (80.3%) received Hyperthermal Intraperitoneal Chemotherapy. Out of the remaining 47 patients, 40 of them were chosen - as part of a different study protocol- to receive CRS alone, while a small number (7 patients) did not consent to the use of Intraperitoneal Chemotherapy. HIPEC was administered using the open “Coliseum” technique, following macroscopic tumor resection and prior to gastrointestinal reconstruction. The skin edges were suspended using long sutures on a Thompson self-retaining retractor to allow infusion of 2-3 liters of prime solution. A HIPEC delivery system (Sun Chip, Gamida Tech, Paris, France) equipped with dual roller pumps, heat exchanger, reservoir, inflow/outflow tubing, and thermal probes was used. Once the mean intra-abdominal temperature reached 40^°C, cytotoxic agents were instilled. HIPEC was performed at 42.5-43^°C for 90 minutes with intraperitoneal cisplatin (50 mg/m²) and doxorubicin (15 mg/m²), along with intravenous ifosfamide (1300 mg/m²) and mesna (260 mg/m²). Mesna was repeated twice at 4-hour intervals. In cases of diaphragmatic breach or resection, bicavitary HIPEC (peritoneal and pleural) was performed. The diaphragmatic defects and the gastrointestinal tract were restored after the completion of HIPEC. All patients were admitted to the Intensive Care Unit (ICU) for a minimum of 24 hours. Postoperative complications were recorded and graded according to the Clavien-Dindo classification [22]. All surgical specimens underwent detailed histopathological examination. Data recorded included tumor type, differentiation grade, and the number and sites of resected and infiltrated lymph nodes. Adjuvant systemic chemotherapy with platinum-based agents and taxanes was administered. From 2019 onward, maintenance therapy with bevacizumab was introduced, and PARP inhibitors became available from 2022.

Follow-Up

All patients were followed-up every 3-4 months during the first year and every 6 months thereafter, with physical examination, hematological and biochemical testing, tumor markers (CEA, CA-125), and imaging studies (abdominal and thoracic CT or MRI). Since 2003, 4 out of the total 239 patients reached the full 20-year follow-up milestone. Recurrence and the exact anatomical sites of recurrence were carefully recorded. Initially, sites of recurrence were categorized as distant or locoregional. Metastatic lesions in the liver parenchyma, lungs, brain, bones, spleen, or lymph nodes were classified as distant metastases. Recurrence involving the peritoneal surfaces (below the diaphragm) or the vaginal vault was classified as locoregional. Disease-Free Survival (DFS) was defined as the interval between initial diagnosis and the first radiological evidence of recurrence. Overall survival (OS) was defined as the interval from initial diagnosis to death or last follow-up.

Statistical Analysis

Statistical analysis was performed using SPSS software (version 22.0, IBM Corp., Armonk, NY, USA). All recorded clinical and pathological variables were analyzed for associations with recurrence. Categorical variables were analyzed using Fisher’s exact test. Multivariate analysis was performed using logistic regression with backward elimination to identify independent prognostic factors for recurrence. Survival curves were generated using the Kaplan-Meier method, and comparisons between groups were performed using the log-rank test. A p value < 0.05 was considered statistically significant.

Results

Analysis

Between January 1^st 2003 and December 31^st 2023, a total of 239 women (mean age 61.3 ± 12 years, range 16-100) underwent complete cytoreductive surgery (CC-0) for advanced epithelial ovarian cancer (FIGO stage III). Of those, 192 patients (80.3%) received CRS combined with HIPEC.

Baseline clinical characteristics are summarized in (Table 1).

• The mean Peritoneal Cancer Index (PCI) was 8 ± 6 (range: 1-35).
• The mean number of Peritonectomy Procedures (PP) was 5 ± 3 (range: 1-13).
• Mean intraoperative blood loss was 203 ± 338 mL (range: 100-2500).
• Mean transfused Blood Units (BU) and fresh frozen plasma (FFP) were 1 ± 1 (range: 0-10) and 3 ± 3 (range: 0-12), respectively.
• Mean ICU stay was 1 ± 1 day (range: 1-8).
• The mean Number Of Suture Lines (NSL) and Anastomoses (NA) was 2 ± 1 (range: 0-10) and 1 ± 1 (range: 0-5), respectively.

The median follow-up duration was 22 months (range: 3-240). Recurrence was observed in 94 patients (39.3%), with 46 (19.2%) presenting with distant and 48 (20.1%) with locoregional recurrence (Table 1). As shown in (Table 2), PSS, HIPEC treatment, and intraoperative FFP transfusion were significantly associated with disease-specific survival (Table 2). Univariate analysis revealed that HIPEC, FFP transfusion, neoadjuvant chemotherapy (NACT), and prior surgical history were associated with recurrence (Table 3). Multivariate analysis identified PSS, NACT, and FFP transfusion as independent predictors of recurrence.

Table 1: Patient Characteristics and Clinical Variables (N: 239).

Explanations: PCI: Peritoneal Cancer Index, PP: Peritonectomy Procedures, BL: Blood Loss, BU: Transfused Blood Units, FFP: Number of Transfused Fresh Frozen Units, NSL: Number of Suture Lines, NA: Number of Anastomoses, DS: Duration of Surgery

Table 2: Recurrence, Progression-Free Survival and Disease-Specific Survival.

Explanations: PCI: Peritoneal Cancer Index, PP: Peritonectomy Procedures, BL: Blood Loss, BU: Transfused Blood Units, FFP: Number of Transfused Fresh Frozen Units, NSL: Number of Suture Lines, NA: Number of Anastomoses, DS: Duration of Surgery

Table 3: Analysis of Recurrence.

Recurrence rates by type of CRS were

• Primary CRS: 59 of 131 (45%)
• Interval CRS: 16 of 25 (64%)
• Secondary CRS: 19 of 24 (79.2%) (p< 0.001)
• The most frequent anatomical site of recurrence was the lymph nodes, followed by the small bowel, liver, and pelvis (Table 4).
• Kaplan-Meier survival analysis showed:
• 1-, 5-, and 10-year DFS: 82.9% ± 2.8%, 39.6% ± 4.4%, and 30.9% ± 5.2%, respectively (Figure 1).
• Mean DFS: 95.7 ± 9.8 months (95% CI: 6.51-114.85)
• Median DFS: 36 ± 4 months (95% CI: 28.14-43.86)

The 5-, 10-, and 20-year OS among patients treated with CC-0 CRS and HIPEC was 78%, 70%, and 70%, respectively (Figure 2). In univariate analysis, performance status, ASA class, extent of peritoneal disease, FFP transfusion, and duration of surgery were significantly associated with overall survival (p< 0.05). Multivariate analysis confirmed performance status as an independent prognostic factor for OS (Table 5). In patients with lymph node recurrence, the 5-year OS was 38%, with a median survival of 29 months. For patients with locoregional recurrence, the 5-year OS was 64%, and the median survival was not reached.

3.2. Figures, Tables and Schemes

Table 4: Location Of Recurrent Disease.

Explanations: PS: Performance Status, ASA: American Society of Anesthesiologists, PSS: Prior Surgery Score, TV: Tumor Volume, LNR: Retroperitoneal Lymph Node Resection, NACT: Neoadjuvant Chemotherapy, PCI: Peritoneal Cancer Index, BL: Blood Loss, BU: Transfused Blood Units, FFP: Number of Transfused Fresh Frozen Units, NSL: Number of Suture Lines, DS: Duration Of Surgery.

Table 5: Analysis of Overall Survival.

Figure 1: Kaplan-Meier Curve For Disease-Free Survival.

Figure 2: Kaplan-Meier Curve For Overall Survival.

Discussion

Historically, the standard surgical approach for advanced epithelial ovarian cancer included infracolic omentectomy and, only rarely, selective resection of macroscopically seeded peritoneal surfaces. Although the pathophysiology of peritoneal carcinomatosis is now well understood, and the introduction of standard peritonectomy procedures has transformed the surgical management of peritoneal disease [21], many surgeons continue to adhere to outdated operative strategies. Importantly, complete cytoreduction cannot be reliably achieved with infracolic omentectomy alone. In such cases, the detection of new disease postoperatively should more appropriately be considered progression rather than true recurrence. The term "recurrence" is most accurately applied in those cases in which standard peritonectomy procedures have been performed, and the surgeon may reliably confirm that complete macroscopic cytoreduction (CC-0) has been achieved. Therefore, we assumed that the precise estimation of the recurrence rate would be reliable if only patients undergoing complete cytoreduction (CC-0 surgery) are included. Despite optimal surgical resection and adjuvant systemic chemotherapy, recurrence remains a frequent event, with reported rates ranging from 62% to 88% [23-25]. As demonstrated in our findings, the recurrence rate differs significantly among primary, interval, and secondary cytoreductive procedures, highlighting the importance of patient selection and timing of intervention [16]. Several prospective studies have demonstrated improved overall and progression-free survival in patients treated with complete CRS followed by normothermic intraperitoneal chemotherapy [26-30]. The addition of HIPEC has been associated with a reduction in recurrence rates, likely due to its capacity to eradicate residual microscopic disease that would otherwise escape detection [17,18].

One major advantage of intraperitoneal chemotherapy lies in its pharmacologic profile, which enables high local drug concentration with minimal systemic exposure [31]. Furthermore, it has been hypothesized that intraperitoneal administration also delivers therapeutic drug levels to the portal circulation, potentially targeting hepatic and lymphatic micrometastases. This is supported by data showing that approximately 90% of intraperitoneally administered agents are absorbed via the visceral peritoneum [32]. In our study, we observed a 10- and 20-year overall survival rate of 70%, which is notably higher than typically reported. This may be attributed to the fact that no recurrence was observed beyond the 10-year follow-up period, suggesting that long-term disease control or cure is achievable in a selected subgroup of patients who undergo complete CRS and HIPEC. Previous studies have shown that the majority of recurrence in epithelial ovarian cancer is locoregional, predominantly involving the abdominal cavity [17,18,33]. Peritoneal recurrence commonly occurs both at previously treated and untreated sites following CRS [33]. Notably, the initial recurrence frequently involves the upper abdomen [34]. This pattern supports the concept of tumor cell entrapment, whereby residual microscopic disease persists despite apparent complete cytoreduction [35,36]. According to this theory, traumatized peritoneal surfaces attract free cancer cells that become entrapped in fibrin clots or blood deposits and later proliferate into macroscopic implants under the influence of growth factors [37]. Interestingly, in our study, distant and locoregional recurrence was equally distributed among cases, diverging from traditional patterns. One possible explanation is our classification of lymph node involvement as distant metastasis, a categorization that remains inconsistently defined in the literature, though it does not contradict previously published findings [18]. A second explanation may lie in the broad application of HIPEC in our cohort, which appears to contribute to more effective locoregional disease control.

This hypothesis aligns with results from Chambers et al., who reported that 50% of ovarian cancer patients treated with CRS and HIPEC experienced extraperitoneal first recurrence [18]. Similar trends have been observed in patients receiving Intravenous/Intraperitoneal (IV/IP) chemotherapy [17,30]. These findings suggest that HIPEC offers comparable efficacy to IV/IP chemotherapy in controlling locoregional disease, while possibly increasing the risk for extraperitoneal relapse [17,30,38]. Patients whose recurrence is primarily lymphatic tend to have better survival outcomes than those with peritoneal or hematogenous metastases [25]. However, our data diverge from this trend, showing a 5-year survival rate of 64% for patients with locoregional recurrence, compared to only 38% in those with lymph node involvement. Amate et al. reported nodal recurrence in 38% of cases, with 87% of those occurring below the diaphragm and 13% above. The main risk factors for nodal recurrence included preoperative nodal involvement and diffuse peritoneal spread [33]. In our cohort, 41.1% of patients developed nodal recurrence. These findings are consistent with previous studies: Esselen et al. and Tanner et al. reported 41% and 45% respectively of extraperitoneal recurrence in patients treated with IP chemotherapy [17,30]. Conversely, Usami et al. demonstrated that 60% of recurrence sites following CRS were confined to the peritoneal cavity [39]. Nevertheless, complete cytoreduction remains the most effective measure to improve outcomes by reducing recurrence risk [40].

Despite aggressive CRS and the adjunctive use of HIPEC, the recurrence rate in our CC-0 cohort remains 39.3%. A plausible contributing factor may be the residual microscopic disease along the mesenteric border of the small intestine, where complete electro-evaporation of tumor nodules is technically challenging. This limitation is particularly evident in recurrent disease, even after meticulous adhesiolysis. Furthermore, tumor emboli trapped within scar tissue may resist eradication by intraperitoneal chemotherapy, unlike freely circulating tumor cells. Patients experiencing early recurrence often have biologically aggressive tumors [41]. Increased risk of recurrence has been associated with lymph node involvement, selective peritonectomy, and incomplete cytoreduction, even when residual disease is less than 0.25 cm [42]. While both peritoneal carcinomatosis extent and nodal infiltration significantly impact progression-free survival, they appear to exert less influence on overall survival [42]. Ultimately, recurrence is determined more by what the surgeon leaves behind than by what is removed [43]. This study has some limitations. Its retrospective nature may introduce selection or reporting biases. Moreover, although high-volume, the study is conducted in a single center, somewhat affecting its reliability. Finally the classification of nodal involvement as distant metastasis remains somewhat arbitrary, as the distinction between intraperitoneal and extraperitoneal lymphatic spread is not clearly defined. In our analysis, we did not differentiate between abdominal and extra-abdominal nodal recurrence. The strengths of our study include the use of strict criteria to define Complete Cytoreduction (CC-0) and the inclusion of a relatively large patient population undergoing uniform treatment protocols in a high-volume center.

Conclusions

Treatment of epithelial ovarian cancer is increasingly trending towards treatment of peritoneal disease, with significant impact on recurrence rate. Complete cytoreduction (CC-0) rises as a major factor affecting recurrence and the addition of HIPEC has been associated with increased disease-free survival rates. Our study focuses mainly on recurrence sites following complete CRS and HIPEC, with the interesting finding of equal distribution between distant and locoregional recurrence. These results may be affected by the categorization of lymph node involvement as distant disease, as well as by the broad application of HIPEC, which seems to offer better locoregional control. Interestingly enough, the 5-year survival rates for patients with locoregional recurrence was 64% compared to the respective 38% of the lymph node involvement sub-group, a finding which contradicts bibliographical data. Despite its limitations, our study contributes to the investigation on recurrence rates and sites of women undergoing treatment for epithelial ovarian cancer, with an emphasis on clearly defined complete cytoreduction criteria and the use of HIPEC in a uniformly applied perioperative protocol in a high-volume center.

Author Contributions: Conceptualization, C.M. and A.A.T.; methodology, C.M. and A.A.T.; validation, M.D. and E.E.; formal analysis, C.M. and D.K.; investigation, C.M.; data curation, A.A.T and A.K..; writing—original draft preparation, C.M. and A.A.T.; writing—review and editing, M.D. and E.E.; visualization, C.M. and G.T.; supervision, C.M.; project administration, M.D. and E.E. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Ethical Considerations: The study was conducted in accordance with the Declaration of Helsinki. Institutional approval was obtained. Informed consent was obtained from all subjects involved in the study.

Data Availability Statement: The original contributions presented in this study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Conflicts of Interest: The authors declare no conflicts of interest.

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