Peritoneal metastases from rare ovarian cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC)

Abstract Objectives There are limited treatment options and no consensus on the management of advanced rare ovarian malignancies. Rare ovarian malignancies can present with peritoneal metastases (PM), featuring a similar presentation to more common ovarian subtypes. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is an effective treatment for PM of non-gynecologic origin and, recently, epithelial ovarian cancer. We evaluated the feasibility of CRS/HIPEC in the management of PM from rare ovarian malignancies and report postoperative outcomes on these patients. Methods A retrospective review of a single center, prospective database (1994–2021) was performed to identify patients with rare ovarian malignancies treated with CRS/HIPEC. Clavien-Dindo 90-day morbidity/mortality and Kaplan–Meier overall (OS) and progression-free survival (PFS) were analyzed. Results Of 44 patients identified, 28 underwent CRS/HIPEC. Six were aborted due to extensive disease. Histologic subtypes included: clear cell (5/28, 17.9 %), endometrioid (5/28, 17.9 %), granulosa cell (3/28, 10.7 %), low-grade serous (6/28, 21.4 %), mesonephric (1/28, 3.6 %), mucinous (6/28, 21.4 %), and small cell (2/28, 7.1 %) carcinomas. Eight (28.6 %) patients had primary and 20 (71.4 %) had recurrent disease. Median peritoneal cancer index (PCI) was 21 (IQR: 6–29). Complete cytoreduction (<2.5 mm residual disease) was achieved in 27/28 (96.4 %). Grade III/IV complications occurred in 9/28 (32.1 %) with one (3.6 %) mortality. After a median follow-up of 65.8 months, 20 patients were alive. Five-year OS and PFS were 68.5 and 52.6 %, respectively. Conclusions In patients with PM from rare ovarian malignancies, CRS/HIPEC is feasible and has an acceptable safety profile. Longer follow-up and multicenter trials are needed.


Introduction
Similar to more common ovarian subtypes, some rare ovarian malignancies (incidence <6/100,000 cases/year) can spread to the peritoneum [1,2], which leads to treatment challenges, as well as significant morbidity and poor survival.There is no clear data regarding management of peritoneal metastases (PM) in rare ovarian malignancies and, despite representing 50 % of all gynecologic malignancies [3][4][5], these patients are under-represented in most cancer trials.The current standard of care for ovarian cancer with PM, including rare subtypes, is cytoreductive surgery (CRS) that aims for removal of all macroscopic disease and systemic chemotherapy.However, the high recurrence rates after CRS and limited effect of systemic chemotherapy in low vascularized peritoneal lesions warrants the use of new strategies that can provide better loco-regional control.
Delivering high concentrations of hyperthermic intraperitoneal chemotherapy (HIPEC) to the peritoneal cavity after a complete CRS successfully controls PM in nongynecologic malignancies, such as appendix and mesothelioma [6,7].Peritoneal spread of ovarian cancer can display a similar clinical presentation to these peritoneal surface malignancies.This is especially true in some rare ovarian tumors (mucinous ovarian cancer), where voluminous, mucinous ascites, and poor chemotherapy response is observed [8][9][10].In line with this, evidence shows that epithelial ovarian cancer can also benefit from CRS/HIPEC by prolonging time to recurrence [11].Thus, CRS/HIPEC may also be useful in rare ovarian subtypes given the similar presentation.
Limited knowledge about these rare tumors and low number of annual cases makes it difficult to design a prospective study and analyze different treatments.Not surprisingly, randomized control trials are lacking and most treatment decisions are drawn from experience with more common ovarian subtypes or tumors with similar pathobiology [5,[12][13][14].In this sense, any knowledge about their course and response to oncologic treatments in advanced stages serves as useful information.Considering the benefit of CRS/HIPEC in the treatment of PM and its safety profile, we hypothesize that patients with PM from rare ovarian malignancies can safely undergo CRS/HIPEC, which may delay disease progression.We evaluated the feasibility of CRS/HIPEC in the management of PM from rare ovarian malignancies and reported the postoperative outcomes for these patients treated at a high-volume center.

Patient selection
A retrospective review  of a prospective database of >1,000 patients with peritoneal dissemination from different primaries (appendix, colon, mesothelioma, and ovarian cancer) treated with CRS/ HIPEC at a single-, high-volume peritoneal surface malignancy center was performed.Patients with newly diagnosed or recurrent PM (The International Federation of Gynecology and Obstetrics [FIGO] stage III/IV) of primary peritoneal, fallopian tube, or ovarian origin with rare histology who underwent CRS/HIPEC at our institution with ≥3 months follow-up were included.All patients were classified according to the World Health Organization (WHO) and re-staged according to FIGO 2014 criteria [13].Histopathology reports from previous biopsies or surgeries were reviewed and confirmed by CRS/ HIPEC experienced, board certified pathologists.Tumors were defined as rare if recording an incidence of less than six cases per 100,000 annually [3], and included non-high grade serous (HGS) tumors, sexcord, and germ cell tumors.Carcinosarcomas, complex and rare tumors that involve both cellular components of epithelium and mesenchyme, were excluded from this study and its outcomes were analyzed separately [15,16].Patients who had an aborted HIPEC were excluded from the post-HIPEC morbidity/mortality analysis.

CRS/HIPEC and data collection
CRS was performed as previously described [17] by both a gynecological and surgical oncologist.Selection criteria for surgical candidates was extrapolated from standard criteria of common indications for CRS/ HIPEC.In brief, patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, adequate bone marrow, renal, hepatic function, and blood coagulation parameters, a sufficient support system, and in whom achieving a complete cytoreduction was feasible were deemed surgical candidates [17].Certain imaging findings (CT scan or PET-CT) were taken into account for determining the feasibility of a complete cytoreduction.These included disease extension outside the peritoneal cavity, biliary obstruction, foreshortened mesentery, diffuse carcinomatosis on the small intestinal loops and at the diaphragmatic level, and/or liver parenchymal involvement [17].Of note, no specific PCI cutoff was used to determine surgical eligibility.
The Institutional Review Board approved this study.Consent was obtained from all patients as part of an ongoing observational cohort study.Patients were aware of the experimental nature of the treatment and counseled on the availability of other therapies.

Postoperative care and follow-up
Patients were transferred to the intensive care unit (ICU) during the first 24 h after surgery and then to the inpatient floor when clinically stable.Length of ICU and hospital stay (LOS) was recorded for each patient.Postoperative follow-up occurred at two and four weeks post-discharge, every three months for two years, and then every six months thereafter.Follow-up included physical exam, tumor markers, and CT/PET-CT.Tumor recurrence was diagnosed based on physical exam, rising tumor markers, imaging studies, biopsy results, and/or clinical presentation.

Statistical analysis
Statistical analysis was performed using SPSS V.23.0.Medians and interquartile ranges (IQR) were used to describe continuous variables not normally distributed.Categorical variables are presented as counts and proportions.Progression-free survival (PFS) was defined as the time in months from CRS/HIPEC to the date of tumor recurrence or death, whichever occurred first.Overall survival (OS) was calculated from the date of CRS/HIPEC to date of death or last follow up.PFS and OS were calculated using the Kaplan-Meier method and compared using the Logrank test.

Discussion
Rare ovarian cancers include a variety of tumors with diverse biology.Given the high recurrence rates and low chemotherapy response for some subtypes (i.e.clear cell and small cell carcinomas), there is an unmet need for additional treatment options [23].Since rare ovarian malignancies can present with extensive, often debilitating loco-regional PM, the addition of HIPEC to CRS poses as a suitable option for peritoneal disease control and treatment in these select patients.We present perioperative and long-term outcomes of a cohort of patients with PM from rare ovarian tumors treated with CRS/HIPEC, including seven histologic subtypes (clear cell, endometrioid, low-grade serous, mesonephric, mucinous, granulosa cell, and small cell carcinomas).For all subtypes, achieving a complete cytoreduction remains a major prognostic factor for ovarian cancer.There is substantial evidence that optimal survival outcomes after CRS are achieved in ovarian cancer patients with little or no residual disease at the completion of surgery [24,25].Maximal efforts should be made to remove all visible disease.Therefore, the ability to achieve a complete cytoreduction is paramount in patient selection for CRS/ HIPEC.In our cohort, 27/28 (96.4 %) patients who underwent CRS/HIPEC had minimal residual disease (tumors <2.5 mm) after CRS.These results are similar to those reported in ovarian cancer trials evaluating CRS/HIPEC [11,26], where minimal residual disease was left in 87 % of patients, demonstrating that a CC-0/1 can also be accomplished for advanced rare ovarian tumors.
Even after a complete CRS, most patients with ovarian cancer (up to 60 %) recur in the peritoneal cavity [27,28].HIPEC can target residual microscopic disease left behind after CRS, improving the quality of CRS and assisting in the delivery of high-dose chemotherapy directly to the peritoneum.These benefits are evidenced by a significantly lower incidence of peritoneal recurrences in patients with ovarian cancer treated with CRS/HIPEC compared to those treated with CRS alone [29][30][31], suggesting that adding HIPEC to interval CRS improves intraperitoneal disease control in HGS ovarian cancer [32].In our study, less than 50 % of patients had disease recurrence after CRS/HIPEC, with Complications of any grade occurred in / patients.Of these, / patients presented with more than one complication of the same or different grade.Major complications (grade III/IV) occurred in / patients.
Falla-Zuniga et al.: Peritoneal metastases from rare ovarian cancer higher rates of extra-vs.intra-peritoneal recurrences (50.0 vs. 25.0 %).This suggests that HIPEC can also provide loco-regional disease control in rare ovarian tumors.Understandably, CRS/HIPEC implementation has been limited by concerns around its safety profile.As an extensive procedure, CRS/HIPEC can pose significant risks for postoperative morbidity and mortality.However, when performed at experienced centers and following defined guidelines, significant surgical trauma can be minimized [33,34].Our cohort had an acceptable major complication (32.1 %) and mortality rate (3.6 %), similar to that reported for CRS alone and in previous HIPEC trials [11,26,33,35,36].A single intra-procedural complication of hypotension occurred, which resulted in a shortened HIPEC perfusion.The most common complication was anemia, which responded to blood transfusion.Accordingly, CRS/HIPEC has an acceptable safety profile in rare ovarian tumors, with results similar to that reported for HGS ovarian cancer.
No prospective trials have evaluated the potential benefit of adding HIPEC to the treatment of rare ovarian tumors.Both of the phase-III clinical trials that demonstrated a survival benefit of adding HIPEC for advanced ovarian cancer treatment only included a few patients with rare ovarian malignancies, but no histology specific outcomes were reported due to limited sample size [11,26].Use of HIPEC in rare ovarian tumors has been mostly documented in retrospective studies.These studies mainly consisted of heterogeneous cohorts including nongynecologic tumors, analyzed all together and with limited information by tumor type [10,37].The PSOGI Working Group (2018) and INDEPSO (2022) have reported two cohorts of patients with rare ovarian cancer treated with CRS/HIPEC [2,9].Both demonstrated an acceptable morbidity (major complication rate: 42.2 and 15.8 %, respectively) and feasibility for achieving complete CRS (CC-0/1: 92.5 and 81.2 %, respectively).No definite conclusions for OS and PFS were possible given the limited data by tumor subtype and diverse treatment groups, including multiple perfusion agents.However, the PSOGI Working Group observed significant differences in PFS within rare cancer subtypes, showing best results for mucinous tumors.Although results from these studies and ours are limited, the addition of HIPEC to treat advanced patients with rare ovarian cancer warrants further consideration and encourages the conduction of more systematic and multi-center investigations.
The main strengths of our study are the rigor of our data collection, a low lost to follow-up rate (0 %) in underreported histologic subtypes, experience as a high-volume peritoneal surface malignancy center, and strict long-term follow-up.We acknowledge that our study has some limitations related to the retrospective nature, inclusion of patients treated over >20 year span (representing variations in patient selection, management and surveillance), small sample size without a comparison group, and the high number of rare ovarian histologies resulting in the use of multiple HIPEC agents and adjuvant chemotherapy recommendations.Nonetheless, this study provides evidence of an available treatment option that is safe and can provide long-term outcomes in select patients with PM from rare ovarian malignancies.
Our study confirms that HIPEC can be safely used to treat PM of rare ovarian tumors after achieving a complete CRS (CC-0/1) for both primary and recurrent patients.The long PFS (median: 75.6 months) and low percentage of peritoneal recurrences (25.0 %) support the hypothesis that CRS/HIPEC may provide loco-regional disease control; however, questions remain around which HIPEC agent should be used and the true survival benefit of CRS/HIPEC for each histology.

Conclusions
We demonstrated that CRS/HIPEC is feasible and has an acceptable safety profile for PM originating from rare ovarian tumors, with the possibility of providing local tumor control.Longer follow-up and multicenter collaborative trials are needed to address this hypothesis and define survival outcomes for each histology.
Research ethics: The Institutional Review Board approved this study.Informed consent: Informed consent was obtained from all individuals included in this study.Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.Competing interests: Authors state no conflict of interest.
Research funding: Funded by an annual fundraising event, Heat It to Beat It.Data availability: Data available on request due to privacy/ethical.