PSM were considered terminal diseases with limited therapeutic options and heralded a poor prognosis [46,47]. A step change occurred at the end of the last millennium [48], as a result of the adoption of novel surgical techniques, such as peritonectomy procedures and multivisceral resections (1995) [49], and the application of intraperitoneal chemotherapy (1980) [50,51,52,53,54]. Aggressive peritoneal therapies are based on the premise that cancer isolated to the peritoneal cavity is a locoregional disease, exhibiting unique behaviors compared with extraperitoneal metastatic disease [55]. Regarding OC, treatment decisions are mainly based on the disease stage and biology, prior therapy and comorbidities. 2.1. CRS in Primary Ovarian Cancer with Peritoneal MetastasesThe standard first-line treatment of advanced OC consists of cytoreductive surgery (CRS), to remove as much of the cancer as possible, followed by taxane and/or platinum-based chemotherapy (every three weeks for six cycles) [1,3,56]. More than two chemotherapy drugs in combination do not improve outcomes. CRS or debulking surgery is defined as “primary” if it is aimed at completing the resection of all macroscopic tumors in patients with their first diagnosis of advanced OC before any other treatment; “interval” when following neoadjuvant chemotherapy (three to six cycles additional cycles) [16,57]; and “consolidation” after a complete response to neoadjuvant chemotherapy [58].Nowadays, preoperative chemotherapy is administered in high-volume diseases (i) to improve tumor resectability [59,60], (ii) to perform a test of in-vivo sensitivity selecting good responders to hyperthermic intraperitoneal chemotherapy (HIPEC), (iii) in women with a poor performance status at presentation due to high-risk comorbidities [61,62] or (iv) to impede the growth of resistant cancer cells that remain after the first round of chemotherapy, delaying disease progression [63,64,65,66,67,68].Rosen et al. reported that 50.1% of patients treated with neoadjuvant therapy achieved a status of no residual disease, compared with 41.5% of patients who underwent primary debulking surgery [69]. Surprisingly, 7-year OS rates were strongly different between interval and primary treatment groups (8.6% vs. 41%, respectively), suggesting the role of chemotherapy in camouflaging microscopic tumor foci remaining after surgery. After the European Organization for Research and Treatment of Cancer (EORTC) trial firstly demonstrated the noninferiority of neoadjuvant therapy followed by interval debulking surgery, it was considered in a wider breadth of patients [70,71]. However, while the CHORUS trial showed similar results [72], the MSKCC trial showed prolonged survival when compared with patients in EORTC study [73]. On the other hand, JCOG0602 failed to demonstrate non-inferiority [74] and SCORPION failed to demonstrate the superiority of preoperative therapy [75]. The next SUNNY trial will evaluate the efficacy and safety of interval CRS in AJCC TNM stage IIIC or IV epithelial OC [76]. The next TRUST trial will compare primary CRS followed by six cycles of platinum-based chemotherapy vs. interval CRS (three cycles of neoadjuvant chemotherapy and three cycles of platinum-based post-operative chemotherapy), in order to clarify the optimal timing of surgical therapy [77]. Finally, the next CHRONO trial will assess the impact of interval CRS after three cycles of neoadjuvant chemotherapy (paclitaxel and carboplatin) compared with delayed surgery after six cycles of neoadjuvant chemotherapy on PFS, in FIGO IIIB–IVA patients unsuitable for complete primary surgery [78]. In addition, host factors, such as BRCA1 and BRCA2 status, predict the response to chemotherapy and, therefore, the time to recurrence, but do not affect long-term OS [5,60,79,80,81].As reported in the literature, CRS is considered “optimal” if the residual tumor is less than 1 cm in maximum diameter or thickness [82]. However, the concept of “optimal debulking” is usually dangerously confused with the complete tumor resection and no residual disease (R0) among the non-expert community [19]. Complete CRS, according to the Gynecologic Cancer Inter Group (GCIG), is a state of no visible residual disease, associated with a significantly increased OS and PFS [71,83,84]. A large meta-analysis recently concluded that a residual tumor is a more powerful prognostic determinant than the FIGO stage [19,85,86]. Biological, genomic and molecular features have been investigated to develop predictive signatures that are correlated with optimal and R0 debulking [87,88,89]. On the other hand, a standardized lymphadenectomy has not yet been designed [90], while currently, the removal of bulky lymph nodes is carried out as part of an attempt to achieve maximum cytoreduction [91]. Moreover, despite a trend toward a longer OS in the total parietal peritonectomy, which comprised removal of the entire parietal peritoneum and the greater and lesser omental rather than selective parietal peritonectomy, its use is more liberally applied [92].Currently, the consensus standard for medical therapy is a combination of carboplatin and paclitaxel, both administered every 3 weeks. Dose-dense chemotherapy should not be considered as a standard because of the lack of evidence in Western studies [93,94,95]. Adjuvant chemotherapy is recommended to begin as soon as possible, possibly after 2–4 weeks, as longer delays lead to worse outcomes [96,97,98].Despite excellent treatment responses in around 70% of women, most patients develop recurrence within the next 3 years [99]. In these cases, second-line or maintenance therapy was performed, given to delay the disease progression [100].There is much debate about the optimum timing of treatment (neoadjuvant or adjuvant chemotherapy, primary or interval CRS) and the best route of administration (intravenous (IV) or intraperitoneal (IP) therapy). Narod [101], focusing on 20% of women surviving for 10 years or more [102], proposed a holistic model in disease insight: if no residual cancer cells persist in the abdomen after treatment, recurrence is impossible; if no intra-abdominal recurrence develops, the patient is cured [103]. Although there is no complete consensus [104,105], R0 seems to be the highest after primary CRS and IP chemotherapy, while the lowest for women who receive neoadjuvant chemotherapy:Among OC patients who achieve a status of no residual disease through neoadjuvant chemotherapy and interval CRS, an estimated 10% have no residual cancer cells [71,72];If an initial visible residual disease after primary CRS goes to complete tumor resection after adjuvant IV or IP chemotherapy, 18% of patients have R0 [106];

If complete tumor resection was obtained after primary CRS, the probability of having no residual cancer cells after adjuvant chemotherapy is estimated to be 33% for those who receive IV chemotherapy and 50% for those who receive IP chemotherapy.

2.2. HIPEC in Primary Ovarian Cancer with Peritoneal MetastasesThe poor prognosis after standard chemotherapy and the attitude of that remaining, confined to the abdomen, has produced an increased interest in the use of IP therapy. IP chemotherapy takes advantage of the blood–peritoneal barrier to achieve a much higher drug concentration at the peritoneal surface [107,108,109,110]. The addition of hyperthermia to IP chemotherapy implies the thermal enhancement of the chemotherapeutic agents used, increased drug uptake in malignant cells secondary to increased membrane permeability, inhibits repair mechanisms, facilitates lysosomal enzyme activation and selectively improves vascular flow in normal cells [18,111,112].The first report of the application of HIPEC in OC was in 1994. Since that time, several studies, enrolling large cohorts of women, evaluate the conjunction of HIPEC with CRS [20,113,114], both in the primary and recurrent disease [115,116]. The most recent meta-analysis [116,117,118,119] reported improved PFS after CRS and HIPEC in patients with primary advanced OC, even after adjustment for potential confounders (such as age, stage, neoadjuvant chemotherapy, grade, ECOG status [120], and histology). However, due to the retrospective nature, their results should be interpreted with caution, conditioned by a wide variety of chemotherapeutic regimens [121]. The goal of CRS–HIPEC is to remove all visible macroscopic disease while preserving organ function as far as possible. When combined, CRS and HIPEC showed better PFS and OS both in an upfront approach [122], and after neoadjuvant chemotherapy (CARCINOHIPEC trial) [123]. To reach the maximum effect of HIPEC therapy, it should be given when an optimal debulking is performed [19,106,119,124,125,126], achieving a long-term survival rate of around 50%. A multi-center French study compared the consolidation, interval and primary HIPEC for advanced OC, registering an increased OS between groups (33.4 vs. 36.5 vs. 52.7 months, respectively). Moreover, patients performing a well-executed CRS at less than 2.5 mm had a median OS of 41.5 months, compared to 21.2 months for all the others [124]. Patients with residual disease undergoing HIPEC after CRS might increase their life expectancy by 1 year, but do not enhance their chance of a cure [96].A surgical procedure for OC has been widely described [113,127]. Firstly, the intraoperative re-staging of the disease is performed, and the peritoneal cancer index (PCI) is calculated, based on the distribution and implant size of the metastases as described by Jacquet and Sugarbaker in 1996. Extensive involvement of the small bowel or hepatic hilum is the main contraindication to CRS and HIPEC, as well as the assessment of incomplete resectability with a large residual tumor.The standard CRS includes the pelvic peritonectomy with en-bloc extra-peritoneal hysterectomy and adnexectomy, until the Douglas pouch (Figure 1). The rectum is also en-bloc removed if it is extensively involved by the tumor and a protective ileostomy is performed, whereas small tumor nodules (if present) are removed with rectal preservation. While appendectomy, radical omentectomy and para-aortic and/or pelvic lymphadenectomy (in cases with clinically involved nodes) generally complete the standard procedure, more extensive peritonectomy or visceral resections are less predictable [129], depending on the presence of extra-pelvic peritoneal nodules (Figure 2).In some selected cases, mesenteric peritonectomy may be indicated, when this is associated with a chance of R0 resection and small bowel wall is not involved (Figure 3).After CRS, five silicon drains are placed in the abdomen, and temperature probes are positioned above the mesocolon and in the pelvis. Finally, the abdominal wall is closed. In SICO centers, HIPEC is generally performed using a specific device outfitted with two pumps (inflow and outflow), a thermal exchanger and a closed circuit with five liters of perfusate (saline solution). A BSA Mosteller formula calculator estimates the maximum volume with which to fill the abdomen. Finally, after reaching an intra-abdominal temperature of 41–42 °C, chemotherapy agents are injected and circulated with a flow rate of 700–800 mL/min for 60 min [124,130]. Preliminary studies are proposing short-course HIPEC after interval CRS [131], Similarly, Batista et al. proposed an “all-in-one approach”, consisting of neoadjuvant chemotherapy followed by fast-track CRS and short-course HIPEC with cisplatin for 30 min [132].Among chemotherapy drugs, cisplatin improves OS but is associated with significant toxicity at high dose [133]. While carboplatin is as effective as cisplatin when administered intravenously, the iPocc trial described an improvement in PFS with IP carboplatin plus paclitaxel compared with IV chemotherapy, but this benefit does not translate to OS [134]. A single-center described placitaxel-based HIPEC as safe, given the low rate of morbidity, in neoadjuvant OC [135]. Other studies described no differences in prognosis between cytotoxic and cytostatic agents [136]. An Italian meta-analysis, aimed at focusing on the optimal chemotherapeutic regimen, identified the superiority of the combination of platinum and taxane on PFS in advanced OC at almost all stages of the disease [137]. Moreover, no advantage to an IP therapy trial was registered when bevacizumab was incorporated [138]. Ongoing TRiPocc study will include the molecular biomarker selection of patients for IP chemotherapy. To date, two recent phase III randomized controlled trials investigated the role of HIPEC in the treatment of primary OC [3,7,139]: (i) Van Driel et al. described HIPEC following neoadjuvant chemotherapy and interval CRS for newly diagnosed FIGO III epithelial OC (OVHIPEC−1) [140], and (ii) Lim et al. evaluated HIPEC following optimal CRS for FIGO III-IV epithelial OC [141] (Table 2).

The Dutch trial included patients who had a partial or complete response following neoadjuvant chemotherapy and demonstrated a survival advantage (OS 45.7 vs. 33.9 months, p-value 0.02; PFS 14.2 vs. 10.7 months, p-value 0.003) with the addition of HIPEC (100 mg/m2 of cisplatin for 90 min via the open technique at a temperature of 40 °C); 90% of patients completed a full six cycles of chemotherapy. In terms of toxicity, the two groups showed similar results. However, this study was not stratified about important prognostic factors such as BRCA status, FIGO stage or the histologic type of tumor.

The Korean trial showed no significant differences in OS and PFS between the HIPEC (75 mg/m2 of cisplatin for 90 min via the closed technique at a temperature of 41.5 °C) and no HIPEC arms (69.5 vs. 61.3 months, p-value 0.43; 19.8 vs. 18.8 months, p-value 0.52). Intra- and post-operative outcomes, such as the extent of surgery, estimated blood loss, residual tumor and length of hospital stay, were not different between both groups. The addition of HIPEC to CRS did not improve survival among patients undergoing primary CRS (p-value 0.29; p-value 0.51, respectively). Interestingly, the neoadjuvant chemotherapy subgroup showed a trend of improved survival in favor of HIPEC (61.8 vs. 48.2, p-value 0.4; 17.4 vs. 15.4 months, p-value 0.04).

In 2021, Marrelli et al. [142] proposed a novel treatment protocol with six cycles of neoadjuvant chemotherapy, consisting of paclitaxel plus cisplatin or carboplatin, repeated every 21 days, in women with FIGO stage III OC. According to RECIST criteria [143], the clinical response to neoadjuvant chemotherapy was observed in 83.9% of cases; HIPEC was completed in 85.2%, while adjuvant therapy in 70.4%. The median survival rates in the entire cohort and HIPEC group were 36 and 53 months, while 5-year OS was 36% and 42%, respectively. However, it is unclear if the six cycles approach is associated with better downstaging of the disease than three cycles of neoadjuvant therapy.To the best of our knowledge, the prognostic effect of HIPEC remains unclear in candidates for primary CRS. OVHIPEC-2 will aim to compare the power of HIPEC (with cisplatinum 100 mg/m2) added to primary CRS (no residual disease or up to 2.5 mm in maximum dimension) on OS in FIGO III OC, with acceptable morbidity, when followed by standard adjuvant chemotherapy [144]. Similar endpoints are present in the ongoing EHTASEOCCS trial, which will focus on PFS as the primary outcome [145].Looking at observational studies [146], a large Spanish case series showed higher PFS in patients treated with primary compared to interval CRS and HIPEC (3-years PFS 63% vs. 18%, p-value 147]. An Italian prospective cohort study, enrolling FIGO IIIC and IV women, observed similar intra- and early post-operative complications, as well as the length of stay and the time to start adjuvant chemotherapy between HIPEC and non-HIPEC groups [82].Interestingly, OC with increased BRCA1 expression has a 36-month survival improvement when treated with IP chemotherapy [148].Nevertheless, too much bias (different drugs and doses, different perfusion times at different temperatures, different time administration and different criteria for evaluating the completeness of cytoreduction) precludes definitive conclusions about the survival results [55]. Thus, the GCIG in 2016 sets benchmark standards to be adopted for clinical trial design [64,149].In 2021, the OVHIPEC group, using the EORTC questionnaires, concluded that the addition of HIPEC to interval CRS does not negatively impact health-related quality of life [144]. Opting for therapeutic choices considering the patients’ clinical conditions [150], comorbidities, age and frailty status is necessary to improve their quality of life and life expectancy [151].Macrì et al. recorded the ECOG score and severe morbidity as predictors of 60-days survival [152,153].Furthermore, Boerner et al. recommend special consideration for OC patients at higher risk for toxicity: a preoperative creatinine level of 1.0–1.5 mg/dL, non-insulin dependent diabetes mellitus, baseline neuropathy and baseline hearing loss [121].On the other hand, IP chemotherapy is associated with long operative times, prolonged hospital stays, high morbidity rates [53,154,155,156,157,158,159] and, ultimately, increased hospital costs. While the European Society for Medical Oncology (ESMO) and European Society of Gynecological Oncology (ESGO) failed to recommend HIPEC as the first-line standard of care for OC [1,160], the latest National Comprehensive Cancer Network (NCCN) guidelines encouraged HIPEC at the time of interval CRS in stage III disease, followed by adjuvant IV chemotherapy [56,161].Although debate is still open, patients undergoing HIPEC showed better (1) survival outcomes, (2) tumor regression and (3) quality of life. “One coincidence is just a coincidence, two coincidences are a clue, three coincidences are a proof.” Believing in Poirot’s philosophy, more research on this technology seems warranted and might be considered in the fight against OC [162]. SICO has been pursuing these goals for over 10 years.