The advanced-stage ovarian cancer management protocol used in our study is described in Fig. 1. All the patients, who were referred to one gynecologic oncologist for HIPEC, were thoroughly evaluated in order to determine the tumor burden of ovarian cancer. The diagnostic workup included esophagogastroduodenoscopy, colonoscopy, and CT of the chest, abdomen, and pelvis, with intravenous contrast agents. Positron-emission tomography CT was considered if extra-abdominal metastasis was suspected or difficult to detect by CT.

Our institution applied the following selection criteria for the use of NAC as the primary treatment strategy. NAC was performed when one of the following three criteria was met: 1) high tumor dissemination was observed on initial imaging studies and was assumed to occur under the following conditions: a) multiple and unresectable extra-abdominal metastases; b) multiple liver parenchymal metastases or pulmonary metastases; and c) extensive small bowel/mesenteric root involvement, 2) patients had a poor performance status and high operative risk because of medical comorbidities, or 3) optimal debulking surgery (residual disease measuring 1 cm or less) was unsuitable because of a high tumor burden (Fagotti score ≥8). For diagnostic laparoscopy, the degree of tumor burden was determined with the peritoneal carcinomatosis index (PCI) described by Harmon and Sugarbaker [7] and the Fagotti score [8].

All patients, preferably, were recommended to receive 3 cycles of NAC, IDS followed by HIPEC, and 3 cycles of postoperative adjuvant chemotherapy (POAC). HIPEC was not incorporated in patients in whom complete remission was achieved after 3 cycles of NAC. After NAC, complete remission was determined by a combination of the response to chemotherapy and radiologic findings and by the absence of operative findings of gross visible tumors. Additionally, HIPEC was not performed in patients with excessive bleeding (estimated blood loss ≥4,000 mL) during surgery and in cases of patient refusal. For NAC and POAC, all patients received carboplatin (area under the curve of 5 to 6) and paclitaxel (175 mg/m²).

At the time of IDS, the degree of tumor burden was also determined with Harmon and Sugarbaker's PCI and the Fagotti score. All patients underwent surgery with the intent to achieve complete cytoreduction (no gross residual disease). Every patient underwent the same routine of procedures, beginning with complete omentectomy, hysterectomy, bilateral salpingo-oophorectomy, and the removal of all macroscopically detectable lesions using surgical resection combined with electrofulguration, after peritonectomy techniques. If the rectosigmoid region was affected, it was resected ‘en bloc’ with digestive reconstruction by mechanical colorectal anastomosis. If the diaphragmatic region was affected, liver mobilization and diaphragmatic peritonectomy were performed. Pelvic and para-aortic lymphadenectomy was performed only for patients with gross nodal disease detected by preoperative imaging studies or operative findings.

HIPEC was performed immediately postoperatively. Of 27 HIPEC cases, 22 were performed using closed methods and 5 were performed using the open method. Paclitaxel was used at a dose of 175 mg/m², and chemotherapeutic agents were diluted in 3 L of 1.5% dextrose solution for peritoneal dialysis. Initially, 3 L of a heated perfusion solution was infused into the abdominal cavity at a rate of 800–1,000 mL/min through the inflow tube using the Belmont Hyperthermic Pump (Belmont Instrument Corporation, Billerica, MA, USA). Three intra-abdominal thermometers (1 positioned in the pelvis and 2 in the diaphragm area) were used to monitor the temperature inside the peritoneal cavity during the infusion, which remained constant between 42°C. The duration of the HIPEC procedure was 90 minutes, after which the perfusion solution was completely drained and bowel anastomosis was performed by the colorectal surgeon (MS Cho) if needed.

The primary endpoint was PFS. The secondary endpoints included treatment morbidity and OS. The analysis was performed on an intention-to-treat basis. All patients who started the treatment were included in the analysis.

Data of patient demographic and clinical characteristics are summarized using standard descriptive statistics. Disease progression was defined according to the response evaluation criteria in solid tumors, version 1.1 or based on an increase from baseline in the cancer antigen (CA)-125 level, whichever one of those criteria was met first, as recommended by the Gynecologic Cancer Intergroup. OS was defined as the time from diagnosis until death due to any cause. PFS and OS curves were estimated using the Kaplan-Meier method. Perioperative complications were graded according to the Memorial Sloan-Kettering Cancer Center surgical secondary events grading system [9]. Major complications were defined as Memorial Sloan-Kettering Cancer Center (MSKCC) grade ≥III. Operative mortality was defined as death occurring within 30 days postoperatively (grade V). Other adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. The analyses were performed using SPSS (version 21.0; IBM Corp., Armonk, NY, USA). Statistical significance was assumed at p<0.05.

During the study period, 65 women were treated by one gynecologic oncologist using the advanced-stage ovarian cancer management protocol. After excluding 25 patients treated with PDS, 40 patients were enrolled in the study. HIPEC was not performed in 13 of the 40 patients for the following reasons: complete remission after NAC in 4 patients, excessive bleeding during the procedure in 3 patients (hepatic segmentectomy, iliac vein rupture, severe adhesions in pelvic cavity), suboptimal cytoreduction in 1 patient, poor performance status in 4 patients, and patient refusal in 1 patient. Twenty-seven patients underwent HIPEC, with a 175 mg/m² paclitaxel infusion administered into the peritoneal cavity over 90 minutes at an inflow temperature of 42°C (Fig. 1). The demographic and baseline disease characteristics and surgical and treatment information are shown in Table 1. At baseline, the median patient age was 63 (range, 43–77) years, 62.5% of the patients presented with comorbidities (hypertension, diabetes, hypothyroidism, etc.), and 57.5% of the patients had stage IV metastasis. Sixteen stage IV patients underwent IDS with HIPEC. Twelve patients had supradiaphragmatic lymph node metastasis, and 4 patients had parenchymal liver metastases. Eleven patients achieved near-complete remission after NAC. The metastatic lesions remained in 5 patients after NAC and was removed from the IDS. The median CA-125 level was 1691.7 (range, 75.2–17,303.1) U/mL. Thirty-seven (92.5%) patients had serous histology. The median number of NAC cycles was 3 (range, 1–4). The median number of PCIs at diagnostic laparoscopy was 10 (range, 8–14). Twenty-four (60.0%) patients underwent diaphragmatic peritonectomy, 11 (27.5%) patients underwent bowel resection at IDS, and 28 (70%) patients underwent pelvic or paraaortic lymph-node dissection. In 14 patients (46.7%), no gross residual tumor was observed after IDS. The mean operative time was 509.0 (range, 129–915) minutes. Twenty-nine (72.5%) patients received blood transfusion during surgery. The median time interval between IDS and POAC initiation was 21 (range, 8–50) days. The surgical findings and postoperative outcomes of patients treated with HIPEC are shown in Table 2. The median value of PCI at IDS was 8 (range, 1–16), and 6 (22.2%) patients showed high tumor burden (Fagotti score ≥8). Two patients showed an estimated blood loss of 2–4 L and 4 patients received more than 5 units of blood transfusion. The mean operative time was 543.8 (range, 277–915) minutes. Five (18.5%) patients had major postoperative morbidity (restricted to grades III–V).

The median hospital stay was 12 (range, 3–131) days. No patients died within 30 days postoperatively (grade V events). Major postoperative morbidity (restricted to grades III–V) was encountered in 5 patients and resolved completely in 4 (Table 3). Among these, 2 patients needed secondary surgical revision. One patient underwent total mastectomy with axillary lymph node dissection because of breast cancer at the time of IDS with HIPEC and underwent emergency surgery for postoperative breast hematoma. The other patient underwent prompt surgical intervention 2 weeks postoperatively because of sudden bleeding in the mesenteric vessel. This patient had deep venous thrombosis in the right infra-popliteal vein due to carcinomatosis at the time of diagnosis, and anticoagulation therapy was continued before and after IDS. The sequela of hypoxic brain damage prevented the administration of POAC.

The median time interval to POAC after IDS was 20 (range, 8–50) days; POAC was initiated for 14 (46.7%) patients after 20 days. This delay was mostly due to postoperative complications of radical surgery. The patient with the greatest delay was reintubated because of severe pulmonary edema and was then readmitted to the intensive care unit.

After a median follow-up of 14.5 months, 42 (64.6%) patients were alive and disease-free, 21 (32.3%) patients were alive but had a relapse, and 2 (3.1%) patient died of disease-related causes.

The median PFS was 19.7 months and the median OS was not reached for those who received NAC (Fig. 2). The median PFS was 21.3 months, and the median OS was not reached for those who received HIPEC (Fig. 3). Considering all 65 patients with advanced-stage disease, including those who underwent PDS, the median PFS was 21.3 months, and the median OS was not reached (Supplementary Fig. 1).