In most cases of advanced ovarian cancer, peritoneal metastasis is the primary site of spread and cause of treatment failure [9]. Several randomized clinical trials have shown that postoperative intraperitoneal and intravenous chemotherapy improved survival in patients with optimally resected stage IIIC ovarian cancer compared with intravenous chemotherapy alone [26, 30–32]. Although the survival benefits of intraperitoneal chemotherapy have been reported in a previous Gynecologic Oncology Group study [31], the toxicity and significantly high incidence of side effects have prevented this treatment from being widely adopted in clinical practice [12, 26]. In recent years, the application of HIPEC to ovarian cancer has garnered interest because of its advantages over standard intraperitoneal chemotherapy [12].
Nevertheless, the therapeutic of HIPEC in ovarian cancer has been controversial. Some studies have demonstrated that HIPEC does not improve OS compared with therapy without HIPEC [13]. However, an increasing number of studies have demonstrated that the addition of HIPEC significantly improves the prognosis of ovarian cancer [1, 22, 33–35], especially in randomized controlled trials [14, 16, 36]. The drug and dose range of HIPEC are important considerations that can affect survival times. In some studies, HIPEC was performed only after optimal cytoreductive surgery, either as an open procedure or a closed system, which used cisplatin or a combination of doxorubicin, paclitaxel, or mitomycin C [8, 18–20]. In other studies, patients underwent HIPEC with different doses of cisplatin [14, 22, 23]. In the study by Antonio et al., patients were treated with HIPEC and paclitaxel alone [21]. Hence, several investigations have shown that dose dense chemotherapy provides clinical benefits. Therefore, this study focused on the feasibility of dense HIPEC, which involves increasing the rate of chemotherapy with three sessions of HIPEC, in FIGO stage III serous EOC.
In the present study, the median PFS was 24 months in the IDS plus dense HIPEC group, which was significantly better than the 19 months observed in the IDS alone control group, suggesting the feasibility of dense HIPEC in patients with FIGO stage III serous EOC. Two groups of patients in this study received similar preoperative treatment and had the same disease stage and pathological type. No significant differences in cytoreductive surgery, pathological grade, or the total number of cycles of systematic intravenous chemotherapy existed between the two groups. Mendivil et al. reported improved PFS with HIPEC compared with intravenous chemotherapy (25.1 months versus 20.0 months, respectively; p = 0.024) [13], which corroborates the results of this study. Similarly, a randomized, controlled, open-label trial also documented an increased PFS (14.2 months versus 10.7 months) in cohorts treated with HIPEC chemotherapy [14].
Although previous studies reported favorable PFS results, OS benefits have conventionally been considered as the most dependable endpoint in assessing cancer-related treatments. In a multicenter, open-label, phase 3 trial [14] 245 patients who received NACT were randomly assigned to undergo interval cytoreductive surgery either with or without HIPEC with cisplatin (100 mg/m2). A significant improvement in OS was seen: 45.7 months versus 33.9 months in the surgery plus HIPEC and surgery alone group, respectively. Notably, our results showing a median OS of 51.0 months for the IDS plus dense HIPEC group versus 40.0 months for the IDS alone group. Nevertheless, a recent retrospective case-control study of 56 patients treated for primary advanced ovarian cancer who underwent interval surgery with or without HIPEC demonstrated that although OS was better in the case group than in the control group (p = 0.048), PFS was not significantly different (13.2 months versus 13.9 months, p = 0.454) [8]. Conversely, another retrospective case-control study showed that PFS was significantly longer with HIPEC than without, but no OS advantages were identified. The differences in these results may have several explanations. First, follow-up differed in the two studies, and a shorter duration was inherent to the HIPEC group [13]. Second, the studies were retrospectively evaluated, and selection bias may have influenced the outcomes [13]. Third, a relatively small number of patients were included to obtain the results. Last, the rate of the peritoneal metastasis differed, which is a critical determinant of survival in advanced ovarian cancer [8].
Unsurprisingly, we observed a reasonable toxicity profile in the patients receiving dense HIPEC. No grade IV adverse events were recorded in any of the 121 patients, and no adverse events were recorded in 55 (45.5%) patients, however, 43 patients developed grade II nausea during the three sessions of HIPEC. Notably, we did not observe any grade III-IV leukocytopenia, thrombocytopenia, or renal failure. Similarly, several retrospective studies did not report any evidence of grade III-IV toxicity in their experience of treating advanced ovarian cancer patients with HIPEC [13, 37].
To the best of our knowledge, HIPEC as a single treatment has only been administered at the end of cytoreductive surgery in the operating room or the ICU [8, 13, 14, 22], thus increasing not only patient safety and comfort but also medical costs [38]. However, in our center, dense HIPEC is delivered with cisplatin after cytoreductive surgery in the general ward, and no adverse events were found to be associated with this. Furthermore, the patient tolerability was excellent. The median time of postoperative systemic treatment with chemotherapy was 22 days, which was significantly lower than the 33–49 days reported in previous studies [8, 14].
In addition, specific pathologic subtypes affect the prognosis of advanced ovarian cancer. To reduce the impact of pathological type and disease stage on survival in the present study, we only included FIGO stage III high-grade serous EOC patients. Several limitations should be considered in this study. First, the retrospective nature of our analysis reduced our ability to draw reliable conclusions. Second, although NACT is increasingly used as the primary treatment for advanced ovarian cancer [39], patients who undergo primary debulking surgery have a significant survival benefit compared with those who undergo NACT. Third, this study showed that significant benefits in OS and PFS were associated with dense HIPEC, however, multivariate analyses were not performed to elucidate the risk factors of prognosis nor evaluate the impact of optimal cytoreductive surgery, CA125 level, age, and other variables. In a retrospective multicenter study of 78 patients by Le Saux, et al., the univariate analysis demonstrated that age ≥ 50 years, peritoneal cancer index (PCI) ≤ 8, and CA125 levels < 100 were significantly associated with long-term survival in patients with EOC following cytoreductive surgery and HIPEC [40]. However, our data were limited to optimal or suboptimal cytoreductive surgery [27], and it may have been preferable to further stratify the surgery categories into complete (R0), optimal < 1 cm (R1), and suboptimal (R2) groups [31].
At present, there are many ongoing randomized Phase 2 and 3 trials involving primary and recurrent disease as well as patients receiving NACT [41]. Many of these trials intend to assess the impact of adding HIPEC to cytoreductive surgery on PFS and OS [41] as well as on morbidity, quality of life, and pharmacokinetics [42]. However, to the best of our knowledge, few randomized controlled clinical trials of dense HIPEC training and administration with the agents and protocols used in our study are ongoing.