Hyperthermic Intraperitoneal Chemotherapy in the Treatment Armamentarium of Epithelial Ovarian Cancer: Time to End the Dichotomy

Abstract

Background

Advanced epithelial ovarian cancer (EOC) is an incurable disease with over 75% of the patients developing recurrence in the peritoneum. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising treatment option for both first-line therapy and treatment of recurrence. In this article, we review the rationale and current evidence for performing HIPEC and the role of HIPEC in the light of targeted systemic therapies.

Summary

There are few randomized trials and several retrospective studies on the role of HIPEC in the management of EOC. A 12-month-overall survival (OS) benefit of the addition of HIPEC to interval cytoreductive surgery (CRS) was demonstrated in 1 randomized trial following which HIPEC has been included as a treatment option for this indication in several national/international guidelines. One retrospective propensity score-matched analysis showed a 16-month OS benefit of adding HIPEC to primary CRS. One randomized trial showed no benefit of the addition of carboplatin HIPEC to secondary CRS over secondary CRS alone. For patients undergoing primary CRS and secondary CRS for recurrence, the results of ongoing randomized trials are needed to define the role of HIPEC in these situations. All clinical trials have shown that the morbidity of HIPEC performed after CRS is acceptable. Along with the emergence of HIPEC as a promising surgical therapy, targeted therapies like bevacizumab and poly adenosine diphosphate-ribose polymerase inhibitors have been developed that have shown a survival benefit in selected patients. In principle, HIPEC and targeted therapies work in different ways and it is plausible to assume that their benefit could be additive, and their combination should be evaluated in clinical trials. The impact of prognostic factors like the disease extent, pathological response to systemic chemotherapy (SC), the histological subtype and molecular profile on the benefit of HIPEC, and targeted therapies has not been evaluated in clinical trials.

Key Messages

HIPEC is an important therapeutic strategy in the treatment of EOC. While its role in patients undergoing interval CRS has been established, the results of ongoing randomized trials are needed to define its benefit at other time points. The morbidity of HIPEC in addition to CRS is acceptable. More research is needed to define subgroups that benefit most from HIPEC based on the extent of disease, response to SC, histology, and molecular profile. The combination of HIPEC and maintenance therapies should be evaluated in well-designed randomized clinical trials that evaluate not just the survival benefit and morbidity but also the cost-effectiveness of each therapy.

Introduction

Advanced epithelial ovarian cancer (EOC), despite the advances in surgical and systemic therapies, remains an incurable disease. Over 75% of the patients develop recurrence/progression, and most of these recurrences are in the peritoneum itself [1]. This makes hyperthermic intraperitoneal chemotherapy (HIPEC) an attractive treatment option in both first-line therapy and recurrent disease. In the near past, most of the evidence favoring or disfavoring the use of HIPEC came from retrospective studies comprising heterogeneous groups of patients, with a greater heterogeneity in the treatment protocols, making it difficult to derive significant conclusions [2]. To date, 3 randomized clinical trials (RCTs) have been published, 2 favoring the use of HIPEC at different time points, 1 disfavoring its use [3, 4, 5]. Along with the emergence of HIPEC as a promising surgical therapy, targeted therapies like bevacizumab and poly adenosine diphosphate-ribose polymerase (PARP) inhibitors have been developed that have shown a survival benefit in selected patients in RCTs [6, 7, 8]. The combination of HIPEC with targeted therapies has not been evaluated in any RCT. Since the survival results in many of these trials are similar, there is skepticism regarding the benefit of HIPEC, given the added morbidity and cost. This is despite the fact that targeted therapies carry a significant morbidity and cost as well [9]. The median progression-free survival (PFS) in most clinical trials after first-line therapy ranges from 10 to 18 months and overall survival (OS) from 30 to 50 months (Table 1) [10, 11, 12, 13, 14]. Clearly, more effective treatments are needed to improve on these results. In principle, HIPEC and systemic therapies work in different ways. It is plausible to assume that the benefit of the 2 could be additive, and they should not be considered complementary treatments. HIPEC is unique as it is an adjuvant surgical therapy that is used in combination with cytoreductive surgery (CRS), and the outcomes are influenced greatly by the quality and extent of CRS. This makes it difficult to quantify and demonstrate the benefit of HIPEC in RCTs. In this article, we review the rationale for performing HIPEC, the current evidence for performing it at different time points, and the role of HIPEC in the light of targeted systemic therapies.

Table 1.

PFS and OS in patients with advanced ovarian cancer undergoing surgery and SC

First author; year [ref]	N	Trial name	Comparator arms	Optimal debulking	CC-0 or complete gross resection	Median PFS	Median OS
Vergote et al. [10]	670	EORTC 55971/NCIC OV13	PDS versus IDS	41.6% (PDS) and 80.6% (IDS)	NR	12 mo in both arms	29 mo (PDS) and 30 mo (IDS)
Kehoe et al. [11]	550	CHORUS	PDS versus IDS	28% (IIIC) 23% (IV)	28% (IIIC) 30% (IV)	107 mo (PDS) and 12 mo (IDS)	22.6 mo (PDS) and 24.1 mo (IDS)
Fagotti et al. [12]	171	SCORPION (NCT01461850)	PDS versus IDS	34.2%	61.4%	15 mo (PDS) and 14 mo (IDS)	41 mo (PDS) and 43 mo (IDS)
Chi et al. [13]	316	Retrospective study	PDS versus IDS	24% (PDS) 54% (IDS)	71% (PDS) 86% (IDS)	13 mo (IDS) and 17 mo (PDS)	37 mo (IDS) and 50 mo (PDS)
Rauh-Hain et al. [14]	242	Retrospective study	PDS versus IDS	NR	7.5% (PDS) and 27% (IDS)	11 mo (PDS) and 14 mo (IDS)	29 mo (PDS) and 33 mo (IDS)

PDS, primary debulking surgery; IDS, interval debulking surgery; mo, months.

Rationale and Pitfalls of HIPEC

HIPEC involves the circulation of a heated chemotherapy solution in the peritoneal cavity for 30–120 min using a roller pump and heat exchanger (or custom-made machines). The theoretical benefits of HIPEC include a direct exposure of tumor cells to the drug, prolonged retention of the drug in the peritoneal cavity resulting in prolonged exposure of the peritoneal surfaces to the drug, and a decreased systemic absorption resulting in reduced systemic toxicity [15, 16]. Thus, higher drug doses can be administered without the resultant systemic toxicity.

Intraperitoneally administered chemotherapeutic agents gain access to peritoneal lymphatics and can act on trans-lymphatic spread [17, 18]. Since these lymphatics are connected sub-peritoneally, the drug can reach different areas of the sub-peritoneal space though the mechanical distribution is uneven, and some areas are underexposed or not exposed at all to the drug [17, 18].

Despite this pharmacokinetic advantage, the depth of penetration of the chemotherapeutic drug into the peritoneum and tumor nodules is not more than 2–3 mm [19, 20]. Thus, HIPEC acts best in the presence of minimal or no residual disease. Following complete CRS, HIPEC can address the free intraperitoneal cancer cells more effectively and reduces the implantation of these cells at the surgical site [21].

There are many theoretical benefits of hyperthermia, but the clinical benefit has not been proven for the treatment of a peritoneal metastasis (PM). Heat itself is cytotoxic; it potentiates the cytotoxicity of the chemotherapeutic drugs and in some instances, helps in overcoming drug resistance [22, 23].

HIPEC Methodology and Factors Influencing the Efficacy of HIPEC

HIPEC is a surgical therapy that is performed by the open, semi-open, or closed methods. There are 3 main components of a HIPEC procedure that could influence its efficacy:

Pharmacological factors having an impact on the efficacy of HIPEC include the pharmacokinetic variables like the drug (combination), dosage, molecular weight, carrier solution and its volume, application time and intra-abdominal pressure and pharmacodynamic variables like tumor nodule size, density, vascularity, interstitial fluid pressure, binding and temperature [25]. The nonpharmacological factors are the extent of peritoneal resection, the method (open or closed), and the chemosensitivity of the tumors cells to the chemotherapeutic agent(s) used.

Even though the mechanical part can be standardized, it is not possible to standardize the other 2 as innumerable permutations and combinations are possible. The drugs with the best pharmacokinetic properties often are not the ones that have the greatest activity against a particular tumor type [26]. Thus, in clinical practice, there is heterogeneity in the HIPEC methodology and the drug/regimen used [26].

Drugs and Drug Regimens for HIPEC in EOC

Cisplatin alone or combined with other drugs is the most commonly used drug for performing HIPEC (Table 2). Cisplatin HIPEC showed a survival benefit in the OVIHIPEC 1 trial and is the drug being used in several other clinical trials [4]. The dose of cisplatin in the OVIHIPEC 1 trial was 100 mg/m² with half the dose being administered at the beginning of HIPEC and a quarter each at 30 and 60 min.

Table 2.

Various drug regimens used for performing HIPEC in ovarian cancer [4, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37]

Regimen	IP drugs	IV drugs	Carrier solution	Duration, min	Indications
OVIHIPEC 1 (and 2) cisplatin regimen [4]	Cisplatin 100 mg/m2	Sodium thiosulfate for renal protection	Peritoneal dialysis solution	90	Advanced ovarian cancer
CHIPASTIN/French cisplatin regimen [27]	Cisplatin 70 mg/m2		Peritoneal dialysis solution	60	Advanced ovarian cancer
HIPEC ROC-1 regimen [28]	Cisplatin 100 mg/m2		Peritoneal dialysis solution	90	Recurrent ovarian cancer
Paclitaxel [29]	Paclitaxel 175 mg/m2		Peritoneal dialysis solution	90	Advanced ovarian cancer
Cisplatin and paclitaxel [30]	Paclitaxel 175 mg/m2 and cisplatin 100 mg/m2		Peritoneal dialysis solution	90	Advanced ovarian cancer
Carboplatin regimen [31]	Carboplatin 800–1,200 mg/m2		Peritoneal dialysis solution	90	Advanced and recurrent ovarian cancer
Sugarbaker regimen [32]	Cisplatin (50 mg/m2) adriamycin (15 mg/m2)	Ifosfamide 1300 mg/m2 and mesna 260 mg/m2	Peritoneal dialysis solution	90	Advanced and recurrent ovarian cancer
National Cancer Institute Milan regimen [33]	Doxorubicin 15.25 mg/L cisplatin 43 mg/L			90	Advanced and recurrent ovarian cancer
High-dose oxaliplatin regimen [34]	Oxaliplatin 460 mg/m2		Dextrose 5%	30	Recurrent
Sugarbaker's gemcitabine-based regimen [35]	Gemcitabine 1,000 mg/m2		Peritoneal dialysis solution	90	Recurrent ovarian cancer
Sugarbaker melphalan-based regimen [36]	Melphalan 50–70 mg/m2		Peritoneal dialysis solution	90	Recurrent ovarian cancer
Sugarbaker liposomal doxorubicin-based regimen [37]	Liposomal doxorubicin 50–100 mg/m2		Peritoneal dialysis solution	180	Recurrent ovarian cancer

Though the pharmacokinetic profile is less favorable, cisplatin is an adequate drug for hyperthermia, and hyperthermia in experimental studies overcomes platinum resistance [38, 39, 40, 41, 42, 43]. The pharmacokinetic profile of carboplatin is similar to that of cisplatin with fewer side effects, but thermal enhancement is poor, and the depth of penetration in tumor nodules is much lower [38, 44, 45]. In a recently published phase II trial, there was no benefit of the addition carboplatin HIPEC to secondary CRS and 5 cycles of systemic chemotherapy (SC) compared to secondary CRS with 6 cycles of SC [5]. Doxorubicin is not an active drug for SC in ovarian cancer but has a highly favorable pharmacokinetic profile and low toxicity that has led to its use for performing HIPEC usually in combination with cisplatin [46, 47, 48].

The taxols, paclitaxel and docetaxel, are large molecules with favorable pharmacokinetic profiles [49, 50, 51]. The main disadvantage is the lack of thermal enhancement [51, 52]. Moreover, taxols are cell-cycle-specific, i.e., it is active only in the mitotic phase of the cell division [51, 52]. An ideal drug for HIPEC should preferably be cell-cycle-nonspecific as HIPEC is a single shot treatment. HIPEC with paclitaxel is being evaluated in the HIPECOVA trial (NCT02681432) for advanced and recurrent EOC both.

Gemcitabine, melphalan, and oxalipatin are the other drugs that have been used for HIPEC in EOC [34, 35, 36]. None of these drugs is being evaluated in RCTs. Currently, 2 clinical trials (NCT01970722 and NCT02567253) are comparing different HIPEC regimens for advanced EOC.

Current Evidence on the Benefit of HIPEC at Different Time Points in the History of Ovarian Cancer

For advanced EOC, surgery is performed during first-line therapy either upfront (primary CRS) or after a few cycles of neoadjuvant chemotherapy (interval CRS). For recurrent disease, it is performed for selected patients with platinum-sensitive (PS) recurrence.

Primary CRS/Debulking

Most of the evidence for performing HIPEC in addition to primary CRS comes from retrospective studies that included patients undergoing surgery for different indications, had a long recruitment period, small number of patients (less than 100 in the majority of studies), and used heterogeneous treatment protocols and SC regimens. The selection criteria were not clearly defined, and several series comprised patients with extensive disease that were referred to specialized units after having undergone unsuccessful prior surgical attempts [2].

There are 3 systematic reviews and meta-analyses; the first one by Chiva et al. [53] included 11 studies, comprising 248 patients. The authors reported no benefit of adding HIPEC to primary CRS [53]. Huo et al. [54] performed a meta-analysis of 9 comparative and 28 noncomparative studies, evaluating the role of HIPEC for primary and recurrent EOC. Contrary to the first meta-analysis, in the primary setting, this meta-analysis performed on patients of 3 studies showed a survival benefit with HIPEC at 2–5 and 8 years. These studies included patients with stages II-III-B EOC as well and did not make a distinction between patients undergoing primary and interval CRS. In a subgroup analysis of patients with stage III and IV alone, the odds ratio for OS was 3.61 (95% CI: 1.55–8.37; p = 0.003) at 3 years, and for OS at 5 years, it was 2.25 (95% CI: 1.07–4.71; p = 0.030), both favoring the use of HIPEC [54]. Zhang et al. [55] performed a similar meta-analysis and demonstrated a benefit of HIPEC for all patients undergoing primary or interval CRS (HR = 0.59, 95% CI: 0.46–0.75 for OS and HR = 0.41, 95% CI: 0.32–0.54 for PFS) as well as those with stage III or IV disease (HR = 0.64, 95% CI: 0.50–0.82 for OS and HR = 0.36, 95% CI: 0.20–0.65 for PFS) [55].

Lei et al. [56] have recently published a retrospective propensity score-matched study including patients with EOC undergoing primary CRS with (N = 425) or without (N = 159) HIPEC [55]. HIPEC was performed with 50 mg/m² of cisplatin on days 1, 3, and 5, which is not the common practice [56].

At a median follow-up of 42.2 months, the addition of HIPEC led to a nearly 16-month benefit in OS (median OS, 49.8 m; 95% CI, 45.2–60.2 m for CRS and HIPEC vs. 34.0 m; 95% CI, 28.9–42.3 months for CRS alone). After inverse probability of treatment weighting adjustment, primary CRS with HIPEC was still associated with better oncologic outcomes, with a median OS of 49.8 (95% CI, 45.2–60.2) months compared 34.0 (95% CI, 28.9–41.5) months in the primary CRS alone group (weighted HR, 0.64; 95% CI, 0.50–0.82; p < 0.001). This implies that there was a 36% reduction in the risk of death with the use of HIPEC. The grade 3–4 morbidity and hematological toxicity were similar in both groups except electrolyte imbalance which was seen in a significantly higher number of patients in the HIPEC group. All the limitations of a randomized study and a retrospective analysis apply to this study.

In the only RCT reported so far, Lim et al. [57] reported no benefit of the addition of HIPEC to primary CRS. One hundred and eighty-four patients undergoing both primary and interval CRS were randomized to undergo HIPEC or no HIPEC. Though the trial has been completed, the final results have not been reported or published. The small sample size, the inclusion or patients undergoing both primary and interval CRS, and performing HIPEC for patients with optimal debulking (residual disease <1 cm) are some of the limitations of this trial [57]. There are 4 RCTs in progress looking at the role of HIPEC in addition to primary CRS (Table 3): the OVIHIPEC 2 trial in Europe, Australia, and the USA (NCT03772028); the CHIPPI trial in France (NCT03842982); and the HIPECOC trial (NC04280185) and EHTASEOCCS trial (NCT03373058) both in China.

Table 3.

Published and ongoing clinical trials on the role of HIPEC in advanced ovarian cancer

ClinicalTrials.gov ID	Phase; primary institution/group	Indication	HIPEC regimen(s)	Control arm	Experimental arm	Main outcomes
Van Driel et al. [4]	Phase 3 randomized controlled trial; Netherlands Cancer Institute	Advanced ovarian cancer (interval CRS)	Cisplatin 100 mg/m2 for CRS + SC 90 min	CRS + HIPEC + SC	Benefit in the HIPEC arm in PFS and OS; similar morbidity
Lim et al. [56] Only abstract; full results not available	Phase 3 randomized controlled trial; National cancer Centre, Korea	Advanced ovarian cancer (PDS and IDS)	Cisplatin 75 mg/m2 for CRS + SC (92) 90 min	CRS + HIPEC + SC (92)	No benefit of HIPEC in the PDS arm; benefit with HIPEC in PFS and OS after 20 mo of follow-up in the IDS arm
NCT03842982 (CHIPPI)	Randomized phase III; Centre Oscar Lambert	Advanced ovarian, FT, and PP cancer	Cisplatin 100 mg/m2 for PDS/IDS + SC 90 min	PDS/IDS + HIPEC + SC
NCT02349958	Non randomized; Bay Area Gynecology Oncology, the USA	Advanced ovarian cancer; other primary sites	Various regimens	CRS + HIPEC + SC
NCT02124421 (HOT trial)	Mercy Medical Center, the USA	Advanced ovarian cancer	Carboplatin (AUC 6) for CRS + SC + IPC 90 min	CRS + HIPEC + SC
NCT01970722	City of Hope Medical center, UC	Advanced ovarian, FT, uterine, and PP cancer	Various regimens	CRS + HIPEC + SC + IPC
NCT02567253 (OvIP1)	Quadruple arm, phase II; University Hospital, Ghent, Belgium	Advanced ovarian cancer	Cisplatin 75 mg/m2 NT or HT for 90 min Cisplatin 100 mg/m2 NT or HT for 90 min	CRS + HIPEC + SC
NCT01628380	Randomized, phase III; A.O. Ospedale Papa Giovanni XXIII, Italy	Advanced ovarian cancer	Cisplatin 100 mg/m2 CRS + SC +paclitaxel 175 mg/m2*	CRS + HIPEC + SC
NCT02681432	Randomized, phase III; Hospital General de la Ciudad Real, Spain	Advanced ovarian cancer	Paclitaxel 175 mg/m2 for CRS + SC 60 min	CRS + HIPEC + SC

PDS, primary debulking surgery; IDS, interval debulking surgery.

^*Time not specified.

Interval CRS/Debulking

The OVIHIPEC 1 trial showed a benefit in both PFS and OS with the addition of HIPEC to interval CRS compared to interval CRS alone. [4] The use of HIPEC led to a reduction in the risk of death by 33% (HR: 0.67; 95% CI: 0.48–0.94; p value = 0.02) [4]. Though the morbidity and mortality were similar in both arms, certain complications like infection and thromboembolism and the rate of stoma formation were more in the HIPEC arm. There were many criticisms of this trial [58, 59]. The survival rates (PFS-10 months and OS-41 months) were similar to studies in which no HIPEC was used. This trial had a very stringent follow-up protocol and strict criteria for diagnosis of recurrence due to which the recurrences may have been reported earlier than usual. Second, since randomization was performed intraoperatively, survival was calculated from the date of surgery and not the time of starting neoadjuvant chemotherapy (approximately reduction of 3 m in PFS and OS). The intraoperative randomization was considered improper and fraught with bias. However, HIPEC is performed only in patients with residual disease measuring less than 2.5 mm. This is because only those patients in whom a complete CRS is feasible or has already been achieved can be randomized to evaluate the benefit of HIPEC over CRS alone. The sample size was considered small and the primary end point, i.e., PFS, was not met with. The long recruitment period of 9 years and reduced benefit in patients recruited at the most experienced centers were some other criticisms. Despite these limitations, an OS benefit of 12 months cannot be ignored, and HIPEC has now been included in many national and international guidelines including the NCCN guidelines as a treatment option for patients undergoing interval CRS [60, 61].

In the trial from Korea discussed in the previous section, there was a trend toward a longer PFS and OS with HIPEC in patients who had a follow-up of more than 2 years [57]. The trial has been completed, but the final results have not been disclosed or published. Ongoing clinical trials on HIPEC in addition to interval CRS are listed in Table 3.

Recurrent Ovarian Cancer

In the recurrent setting, the role of secondary CRS itself was put to question by the results of 1 RCT that showed no difference in patients treated with SC and bevacizumab with or without CRS [62]. However, 2 subsequent RCTs have shown a survival benefit of secondary CRS in selected patients with platinum-sensitive recurrence [63, 64]. Similar to the upfront setting, the majority of data evaluating HIPEC in recurrent ovarian cancer with PS and platinum-resistant (PR) disease has been based on retrospective studies [2]. Several case control studies have compared secondary CRS and HIPEC with CRS alone [65, 66, 67, 68, 69, 70]. In 4 of these, there was a statistically significant benefit of CRS and HIPEC over CRS alone (Table 4). Most of these studies have a small number of patients, and 1 study combined patients with advanced and recurrent disease both.

Table 4.

Case control studies comparing CRS and HIPEC with CRS alone as second-line therapy

Ref No	Year of publication	Type of recurrence	N	CRS + HIPEC	CRS	Survival for CRS + HIPEC	Survival for CRS alone	p value
Munoz-casarez et al. [65]	2009	NS	26	14	12	58% (5 yr OS)	17% (5 yr OS)	0.011
Spillitois et al. [66]	2011	NS	48	24	24	50% (3 yr OS)	18% (3 yr OS)	<0.01
Fagotti et al. [67]	2012	PS	67	30	37	68% (5 yr OS)	42% (5 yr OS)	0.017
Cascales Campos et al. [68]	2014	PS	54	32	22	45 (3 yr DFS)	23 (3 yr DFS)	0.078
Le Brun et al. [69]	2014	PS	42	23	19	75.6% (4 yr OS)	19.4% (4 yr OS)	0.013
Biaocchi et al. [70]	2016	PS	79	29	50	59.3 mo (median OS)	58.3 mo (median OS)	0.95

NS, not specified; DFS, disease-free survival; mo, months; yr, years.

There are 2 RCTs that have been published (Table 5). In the first one by Spiliotis et al. [3] that included 120 patients with both platinum-sensitive and PR disease, patients undergoing HIPEC had a significantly longer OS compared to those undergoing CRS alone. This trial had several methodological limitations: use of heterogeneous chemotherapy regimens and the morbidity was not reported.

Table 5.

Published and ongoing clinical trials evaluating the role of HIPEC in recurrent ovarian cancer

First author [ref]	Phase	Indication	Primary institution/group	HIPEC drugs	Control (N)	Experimental arm (N)	Main outcomes
Spiliotis et al [3]	Phase 3 randomized controlled trial	Recurrent ovarian cancer (PS and PR)	Metaxa Cancer Hospital, Greece	PS: cisplatin 100 mg/m2 and paclitaxel 175 mg/m2 for 60 min PR: doxorubicin 35 mg/m2 and (paclitaxel 175 mg/m2 or mitomycin C 15 MG/M2)	CRS + SC (60)	CRS + HIPEC SC (60)	HIPEC resulted in the superior OS; significant difference in the PS group but not in the PR group
Zivanovic et al [5]	Phase 2 randomized controlled trial	PS recurrent ovarian cancer	Memorial Sloan Kettering Cancer Centre	Carboplatin 800 mg/m2 for 90 min	CRS + 6#SC (49)	CRS + HIPEC + 5# SC (49)	No difference in survival between the 2 arms; similar morbidity
NCT01539785 (HORSE/MITO 18)	Randomized, phase III	PS recurrence	Catholic University of the Sacred Heart, Italy	Cisplatin 75 mg/m2 for 60 min	CRS + SC	CRS + HIPEC + SC
NCT01376752 (CHIPOR)	Randomized, phase III	PS recurrence	UNICANCER Europe	Cisplatin 75 mg/m2 for 60 min	SC + CRS	SC + CRS + HIPEC
NCT03220932 (HIPOVA-1)	Randomized, phase III	PR recurrence	UNICANCER Europe	Cisplatin 70 mg/m2	SC + Bev	SC + Bev + CRS + HIPEC
NCT02672098	Phase 1	PS recurrence	Loma Linda University Cancer Center, the USA	Carboplatin 80 mg/m2 for 90 min		CRS + HIPEC +SC

Bev, bevacizumab.

In the other trial by Zivanovic et al. [5] that had a pick-the-winner superiority design, 98 patients were randomized to either secondary CRS with carboplatin HIPEC or CRS alone. Patients in the HIPEC arm received only 5 cycles of adjuvant chemotherapy compared to 6 in the CRS alone arm. There was no difference in the median PFS (15.4 vs. 12.3 months; p = 0.17) or median OS (69.2 vs. 53.1 months; p = 0.32) between the 2 arms, and the morbidity and mortality between the 2 was also similar [5]. There were significantly fewer bowel anastomoses in the HIPEC arm, and a low dose of carboplatin was used. The authors stated that the results should be interpreted with caution since the trial design did not allow a direct arm-to-arm comparison, and the conclusions were based on a post hoc analysis. There are 2 phase III trials evaluating the role of HIPEC for PS recurrence − the CHIPOR (NCT01376752) trial in France and the HORSE (NCT01539785) trial in Italy. Another trial being conducted in France, the HIPOVA-1 trial (NCT03220932), is evaluating the role of HIPEC in PR disease.

Clinical End Points for Evaluating the Benefit of HIPEC

The OVIHIPEC 1 trial showed a greater benefit of HIPEC in terms of OS compared to PFS, the primary end point. There are 2 plausible reasons for this unexpected finding. As a locoregional treatment, HIPEC is expected to result in better locoregional control and therefore delayed recurrence. In advanced EOC which is an incurable disease, the time to second-line platinum therapy or the platinum-free interval is an important prognostic factor that has an impact on OS [71, 72]. By delaying recurrence, this interval is prolonged which could result in a longer OS. By eradicating microscopic disease, the response to second-line therapy could be better. PMs lead to ascites and bowel obstruction and bring down the quality of life. For the PM of gastrointestinal origin, obstruction-free survival has been proposed as a suitable end point to demonstrate the benefit of HIPEC [73]. One retrospective study on the patterns of recurrence following interval CRS and HIPEC showed a reduced incidence of peritoneal recurrence compared to previous reports that could be attributed to the use of HIPEC [74]. Theoretically, HIPEC should not just prolong PFS but OS as well.

In addition to aggressive locoregional treatment, the time to recurrence is influenced by another factor, i.e., the response to SC. Böhm et al. [75] demonstrated a 50% longer PFS in patients with complete or near complete response to SC compared to the moderate and poor responders. Contrary to the results obtained with HIPEC, the difference in OS between the different responders was less compared to the difference in PFS between these groups. Locoregional therapies should have a greater impact on the OS compared to the response to SC by reducing the burden of chemotherapy-resistant cells and thus enhancing the response to subsequent therapies. Thus, though HIPEC is a locoregional therapy, it is plausible that OS is a better primary end point compared to PFS for evaluating its benefit in clinical trials. A recent systematic review of clinical trials in ovarian cancer demonstrated that PFS is not an established surrogate for OS in ovarian cancer [76]. The results suggested that when PFS is the primary end point, OS should be a secondary end point.

The Role of HIPEC in BRCA-Mutated Tumors and Patients Receiving PARP Inhibitors and Bevacizumab

Both germ line and somatic BRCA mutations in EOC have been associated with a greater response to SC and a prolonged OS [77]. The use of PARP inhibitors as maintenance therapies in these patients results in a greater benefit in PFS compared to those without such mutations in the first-line and recurrent setting both [9].

It is assumed that HIPEC may have a lesser or no benefit in such patients given their favorable prognosis. It must be borne in mind however that HIPEC is a surgical therapy and has a different mechanism of action compared to the targeted at systemic therapies. HIPEC acts on microscopic residual disease as well as free cancer cells shed during surgery minimizing their implantation at sites of resection. It could thus be assumed that the opposite is true − HIPEC adds to the benefit of both systemic and targeted therapies in patients with BRCA-mutated tumors, though there is no evidence to support either claim. There are other factors that could be used to define subgroups that are likely to derive maximum benefit from each therapy. The disease extent (as estimated by the peritoneal cancer index [PCI]) has still not been established as a robust prognostic factor in advanced ovarian cancer though several studies have shown inferior survival in patients with a PCI >20 [78, 79]. With more extensive disease, the probability of residual disease is also likely to be higher, and perhaps, this is 1 subgroup in which HIPEC could have a greater role compared to those with a lower PCI even with BRCA-mutated tumors. The other important factor to be considered is the pathological response to SC [75]. Patients who have a complete or near complete response are likely to have less microscopic residual disease as well and could represent a subgroup that derives less benefit from HIPEC. The only drawback is that it is known only after completion of surgery.

Similarly, maintenance therapy with bevacizumab has shown a benefit in PFS but added no benefit to the OS [80, 81]. A benefit in OS was only seen in patients who had suboptimal debulking or residual disease measuring more than 1 cm in size [82, 83]. Bevacizumab is a cytostatic drug [84]. Thus, it can best control the disease but cannot lead to a complete response as demonstrated with PARP inhibitors. No study has looked at the impact of HIPEC in patients receiving bevacizumab.

There are some histological subtypes like the serous and mucinous variety that may derive a greater benefit from HIPEC. Another important factor is the cost-effectiveness of each of these therapies especially in healthcare systems where such treatments are not covered by public or private insurance. A cost-effectiveness study on the OVIHIPEC 1 data demonstrated that HIPEC was cost-effective in the Netherlands for this indication [85]. Contrary to this, a study from the USA published in 2020 concluded that none of the maintenance therapies was cost-effective regardless of the molecular signature [86].

Conclusions

HIPEC is an important therapeutic strategy in the treatment of ovarian cancer. While its role in patients undergoing interval CRS has been established, the results of ongoing randomized trials are needed to define its benefit at other time points. The morbidity of HIPEC in addition to CRS is acceptable. More research is needed to define subgroups that benefit most from HIPEC at different time points based on the extent of disease, response to SC, histology, and molecular profile. The combination of HIPEC and maintenance therapies should be evaluated in well-designed RCTs that evaluate not just the survival benefit and morbidity but also the cost-effectiveness of each therapy.

Conflict of Interest Statement

O. Glehen is a consultant for Gamida. A. Bhatt has no disclosures. The authors have no conflicts of interest to declare.

Funding Sources

The authors received no funding for this study.

Author Contributions

Aditi Bhatt was responsible for conceptualizing this review, performing the review, interpretation, original draft, reviewing, and editing. Olivier Glehen was responsible for conceptualization, reviewing, and editing the manuscript. Both the authors approved the final version of the manuscript.