Academic Editor: Enrique Hernandez
The rationale behind the use of hyperthermic intraperitoneal chemotherapy
(HIPEC) after cytoreductive surgery is the association between pharmacological
activity of chemotherapy delivered to the peritoneal cavity with the enhanced
cytotoxic effect of hyperthermia. Data on the efficacy of HIPEC in the primary
debulking surgery (PDS) setting are still controversial and limited by the small
sample size of most of the studies, the inclusion of different treatment settings
and chemotherapy regimens. Among the ongoing prospective trials, only the
OVHIPEC-2 trial is investigating exclusively patients submitted to PDS
Ovarian cancer is the most lethal among all gynecological malignancies, ranking the eighth in both incidence and mortality in women’s cancers  with 75% of patients diagnosed with an advanced stage disease . In presence of peritoneal carcinomatosis, the role of primary cytoreductive surgery to no gross residual disease (NGR) followed by platinum-based adjuvant chemotherapy has been widely demonstrated to significantly improve patient’s prognosis [3, 4, 5].
Due to the typical spreading pattern of the disease, the option of delivering chemotherapy agents directly to peritoneal cavity in addition to standard treatment has been investigated over the past decade . Also, the addition of hyperthermia to intraperitoneal drug delivery has shown to increase the cytotoxic effect of chemotherapy, further enabling this treatment to target microscopic tumor deposits inside peritoneal cavity .
Despite available data on this topic appear to be heterogeneous in terms of timing of therapy delivery and choice of chemotherapy agents, high quality data coming from a recent phase-III trial  are supporting the positive effect of hyperthermic intraperitoneal chemotherapy (HIPEC) in prolonging patient’s survival.
On this background, with this manuscript we provide a comprehensive review of available data on HIPEC administration and efficacy in advanced ovarian cancer patients.
Overall, the rationale behind the use of HIPEC after cytoreductive surgery is the association between pharmacological activity of chemotherapy directly delivered to the peritoneal cavity, with the enhanced cytotoxic effect of hyperthermia .
Historically, this latter aspect was firstly described by Conley  in 1893, who noticed a spontaneous tumor regression in patients with high body temperature due to erysipela inoculation.
Indeed, hyperthermia appeared to be able to cause tumor cells necrosis due to cytoplasmatic swelling, direct nucleus and DNA damage and disruption of cell membrane .
In epithelial ovarian cancer, the mechanism according to which hyperthermia is able to cause tumor damage seems to be multifactorial. Firstly, causing vasodilation, high temperature appears to increase cancer cells exposure to chemotherapy agents, thus overcoming potential chemotherapy resistance due to dysfunctional microcirculation .
Secondly, the vasodilation and subsequent improved perfusion, appear to increase the concentration of immune cells at tumor site and promote their adhesion to cancer cells .
Thirdly, there is evidence that hyperthermia can interfere with DNA repair mechanisms and therefore obstruct cancer treatment resistance .
Ultimately, hyperthermia can facilitate chemotherapy intracellular uptake and therefore positively enhance treatment effect .
Since there is no evidence that surgical disruption of plasma-peritoneal barrier has a negative impact on intraperitoneal chemotherapy uptake , the potential effect of this treatment in association with various timing of cytoreductive surgery has been widely investigated with promising and heterogeneous results.
Currently, data on HIPEC at the time of primary debulking surgery (PDS) are overall lacking.
Indeed, available data on safety and feasibility of HIPEC at the time of PDS are mainly limited by the inclusion of different treatment settings and chemotherapy regimens and by an overall small sample size.
Despite the above-mentioned limitations, the only study providing survival results on this topic is a still unpublished prospective phase II trial presented at American Society of Clinical Oncology (ASCO) meeting in 2017 by Lim et al. . This trial failed to demonstrate a survival advantage in patients treated with HIPEC compared to patients submitted to cytoreduction only, despite a comparable morbidity. Indeed, out of 184 patients, the 5-year progression-free survival (PFS) was 20.9% and 16.0% in HIPEC and non-HIPEC group respectively (p = 0.569) and 5-year overall survival (OS) was 51.0% and 49.4% respectively (p = 0.574). However, this study included a 69% of patients who received neo-adjuvant chemotherapy (NACT) due to higher disease distribution, therefore, despite not significant and deserving further evaluation, these data show an increasing trend towards better survival in HIPEC group.
In terms of reproducibility of HIPEC treatment in this subset of patients, positive results were achieved by Paris et al.  in a phase II monocentric single arm study, who however reported a lower rate of post-operative G3 and G4 complications (12.5% and 7.5%, respectively) among 40 patients submitted to HIPEC with carboplatinum and paclitaxel at the time of PDS, subsequently treated with Bevacizumab as a maintenance therapy (82.5% of the included population).
On this background, some prospective randomized trials have been designed and are currently ongoing in order to overcome existing issues on this subject and provide additional survival results.
Among them, the multicentric international OVHIPEC-2 trial  is planning to
enroll 538 International Federation of Gynecology and Obstetrics (FIGO) 
stage III ovarian cancer patients undergoing PDS to
Parallel to that, similar endpoints are present in the HIPEC-04 , a
prospective randomized trial which is currently recruiting newly diagnosed
ovarian cancer patients undergoing cytoreductive surgery
The results of the above-mentioned trials are awaited to help assess safety and oncological outcomes of HIPEC in the upfront setting for advanced ovarian cancer patients.
Before November 2018, data on the use of HIPEC in the interval cytoreductive setting suffered from the same limitations described for patients undergoing upfront surgery, being available evidence overall scarce, mainly retrospective and carried out in very heterogeneous patient populations (primary, recurrence) .
So far, the largest high-quality evidence supporting the use of HIPEC exclusively in patients candidate to NACT followed by interval debulking surgery (IDS) are coming from the results of a prospective randomized trial (OVHIPEC-1) published by Van Driel et al. .
Indeed, the OVHIPEC-1 trial  enrolled 245 FIGO stage  III ovarian cancer
patients undergoing IDS, randomly assigning them to receive or not receive HIPEC
with cisplatin100 mg/m
Interestingly, survival analysis showed a gain of nearly 4 months in median PFS (14.2 months vs. 10.7 months; p = 0.003) and almost 12 months in median OS (45.7 months vs. 33.9 months; p = 0.02) for HIPEC treated patients compared to no HIPEC group.
Also, for the analyzed populations the time of chemotherapy re-initiation was comparable in the two groups (30 days in the surgery group and 33 days in the surgery-plus-HIPEC group), as well as adverse events rate/toxicity profile which appeared not to be affected by HIPEC administration (p = 0.760). As a matter of fact, HIPEC toxicity has been a major concern since the IP administration of chemotherapy agents started to become a promising option in advanced ovarian cancer patients, being acute renal failure the most common adverse event. However, this side effect appeared to be preventable by the infusion of Sodium Tiosulphate in case of Cisplatin IP administration , as demonstrated in the OVHIPEC-1 trial .
On this setting, the feasibility of HIPEC at the time of IDS was further
confirmed by another prospective study , which also reported similar rate of
intra-operative and post-operative complications (p = 0.189 and
p = 0.238; respectively) in the group of patients receiving HIPEC with
cisplatin 100 mg/m
Those results have been supported by a very recently published prospective Phase
II trial , which analyzed 70 IDS patients, 50% of them randomized to receive
HIPEC with cisplatin 75 mg/m
Despite being the largest study of prospective nature available on this topic, the results of OVHIPEC-1 trial  have been object of controversies between the experts on this field.
The main criticisms raised to the study  included the overall small sample size, the long recruitment period, the timing randomization as a possible surgical bias, the imbalance of histology subtypes (despite not statistically significant) and the incorrect reporting of treatment adverse effects . For these reasons, many authors do not agree in including HIPEC in daily clinical practice until more data on its efficacy and safety are provided .
The skepticism expressed by some authors on the results of OVHIPEC-1 trial  have been reinforced by the fact that its results are in contrast with data provided by Lim et al. , which did not demonstrate a survival advantage in ovarian cancer patients treated with HIPEC after cytoreductive procedure. However, the authors themselves stated that a longer follow-up is required to confirm the survival outcomes of their study, especially in the group of patients receiving NACT.
Indeed, as previously discussed, their data appear to be weakened by the heterogeneity and the limited numerosity of the included population (both PDS and NACT-IDS treated patients).
Overall, as other large prospective studies are needed to assess whether OVHIPEC-1  results are confirmed, the most recent ESMO-ESGO guidelines  recommended not to consider HIPEC as standard therapy and to limit its use to well-designed prospective RCTs . On the contrary, the National Comprehensive cancer network (NCCN) guidelines  states that HIPEC can be considered at the time of IDS for FIGO stage III  disease.
Currently, other trials are ongoing with the aim to investigate the role of HIPEC in the IDS setting.
The HIPEC-03 trial  is a still not recruiting Phase III Multicenter
Prospective Randomized Trial. This trial is planning to randomize at least FIGO
stage  III ovarian cancer patients to receive standard regimen of NACT
followed by IDS, or to receive paclitaxel 175 mg/m
Alongside with that, the CHIPPI trial  is currently randomizing advanced
ovarian cancer patients to receive or not receive HIPEC with cisplatin 100
Results of the previously mentioned RCTs are awaited to potentially confirm OVHIPEC-1 trial  results and overcome highlighted limitations in order to further improve in identifying patients who are the best candidate and may benefit the most from HIPEC administration.
The administration of HIPEC in recurrent advanced ovarian cancer and its correlation with patient’s survival has been evaluated in few prospective studies.
Evidence from a prospective multicenter observational study published in 2015 by Coccolini et al. , showed HIPEC with cisplatin + paclitaxel at the time of cytoreductive surgery to be feasible, with a 35% of patients undergoing Grade 3 and Grade 4 post-operative complications according to the Common Terminology Criteria for Adverse Events (CTCAE) scale .
However, the results appear to be weakened by the inclusion in this study of 54 patients undergoing surgery in the upfront setting but also for disease recurrence. In addition, both platinum sensitive and resistant diseases were included.
In 2015 Spiliotis et al. , randomly assigned 120 patients with
recurrent disease to receive secondary cytoreductive surgery
Despite their promising results, the main limitation of this study consists in
the inclusion of recurrent ovarian cancer patients with both platinum sensitive
and resistant disease, the latter population accounting for 38% of the entire
cohort. Due to that, two different HIPEC protocols were administered in relation
to platinum sensitivity of the patient: cisplatin 100 mg/m
Also, the study did not provide data on PFS, previous chemotherapy regimen was not reported as well as toxicity related to HIPEC administration, if any.
Interestingly, in a subgroup analysis of HIPEC group, mean survival was not different between patients with platinum-resistant disease versus platinum-sensitive disease (26.6 vs 26.8 months).
On this topic the positive effect of platinum based-HIPEC in platinum sensitive recurrent ovarian cancer patients has been initially evaluated by Petrillo et al.  ,who retrospectively analysed data on 70 consecutive patients treated with secondary cytoreductive surgery and HIPEC.
With a median follow-up time of 73 months and a median Platinum free interval of 19 months, 5- and 7-year post-recurrence survival rates were 52.8 and 44.7 for HIPEC and no-HIPEC treated patients, respectively.
More recently, prospective data coming from a phase II randomized trial 
showed different results, failing to demonstrate a survival gain of recurrent
ovarian cancer patients treated with secondary cytoreductive surgery + HIPEC with
carboplatin (800 mg/m
However, this study did not report any difference in intra and post-operative morbidity in terms of oostomy rate, length of stay and treatment related toxicity between the two arms.
Overall, in recurrent ovarian cancer as in other previously discussed treatment settings, available data appear to be controversial in terms of which population may benefit the most from HIPEC administration after surgery (platinum sensive or resistant disease) and which intraperitoneal chemotherapy regimen is preferrable, as carboplatin appear to have a lower synergistc effect with hyperthermia compared to cisplatin .
Currently, of the two ongoing trials exclusively focusing on the use of HIPEC in
relapsed ovarian cancer one, the HIPOVA-01 trial  aims to recruit 132
patients with platinum refractory disease and treat them with surgery + HIPEC
with cisplatin 70 mg/m
Alongside with that, the CHIPOR trial  is planning to enroll platinum
sensitive recurrent ovarian cancer patients and randomizing them to receive
either 6 platinum-based chemotherapy cycles followed by secondary cytoreductive
surgery + HIPEC with cisplatin 75 mg/m
However in this moment both trials appear to be active but still not recruiting. Parallel to that, results on a concluded randomized trials on the use of HIPEC in platinum-sensitive recurrent ovarian cancer are awaited .
The positive association of hyperthermia to intraperitoneal chemotherapy has been studied in many types of peritoneal cancer  so far, not only of gynecological origin.
The interest in HIPEC as a treatment able to prolong ovarian cancer patients’ survival is quite novel in the gynecologic oncology literature and it has been raising in the last decade due to encouraging upcoming evidences.
So far, despite not universally accepted, the addition of platinum-based HIPEC only after interval cytoreductive surgery appear to be supported by enough evidence [26, 31] to be introduced in daily clinical practice, also in view of its demonstrated not increased morbidity rate compared to standard treatment .
Same level of evidence are currently lacking in upfront surgery and recurrent setting, however promising results are awaited from ongoing randomized controlled trials.
Future aspects of interest in this field will be the potential influence of tumor’s molecular biomarkers on HIPEC efficacy or the influence of specific patient’s genetic patterns on its effectiveness, such as Breast Cancer Gene (BRCA) mutation. Also, studies on a potential different recurrence pattern after HIPEC treatment (e.g., potential increased rate of extra-abominal or retroperitoneal relapse ) are highly encouraged to further personalize our patients treatment and improve their prognosis.
VG—Conceptualization, writing original draft, review and editing; RT—Conceptualization, review; EG—Conceptualization, review; GS—Conceptualization, review and editing; AF—Conceptualization, writing original draft, review and editing. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
We would like to express our gratitude to all people who helped us and gave their contribution during the writing of this manuscript.
This research received no external funding.
The authors declare no conflict of interest.