Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for treatment of ovarian cancer

Abstract

Hyperthermic intraperitoneal chemotherapy (HIPEC), a strategy combining maximal cytoreductive surgery and maximal regional chemotherapy, has been applied to treat ovarian cancer resulting in long-term survival rates in selected patients. However, the status of HIPEC in ovarian cancer remains an experimental procedure, given the many variables among the data and trials reviewed, to enable us to derive strong conclusions about its role from this overview. In this review we discuss treatment with HIPEC in patients with ovarian cancer and future prospective of its use in clinical setting. HIPEC is an effective tool in the treatment of selected patients with peritoneal carcinomatosis from ovarian cancer. Unfortunately, due to the lack of randomised trials, the evidence of HIPEC is very limited. Future randomised studies are awaited to define the role and clinical impact of HIPEC in ovarian cancer.

Keywords:

• Cytoreductive surgery
• Epithelial ovarian cancer
• HIPEC
• Hyperthermic intraperitoneal chemotherapy

Introduction

Ovarian cancer (OC) is the sixth most common neoplasm in women and accounts for 25% of all malignancies affecting the female genital tract, with age-standardised incidence and mortality rates reaching the highest values in north-western Europe and northern America [1]. OC is currently the seventh most common female cancer worldwide and the eighth most common cause of death worldwide [2]. A fundamental reason for mortality from this disease is due to the lack of specific symptoms and a marked propensity for peritoneal spread, also known as ‘peritoneal carcinomatosis’ (PC) [3]. The peritoneal dissemination from OC may be present at the time of diagnosis of the primary tumour, but it can also arise as a tumour recurrence after radical surgical treatment [4]. Approximately 70% of patients with this type of tumour present an advanced disease (stage III or IV), and approximately 50–75% of women with OC will develop persistent or recurrent disease [5].

The first use of hyperthermic intraperitoneal chemotherapy (HIPEC) for OC was reported in 1994 [6]. Since then, there has been a large body of research evaluating this therapeutic approach associated with cytoreductive surgery (CRS). The rationale for HIPEC is based on 1) direct cytotoxicity of hyperthermia against malignant cells, 2) enhancement of the cytotoxicity of anticancer drugs, and 3) the pharmacokinetic advantages of the intraperitoneal route for chemotherapy [7–9]. However, HIPEC, which does not reach more than 5 mm depth in tissue, requires complete surgical removal of PC [10]. Although the positive impacts of the combination of the peritonectomy with HIPEC in advanced OC have been widely reported in terms of survival effects [4], this procedure remains ‘experimental’ because of lack of randomised trials. This treatment requires not only highly specialised human resources but also complex technological facilities.

In this review we summarise and discuss the current knowledge of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of PC in OC.

Timing and patient selection

The natural history of OC presents several time points at which HIPEC can be performed: 1) in primary OC (first-line treatment), 2) as consolidation treatment, and 3) in persistent, progressive and recurrent disease (second-line treatment) [11–13]. Therefore, the heterogeneous group of patients who are candidates for CS and HIPEC range from primary OC or recurrent OC treated with surgery and chemotherapy to chemoresistant OC patients with a history of multiple treatments [5]. This heterogeneity in treatment procedures results in a difficult statement of the correct timing to perform HIPEC. For this reason, to address the optimal therapy response, an adequate patient selection is more clinically relevant than the proper HIPEC timing.

Exclusion criteria for a safe procedure [3,7] are 1) age > 70 years old, 2) serious medical histories (especially cardiorespiratory, neurological or renal), 3) clinical aggravation with systemic chemotherapy, 4) malnutrition, 5) concomitant extra-abdominal metastasis (aggressive locoregional treatment is not appropriate in non-controlled systemic disease), 6) unresectable liver metastases; 7) massive retroperitoneal bulk disease or lymph node involvement; 8) any contraindication for chemotherapy. Additional minor exclusion criteria are 1) no drop markers with neoadjuvant chemotherapy, 2) overweight (BMI > 40), 3) history of pelvic irradiation, 4) carcinomatosis extended at the scanner or clinically significant, 5) more than four surgical procedures, and 6) occlusion. With a particular focus on age, Votanopoulos et al. [14] demonstrated that HIPEC in patients older than 70 years is associated with considerable morbidity and mortality. Additionally, Cascales-Campos et al. [15], in a study on patients older than 75 years submitted to surgical debulking after neoadjuvant chemotherapy plus HIPEC, reported no advantages in terms of prognosis with high post-operative morbidity. Therefore, this age group should be excluded from this therapeutic procedure. However, age alone is not a contraindication for HIPEC. High-volume centres and rigorous patient selection are key factors for prolonged survival.

Preoperative assessment

Preoperative selection of patients is essential to minimise the incidence and the lethality of HIPEC post-operative complications. More recently, although it has been shown that magnetic resonance imaging (MRI) seems more accurately to predict preoperative Peritoneal Cancer Index (PCI) in patients undergoing evaluation for cytoreductive surgery compared with computed tomography (CT) [16], at present, only direct exploration of the peritoneum allows the detection of ideal candidates for HIPEC in OC. Additionally, fluoro- D-glucose (FDG)-PET/CT was investigated for detection of PC before HIPEC in OC. Razzouk-Cadet et al. [17] stated that FDG-PET/CT can be considered an useful tool for the selection of patients for HIPEC without distant metastasis. Nevertheless, the sensitivity of this procedure is limited in regard to the millimetric metastatic spots. Moreover, Fagotti et al. [18] reported encouraging results of FDG-PET combined with staging laparoscopy performed immediately before secondary cytoreductive surgery with HIPEC. Notwithstanding, the current gold standard continues to be direct peritoneal visualisation, either by laparotomy or laparoscopy. However, the debate regarding which staging system is better in determining the prediction of complete cytoreduction is still open. In 1994, Gilly [19] proposed a staging system of PC based on the size and distribution of malignant granulations. Several clinical trials [7,11] demonstrated the validity of this classification system as a prognostic indicator in patients affected by PC, suggesting a correlation with prognosis. The PCI, described by Jacquet and Sugarbaker [20], is a widely cited system of PC staging that is more accurate than the Gilly system in carcinomatosis assessment [19]. The PCI assesses the carcinomatosis quantification and distribution and has demonstrated a high prognostic value [11].

Currently, many new therapeutic options and diagnostic tools are available in current OC oncology [21–24]. For OC staging evaluation, we can also use a new technology that uses invisible light. Near infrared florescence (NIRF)-guided surgery seems to be a future technology that may improve safety and visualisation of cancer spread. NIRF has been a useful tool in many fields of medicine, such as surgery, urology and others [25–32]. In advanced surgical approaches in performing peritonectomy, the need for ureter preservation is a primary issue. NIRF helps the visualisation of the ureter through the fatty tissue [25]. The other usage of NIRF is visualisation of peritoneal metastases [33,34]. Van Dam et al. [33] first proposed intraoperative tumour-specific fluorescence imaging of OC in humans. The fluorescent dye binds to the folate receptor α in OC. As an overexpression of this antigen occurs in most OC cases, the authors considered tumour-specific fluorescence imaging to be appropriate. Many more new foci of peritoneal spread were visible [34]. In a study by Kosaka et al. [35], peritoneal spread from the OC origin was detected in an animal model using IGG alone or IR 800 albumin. These researchers considered the potential use of ICG in clinical practice. This new technology may guide a surgeon for a more efficient cytoreduction in the future, which will lead to an improvement from an oncology perspective. Currently, new trials are ongoing to evaluate the use of NIRF technology in improving detection of PC in various cancers (as NCT02032485, NCT01982227). Other dyes such as 5-aminolevulinic acid (5-ALA) that are visible at various wavelengths could also be considered for the procedures. Kishi et al. [36] reported that during staging laparoscopy, using 5-ALA improved the detection of peritoneal metastases in 21% of patients without laparoscopic signs of PC. Results from the phase I clinical trial were published by Liu et al. using aminolevulinic acid photodynamic visualisation for CRS and additionally HIPEC in patients with OC or primary PC [37]. In 95% of patients (19/20 analysed cases) strong red fluorescence was detected in the analysed tissue invaded by cancer with a specificity of 100%. It is possible this new improved intraoperative visualisation of cancer deposits using fluorescent guided surgery could help in further improvement of CRS for OC in the future.

Prognostic scoring systems

Complete cytoreduction is the mainstay of CRS with HIPEC [38,39]. Currently, two classification systems are used to assess the completeness of cytoreduction [7,20]. The definition of optimal cytoreduction, however, remains controversial and often differs among studies. The experience with aggressive cytoreductive surgery and heated intraoperative chemotherapy shows a more restrictive definition of optimal CRS (< 2.5 mm) resulting in a better correlation with outcomes such as survival. Some authors have indicated that optimal cytoreduction requires no visible residual disease [4]. However, it is clear that there is a significant positive correlation between maximal cytoreduction and median survival time. Therefore, the extent of cytoreduction is one of the most crucial prognostic factors to improve OS greatly in all stages of disease [40]. It was estimated that each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time [38]. Several studies have emphasised the relationship between complete cytoreduction and improved outcomes. Ryu et al. [41] reported that a cytoreduction of less than 1 cm conferred a significantly better disease-free interval (hazard ratio 0.355, p = 0.0005) as well as overall survival (hazard ratio 0.38, p = 0.003). Raspagliesi [42] found that the outcomes were positively affected by CCR score in addition to the World Health Organization performance status and the extent of the carcinomatosis. Similarly, Look et al. [43] found a complete cytoreduction (residual disease of < 2.5 mm) was associated with improved median survival (55.9 versus 8 months, p = 0.037) in multivariate analysis. Therefore, only by assuring that the majority of women with OC have access to a maximal primary surgical effort can we expect to realise the population-based survival benefits of cytoreductive surgery. In the recurrent OC setting, several authors demonstrated the undifferentiated histological subtype represented (hazard ratio, 2.57 p < 0.05) an independent factor associated with reduced disease-free survival [44], whereas BRCA status did not affect progression-free survival [45]. Age, performance status, interval from initial treatment to recurrent, PCI, presence of lymph nodes, initial platinum response and completeness of cytoreduction still remains the most important prognostic indicators in OC.

Morbidity and mortality

Many criticisms against procedures combining CRS and HIPEC were due to the high mortality and morbidity rates reported in the medical literature for the treatment of non-gynaecological peritoneal surface malignancies. However, it is still unclear whether the increased rate of morbidity and mortality are related to CRS or HIPEC. Many authors have published their experiences using various criteria for defining the post-operative or post-HIPEC morbidity and mortality. Due to the lack of uniformity in grading the morbidity as well as in reporting the differences in HIPEC administration (eg, variation in the perfused temperature, chemotherapy protocols, open or closed surgical technique, HIPEC devices), the comparison of the results is inaccurate and inadequate [46–49]. In this context, data from two systematic reviews [4,5] suggested that the morbidity and mortality rates are around 0–40% and 0–10% respectively however, it has been demonstrated by a recent systematic review that the mortality and morbidity rates are lower, in the tertiary high volume centres [50].

Nevertheless locoregional administration of chemo-perfusate should reduce the risk of the chemotherapy agent systemic effects, the complications mainly related to the HIPEC procedure are haematological toxic effects (0–31%) due to transitory bone marrow suppression and renal insufficiency (0–7%), mainly in cisplatin-delivered HIPEC [4] even the real influence of intraperitoneal cisplatin concentrations or dose along with the HIPEC duration and temperature on renal or haematological toxicity remains unknown. The maximum tolerated chemotherapy dose has not yet been clarified and further investigations are warranted. In addition, other significant complications were ileus, anastomotic leakage, intestinal perforation, fistula, abscess, sepsis, bleeding and wound infection/dehiscence. Reoperation for complications was required in 0% to 16% of cases [51]. Moreover, the morbidity and mortality in OC patients submitted to CRS plus HIPEC still remains dependent on the patient’s age, performance status, number and type of peritonectomy procedures, and on the duration of HIPEC. In particular, recent studies [3,12] have shown performance status, chemotherapy dose, duration, the extent of surgery, visceral resection and number of digestive anastomoses were correlated with a higher morbidity rate as independent factors [4]. The extent of carcinomatosis and incomplete cytoreduction has also been reported as a predictive factor of morbidity [3,12,52]. Particularly, the complication rate of patients with stage III–IV carcinomatosis is higher than those with stage I–II disease [3,12,52]. Recently, a retrospective Italian multicentre study [53] of 683 patients showed older age and a higher value of PCI were correlated with higher mortality; instead, older age, ovarian origin of tumour, presence of ascites, closed technique and longer operative time were predictors of higher morbidity. In a recently published meta-analysis [54], the post-HIPEC mortality rates for primary and for recurrent OC were equal at 1.8%. The pooled rates for minor morbidities (grades I–II) were for primary OC 40% and for recurrent OC 27.5%, and for grades III–IV 31.3% and 26.2% respectively. Comparing CRS with HIPEC versus CRS alone, the major morbidities were similarly independent of the usage of HIPEC (26.7% versus 28.6%, p = 0.784) as reported by Warschkow et al. [55].

Search strategy

On 1 December 2015 we searched the PubMed database for trials containing the keywords ‘ovarian cancer’, ‘hyperthermic intraperitoneal chemotherapy’ and ‘HIPEC.’

All studies involved patients with OC who were treated with HIPEC during different stages of disease. Studies were excluded from the review if they did not contain a HIPEC-based procedure and/or complete information. Data on HIPEC as a front-line strategy of several selected studies including patients with primary OC treated with HIPEC, as well as interval cytoreduction (during primary chemotherapy) and consolidation treatment, are presented in Table 1, while studies of HIPEC as a second-line treatment including HIPEC during ‘secondary surgery’ are reported in Table 2. Finally, in Table 3, the available ongoing clinical trials that deal with different factors contributing to survival as a front line as well as additional treatment are reported.

Table 1. HIPEC in ovarian cancer studies as first line treatment during primary cytoreductive surgery presented in more relevant publications.

Study	No. of Patients	Drug	Morbidity (%)	Mortality (%)	Median PFS months	Median OS months	5-year OS (%)	Median FU
Ansaloni et al. (2012) [56]	39	Cisplatin + paclitaxel (11) Cisplatin + doxorubicin (26) Paclitaxel + doxorubicin (1) Doxorubicin (1)	18	2.6	14	NR	NR	NR
Bakrin et al. (2013) [57]	92	Cisplatin; Doxorubicin; Oxaliplatin; Mitomycin Cisplatin + mitomycin Cisplatin + doxorubicin	31 ≥grade III	1	12	35	17	40
Carrabin et al. (2010) [58]	12 (8)	Oxaliplatin	56 grade III	0	17	NR	NR	38
Cascales Campos et al. (2011) [59]	35	Paclitaxel (32) Cisplatin (3)	13 grade III, 2 grade IV	0	NR	NR	NR	NR
Cascales Campos et al. (2014) [60]	52	Paclitaxel	NR	NR	63% at 3 years	NR	NR	NR
Coccoloni et al. (2015) [61]	54	Cisplatin; Paclitaxel	35 grade III/IV	6	12	33	NR	20
Deraco et al. (2011) [62]	26	Cisplatin + doxorubicin	15	4	30	NR	61	25
Di Giorgio et al. (2008) [63]	22	Cisplatin	21	4	20	24	17	NR
Frenel et al. (2011) [64]	19	Oxaliplatin	29 grade III; 3 grade IV	NR	13	NR	NR	14
Helm et al. (2010) [65] (HYPER-O)	26	Cisplatin + carboplatin + mitomycin combination	NR	0.5	25	42	33	18
Helm et al. (2010) [65] (HYPER-O)	19	Cisplatin + carboplatin + mitomycin combination	NR	0.5	17	69	50	18
Kim et al. (2010) [66]	19	Paclitaxel	16 grade III	0	NR	NR	84	80
Lim et al. (2009) [67]	30	Cisplatin	40 grade III	0	NR	NR	NR	NR
Pavlov et al. (2009) [68]	31	Doxorubicin + cisplatin	18	2	NR	34	55	60
Pomel et al. (2010) [69]	31	Oxaliplatin	3	0	NR	NR	67 (2 years)	NR
Rettenmaier et al. (2015) [70]	37	Carboplatin	16 grade III/IV	0	13	14	NR	NR
Roviello et al. (2010) [71]	14	Cisplatin + mitomycin	23 grade III, 4 grade IV	0	NR	NR	55	27
Roviello et al. (2010) [71]	31	Cisplatin + mitomycin	23 grade III; 4 grade IV	0	NR	NR	58	27
Rufian et al. (2006) [72]	19	Paclitaxel	36	0	25	38	37	NR

FU, follow-up; NR, not reported, OS, overall survival.

Studies by Ansaloni et al. [73], and Coccoloni et al. [74] also separately present groups of patients with recurrence ovarian cancer. Studies by Frenel et al. [75], Kim et al. [76], Pommel et al. [77], and trials by Ansaloni et al. [78] present HIPEC in ovarian cancer as a variant with consolidation treatment. Studies by Carrabin et al. [79], Helm et al. [80], and Roviello et al. [81] present patients with HIPEC during interval cytoreductive surgery.

Table 2. HIPEC as a treatment in recurrence OC presented in more relevant publications and ongoing trials.

Study	No. of patients	Type of recurrence	Morbidity (%)	Mortality (%)	Median PFS	Median OS	5-year OS (%)	Median FU
Argenta et al. (2013) [82]	10	Previous optimal tumour cytoreduction (< 1 cm) followed by platinum and taxane-based adjuvant chemotherapy; platinum sensitive disease, defined as > 6 months since their last chemotherapy administration	2 grade IV	0	NR	NR	NR	16
Bae et al. (2007) [83]	44	HIPEC during ‘secondary surgery’	NR	NR	56	NR	66	NR
Bakrin et al. (2013) [57]	474	Chemoresistant 247 Chemosensitive EOC : recurrence in 223; 4 undetermined	31 ≥grade III	1	NR	46	37	40
Carrabin et al. (2010) [58]	10	1 platin resistant; All had 1–3 lines of previous chemotherapy	56 grade III/IV	0	10	NR	NR	38
Cascales Campos et al. (2014) [60]	32	No information	21 grade III/IV	NR	45% at 3 years	NR	NR	18
Ceelen et al. (2012) [84]	42	17 patients (41%) were platin resistant	21	0	13	37	42	21
Cotte et al. (2007) [85]	81	16 chemoresistant, 4 with large-volume residual tumours following 1st-line chemo, 12 with recurrence after PFI < 6 months); 65 had recurrent lesions, 8 with 1st recurrence after PFI 6–18 months; 57 after 2nd or 3rd recurrence. 29/57 had 2nd recurrence, 20 had 3rd or 4th recurrence, 8 had ≥5 recurrences >4 years after initial treatment	14	2	19	28	NR	47
de Bree et al. (2003) [84]	19	Patients with early recurrence (<6 months after chemotherapy), or persistent carcinomatosis after primary systemic chemotherapy	58	11	26	54	42	21
Deraco et al. (2012) [85]	56	23% of patients (13) were platinum resistant	26 major complications	5	19	28	NR	47
Di Giorgio et al. (2008) [86]	25	All 1 or more operations for OC (range 1–4 laparotomies)+chemo (range 1–3 lines). 18 recurrent disease, 4 interval debulking, 3 2nd-look surgery	21	4	26	54	42	30
Fagotti et al.(2011) [63]	41	All patients were platinum sensitive	35	0	11	26	23	23
Frenel et al.(2011) [87]	12	75% 1st relapse, 17% 2nd, 8% 3rd relapse	29 grade III 3 grade IV	0	20	24	17	NR
Gori et al. (2005) [51]	29	HIPEC during ‘secondary surgery’	NR	0	24	38	NR	38
Helm et al. (2010) [64] (HYPER-O)	83	78/83 patients received before platinum chemo, 76 platinum sensitive	NR	0,5	14	24	18	23
Helm et al. (2007) [88]	18	Mean prior laparotomies 1.4 (0–3), mean chemotherapy agents 3.2 (0–7) 2 had previous pelvic radiotherapy. 8 platinum resistant (44%)	28 ≥grade III haematological 72 ≥grade III metabolic/other	6	57	64	NR	64
Le Brun et al. (2014) [65]	23	Only 1st relapse patients, >6 months after the end of the initial treatment 1st and 2nd line chemo always given	NR	0	14	24	18	18
Koningsrainer et al. (2014) [89]	90	47% preoperative chemo, 13% platin resistant	42	0	10	31	NR	20
Muñoz-Casares et al (2009) [90]	14	No detailed information	20	0	24	NR	76 (4 years)	24
Massari et al. (2014) [52]	11	All patients previously had surgery and chemo	16	8	NR	35 vs 14 (CC0/1 vs 2/3)	NR	19
Pavlov et al. (2009) [91]	25	No detailed information	18	2	48	NR	58	NR
Piso et al. (2004) [92]	11	10 platin-based chemo, (3 with taxanes), and 1 with only taxanes	36	5	12	27	NR	NR
Raspagliesi et al. (2006) [68]	40	13 presented partial response to 1st-line chemo and treated in a 2nd-look setting. 27 had advanced relapsing disease and had received a median 2 lines (range 1–5) of systemic chemo, of cisplatin, taxol or taxol/platinum	20	0	NR	40	72	60
Robella et al (2014) [93]	25	No detailed information	36	7	NR	47	27	20
Rufian et al. (2006) [42]	14	Patients were previously treated by surgery with/without chemo	36	0	24	41	15	26
Ryu et al. (2004) [41]	35	Positive partial response after platin-based chemo after previous operation	36	0	49	72	63	NR
Ryu et al. (2004) [41]	26	HIPEC during ‘secondary surgery’	NR	NR	41	NR	55	NR
Safra et al. (2014) [45]	27	All patients were platin sensitive	NR	NR	15	NR	79	NR
Zanon et al. (2004) [95]	30	8 previously treated with systemic chemo alone had hysterectomy, ovariectomy, and omentectomy during cytoreductive surgery. 13/22 who had had primary surgery had had 1 line previous systemic chemo and 9 had had 2 or more	17	3	17	28	NR	19

FU, follow-up; chemo, chemotherapy; PFI, progression-free interval; NR, not reported; PFS, progression-free survival; OS, overall survival.

Table 3. Selected ongoing trials for HIPEC in ovarian cancer.

Clinical trial identifier	Patient no.	Disease status	Primary end point	Drug	Status
NCT02124421	48	Primary CRS	Assess the feasibility of recruitment compare complication rates	Carboplatin, paclitaxel, cisplatin	Recruiting
NCT01091636	170	Primary CRS	Progression-free survival; assess progression-free survival rate for 2 years after HIPEC with adjuvant treatment	Cisplatin	Recruiting
NCT01628380	94	HIPEC consolidation treatment	Disease free survival	Cisplatin + paclitaxel	Recruiting
NCT02328716	32	Primary CRS	Disease-free survival	Cisplatin	Ongoing not recruiting
NCT01709487	24	Primary CRS	Mortality rate	Cisplatin	Recruiting
NCT02249013	20	Primary CRS	Progression-free survival	Cisplatin	Recruiting
NCT02199171	30	Primary CRS	Maximum tolerated dose, adverse events	Carboplatin	Recruiting
NCT02217956	30	HIPEC consolidation treatment	Toxicity	Cisplatin, bevacizumab	Recruiting
NCT02567253	48	Primary and recurrent OC	Tissue penetration distance of cisplatin in peritoneal tumour tissue nodules using laser-ablation inductively coupled plasma mass spectrometry	Cisplatin	Not open
NCT00426257	280	HIPEC during secondary surgery	Duration of recurrence free survival	Cisplatin	Recruiting
NCT01539785	158	HIPEC in recurrent OC	Estimate of progression free interval	Cisplatin	Recruiting
NCT01767675	98	HIPEC in recurrent OC	Estimate of progression free interval	Carboplatin	Recruiting
NCT01376752	444	HIPEC in recurrent OC	Overall survival	Cisplatin	Recruiting
NCT01970722	50	HIPEC in primary or recurrent OC with/without normothermic post-operative intraperitoneal chemo	Treatment-related toxicities	Different for specific cancer	Recruiting
NCT01588964	30	HIPEC in recurrent OC	Progression free survival, overall survival, post-operative complications, efficacy and tolerability of the treatment	Oxaliplatin	Study completed
NCT02217956	30	HIPEC consolidation treatment	Toxicity	Cisplatin	Recruiting

OC, ovarian cancer; CRS, cytoreductive surgery.

An overview of HIPEC efficacy

Considering the small number of patients per centre, a number of collaborative experiences of HIPEC in OC have been developed. Recently in the USA, surgical and gynaecological oncologists participated in a collaborative Internet-based registry (HYPER-O) [65], collecting and analysing data from multiple centres to achieve an understanding of current practice and outcomes. In the initial report, 141 women were treated as frontline (n = 26), as interval debulking (n = 19), for consolidation (n = 12), or for recurrence (n = 83). The median duration of HIPEC was 100 min (range 30–120), and the average perfusion temperature was 38.5–43.0 °C (median 41.9°C). The HIPEC drug was based on the administration of cisplatin (n = 72), mitomycin (n = 53), or their combination (n = 14). The median overall survival of the entire population was 30.3 months. In addition, a retrospective cohort multicentre study from French centres was reported [57] including consecutive patients treated with CRS and HIPEC for advanced and/or recurrent OC. The study involved 566 patients from 13 centres who underwent 607 procedures between 1991 and 2010. There were 92 patients with advanced OC (first-line treatment) and 474 patients with recurrent OC, representing altogether one of the largest cohorts of OC patients treated with HIPEC. HIPEC + CRS yielded a median survival of 35.4 months for OC and 45.7 months for recurrent OC. After CRS has been completed, the median survival was 41.5 months in advanced OC and 47.2 months and 51.6 months in chemosensitive and chemoresistant OC, respectively. Interestingly, the result from this analysis was that no significant difference in survival between patients with chemoresistant and chemosensitive subgroups has been noted. Recently, the first randomised study evaluating the role of HIPEC in recurrent OC was conducted. HIPEC was associated with a significantly prolonged OS (26.7 versus 13.4 months in the non-HIPEC group, p = 0.006) [104]. Additionally, in this study, survival was 26.6 months in platinum-sensitive and 26.8 months in platinum-resistant disease. These data have confirmed the recent similar results reported by Bakrin et al. for chemoresistant and chemosensitive patients [57]. Recently, meta-analysis was published [54] analysing data based on available results from studies comparing CRS + chemotherapy with or without the combination of HIPEC in primary or recurrent OC. The authors proved statistically significant benefit in 2-,3-,4-,5- and 8-year survival with comparable morbidity and mortality between the two procedures. In case of recurrent OC, CRS with or without chemotherapy definitely improves long-term results. The combination of HIPEC and CRS along standard chemotherapy had higher 1-, 3- and 5-year overall survival in comparison with chemotherapy only (100%, 91%, 57% versus 83%, 66%, 41%). Analysing the magnitude of effect related to HIPEC alone, the studies comparing HIPEC + CRS + chemotherapy versus CRS + chemotherapy, small benefit of HIPEC for recurrent OC only has been shown in case of 1- and 3-year OS rate (OR:3.48; OR 7.39, p < 0.01)

Front-line therapy

HIPEC during primary cytoreductive surgery

The standard treatment for patients with advanced ovarian disease (stage III or IV) is considered surgical debulking followed by platinum/paclitaxel-based adjuvant therapy [105,106]. The prognostic impact of maximal cytoreductive surgery in the treatment of PC from OC is well established [107]. Although 60–80% of cases diagnosed at an advanced stage respond to platinum-based systemic chemotherapy [4], the prognosis remains poor due to a high rate of recurrence (5-year survival rate < 25%) [5]. HIPEC performed at the time of initial surgery would have several advantages due to the characteristics of patients (best performance status and less toxicities from prior treatments) and to the characteristics of the tumour (less possibility of pharmacological resistances) [108].

Although, the best outcome has been observed after complete CRS, considering the lack of randomised trials and the weakness of published studies, it is hazardous to conclude that HIPEC used as a front-line treatment or as a delayed first-line chemotherapy impacts the OS of patients.

HIPEC during interval cytoreductive surgery

A major controversy concerns the optimal time-point in the natural history of OC for the performance of CRS along with the HIPEC [109]. The patient numbers from various studies are small, and the data seems difficult to interpret. Additionally, initial maximal CRS was not always reported. Therefore, neoadjuvant chemotherapy for two or three cycles may reduce disease burden and increase tumour resectability while simultaneously allowing performance status to improve. Many advantages are possible if surgery is performed after neoadjuvant chemotherapy (i.e. less intraoperative blood loss, shorter operative time, fewer intensive care unit admissions, and a shorter duration of hospital stay) [110,111]. No significant differences resulted in the survival rate between patients submitted to HIPEC as a first-line treatment and as a second-line treatment following neo-adjuvant chemotherapy [65]. However, a recent randomised trial showed that primary systemic chemotherapy followed by delayed CRS and subsequent systemic chemotherapy facilitates optimal CRS with a decrease in morbidity without being less effective than primary debulking surgery followed by systemic chemotherapy [112]. Spiliotis et al. [113] are conducting an ongoing trial of laparoscopic-assisted neoadjuvant HIPEC in patients with stage IIIC or IV OC, in combination with systemic chemotherapy followed by interval debulking + HIPEC and then further systemic chemotherapy. However, the experience with this indication is limited.

Consolidation treatment

Despite the high initial response rates to front-line CRS and HIPEC in OC, most patients experienced recurrence. It was shown even after a documented complete pathological response, approximately 60% of the patients with OC will present recurrent disease [114]. Therefore, there is a need for approaches in ‘consolidating’ initial disease control, as additional therapy may be beneficial in maintaining the disease control [115]. However, large randomised comparative studies with prolonged follow-up are needed to support the ‘consolidation treatment’ in a clinical setting after CRS and HIPEC.

Recurrent OC

In patients initially presenting with advanced disease, recurrence is frequent. One of the most important factors affecting survival in patients with recurrence is the time between the initial cancer treatment and the time of recurrence [116,117]. Those patients progressing after front-line therapy or within 6 months of completion have ‘platinum-resistant’ tumours, with response rates of 8–28% and a median overall survival time of 6–12 months, whereas those recurring after 6 months have ‘platinum-sensitive’ tumours, with response rates up to 77% and a median survival duration of 12–40 months [118,119]. Survival of patients with recurrent OC treated by chemotherapy alone tends to be inferior to that reported in secondary CRS. The influence of secondary CRS without HIPEC on survival outcomes has been addressed in a substantial amount of studies and has been recently systematically reviewed [120]. The addition of HIPEC is an interesting and promising treatment in recurrent OC if it is combined with complete cytoreduction. HIPEC has been mainly investigated in the setting of persistent or recurrent disease. However, a significant number of patients presented with early recurrent disease or heavily pre-treated (re)recurrent disease with diffuse PC, and these patients’ characteristics suggest poor outcomes. In most studies, median OS was longer than that reported in secondary CRS only [121]. In the ‘platinum sensitive setting’, HIPEC resulted in a statistically significant improvement in PFS and OS [122]. HIPEC seems to achieve similar survival benefits in patients with chemoresistant or chemosensitive disease.

Critique of current evidence

Although the standard front-line therapy for OC is considered to be CRS followed by intravenous chemotherapy with a platinum and taxane combination, this approach is not curative, and approximately 60% of all patients with OC have recurrence [123–126]. To improve these results along with the encouraging data achieved from intraperitoneal administration of chemotherapeutic drugs, the combination of the intraperitoneal route with intravenous administration in primary stage III OC has subsequently been studied. Therefore, three randomised trials conducted by the Gynaecological Oncology Group (GOG) [127–129] assessed the efficacy and safety of intraperitoneal chemotherapy in advanced OC. In these studies survival data were clearly in favour of the combination if compared to the conventional systemic chemotherapy alone. Based on these results, the National Cancer Institute issued a clinical announcement in January 2006, recommending that women with stage III OC who undergo optimal surgical cytoreduction should be considered for intraperitoneal chemotherapy [130]. However, these trials considered only patients submitted to optimal cytoreduction, and several complaints mainly related to the management of the catheter for intraperitoneal and patient compliance were reported, resulting in less than half of patients completing the treatment [130]. Moreover, normothermic intraperitoneal chemotherapy still presents several limits, which consist of the inability of this technique to penetrate tumour nodules of 3 mm or greater [131]. Therefore, the pharmacokinetics of intraperitoneal platinum compounds with hyperthermic perfusion after CRS have been successively investigated. However, despite the promise of better results, after approximately 20 years from the first report of HIPEC, little is known currently on the real long-term prognostic impact of this treatment modality. The levels of evidence in the published studies are mostly class II or class III (non-randomised comparative studies and observational studies). Additionally, the patients’ cohort treated was heterogeneous and differed in age, previous systemic therapy, tumour size and timing (primary OC, consolidation treatment and recurrent/persistent disease) [5]. The timing of HIPEC differed greatly, including cases with either advanced OC which had or had not undergone previous surgery and chemotherapy, and cases of recurrent OC pre-treated with many types of therapy or second-look surgery. The lack of homogeneity also consists of differences in administering HIPEC, such as variation in the perfused temperature, chemotherapy protocols, surgical approach (open or closed technique) and HIPEC devices, which further influences the differences in complications. Moreover, different criteria and different classifications for complications were used to evaluate the completeness of cytoreduction. Finally, the surgeon experience as a variable parameter leads to an insufficient CRS [132]. Nevertheless, although non-randomised, some studies [41,66,83,88,91,112,133] have compared HIPEC to another arm consisting of no treatment or CRS. However, even if the small group of patients evaluated in these studies do not allow definitive conclusions, HIPEC may be a feasible treatment with a potential benefit and provide superior survival compared to CRS only or no treatment. However, the nature and small number of patients reported in these studies are not enough to increase the level of evidence for HIPEC in OC treatment. Recently, the first randomised study evaluating the role of HIPEC in recurrent OC showed that HIPEC significantly prolonged OS (26.7 versus 13.4 months in the non-HIPEC group, p = 0.006) [104]. However, one study alone is not sufficient to recommend the use of HIPEC in OC patients, and currently neither the relevant international guidelines nor recent consensus has included HIPEC as a standard treatment for primary or recurrent cancer [134–137]. The AGO-OVAR group also stated ‘the use of HIPEC outside of well-designed, prospective and controlled clinical trials is therefore disregarded’ [138]. In this setting, a recent systemic review [139] regarding the published retrospective data on the use of HIPEC for primary advanced OC and for recurrent OC failed to exhibit a clear survival benefit that justifies the use of this technique as a standard daily practice. HIPEC has obtained modest results concerning survival compared to other studies that have examined standard approaches. The weighted median OS was 37.3 months, which has been historically observed in patients who have undergone suboptimal de-bulking or neoadjuvant therapy [140,141] without HIPEC.

The important issue is to keep the temperature at the optimal level in the whole abdomen during the HIPEC procedure for OC. Rettenmaier et al. [142] proved the temperature variations according to the abdominal site and time intervals were minimal so that the effective time of the hyperthermia was achieved in all sites of the abdomen during the whole procedure.

An interesting report was published by a group from the USA [143] based on HIPEC usage in paediatric patients with paediatric ovarian tumours. The study is based on only eight patients aged 4–18 years, which highlights an important usage of this aggressive treatment in the paediatric field of oncology, with good results of OS and RFS of 64% and 62%, respectively. In 2012, the same group proved the safety profile of HIPEC with cisplatin for use in children [144].

In conclusion, the heterogeneity of patient selection, the timing of disease and HIPEC administration preclude a definitive conclusion from the survival results and make of HIPEC an investigational procedure with a low level of evidence.

State of the art and future prospects

In the last few years, various groups of surgeons have become involved in the use of HIPEC for PC from OC. However, only a few centres have reached experience exceeding 100 cases, and the HIPEC procedure has not been standardised yet. Some authors have reported that the performance of at least 130 procedures is necessary to consider the physician an expert in cytoreduction using the ‘Sugarbaker’ technique [141]. Generally, HIPEC seems well tolerated and associated with acceptable morbidity if patient selection is appropriate and adequate experience is gained in a referral centre. However, the most essential question is whether it provides a survival advantage [85]. To resolve this issue, many centres initiated randomised trials for various stages of disease. To the best of our knowledge, few randomised controlled trials are evaluating the effectiveness of HIPEC in primary or recurrent OC; two have just been proposed, whereas five are already on course [74,75,96,97,99,102]. Amongst the ongoing trials, a Korean study (NCT01091636) [74] has evaluated the efficacy of HIPEC in the treatment of primary and recurrent OC. NCT00426257 [96] is a phase III randomised trial studying the efficacy of HIPEC after secondary debulking surgery. Two more trials are related to HIPEC efficacy in recurrent OC: a multicentre phase III trial from France, the CHIPOR study (NCT01376752) [99], and an Italian multicentre phase III trial, the HORSE study (NCT01539785) [97]. This Italian multicentre trial is to study the role of HIPEC after chemotherapy in those patients who responded to treatment. Finally, another randomised study on HIPEC by the Italian Society of Integrated Locoregional Therapy (STILO) looking at the role of HIPEC in persistent OC had to be closed prematurely almost a decade ago due to poor patient accrual [145]. To date, there are no ongoing trials that offer sequential intraperitoneal chemotherapy as a control arm, and intraperitoneal chemotherapy has resulted in the best results that have yet been reported in newly diagnosed patients. A phase I clinical trial currently recruiting for unresectable stage IIIC OC is also trialling the use of post-operative bevacizumab to change effect with efficacy and delay against cancer (NCT02217956) [102]. Antigen for bevacizumab-VEGF is elevated in the peritoneal cavity with malignant ascites and leads to increasing endothelial cell permeability [146].

The field of uncertainty in OC treatment is the presence of malignant ascites. We have to underline that in recurrent OC in the presence of ascites the usage of HIPEC is known as a contraindication of curative treatment. A paper by Ba et al. investigated the efficacy of HIPEC preceded or followed by CRS because of instability of vital signs in 32 patients with malignant ascites caused by OC [147]. HIPEC under ultrasound guidance in unstable patients with delayed CRS after vital sign stability showed the same results in long-term survival as patients treated with HIPEC and CRS. This approach may be interesting, especially as malignant ascites reduce significantly patients’ quality of life, promote metastatic process, and affect respiratory and circulatory functions [148,149]. For current usage with malignant ascites, HIPEC should be selected only in very specific cases. Further studies are needed to prove the role of palliative treatment of malignant ascites by HIPEC not only because of hypothetical survival benefit, but especially to improve quality of life.

Iterative HIPEC procedures

As the nature of peritoneal spread is associated with recurrence, another interesting issue that has to be mentioned is repeated HIPEC procedure. A paper by Wong et al. [150] describes eight patients who underwent repeat HIPEC procedure because of recurrent mesothelioma. No significant differences were observed between initial and repeated HIPEC in terms of blood loss, hospital stay, and operation time. Also median treatment-free time was no different. Statistically significant patients who had repeated HIPEC showed improved median OS (80 versus 27.2 months, p = 0.007). A paper by Vaira et al. [151] describes patients showing recurrence after HIPEC were treated initially because of different malignancies, but it also showed on a small group of OC patients that in a selected group of recurrent diseases repeated HIPEC is a clinical option. No difference was observed in disease-free survival between initial and repeated HIPEC. Worth mentioning is the acceptable rate of complications grade III and IV, at −18.7% of patients.

Finally, the first experience of minimally invasive CRS plus HIPEC in OC has been published. Fagotti et al. [18] retrospectively evaluated a consecutive series of OC patients with isolated platinum-sensitive relapse. Ten cases were treated with laparoscopic/robotic secondary CRS + HIPEC. In all cases, complete debulking was achieved. No grade III/IV surgical, metabolic, or haematological complications occurred. In all patients, post-operative FDG-PET/CT scan was negative, and after a median time of 10 months (6–37) from secondary CRS + HIPEC, no secondary recurrence was observed. Also, Rettenmaier et al. presented their first experience in laparoscopic debulking surgery and HIPEC procedure together with consolidation chemotherapy [70]. Although the small numbers of patients and the retrospective data do not allow definitive conclusions, minimally invasive CRS + HIPEC may be a safe option in selected OC patients, and further studies are required.

Conclusions

CRS and HIPEC represent an aggressive multidisciplinary approach to an aggressive type of cancer such as OC, and it demonstrates a positive emerging trend towards expected survival rates in patients with PC. Despite encouraging survival rates, HIPEC remains an experimental procedure. It is also clear that CRS plus HIPEC is not indicated for all patients with PC, but has an established role in selected patients [152]. As it is fundamental to achieve the related survival advantage, completeness of CRS must be considered the basic prerequisite for the use of HIPEC. In highly specialised treatment centres, mortality and morbidity rates are lower; thus, criticism against the feasibility of this procedure is no longer acceptable. Combined treatment with CRS and HIPEC is currently suggested by the international consensus group as the most likely to affect survival favourably in stage III OC. Centralisation could also give patients the possibility of undergoing real, complete cytoreduction without the risk of residual disease, with a possible positive impact on survival. However, failure of widespread adoption may reflect the lack of convincing evidence because of lack of randomised trials [5,153]. The growing interest and ongoing clinical trials in the field of HIPEC show the importance of this technique in the modern treatment of advanced OC [153]. Moreover, new criteria are needed to include a unique system for peritoneal disease staging, the optimal extension of surgical resection associated with HIPEC, the best method of performing HIPEC, and the type and dose of anticancer drugs to use in HIPEC treatment.

Acknowledgements

All authors contributed equally to this work.

Disclosure statement

The Authors have no conflict of interest or financial ties to disclose. The authors alone are responsible for the content and writing of the paper.