The role of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Ovarian Cancer: A Review

Abstract

Ovarian cancer is one of the leading causes of cancer related deaths in women worldwide. It is usually diagnosed in an advanced stage (Stages III and IV) when peritoneal cancer spread has already occurred. The standard treatment comprises of surgery to remove all macroscopic disease followed by systemic chemotherapy. Despite all efforts, it recurs in over 75 % of the cases, most of these recurrences being confined to the peritoneal cavity. Recurrent ovarian cancer has a poor long term outcome and is generally treated with multiple lines of systemic chemotherapy and targeted therapy. The propensity of ovarian cancer to remain confined to the peritoneal cavity warrants an aggressive locoregional approach. The combined treatment comprising of cytoreductive surgery (CRS) that removes all macroscopic disease and HIPEC (Hyperthermic Intraperitoneal Chemotherapy) has been effective in providing long term survival in selected patients with peritoneal metastases of gastrointestinal origin. Intraperitoneal chemotherapy used as adjuvant therapy has shown a survival benefit in ovarian cancer. This has prompted the use of CRS and HIPEC in the management of ovarian cancer as a part of first line therapy and second line therapy for recurrent disease. This article reviews the current literature and evidence for the use of HIPEC in ovarian cancer.

Introduction

Worldwide, ovarian cancer accounts for almost 200,000 cancer cases in women and is a leading cause of cancer related death, with over 100,000 deaths due to disease each year. [1] Majority of the patients are diagnosed in stages III and IV. In FIGO stage III and IV, the peritoneum is involved in at least 75 % of the patients. [2] The standard treatment of advanced ovarian cancer is cytoreductive surgery with the goal of removal of all macroscopic disease and systemic chemotherapy comprising of a platinum compound and a taxol. [3] With this treatment there is a complete remission in 60–80 % of the cases with a median survival of 35–38 months. Though there is a high initial response, most patients recur and majority of the recurrences are in the peritoneum. Even after recurrence, the disease remains confined to the peritoneal cavity for a long time making it an ideal target for loco regional therapy. [4] Thus an aggressive loco regional strategy is warranted in the management of both advanced and recurrent ovarian cancer.

Rational for Complete Cytoreductive Surgery (CRS)

For Stage III and IV Ovarian Cancer

Cytoreductive surgery (CRS), which comprises of removal of all macroscopic disease, is the current standard of care for surgery for ovarian cancer. The earliest evidence to support the benefit of cytoreductive surgery for ovarian cancer came from the retrospective review of 102 patients by Griffiths et al. in which they showed that the survival time was inversely proportional to residual mass size under 1.6 cm, and surgery improved survival relative to reduction in mass size below this limit. [5] In another study by Hoskins et al., of a subgroup of 294 patients from a GOG study, all of whom had residual disease >1 cm, patient with residual disease <2 cm survived longer than those with larger residual disease. Among those with larger residual disease, size does not affect prognosis appreciably. [6] This study forms the basis of the GOG recommendation of optimal debulking which as residual implants <1 cm. The same authors retrospectively reviewed 394 patients from a GOG study all of whom had residual disease <1 cm and concluded that apart from the size of residual disease, the other factors influencing survival are extent of disease, age, tumor grade and the number of residual lesions. [7] The Gynecologic Oncology Group (GOG) has defined optimal debulking as residual implants less than 1 cm. [8] However, Chi et al. pointed out, such measurements are subjectively determined at the completion of surgery and due to tissue induration or inadequate exploration, assessments of residual tumor size are often not entirely accurate. [9] A meta-analysis by Bristow et al. of data from 53 studies including 6885 patients with stage III-IV epithelial ovarian cancer who underwent CRS followed by cisplatin or carboplatin based chemotherapy showed that the percent maximal CRS was an independent prognostic variable for survival (P < 0.001). When patients with no residual tumor were compared to those with any size of residual tumor, there was a difference in median survival of 46.9 months between the 2 groups for stage IIIC and 30 months for stage IV favoring no residual disease. Similarly, when patients with residual tumor size of 1–10 mm were compared with those having residual disease >10 mm there was a difference in median survival in favor of the first group of 4.9 months for stage 3C and 2.3 months for stage 4. [10] This provides sufficient evidence to conclude that the goal of CRS for ovarian cancer should be to achieve complete tumor removal with no visible or palpable disease anywhere in the abdomen. When required, extensive upper abdominal surgery including diaphragm resection and splenectomy should be employed to achieve complete tumor removal. [11, 12] Though spread to these regions is considered indicative of aggressive tumor biology, complete cytoreduction in this area has shown to have a survival benefit as well. [7, 13, 14].

For Recurrent Ovarian Cancer

Recurrent ovarian cancer is described as platinum sensitive if it recurs after 6 months of completion of initial therapy and platinum resistant if it recurs within 6 months. [15] The role of CRS for recurrent ovarian cancer has been evaluated by several studies. A retrospective review by Munkarah et al. showed that patients left with no gross residual disease after CRS for recurrent ovarian cancer had a survival of 44–60 months as compared to 35 months in those receiving chemotherapy alone. However the authors concluded that it was not clear whether surgery added to the benefit produced by chemotherapy alone in this group of patients [16]. Bristow et al. carried out a meta-analysis including 2019 patients to determine the relative effect of multiple prognostic variables on overall post-recurrence survival time among cohorts of patients with recurrent ovarian cancer undergoing CRS. The only statistically significant clinical variable independently associated with post-recurrence survival time was the proportion of patients undergoing complete CRS (p = 0.019). After controlling for all other factors, each 10 % increase in the proportion of patients undergoing complete CRS was associated with a 3.0 month increase in median cohort survival time. [17].

Patient selection becomes important in CRS for recurrence since recurrent ovarian cancer is a very heterogeneous disease. In general better outcome is expected in patients with a limited disease extent or more localized relapse, a long disease-free interval after completion of primary therapy (i.e., more than 12 months), when the patient is in good general health, and complete resection or minimal residual disease is possible (Completeness of cytoreduction score of CC-0/CC-1). In contrast, women with symptomatic ascites, carcinomatosis, early relapse (i.e., less than 6 months), and poor general health are least likely to benefit. [18–20].

The retrospective AGO-DESKTOP study retrospectively analyzed 267 patients who had undergone CRS for recurrent ovarian cancer and found completeness of cytoreduction as the only factor leading to prolonged survival. A combination of PS, early FIGO stage initially or no residual tumor after first surgery, and absence of ascites could predict complete resection in 79 % of patients. [21] The DESKTOP 2 study prospectively analyzed the predictive value of 3 of these criteria (complete resection at first surgery, good performance status, and absence of ascites and found that when all 3 are met complete cytoreduction can be achieved in 79 % of the patients with a morbidity of 11 %. [22] These criteria exclude a subgroup of patients who never had surgery by a gynecologic oncologist/surgical oncologist and hence have had an incomplete CRS. These studies also do not evaluate patients in terms of extent of carcinomatosis as determined by the Peritoneal Cancer Index (PCI) which is an important prognostic factor (Bakrin et al. EJSO). Though there is sufficient evidence to support the use of cytoreductive surgery for recurrent ovarian cancer, the selection criteria still need to be defined.

Rational for intraperitoneal chemotherapy for Ovarian Cancer

Since ovarian cancer tends to remain confined to the peritoneal cavity, there is a strong rationale for using intraperitoneal chemotherapy. Intraperitoneal delivery of chemotherapy allows exposure of the poorly vascularized tumor tissue to high concentrations of cytotoxic agents. The blood-peritoneal barrier limits passage of these high doses into the plasma and reduces the risk of systemic toxicity [23]. Local chemotherapy is unable to penetrate deeply into tissues so it is only likely to be suitable for patients who have undergone optimal CRS with minimal residual disease. This form of intraperitoneal chemotherapy is delivered after surgery as multiple cycles through a port connected to a catheter placed intraperitoneally. There have been three large phase III trials comparing intraperitoneal (IP) chemotherapy with IV chemotherapy. The first study was carried out in the pre-taxane era and is of questionable significance now. [24] In the second study there was a high morbidity in the experimental arm and there was only a marginal benefit in the overall survival. [25] A third trial, GOG 172, randomized 415 patients with residual disease ≤1 cm to receive IV paclitaxel and cisplatin or IV paclitaxel followed by IP cisplatin (day 1) and paclitaxel (day 8). A significant improvement in OS was demonstrated: 65.6 months in the IP arm compared with 49.7 months in the IV arm (P = 0.03). This was despite only 42 % of patients completing six cycles of IP chemotherapy. Grade ¾ toxicity was significantly greater and quality of life scores significantly worse in the IP arm. [26] Elit et al. published a meta-analysis of 7 randomized controlled trials for adjuvant intraperitoneal chemotherapy. A pooled analysis from 6 of the 7 studies confirmed the survival benefit of IP chemotherapy compared with IV chemotherapy alone (Relative risk, 0.88; 95 % confidence interval, 0.81–0.95) Adverse events and catheter related problems were more common in the IP chemotherapy group and often led to discontinuation of therapy. This study concluded that where the institutional facilities are available, cisplatin based intraperitoneal chemotherapy should be offered to patient who had complete CRS. [27] However, there are several problems with intraperitoneal chemotherapy like non-optimal systemic regimens, toxicity leading to discontinuation of therapy and the complexity of the regimens.

Rationale for Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

The survival benefit shown by the use of intraperitoneal chemotherapy in ovarian cancer has prompted the use of HIPEC for the same. HIPEC has the added advantage of using heat which has several theoretical benefits. Heat has a direct cytotoxic effect. It potentiates the action of certain chemotherapeautic agents (mitomycin C, cisplatin, oxaliplatin) and increases their penetration into tumor tissue. Hyperthermia also reduces the mechanisms of cellular resistance to cisplatin. [28–30] It has been demonstrated that heat increases cisplatin accumulation in platinum resistant cell lines. In both platinum sensitive and platinum resistant cell lines both, it sensitizes the cells for cisplatin by mechanisms like increase accumulation in the cells, increased cisplatin and DNA adduct formation and decreased removal of these adducts from the cells. This effect is seen at a depth of 3-5 mm.

Giving intraperitoneal chemotherapy immediately after tumor removal also has the benefit of reducing tumor cell entrapment that is common after surgery. Further evidence to support HIPEC for ovarian cancer comes from the benefit shown in the treatment of gastrointestinal peritoneal carcinomatosis. Cytoreductive surgery and HIPEC is now the standard of care of pseudomyxoma peritonei and peritoneal mesothelioma. [31, 32] It is considered the standard of care for colorectal peritoneal metastases with a limited peritoneal spread. [33, 34] It is also shown benefit for gastric cancer with limited peritoneal spread and has been the only modality that has the potential to prolong survival in this sub group of patients with a very poor prognosis otherwise. [35, 36].

HIPEC at various time points in the history of ovarian cancer

HIPEC can be used at various time points in the history of ovarian cancer as summarized by Mulier et al. [37] HIPEC can be used at the time of first line therapy i.e. at the time of primary CRS (upfront CRS and HIPEC), or at the time of interval CRS which is performed after neoadjuvant chemotherapy (Interval CRS and HIPEC) or as a consolidation therapy following completion of first line therapy along with second look surgery (Consolidation CRS and HIPEC). HIPEC can be used along with CRS performed as second line therapy, in patients who have had suboptimal surgery followed by chemotherapy and therefore have residual disease (secondary CRS and HIPEC) or in patients who have recurred after complete response to first line therapy (salvage CRS and HIPEC). [37] A recent meta-analysis which pooled 9 comparative studies and 28 examining CRS + HIPEC for primary and/or recurrent ovarian cancer showed that the addition of HIPEC to CRS and systemic chemotherapy improves survival for both primary and recurrent ovarian cancer. [38].

HIPEC as First line therapy for Ovarian Cancer

There are many studies evaluating the role of HIPEC in first line therapy for ovarian cancer. Most of these studies are single institution studies with a limited number of patients. [39–46] and a few are multi institutional studies [47–49]. Most of the studies report results of HIPEC for first line and second line therapy together. The details of the studies are provided in Table 1.

Table 1.

HIPEC as part of first line therapy for treatment of advanced ovarian cancer

Ref no	Type of study	Year of Publication	No of Pts	Indication	HIPEC	Open/closed	Drug/s	Median DFS (months)	Median OS (months)	3 Yr OS	5 yr. OS
[39]	SI Prospective	2004	8	Primary	+	Open	Cisplatin + Mitomycin		33 ± 6		15 %
[40]	SI Prospective	2005	10	Primary Interval 2nd Look	+	Open	Cisplatin + Mitomycin + Etoposide	41.2	70.2
[41]	SI Prospective	2006	19	Primary	+		Paclitaxel				63 %
[42]	SI Prospective	2009	31	Primary	+		Doxorubicin	26.2	34.1
[43]	Multi-institutional, prospective	2010	31	Second look	+	Open	Oxaliplatin			67 % (2 yrs)
[44]	SI Prospective	2010	45	Primary	+	Closed	Cisplatin + Mitomycin				55 % (70 % for CC-0)
[50]	Case Control study	2005	29 + 19	Second look	+	Open	Cisplatin		64.4
[47]	Prospective, Multi-institutional registry	2010	57	Primary Interval Second Look	+	Open/Closed	Platinum/Mitomycin/Combination		30.0
[48]	Multi-institutional Phase 2 study	2011	26	Primary	+	Closed	Cisplatin + Mitomycin	30			60.7 %
[45]	Single Institution Retrospective study		51	Primary	+	Closed	Carboplatin or Mitomycin		28.5		28 ± 7 %
[46]	Single Institution Retrospective	2013	15	Primary	+			21.1	77.8		72 %
[49]	Multi- institutional Retrospective	2013	92	Primary	+	Open/Closed	Cisplatin	11.8	35.4	47 %	17 %
							Oxaliplatin
							Mitomycin
							Doxorubicin
							Cisplatin + Doxorubicin
							Cisplatin + Mitomycin

Abbreviations: SI: Single Institution; DFS: Disease Free Survival; OS: Overall Survival

There is a lot of heterogeneity in the drugs, regimens and HIPEC methodology and patient selection thus making comparison and pooling of results extremely difficult.

The median disease free survival reported in these studies ranged from 11.8 to 41.2 months and the median overall survival ranged from 30.0 to 77.8 months. The 5 year overall survival ranged from 15 to 63 %. The most significant factors affecting outcome were the completeness of cytoreduction and the extent of disease evaluated by PCI (Peritoneal Carcinomatosis Index) [42, 43, 48, 49].

In comparison studies reporting the outcomes for frontline therapy for ovarian cancer that did not include HIPEC have reported a median disease free survival ranging from 12 to 33.2 months, median overall survival ranging from 26 to 58.2 months and 5 year overall survival ranging from 19.5 to 49 %. [13, 14, 25, 26, 51–57]. Thus, most of the results obtained with the addition of HIPEC to standard frontline therapy seem to be similar or inferior to the results obtained without the use of HIPEC. Only a few studies have reported a survival that is superior to that obtained without the use of HIPEC [43, 46], the patient numbers in these being small. Notably, one of the worst outcomes was reported by the French multicentric retrospective study [49] comprising of 92 patients treated with HIPEC in addition to standard frontline therapy. The authors mentioned that most of the patients in this series have stage IV or advanced ovarian cancer that cannot be completed resected initially, that are referred to tertiary centers and cannot be compared to patients whose outcomes are reported in other series.

Based on the above data it can be said that there is no substantial evidence to recommend HIPEC as part of first line therapy outside the setting of a clinical trial. Randomized controlled trials are underway to evaluate the role of HIPEC as a part of first line therapy for advanced epithelial ovarian cancer. A phase III randomized trial in the interval setting by the Netherlands Cancer Institute (OVHIPEC trial; Clinical Trials.gov identifier NCT00426257) has finished accrual in 2013. In this trial, patients not eligible for complete cytoreduction upfront are given 3 cycles of chemotherapy and then taken up for surgery. Patients with complete cytoreduction are then randomized to receive HIPEC or no HIPEC. A similar multicenter phase III randomized trial in the interval setting has just started in Italy (CHORINE: Cytoreduction and HIPEC in the treatment of OvaRIaN cancEr) [58].

HIPEC as Second Line Therapy

CRS and HIPEC can be used as second line therapy after initial complete response, i.e. salvage CRS and HIPEC or in patients after incomplete CRS and chemotherapy leading to partial response or stable disease, secondary CRS and HIPEC. There is stronger evidence to support CRS and HIPEC as second line therapy as compared to first line therapy. Studies reporting the results of second line therapy are listed in Table 2. These studies have reported a median disease free survival ranging from 10 months to 26.2 months, median overall survival ranging from 24 to 45.7 months and a 5 year overall survival ranging from 15 % to 63 %. The largest series is the French retrospective study comprising of 474 patients. [49] The median overall survival was 45.7 months. Patients with platinum sensitive disease with a CCR score of CC-0 had a median OS of 47.2 months compared to that of 51.6 months for patients with platinum resistant disease. This difference was not statistically significant. This study showed that when treated with CRS and HIPEC patients with platinum resistant disease could also have a survival similar to those with platinum sensitive disease. A PCI of >8 was found to be a significant factor affecting both disease free and overall survival.

Table 2.

CRS and HIPEC as second line therapy for ovarian cancer

Ref no	Type of Study	N	Year of Publication	HIPEC	Method	Drug/s	Median PCI	CC-0/1	Median DFS (months)	Median OS (months)	3 Year OS	5 Year OS
[58]	Pilot	5	2000	+		Cisplatin			3	16
[59]	SI Prospective	30	2004	+		Cisplatin		77 %	17.1 [CC-0: 24.4]	28.1 [CC-0:37.8]
[39]	SI Prospective	11	2004	+		Cisplatin/Mitoxantrone		50 %		30 ± 6		15 %
[41]	SI Prospective	14	2006	+		Paclitaxel						63 %
[60]	SI Prospective	81	2007	+	Closed	Cisplatin		55.5 %	19.2 [CC-0: 26.9]	28.4 [CC-0: 54.9]
[61]	SI Prospective	18	2008	+	Closed	Cisplatin	14.9	87.3		24		16.7 %
[42]	SI Prospective	25	2009	+		Doxorubicin	13.4	92.8 %	26.2	40
[62]	SI Prospective	10	2010	+		Oxaliplatin	6	100 %	10		83 %
[44]	SI Prospective	8	2010	+	Closed	Cisplatin and Mitomycin		70 %				55 %
[47]	Multi institutional Prospective	83	2010	+	Open/Closed	Platinum/Mitomycin/Combination				30.43		25.4 %
[63]	SI Prospective	31	2011	+				65 %	13.3
[64]	Pilot	12	2011	+		Oxaliplatin		100 %	14.3
[65]	SI Prospective	42	2012	+		Cisplatin Oxaliplatin		77 %	13	37
[49]	Multi-institutional Retrospective	474	2013	+	Open/Closed	Cisplatin	10.6	92.1 %		45.7	59 %	37 %
						Oxaliplatin
						Mitomycin
						Doxorubicin
						Cisplatin + Doxorubicin
						Cisplatin + Mitomycin
[66]	SI Prospective	54	2015	+		Cisplatin + Paclitaxel	10	100 %	12.4	32.9

Abbreviations: SI Single Institution, DFS Disease Free Survival, OS Overall Survival

There are 5 case control studies that have compared CRS and HIPEC with CRS alone [67–71] and all but one have shown a statistically significant benefit of CRS and HIPEC over CRS alone. These studies are listed in Table 3. Thus CRS and HIPEC appears to be a beneficial option for patients with recurrent ovarian cancer where currently there is no standard therapy and though surgery has shown benefit over chemotherapy alone, most patients continue to be treated with multiple lines of chemotherapy. Selecting patients is the key, and as suggested by the French study, patients with a limited PCI derive the maximum benefit from this procedure. [49] Other important variable are the completeness of cytoreduction and time to recurrence.

Table 3.

Case control studies comparing CRS and HIPEC with CRS alone as 2nd line therapy

Ref No	Year of Publication	N	CRS+ HIPEC	CRS	Survival for CRS+ HIPEC	Survival for CRS alone	p Value
[67]	2009	26	14	12	58 % (5 yrs. OS)	17 (5 yrs. OS)	0.011
[68]	2011	48	24	24	50 % (3 yrs. OS)	18 % (3 yrs. OS)	<0.01
[69]	2012	67	30	37	68 % (5 yrs. OS)	42 % (5 yrs. OS)	0.017
[70]	2014	111	27	81	79 M (Median OS)	45 M (Median OS)	0.016
[71]	2015	54	32	22	23 (3 yrs. DFS)	45 (3 yrs. DFS)	0.078

Abbreviations: SI Single Institution, DFS Disease Free Survival, OS Overall Survival, M Months; yrs. years

Currently, trials are underway to further define the role of HIPEC in this setting. The CHIPOR trial is currently underway in France (NCT01376752) in which patients with recurrent ovarian cancer receive six cycles of chemotherapy followed by cytoreductive surgery if complete cytoreduction is deemed feasible. Patient who have had complete cytoreduction are then randomized to receive HIPEC or no HIPEC. Another trial for secondary CRS and HIPEC called the OVIHIPEC trial (NCT00426257) is currently underway in the Netherlands.

Morbidity and Mortality of CRS and HIPEC in Ovarian Cancer

The greatest criticism of HIPEC has been the morbidity and mortality of the procedure. HIPEC has a well demonstrated learning curve. [72] Over the years, the morbidity and mortality of this procedure has declined and is comparable to that of CRS alone. Table 4 lists that morbidity and mortality rates reported in various studies with HIPEC for ovarian cancer. Reported morbidity rates range from 0 % to 31.3 % (Grade 3 and 4 morbidity according to the Clavien-Dindo classification) and mortality rates from 0 to 4.2 % which are similar to those reported by Bristow et al. in their meta-analysis of patients undergoing CRS alone [17].

Table 4.

Morbidity and mortality of CRS and HIPEC for ovarian cancer

Ref No	Year of Publication	No of patients	Indication	Drug/s	Morbidity	30-day Mortality
[59]	2004	30	Second line	Cisplatin	16.7 %	3.3 %
[41]	2006	33	First line Second line	Paclitaxel	6 %	0 %
[73]	2006	40	First line Second line		0 %	0 %
[60]	2007	81	Second line	Cisplatin	13.6 %
[61]	2008	47	First line Second line	Cisplatin	21.3 %	4.2 %
[42]	2009	56	First line Second line	Doxorubicin	17.8 %	1.8 %
[43]	2010	31	First line	Oxaliplatin	29 %	0 %
[44]	2010	53	First line Second line	Cisplatin + Mitomycin	23 %	0 %
[47]	2010	141	First line Second line	Platinum/Mitomycin/Both		0.5 %
[74]	2010	19	First line	Paclitaxel	7 %	3.5 %
[48]	2011	26	First line	Cisplatin + Doxorubicin	15.3 %	3.9 %
[64]	2011	31	First line Second line	Oxaliplatin	29.03 %	0 %
[65]	2012	42	Second line	Cisplatin/Oxaliplatin	21 %	0 %
[49]	2013	566	First line Second line	Cisplatin	31.3 %	0.8 %
				Oxaliplatin
				Mitomycin
				Doxorubicin
				Cisplatin + Doxorubicin
				Cisplatin + Mitomycin

Major complications include anastomotic leakage, bowel perforation, intraperitoneal hemorrhage and wound dehiscence. Complications specific to the administration of chemotherapy are neutropenia which is caused by systemic absorption of the drug. Grade 3–4 toxicity has been reported in 8 to 31 % of the patients. In the CHIPOVAC study which used intraperitoneal oxaliplatin, the authors reported a high morbidity of 29 % due to which the study had to be closed prematurely. [43] Most of complications were hemorrhages that may be due to the drug used. However, other studies using oxaliplatin have not found a similar morbidity. [64, 65] In the French retrospective study, 8 % of the patients had acute renal insufficiency out of which 2 % developed chronic renal disease and 1 % required long term dialysis. The risk factors for major morbidity on multivariate analysis were PCI, CCR score, duration of surgery and the number of anastomoses [49, 75, 76].

Morris et al. reviewed 24 studies for the morbidity and mortality rates (including patients undergoing CRS and HIPEC for non-ovarian primary tumors) and found a mean major or grade III/IV morbidity of 28.8 % (range 0 % to 52 %); in high-volume centers it ranged from 12 % to 52 %. Re-operation rates following treatment that occurred in the perioperative period ranged from 0 % to 23 %. Overall, mean mortality rate was 2.9 % (range 0 % to 17 %); in high-volume centers it ranged from 0.9 % to 5.8 %. The authors concluded that morbidity and mortality rates following CRS and HIPEC are not different from those caused by major gastrointestinal surgeries. [75] The same conclusion was reached in the French study of 1290 patients that included patients with non-gynecologic primaries [76] Thus, it can be concluded that HIPEC does not add to the morbidity and mortality of CRS alone.

HIPEC methodology and drugs

HIPEC is performed by the open and closed techniques. Till date no study has shown benefit of one technique over the other. The intraperitoneal temperature is maintained between 41 and 43 degrees Celsius. HIPEC is performed only in those patients in whom complete cytoreduction is attained (CC-0 or CC-1) since the treatment is ineffective on residual disease more than 2–3 mm in size. [77] Commonly used drugs are cisplatin, oxaliplatin, mitomycin, doxorubicin, carboplatin and paclitaxel. [41–43, 50, 57, 60, 61] Other drugs like gemcitabine and irinotecan have also been used. [76] The choice of drug depends on its pharmacokinetic properties. The drug should be retained in the peritoneal cavity with limited systemic absorption. [23] Cisplatin is a drug that is retained in the peritoneal cavity and its penetration into the adjacent tissues is potentiated by heat in both platinum sensitive and platinum resistant cells lines. [78] The ideal dose of cisplatin has being evaluated in the CHIPASTIN trial. This phase I-II escalating dose trial established that the use of 70 mg/m2 of cisplatin for one hour at 42 °C was the most appropriate protocol (Clinical Trials identifier: NCT02217956).

Conclusions

Thus, there is a strong rationale for using CRS and HIPEC in the treatment of ovarian cancer. This form of aggressive loco regional therapy has the potential to cure patients as shown in patients with peritoneal metastases of gastrointestinal origin. HIPEC do not increase significantly mortality and morbidity of CRS alone. PCI should be used as a tool to select patients and also as a prognostic marker. Currently, there is insufficient evidence to recommend its routine use as part of first line therapy outside the setting of a clinical trial. However, there is sufficient evidence in the form of large retrospective studies, case control studies, and recent meta-analysis demonstrating its benefit as second line therapy, where it can be used in both platinum resistant and platinum sensitive cases. Its role in this setting also needs to be evaluated in randomized controlled trials. Patient selection is very important and such treatment should be offered at experienced centers after meticulous patient selection.