Current Pharmaceutical Design, 2012, 18, 3793-3803 3793 Survival Benefit of Adding Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) at the Different Time-points of Treatment of Ovarian Cancer: Review of Evidence Stefaan Mulier1*, Jean-Pierre Claes2, Vincent Dierieck1, Jean-Olivier Amiel3, Jean-Philippe Pahaut3, Luc Marcelis4, Fabienne Bastin4, Denis Vanderbeeken4, Claude Finet5, Sophie Cran6 and Thierry Velu7 1Department of Surgery, Leopold Park Clinic, CHIREC Cancer Institute, Froissartstraat 38, 1040 Brussels, Belgium; 2Department of Gynaecology, Leopold Park Clinic, CHIREC Cancer Institute, Froissartstraat 38, 1040 Brussels, Belgium; 3Department of Anaesthe- siology, Leopold Park Clinic, CHIREC Cancer Institute, Froissartstraat 38, 1040 Brussels, Belgium; 4Department of Oncology, Leo- pold Park Clinic, CHIREC Cancer Institute, Froissartstraat 38, 1040 Brussels, Belgium; 5Department of Oncology, Braine l'Alleud- Waterloo Hospital, CHIREC Cancer Institute, Rue Wayez 35, 1420 Braine-l'Alleud, Belgium; 6Department of Intensive Care, Leopold Park Clinic, CHIREC Cancer Institute, Froissartstraat 38, 1040 Brussels, Belgium; 7Department of Oncology, Edith Cavell Clinic, CHIREC Cancer Institute, Edith Cavellstraat 32, 1180 Brussels, Belgium Abstract: The standard treatment for advanced ovarian cancer consists in complete cytoreductive surgery (CRS) and intravenous combi- nation chemotherapy with a platinum compound and a taxane. Although response rates to initial therapy are high, many patients will re- cur and die of peritoneal carcinomatosis. The addition of Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) to the standard therapy aims at increasing survival by reducing peritoneal recurrence. This review describes the survival results of HIPEC at the different time-points of the treatment of ovarian cancer: at upfront CRS, at in- terval CRS, at consolidation CRS after complete response to initial therapy, at secondary CRS after incomplete response, at salvage CRS for recurrence and as palliative treatment without CRS for unresectable ovarian cancer with chemotherapy resistant ascites. The available evidence suggests that a potential survival benefit of adding HIPEC may be largest in the settings of secondary CRS for stage III ovarian cancer and salvage CRS for recurrent ovarian cancer, two time-points representing failure of initial standard therapy. There is much less evidence for a potential benefit of HIPEC for less advanced stages (I-II) and for earlier time-points in the treatment of ovarian cancer (upfront, interval and consolidation). Postoperative mortality is not higher after CRS and HIPEC (0.7%) than after CRS only (1.4%). Four randomised trials are ongoing and their results are eagerly awaited. Palliative HIPEC without CRS might be used more in patients with incapacitating ascites due to recurrent ovarian cancer which has be- come resistant to systemic chemotherapy. Keywords: Hyperthermic intraperitoneal chemotherapy (HIPEC); cytoreductive surgery, ovarian cancer; survival, time-points, review. INTRODUCTION key words [hyperthermic intraperitoneal chemotherapy] and Ovarian cancer has a high tendency for early peritoneal spread [ovarian cancer]. All papers in English and French reporting results of HIPEC in ovarian cancer were included. Additional papers were so that many patients present peritoneal carcinomatosis at diagno- sis. On the other hand, it tends to stay confined to the peritoneal identified by a cross-reference search. In case of multiple publica- cavity for a long time before seeding to other organs. The early tions on the same group of patients, only the most recent and com- plete paper was retained. All types of study design were included. spread to the peritoneal cavity without hematogenous metastases for a long period makes ovarian cancer very suitable for aggressive There was no restriction on the patient number except for single locoregional therapies. case reports that were excluded. Studies on both primary and recur- rent ovarian cancer were included, as well as studies on the pallia- Since the mid-1980s, cytoreductive surgery (CRS) and intrave- tive use of HIPEC for recurrent malignant ascites. Only studies nous combination chemotherapy with a platinum compound and a describing HIPEC exclusively for ovarian cancer were considered. taxane have become the standard of care for patients with ovarian Studies that did not report separate results for distinct time-points cancer [1]. Although response rates to initial therapy are high, many were not included. patients will recur, mainly in the peritoneal cavity, resulting in an The following data were analyzed: type of study design, year of overall 5-year survival of only 50% for FIGO III ovarian cancer [1]. The addition of Hyperthermic IntraPEritoneal Chemotherapy publication, number of patients, FIGO stage, timing of HIPEC in the course of the disease (Table 1), percentage of patients with (HIPEC) to the standard therapy aims at increasing survival by Sugarbaker's completeness of cytoreduction (CC) scores CC0 (no reducing peritoneal recurrence. This paper provides an update of the survival results after CRS and HIPEC and discusses its potential macroscopic tumor visible), CC1 (largest residual tumor nodules < 2.5 mm), CC2 (largest residual tumor nodules between 2.5 mm role at the different time-points of the treatment of ovarian cancer. and 2.5 cm), CC3 (largest residual tumor nodules > 2.5 cm) [2], MATERIALS AND METHODS hospital mortality, follow-up (median and range), disease free sur- vival (DFS) (median, at 5 years), overall survival (OS) in the whole A PubMed search of the world literature published between patient group (median, at 5 years) and OS in the subgroup of pa- January 1st, 1980, to January 31st, 2012 was performed using the tients with CC0 CRS (median, at 5 years). Morbidity could not be compared in a meaningful way between CRS and HIPEC versus CRS only because of absent or different definitions of morbidity *Address correspondence to this author at the Department of Surgery, Leo- between series. pold Park Clinic, CHIREC Cancer Institute, Froissartstraat 38, 1040 Brus- sels, Belgium; Tel: +32 498 78 73 57; E-mail: [email protected] 1381-6128/12 $58.00+.00 © 2012 Bentham Science Publishers 3794 Current Pharmaceutical Design, 2012, Vol. 18, No. 25 Mulier et al. Table 1. Timing of HIPEC in the Course of Ovarian Cancer One of these studies compared CRS and HIPEC with no treat- Treatment ment in a prospective non randomised study [27] ((Fig. 1), Table 4). Median overall survival was 64.4 months in the CRS and HIPEC group versus 46.4 months for the control group (p = 0.056, NS). in combination with cytoreductive surgery (CRS): 1. upfront CRS and HIPEC: as first treatment for newly diagnosed ovarian cancer 2. interval CRS and HIPEC: after neo-adjuvant chemotherapy without previous resection except for biopsies 3a. consolidation CRS and HIPEC: after upfront (near) complete CRS and a full course of chemotherapy in patients with a clinically complete response 3b. secondary CRS and HIPEC: after upfront incomplete CRS fol- lowed by chemotherapy in patients with a partial response or stable disease 4. salvage CRS and HIPEC: for recurrent ovarian cancer after initial complete response to CRS and chemotherapy Fig. (1). Overall survival after consolidation CRS and HIPEC (IPCT + HT) versus no treatment (control) in stage III ovarian cancer with a residual mass without cytoreductive surgery (CRS): less than 2 cm after initial surgery; p = NS (reproduced with permission from 27) 5. palliative HIPEC without CRS for unresectable ovarian cancer with refractory ascites We found one paper published in the same period on a compa- rable (sub)group of patients with a clinically complete response after (near) complete CRS and adjuvant chemotherapy for ovarian RESULTS cancer [28] (Table 4). Patients were randomised between 3 and 12 cycles of paclitaxel as consolidation therapy. They did not receive Upfront CRS and HIPEC consolidation CRS and HIPEC. Median OS and DFS were 48 ver- Eight papers described the results of (sub)groups of patients sus 53 months and 14 versus 22 months for the groups receiving 3 who underwent CRS and HIPEC as first treatment for newly and 12 cycles respectively. diagnosed stage III/IV ovarian cancer [3-10] (Table 2). Median and 5 year overall survival (OS) were 14.5-41.7 months Secondary CRS and HIPEC and 28-60.7% for the whole group respectively and 47 months [4] Four papers described the results of (sub)groups of patients who and 60.0% [7] after complete resection (CC0). Median and 5 year underwent secondary CRS and HIPEC after upfront incomplete DFS were 5-30 months and 15.2-19.7% respectively. CRS followed by chemotherapy in patients with a partial response The results were compared with ten papers published in the or stable disease [29-32] (Table 5). Median and 5 year OS for stage same period on comparable (sub)groups of patients who underwent III ovarian cancer were at least 60 months [29, 30] and 53.8-66.1% CRS without HIPEC as first treatment for newly diagnosed stage [29, 30]. Median and 5 year DFS for stage III ovarian cancer were III/IV ovarian cancer [11-20] (Table 2). 26.4-56 months and 26.9% respectively. Median and 5 year OS were 29-58.2 months and 19.5-49% for Two of these papers compared CRS and HIPEC with CRS the whole group and 45-78 months and 31.3% in case of complete alone in a retrospective study [29, 30]. In both studies, disease-free resection (CC0). Median and 5 year DFS were 12-33.2 months and and overall survival were significantly better for CRS and HIPEC 31.0% respectively. versus CRS alone in stage III ovarian cancer but not in stage I-II (Figs. 2 and 3, Table 5). Interval CRS and HIPEC Six papers described the results of (sub)groups of patients who underwent CRS and HIPEC after neo-adjuvant chemotherapy with- out previous resection for stage III/IV ovarian cancer [3, 8, 10, 21- 23] (Table 3). Median and 5 year OS were 38.0-68.6 months and 50.2-62%. Median DFS was 8.4-16.9 months. The results were compared with six papers published in the same period on comparable (sub)groups of patients who underwent CRS without HIPEC after neo-adjuvant chemotherapy without previous resection for advanced ovarian cancer [11, 12, 17, 24-26] (Table 3). Median and 5 year OS were 26-53 months and 21.2%. Median DFS was 12-15 months. Consolidation CRS and HIPEC Three papers described the results of consolidation CRS and HIPEC in (sub)groups of patients with a clinically complete re- sponse after (near) complete CRS and adjuvant chemotherapy for Fig. (2). Overall survival after secondary CRS and HIPEC with either Taxol ovarian cancer [3, 8, 27] (Table 4). Median and 5 year OS were or Carboplatin versus CRS only (control) in stage III ovarian cancer with a 53.7-130.3 months and 42.4%. Median and 5 year DFS were 29.6- residual mass less than 1 cm after secondary surgery; p = 0.003 (reproduced 82.8 months and 24.2% respectively. with permission from 29) Survival Benefit of HIPEC for Ovarian Cancer Current Pharmaceutical Design, 2012, Vol. 18, No. 25 3795 The results were compared with those of a trial published in the Two of these papers compared CRS and HIPEC with CRS same period on a comparable group of patients who were random- alone in a prospective study [34, 35]. Disease-free [34] and overall ised between secondary CRS without HIPEC versus chemotherapy survival [34, 35] were significantly better for CRS and HIPEC ver- alone after upfront maximal but incomplete CRS followed by che- sus CRS alone ((Fig. 4), Table 6). motherapy in patients with a partial response or stable disease [33] The results were compared with three papers published in the (Table 5). Median OS and DFS were 33.9 versus 33.7 months and same period on comparable (sub)groups of patients who underwent 10.5 versus 10.7 months for the groups receiving CRS without salvage CRS without HIPEC for recurrent ovarian cancer [43-45] HIPEC versus chemotherapy alone respectively. (Table 6). Median and 5 year OS were 16-29.2 months and 11.5% for the whole group and 19-45.2 months and 53% in case of com- Salvage CRS and HIPEC for Recurrent Ovarian Cancer plete resection (CC0). Seventeen papers described the results of (sub)groups of pa- tients who underwent salvage CRS and HIPEC for recurrent ovar- Palliative HIPEC without CRS for Unresectable Ovarian Can- ian cancer after initial complete response to CRS and chemotherapy cer with Refractory Ascites [5-8, 10, 21, 23, 31, 34-42,] (Table 6). Median and 5 year OS were One paper described the results of palliative HIPEC without 15.5-57 months and 18-57% for the whole group and 97.4 months CRS in seventeen patients with chemotherapy resistant ovarian [39] and 63-67% [7, 34] after macroscopically complete resection cancer with ascites [46]. The average number of chemotherapy (CC0). Median and 5 year DFS were 3-48 months and 0-12.5% respectively. Table 2. Upfront CRS and HIPEC FIGO FIGO FIGO 5 y OS 5 y OS OS OS Reference treatment n CC0 mortality follow-up 5 y PFS PFS III-IV III IV (all) (CC0) (all) (CC0) 3 CRS and HIPEC 2 100% 100% 0% 0% 5 m 14.5 m 4 CRS and HIPEC 51 100% 40% 98 m 28% 28.5m 47 m 5 CRS and HIPEC 8 100% 75% 25% 29 m * 6 CRS and HIPEC 31 100% 100% 0% 34.1 m 7 CRS and HIPEC 19 100% 100% 0% 47% 0% 25 m 37% 60% 38 m* 8 CRS and HIPEC 26 19.7% 24.8 m 33.3% 41.7 m 8 CRS and HIPEC 26 100% 96% 4% 58% 3.8% 25 m 15.2% 30 m 60.7% NR 10 CRS and HIPEC 14 100% 100% 0% 79% 0% 55% NR 11 CRS only 336 100% 76% 24% 20% 2.6% 56 m 12 m 19.5% 31.3 % 29 m 45.0 m 12 CRS only 68 100% 42 m 15 m 39 m 13 CRS only 279 100% 100% 0% 26% 41 m 14 CRS only 55 100% 100% 0% 0% 74 m 48 m 15 CRS only 210 100% 100% 0% 68% 48 m 18.3 m 49.7 m 16 CRS only 285 100% 87% 13% 24% 0.7% 17 m 50 m 78 m 17 CRS only 332 100% 78% 22% 60% 2.7% 23 m* 33.2 m 51.3 m 65.4 m 18 CRS only 227 100% 100% 0% 36% 0.9% 22.2 m 52.2 m 19 CRS only 210 100% 83% 17% 27% 1.0% 54 m 31.0% 47.0% 54.0 m 20 CRS only 408 100% 100% 0% 86% 33 m 49.0% 58.2 m 76.2 m follow-up and survival figures are expressed as median values in months unless specified otherwise n = number of patients * = mean CC0: macroscopically complete cytoreduction 5 y = 5 year DFS = disease free survival OS = overall survival NR = not reached 3796 Current Pharmaceutical Design, 2012, Vol. 18, No. 25 Mulier et al. Table 3. Interval CRS and HIPEC 5 y OS 5 y OS OS OS Reference Treatment n FIGO III-IV FIGO III FIGO IV CC0 Mortality Follow-up 5 y DFS DFS (all) (CC0) (all) (CC0) 21 CRS and HIPEC 4 100% 0% 8.4 m 3 CRS and HIPEC 4 100% 100% 0% 0% 17.8 m 38.0 m 8 CRS and HIPEC 19 9.6% 16.8 m 50.2% 68.6 m 10 CRS and HIPEC 31 100% 100% 0% 65% 0% 58% NR 22 CRS and HIPEC 9 100% 100% 0% 78% 1/9 39 m* 62% NR 23 CRS and HIPEC 10 100% 100% 0% 80% 0% 16.9 m 24 CRS only 34 100% 88% 12% 0% >24 m 26 m 11 CRS only 334 100% 76% 24% 47% 0.7% 56 m 12 m 21.1% 27.5% 30 m 38.2 m 17 CRS only 40 100% 78% 22% 88% 0% 23 m* 14.6 m 36.5 m 37.9 m 12 CRS only 71 100% 42 m 15 m 41 m 25 CRS only 53 100% 66% 34% 55% 0% 39 m 14 m 45 m 26 CRS only 18 100% 89% 11% 0% 20 m 15 m 53 m follow-up and survival figures are expressed as median values in months unless specified otherwise n = number of patients * = mean CC0: macroscopically complete cytoreduction 5 y = 5 year DFS = disease free survival OS = overall survival NR = not reached Table 4. Consolidation CRS and HIPEC FIGO FIGO FIGO mortal- follow- 5 y OS 5 y OS OS OS Reference Treatment n CC0 5 y DFS DFS p value III-IV III IV ity up (all) (CC0) (all) (CC0) 27 CRS and HIPEC 29 100% 100% 0% 100% 0% 73 m 64.4 m 64.4 m (1) 27 no treatment 19 100% 100% 0% 73 m 46.4 m (1) 8 CRS and HIPEC 12 24.2% 29.6 m 42.4% 53.7 m 3 CRS and HIPEC 4 100% 100% 0% 0% 82.8 m 130.3 m 28 paclitaxel IV x 3 146 100% 14 m 48 m 28 paclitaxel IV x 12 150 100% 22 m 53 m follow-up and survival figures are expressed as median values in months unless specified otherwise n = number of patients * = mean CC0: macroscopically complete cytoreduction 5 y = 5 year DFS = disease free survival OS = overall survival NR = not reached (1) p not significant for OS after CRS and HIPEC versus after no treatment Survival Benefit of HIPEC for Ovarian Cancer Current Pharmaceutical Design, 2012, Vol. 18, No. 25 3797 Table 5. Secondary CRS and HIPEC FIGO FIGO FIGO Follow- 5 y 5 y OS 5 y OS OS OS Reference Treatment n CC0 Mortality DFS p value III-IV III IV up DFS (all) (CC0) (all) (CC0) 29 CRS and HIPEC stage I-II 23 0% 0% 0% 0% 62* NR 82.4% NR (1) 29 CRS only stage I-II 5 0% 0% 0% 0% 52* NR 60.0% NR (1) 29 CRS and HIPEC stage III 44 100% 100% 0% 0% 62* 56 m 66.1% >60 m (2) 29 CRS only stage III 24 100% 100% 0% 0% 52* 15 m 32.8% 31 m (2) 30 CRS and HIPEC (all) 57 61.4% 61.4% 0% 3.5% 47* 48.7 m 63.4% 76.1 m (3) 30 CRS only (all) 60 65% 65% 0% 0% 46* 19.8 m 52.8% 62.9 m (3) 30 CRS and HIPEC stage I-II 22 0% 0% 0% 47* 69.6% 78.4% (4) 30 CRS only stage I-II 21 0% 0% 0% 46* 77.8% 89.6% (4) 30 CRS and HIPEC stage III 35 100% 100% 0% 47* 26.9% 26.4 m 53.8% 60.9 m (5) 30 CRS only stage III 39 100% 100% 0% 46* 10.3% 6.1 m 33.3% 22.3 m (5) 31 CRS and HIPEC 16 8 m 24.3 m 32 CRS and HIPEC 31 100% 100% 0% 0% 14.1 m NR 33 CRS and IV chemotherapy only 216 100% 93% 7% 47 m 10.5 m 33.9 m 33 IV chemotherapy only 208 100% 96% 4% 48 m 10.7 m 33.7 m follow-up and survival figures are expressed as median values in months unless specified otherwise n = number of patients * = mean CC0: macroscopically complete cytoreduction 5 y = 5 year; DFS = disease free survival; OS = overall survival NR = not reached (1) p not significant for DFS and OS after CRS and HIPEC versus after CRS only (2) p = 0.003 for DFS and OS after CRS and HIPEC versus after CRS only (3) p = 0.002 for DFS; p = 0.008 for OS after CRS and HIPEC versus after CRS only (4) p not significant for DFS and OS after CRS and HIPEC versus after CRS only (5) p = 0.007 for DFS; p = 0.002 for OS between CRS and HIPEC versus after CRS only cycles given before the first HIPEC was 12.5. The patients' average DISCUSSION Karnofsky performance status was 60%. HIPEC was performed by circulating dialysate with cisplatin or carboplatin at 42-43° C in the In 1978, Dedrick proposed the intraperitoneal administration of peritoneal cavity for one hour through a specially designed needle. chemotherapy which allowed a significantly higher intraperitoneal One cycle of HIPEC consisted of two to three treatments at inter- concentration than by the intravenous route [47]. Because ovarian vals of 5-7 days. The next cycle of HIPEC was performed after 4-6 cancer remains confined to the peritoneal cavity for much of its weeks. The treatments were repeated as long as the treatment was natural history and is relatively sensitive to chemotherapy, it should feasible and convenient for the patient. The adverse effects were be a good target for intraperitoneal treatment. For drugs most active mild especially compared to systemic chemotherapy with nausea in ovarian cancer, the ratio of their intraperitoneal to plasma con- and vomiting in 70%, peritoneal irritation in 5% and subileus in 2% centrations varies from 18-20 times for carboplatin and cisplatin to of treatments. Malignant ascites frequently diminished after a single 500-1000 times for docetaxel and paclitaxel [48]. The addition of HIPEC treatment and vanished within less than 3-5 administrations. postoperative normothermic intraperitoneal administration of che- Quality of life could be improved. It was concluded that HIPEC motherapy to standard upfront CRS for patients with FIGO III ovar- was safe and associated with a marked improvement in quality of ian cancer and intravenous chemotherapy was analysed in 3 phase life. Even heavily pretreated patients could be treated safely. Some III trials, all suggesting a survival benefit for patients treated with patients did respond to HIPEC even after 25 HIPEC treatments. intraperitoneal chemotherapy [13, 15, 18]. These trials have been contested however because drugs and doses used in the control Mortality after HIPEC and CRS Versus CRS only arms were different from the standard chemotherapy regimen (car- boplatin dosed to an area under the concentration-time curve (AUC) Mean postoperative mortality was 0.7% (4/547) after CRS and of 5-7.5, in combination with paclitaxel at a dose of 175 mg/m2 HIPEC versus 1.4% (31/2206) after CRS only for all series taken together. 3798 Current Pharmaceutical Design, 2012, Vol. 18, No. 25 Mulier et al. A survival benefit of HIPEC + CRS versus CRS alone has been shown very recently in digestive cancers. In animal models of colo- rectal peritoneal carcinomatosis in rats [57-59] and gastric perito- neal carcinomatosis in rabbits [60], a better survival was found in the HIPEC groups. In humans, the results of the first phase III ran- domised trial studying this question has been published in 2011 [61]. Sixty-eight gastric peritoneal carcinomatosis patients were randomized to CRS alone or to CRS + HIPEC receiving cisplatin 120 mg and mitomycin C 30 mg. Median overall survival was 6.5 months after CRS versus 11.0 months after CRS + HIPEC (P = 0.046). The authors concluded that CRS + HIPEC improved sur- vival compared to CRS alone. HIPEC for ovarian cancer was first reported in 1993 [62]. Up till November 1st 2011, 37 series have been published reporting on the results of HIPEC in 1362 patients [3-10, 21-23, 27, 29-32, 34- 42, 46, 63-72]. Most studies are retrospective. Only a few studies have analysed the results of HIPEC with CRS versus CRS alone in non randomized studies [29, 30, 34, 35]. Several randomised trials have been initiated but it will take some years for their results to be known. In the mean time, this review tries to summarise the avail- able evidence for the potential benefit of HIPEC at the different Fig. (3). Overall survival after secondary CRS and HIPEC (IPHC group) time-points of treatment of ovarian cancer. versus CRS only (control group) in stage III ovarian cancer with a residual mass less than 1 cm after secondary surgery; p = 0.002 (reproduced with Upfront CRS and HIPEC permission from 30). No studies were found directly comparing upfront CRS and HIPEC with CRS alone in their patient population. Median overall survival is < 38.5 months in 5 out of 6 papers on CRS and HIPEC while it is > 38.5 months in 9 out of 10 papers on CRS alone (Table 2). Although it is impossible to reach firm conclusions out of this comparison, there doesn't seems to be a striking survival advantage by adding HIPEC to upfront CRS, rather on the contrary. Interval CRS and HIPEC No studies were found directly comparing interval CRS and HIPEC with CRS alone in their patient population. Overall survival seems to be somewhat better after CRS and HIPEC than after on CRS alone (Table 3). Patient numbers however are very small and FIGO stages seem more favourable in the CRS and HIPEC studies. A phase III randomised trial in the interval setting is ongoing at the Netherlands Cancer Institute (OVHIPEC trial; Clinical Trials.gov identifier NCT00426257). The study started in February 2007 and is estimated to close in December 2013. Two hundred eighty patients with epithelial ovarian cancer FIGO stage III in whom upfront CRS was not feasible due to tumour extension or general condition (group 'interval CRS') or patients treated with incomplete upfront CRS with residual disease > 1 cm (group 'sec- Fig. (4). Overall survival after salvage CRS and HIPEC versus CRS ondary CRS') will receive 3 courses of carboplatin or cisplatin only in stage III recurrent ovarian cancer with a residual mass less combined with taxol. In case of tumour response, they will be ran- than 1 cm after salvage surgery; p = p = 0.046 (reproduced with domised to undergo a second CRS with or without HIPEC. This permission from 34). trial therefore studies the effect of adding HIPEC to CRS in two distinct patient populations: patients undergoing interval CRS after every 3 weeks for 6 cycles) [49]. In addition, significant rates of neoadjuvant chemotherapy and patients receiving secondary CRS catheter complications were noted with postoperative intraperito- after upfront incomplete CRS followed by chemotherapy. neal chemotherapy [50]. A similar multicenter phase III randomised trial in the interval The administration of intraperitoneal chemotherapy during in setting has just started in Italy (CHORINE: Cytoreduction and stead of after the operation and the combination with hyperthermia Hipec in the treatment of OvaRIaNcancEr) [73]. This study com- has first been proposed by Spratt [51, 52]. HIPEC has several theo- pares CRS+HIPEC (cisplatin+paclitaxel) vs. CRS alone in Stage retical advantages over postoperative intraperitoneal chemotherapy. IIIC unresectable ovarian cancer with partial or complete response The intraoperative administration, especially during an open abdo- after 3 systemic cycles of carboplatin and paclitaxel, followed by 3 men approach (Coliseum technique) guarantees the homogeneous further cycles of carboplatin and paclitaxel. The primary outcome is spread of the drug and a good exposure of the whole peritoneal two year disease-free survival. surface. It also avoids catheter related complications. While hyper- thermia in itself is tumoricidal [53], it has also been shown to in- Consolidation CRS and HIPEC crease the cytotoxicity of many chemotherapeutic agents in human In a prospective non randomised study, consolidation CRS and cell culture and animal models [54, 55]. Furthermore, hyperthermia HIPEC (29 patients) was compared with no treatment (19 patients deepens penetration into peritoneal tumor implants of intraperito- in the same period who refused CRS and HIPEC) in patients with neally delivered chemotherapy [56]. FIGO stage III ovarian cancer after upfront (near) complete CRS Survival Benefit of HIPEC for Ovarian Cancer Current Pharmaceutical Design, 2012, Vol. 18, No. 25 3799 followed by adjuvant systemic chemotherapy [27] (Fig. 1). Median lowed by chemotherapy in patients with a partial response or stable overall survival was 64.4 months in the CRS and HIPEC group disease. Two retrospective but well stratified studies compared CRS versus 46.4 months for the control group but the difference failed to and HIPEC with CRS alone [29, 30]. In both studies, disease-free reach statistical significance (p = 0.56). and overall survival were impressive and significantly better for CRS and HIPEC versus CRS alone in stage III ovarian cancer but Secondary CRS and HIPEC not in stage I-II (Table 5). Of note, a randomised trial in the same In contrast to the previous time-points, there is more evidence period showed no survival benefit in adding secondary CRS alone for a potential benefit in adding HIPEC to CRS for ovarian cancer to systemic chemotherapy in a comparable group of patients [33] in the setting of secondary CRS after upfront incomplete CRS fol- (Table 5). Table 6. Salvage CRS and HIPEC FIGO FIGO FIGO follow- 5 y 5 y OS 5 y OS OS OS Reference treatment n CC0 mortality DFS p value III-IV III IV up DFS (all) (CC0) (all) (CC0) 34 CRS and HIPEC 14 100% 100% 0% 64% 0% 48 m* 57% 67% NR NR (1) 34 CRS only 12 100% 100% 0% 58% 0% 24 m* 17% 29% (1) 35 CRS and HIPEC 24 100% 46% 0% 24 19.4 m (2) 35 CRS only 24 100% 25% 0% 24 11.2 m (2) 36 CRS and HIPEC 25 100% 22.5 m 15.5 m 37 CRS and HIPEC 5 100% 0% 16 3 m 16 m 8 CRS and HIPEC 83 9.6% 13.7 m 18.0% 23.5 m 38 CRS and HIPEC 30 100% 0% 19* 17.1 m 28.1 m 31 CRS and HIPEC 65 8.5 m 28.4 m 5 CRS and HIPEC 11 100% 73% 27% 30 m* 39 CRS and HIPEC 42 100% 50% 0% 20.8* 12.5 % 13 m 41.3% 37 m 97.4 m* 40 CRS and HIPEC 43 100% 95% 0% 29 24 m 38 m 6 CRS and HIPEC 25 100% 40.1 m 7 CRS and HIPEC 14 100% 100% 0% 57% 0% 31 m 51% 63% 57 m* 41 CRS and HIPEC 31 100% 97% 3% 65% 0% 27 0% 13.3 m NR 10 CRS and HIPEC 8 100% 100% 0% 75% 0% 44% NR 23 CRS and HIPEC 8 100% 100% 0% 100% 0% 10 m 42 CRS and HIPEC 12 100% 8/12 0% 100% 0% 14 14.3 m 21 CRS and HIPEC 9 100% 0% 20.3 m 43 CRS only 267 69% 65% 4% 50% 19 29.2 m 45.2 m 44 CRS only 44 100% 100% 0% 77% 0 16 m 19 m 45 CRS only 149 79% 69% 10% 36% 3.3% 27 11.5% 53% follow-up and survival figures are expressed as median values in months unless specified otherwise n = number of patients; * = mean CC0: macroscopically complete cytoreduction 5 y = 5 year; DFS = disease free survival; OS = overall survival; NR = not reached (1) p not mentioned for DFS; p = 0.046 for OS after CRS and HIPEC versus after CRS only (2) p < 0.05 for OS after CRS and HIPEC versus after CRS only 3800 Current Pharmaceutical Design, 2012, Vol. 18, No. 25 Mulier et al. Table 7. Summary of Evidence for the Potential Benefit of HIPEC at the Different Time-points of Ovarian Cancer Treatment Time-point Non Comparative Trials* Comparative Trials Randomized Phase 3 Trials upfront CRS (-) interval CRS (+) 1 ongoing (the Netherlands) 1 ongoing (Italy) consolidation CRS (0) (+) secondary CRS stage I-II 0 secondary CRS stage III 0 + 1 ongoing (the Netherlands) salvage CRS + + 2 ongoing (France, Italy) palliative (HIPEC only) quality of life (cid:1) * versus contemporary studies on CRS only - survival worse after HIPEC 0 no survival difference + survival better after HIPEC The setting of secondary CRS therefore seems to be a very in- patients with refractory ascites as main complaint, palliative HIPEC teresting time-point to conduct a randomised trial between CRS and without CRS may be a safe and effective palliative treatment to HIPEC versus CRS alone in stage III ovarian cancer. Such a trial is improve quality of life. Good results of the palliative (laparoscopic) ongoing at the Netherlands Cancer Institute (OVHIPEC trial; Clini- administration of HIPEC without CRS have been reported recently calTrials.gov identifier NCT00426257; see above). There is no in patients with refractory ascites due to recurrent gastric cancer, evidence for a potential benefit of adding HIPEC to secondary CRS colorectal cancer, ovarian cancer, breast cancer and peritoneal in stage I-II ovarian cancer. mesothelioma with limited morbidity, complete clinical and radio- logical disappearance of ascites in 94% of cases, and improvement Salvage CRS and HIPEC for Recurrent Ovarian Cancer of the Karnofsky index [74-76]. There is also more evidence for a potential benefit in adding HIPEC to CRS in the setting of recurrent ovarian cancer. Two pro- Morbidity and Mortality After HIPEC and CRS Versus After CRS Only spective non randomised trials compared CRS and HIPEC with CRS alone [29, 30] (Table 6). In the first study on 26 patients, me- Morbidity could not be compared in a meaningful way between dian DFS (48 m) and 5 year OS (67%) were impressive for CRS CRS and HIPEC versus after CRS only because of absent or differ- and HIPEC and significantly better than after CRS alone (24 m and ent definitions of morbidity between series. Postoperative mortality 29% respectively) [34]. In the second study on 48 patients, survival however was not higher after CRS and HIPEC (0.7%) versus after figures were less favourable. Nevertheless, median OS was signifi- CRS only (1.4%). The morbidity analysis of the ongoing and cantly better for CRS and HIPEC (19.4 m) than for CRS alone planned randomized controlled trials will have to be awaited to (11.2 m) [35]. When comparing the results in the seventeen papers allow a correct comparison of morbidity rates after HIPEC and on CRS and HIPEC with the results of three contemporary papers CRS versus CRS only. on CRS only in the setting of recurrent ovarian cancer, survival figures after CRS and HIPEC tend to be better than after CRS alone CONCLUSION in many studies. For all these reasons, the setting of recurrent ovar- The addition of HIPEC to CRS for peritoneal carcinomatosis ian cancer seems to be a promising time-point to conduct a random- has a sound theoretical rationale which has been confirmed in sur- ised trial between CRS and HIPEC versus CRS alone. Such a trial vival experiments in animal models and in one randomised trial in is ongoing in France sponsored by the Fédération Nationale des patients with gastric cancer. More specifically for ovarian cancer, Centres de Lutte Contre le Cancer (CHIPOR trial; ClinicalTri- indirect evidence for a potential benefit of adding HIPEC to CRS als.gov identifier NCT01376752). comes from three randomised trials on postoperative normothermic The study started in April 2011 and is estimated to close in intraperitoneal chemotherapy, a handful of non randomised com- December 2018. Four hundred forty four patients with FIGO III parative trials and about thirty non comparative trials on HIPEC. A recurrent epithelial ovarian cancer will receive six courses of car- summary of the current clinical evidence (Table 7) suggests that the boplatin - paclitaxel or carboplatin - caelyx. In case of tumour re- most interesting settings first to explore in randomised trials are sponse and if a (near) complete (CC0-1) CRS seems possible, they secondary CRS after upfront incomplete CRS for stage III ovarian will be randomised to undergo a second CRS with or without cancer and salvage CRS for recurrent ovarian cancer, two time- HIPEC. A second randomised trial in patients with recurrent ovar- points representing failure of initial standard therapy. There is much ian cancer is ongoing in Rome [40]. less indirect evidence for a potential benefit of HIPEC for less ad- vanced stages (I-II) and for earlier time-points in the treatment of Palliative HIPEC without CRS for Unresectable Ovarian Can- ovarian cancer (upfront, interval and consolidation). Postoperative cer with Refractory Ascites mortality is not higher after CRS and HIPEC (0.7%) than after CRS only (1.4%). Four randomised trials are ongoing and their results Despite all surgical and medical efforts, ovarian cancer will are eagerly awaited. Palliative HIPEC without CRS might be used recur in many patients, often leading to a miserable situation of refractory ascites with discomfort, dyspnoea and anorexia. In more in patients with incapacitating ascites due to recurrent ovarian cancer which has become resistant to systemic chemotherapy. Survival Benefit of HIPEC for Ovarian Cancer Current Pharmaceutical Design, 2012, Vol. 18, No. 25 3801 ACKNOWLEDGEMENTS vanced ovarian cancer: results from a systematic single-center analysis. Int J Gynecol Cancer 2010; 20(8): 1331-40. The HIPEC project at the Leopold Park Clinic, CHIREC Can- [18] Markman M, Bundy BN, Alberts DS, et al. Phase III trial of stan- cer Institute, Brussels, Belgium, has been funded in part by the dard-dose intravenous cisplatin plus paclitaxel versus moderately CARE foundation. high-dose carboplatin followed by intravenous paclitaxel and in- traperitoneal cisplatin in small-volume stage III ovarian carcinoma: CONFLICTS OF INTEREST an intergroup study of the Gynecologic Oncology Group, South- None declared. western Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 2001; 19: 1001-1007. REFERENCES [19] Chi DS, Eisenhauer EL, Zivanovic O et al. Improved progression- free and overall survival in advanced ovarian cancer as a result of a [1] Dovern E, de Hingh IH, Verwaal VJ, van Driel WJ, Nienhuijs SW. change in surgical paradigm. Gynecol Oncol 2009 Jul; 114(1): 26- Hyperthermic intraperitoneal chemotherapy added to the treatment 31. of ovarian cancer. A review of achieved results and complications. 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