Randomized controlled trials evaluating cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in prevention and therapy of peritoneal metastasis: a systematic review

Therapeutic indication (peritoneal metastasis)

Five RCTs have been designed in patients with synchronous, isolated PM of colorectal origin, with a planned total accrual of 781 patients. One trial is now closed and results have been published. Two further trials are active, have closed patient recruitment and are waiting for follow-up data. Two additional RCTs are currently recruiting patients.

The first monocentric Dutch trial was published in 2003 and results were updated in 2008 after 8-year follow-up [22, 23]. In this study, 105 patients with PM of colorectal origin were randomly assigned to palliative systemic chemotherapy (control group) or to CRS and HIPEC followed by palliative systemic chemotherapy (test group). Patients with extraperitoneal metastases were excluded. In the test group, surgery was performed with the aim of complete cytoreduction (CC-0) and included subtotal peritonectomy, omentectomy as well as, if needed, resection of other organs involved. Completeness of cytoreduction was assessed at the end of surgery. Then, HIPEC was administered for 90 min using mitomycin C. Only palliative surgery, no CRS, was allowed in the control group, i. e. bypass surgery or ostomy for relief of bowel obstruction. Safety results showed a higher morbidity and mortality in the test group (CRS and HIPEC), notably a postoperative mortality of 8 %. The most important surgical complications were gastrointestinal leakage and peritonitis in 15 % patients. Also systemic side effects such as Grade 3 or 4 leukopenia were registered in a significant proportion of patients. In contrast, oncological results showed a significant advantage for the test group. After a median follow-up of 21.6 months, 39 % patients in the control group were alive compared with 55 % patients in the test group (HR for death, 0.55; 95 % CI, 0.32–0.95; p=0.03). Median overall survival in the control group was 12.6 months compared with 22.4 months in the test group. Overall, survival was poor (5 months) in patients in whom complete cytoreduction could not be achieved (CC-2) and in patients with extensive peritoneal disease (more than six anatomic regions involved according to PCI). Long-term oncological results were published as minimum follow-up was 6 years for all patients (median, 7.8 years; range, 6–9.6). At this point of time, four patients were still alive in the control group (two with disease and two without disease) versus five patients in the experimental group (two with disease and three without disease). Median disease-specific survival was 12.6 months in the control arm and 22.2 months in the CRS/HIPEC group (p=0.03). Median PFS was 7.7 months in the control group and 12.6 months in the CRS/HIPEC group (p=0.02).

This RCT was the first to demonstrate the positive effect of combined CRS and HIPEC on survival of patients with PM and was pivotal in the further development of this therapeutic strategy, as documented by the high number of citations of this work. However, both the design and the results of this study have been challenged:

1. Although this study showed that a multimodal therapy consisting of CRS, HIPEC and systemic chemotherapy nearly doubled survival compared with systemic chemotherapy alone, it did not show how much of this benefit is achieved by surgery and how much by HIPEC.

2. HIPEC might not contribute to the improved survival but cause additional morbidity [24].

3. Survival figures in the control group (chemotherapy alone) were relatively disappointing and do not match results obtained with modern chemotherapeutic agents such as oxaliplatin, irinotecan, bevacizumab and others.

4. If the aim of therapy was curative, the proportion of long-term survivors without evidence of disease was not different between groups.

5. If the aim of therapy was palliative, no patient-reported outcomes (PROs) are reported that would be significant in this situation. In fact, the long hospital stay (29 days) and the incidence of major complications suggest indirectly that QoL might have been compromised in the test group, at least in the short term [25].

In contrast to the trial of Verwaal described above, the French PRODIGE 7 trial (NCT00769405) does not compare CRS and HIPEC versus palliative systemic chemotherapy but investigates the potential additional benefit of CRS and HIPEC over CRS alone. This larger multicentric study is randomizing patients intraoperatively following complete CRS (CC-0 or CC-1) with or without HIPEC with oxaliplatin. Six months of systemic chemotherapy (physician’s best choice) are scheduled and can be performed before and/or after the HIPEC procedure. The majority of surgical teams selected a program with 3 months of chemotherapy before CRS and HIPEC and 3 months after the procedure. The type of systemic chemotherapy is not predefined, and the oncologist is free to administer the therapy of his choice. Enrolment is now completed and first survival results are expected already in 2017.

The German COMBATAC trial [26] is a smaller trial with an intended accrual of 60 patients and was designed to evaluate the feasibility and efficacy of the combined multidisciplinary treatment regimen consisting of perioperative systemic combination chemotherapy plus cetuximab followed by CRS and bidirectional chemotherapy (HIPEC with intraperitoneal oxaliplatin). The trial was stopped after inclusion of 20 patients. Morbidity and mortality data have been presented. First survival data are expected in 2017.

HIPEC in patients with colon cancer at high risk of peritoneal metastasis (prophylactic indication)

Six RCT totalizing an accrual of 1,107 patients have been initiated to analyze the prophylactic role of HIPEC in patients with colon cancer at high risk of developing PM. One trial has completed the accrual; five trials are currently recruiting patients.

The French Prophylochip (or PRODIGE 15) trial (NCT01226394) investigates a potential favorable effect of HIPEC in colorectal patients at risk of developing colorectal PM. Intended accrual was 130 patients. Inclusion criteria at the time point of colectomy are resected minimal synchronous PM, ovarian metastases and/or tumor perforation. All patients are then treated for 6 months with adjuvant systemic chemotherapy, in the rule FOLFOX-4. Then, in the presence of peritoneal recurrence, patients receive best choice therapy and were excluded of the study. In the absence of recurrence, patients are randomized into surveillance alone, or exploratory laparotomy and HIPEC. The end point is 3 years of disease-free survival. The study is now closed for inclusion and first survival results are expected at the beginning of 2019.

The Dutch COLOPEC trial [27] investigates the oncological effectiveness of adjuvant HIPEC using oxaliplatin, following a curative resection of a T4 or intraabdominally perforated colon carcinoma in preventing the development of PM. Intended accrual was 174 but has been up scaled to 200 patients. Patients who underwent curative resection for a UICC category T4 (or perforated) colon cancer are randomized to receive adjuvant HIPEC performed simultaneously with colectomy, or as a staged procedure (less than 10 days or 5–8 weeks postoperatively). Standard adjuvant systemic chemotherapy is given within 3 weeks after HIPEC in both study groups. Secondary aims are to determine the incidence of PM in pT4 and perforated colon cancer as determined by laparoscopy as a new gold standard, to identify molecular parameters indicating high risk of developing PM and to determine treatment-related morbidity of open and laparoscopic adjuvant HIPEC. Presence or absence of peritoneal recurrence is evaluated 18 months postoperatively by CEA and CT thorax/abdomen; in the absence of radiological signs of recurrence, a diagnostic laparoscopy is performed. The study has already recruited 90 % of the intended patients and is expected to be completed in 2017. Oncological results are expected at the beginning of 2019.

In China, a further RCT (NCT 02179489) has been opened in October 2014 and is currently recruiting 300 patients at risk of developing colorectal PM. No information is available on the number of patients included to date. Patients with pT4 colon cancer or metastases to ovary will be randomized to receive mitomycin C-based HIPEC or not. The primary end point is 3 years of disease-free survival.

Front-line therapy

So far, there is no published RCT evaluating the contribution of HIPEC in front-line line treatment of ovarian cancer. Five RCTs are ongoing in this indication, totalizing 438 patients. The most advanced Phase II–III randomized study from Korea has completed enrolment of 185 patients for a needed accrual of 170 [28]. Aim of this study is to assess progression-free survival rate after CRS as a front-line therapy, combined or not with HIPEC and followed by intravenous chemotherapy. Only patients with optimal cytoreduction were included and randomization was intraoperative. Drug administered intraperitoneally was cisplatin (75 mg/m² body surface). Oncological results are expected within 2 years from now.

Four further RCTs are currently recruiting patients in this indication, two in Spain (NCT02681432 and NCT02328716), one in Italy (NCT01628380) and one in Baltimore, USA (NCT02124421). All four studies are relatively small sized, recruiting for more than 4 years, and did not reach the intended accrual of patients. The CHORINE study from Italy, for example, has enrolled so far 41 patients out of 94 needed, and the recruitment period has been extended by 2 years. This study includes women with ovarian cancer who responded to three cycles systemic chemotherapy (carboplatin/taxol). After complete CRS (CC-0 or CC-1) could be achieved, patients are randomized intraoperatively to receive or not a combination HIPEC with cisplatin 100 mg/m² and paclitaxel 175 mg/m² body surface. Since the primary outcome criteria is progression-free survival over a follow-up period of 2 years, no oncological results are expected before 2020.

Therapy of intraperitoneal recurrence

Six RCTs totalizing 1110 women have been performed or are ongoing in this recurrent ovarian cancer, but the results of only 1 single study have been published so far. This monocentric randomized study from Greece [21] examined 120 women with advanced ovarian cancer (FIGO stage IIIc and IV) who experienced disease recurrence after initial treatment with conservative or debulking surgery and systemic chemotherapy. Eligible women were randomized preoperatively by computer assignment to CRS/HIPEC (test group) or to CRS alone followed by systemic chemotherapy (control group). IPC was cisplatin plus paclitaxel for platinum-sensitive disease or doxorubicin plus paclitaxel or mitomycin for platinum-resistant disease. Overall survival was much better in the CRS/HIPEC group than in the control group (26.7 months vs. 13.4 months, p=0.006). Completeness of cytoreduction and PCI score were associated with survival. This study was the first one to demonstrate in a random manner the additional effect of HIPEC on complete CRS, which is an important validation for this strategy. However, this study has several limitations. The trial was not registered in an official trial database. No size sample calculation was provided a priori. Statistical methods applied were incompletely reported. Treatment-related morbidity and mortality were not reported. Control and test groups were not completely comparable:

1. Due to preoperative randomization, more patients in the test group had complete cytoreduction than in the control group (65 % vs. 55 %).

2. The experimental group (HIPEC) had more patients with earlier disease (FIGO IIIc) (68 %) compared with the control group (60 %).

In platinum-sensitive disease, survival was 26.8 months in the HIPEC group versus 15.2 months in the non-HIPEC group (p=0.035), but in platinum-resistant disease, survival did not differ statistically between groups (26.6 months in the HIPEC group vs. 10.2 months in the non-HIPEC group; p value not reported). These various factors make the interpretation of the trial results somewhat challenging. Extrapolation to other patients is difficult [29].

The most advanced ongoing RCT (OVHIPEC) in recurrent ovarian cancer was opened for recruitment in 2007 by the Dutch Gynecological Oncology Group [30]. Women with ovarian cancer FIGO III were randomized into secondary CRS with or without HIPEC. Inclusion criteria were women eligible for interval debulking for the following two reasons:

1. primary debulking surgery not feasible due to tumor extension or general condition (patients treated by primary chemotherapy).

or

1. incomplete primary debulking with residual disease >1 cm.

2. After 9 years, thus study has recruited all patients needed (245 patients for an accrual needed of 240) and survival results are expected in 2017.

The CHIPOR study [31], which opened in April 2011 in France with an intended accrual of 444 patients, is a multicentric study designed to evaluate the effectiveness of adjoining HIPEC to CRS as treatment for the first recurrence of ovarian cancer in patients with platinum-sensitive ovarian cancer. Only patients with complete CRS are included into this trial (intraoperative randomization). By November 2016, 243 patients (55 %) were recruited, inclusion rate being lower than planned. Obviously, there is some difficulty in recruiting patients for this trial after the orphan-drug designation granted in October 2014 by the European Medicine Agency to olaparib for use as monotherapy for the maintenance treatment of women with relapsed platinum-sensitive epithelial ovarian with BRCA mutations who have already responded to platinum-based chemotherapy, as the trial includes only first recurrence cases [32].

Two further RCTs are currently recruiting patients in recurrent ovarian cancer, including the HORSE study (Rome, Italy) where 2/3 of the accrual has already been achieved [33] and a smaller randomized Phase II trial from the United States (MSKK, New York) [34]. In contrast to most trials above applying CDDP (cisplatin) intraperitoneally, the latter study investigates the efficacy and the safety of intraperitoneal carboplatin.

Prophylactic indication (prevention of metachronous peritoneal metastasis) in gastric cancer

Peritoneal recurrence eventually in 40–60 % of patients after radical surgery (gastrectomy and extended (D2) lymphadenectomy). Risk factors for such recurrence are serosa invasion, positive peritoneal cytology, lymph node involvement and signet ring histology. Thus, there is a rationale to offer preventive treatment to gastric cancer patients [35]. This is confirmed by the large number of ongoing trials, in particular in China, where the incidence of gastric cancer is particularly high [36].

In the 1980s, five Japanese studies analysed the efficacy of HIPEC after gastrectomy for gastric cancer with serosal invasion and no synchronous PM [37–41]. The denomination CHPP (continuous hyperthermic peritoneal perfusion) was used at that time since a standard terminology (HIPEC) was not introduced before the PSOGI congress in Milan in 2006. Hyperthermic chemoperfusion was performed with a solution of mitomycin C with a closed circulation technique. All five studies favored the experimental group (CHPP) with a survival gain between 10 % and 20 %.

Nine RCTs with a planned total of 3,076 participants are currently investigating a potential role of HIPEC for preventing development of PM after surgery for gastric cancer. These trials use various substances for IPC, including platin-based drugs (cisplatin or oxaliplatin), mitomycin C or taxanes (paclitaxel or docetaxel).

The most advanced of these preventive trials is the French GASTRICHIP study [42], with 150 out of 321 patients recruited to date. GASTRICHIP is a prospective, open, randomized multicenter phase III clinical study with two arms that aims to evaluate the effects of HIPEC with oxaliplatin on patients with gastric cancer involving the serosa and/or lymph node involvement and/or with positive cytology at peritoneal washing, treated with perioperative systemic chemotherapy and D1–D2 curative gastrectomy. There is an intraoperative randomization in patients where complete curative gastrectomy was possible. Primary end point is overall survival from the date of surgery to death or to the end of follow-up (5 years). Secondary end points are 3- and 5-year recurrence-free survival, site of recurrence, morbidity and quality of life. An ancillary study will compare the incidence of positive peritoneal cytology pre- and post-gastrectomy in two arms of the study and assess its impact on 5-year survival [43]. Survival results of this trial are not expected within the next 5 years.

The largest trial in the prophylactic indication has been initiated 3 years ago at Guangzhou Medical University in Guangzhou, China, with an intended accrual of 582 patients [44]. Primary outcome criteria are overall 5-year survival. In contrast to the GASTRICHIP trial where oxaliplatin is administered, this study is applying paclitaxel intraperitoneally. Estimated study completion date is July 2019. No information on the recruitment is available, but results cannot be reasonably expected before several years.

A second RCT in the prophylactic indication is currently being initiated at the Sun Yat-sen University in the same city of Guangzhou, China [45]. The intended accrual is 640 patients. The investigators intend to find out if, after neoadjuvant chemotherapy, combining HIPEC with gastrectomy and D2 resection could improve survival for patients with advanced gastric cancer, while comparing with the traditional approach of D2 resection. Intraperitoneal drug is paclitaxel. The trial is not yet recruiting.

A further RCT aiming at determining the efficacy of HIPEC in the treatment of locally advanced gastric cancer has been recently initiated at Wuhan University, China [46]. Patients are randomized into HIPEC group and control group. In the HIPEC group, the patients undergo radical gastrectomy with D2 lymphadenectomy and HIPEC with paclitaxel and 5-FU. Patients in the control group undergo radical gastrectomy with D2 lymphadenectomy. Patients in both groups receive six cycles of postoperative chemotherapy (SOX or XELOX) and are followed up for 5 years or until death. Accrual needed is 500 patients and the trial is not yet recruiting.

Two further, smaller trials have been recently opened in China in the prophylactic indication in gastric cancer [47, 48].

Therapy of recurrent gastric cancer

Only three trials with a total accrual needed of 264 patients are investigating a potential beneficial effect of HIPEC in the treatment of PMGC.

Two of these trials are small and have already been published:

1. Finals results of the first study (from China) were published 5 years ago [49]. This randomized phase III study with a limited number of patients (n=68) evaluated the efficacy and safety of adding HIPEC to CRS for the treatment of PMGC. The primary end point was overall survival, and the secondary end points were safety profiles. Patients were randomized into CRS alone (n=34) or CRS+HIPEC (n=34) receiving a combination of CDDP 120 mg and MMC 30 mg intraperitoneally. The completeness of cytoreduction was identical in both groups (58.8 %). There was no significant difference in mortality and morbidity (11.7 % vs. 14.7 % when HIPEC was added). Median survival was significantly increased in the group who received HIPEC (11 months), compared to 6.5 months in the surgery alone group (p=0.046).

2. In contrast to the first study, the second RCT did not compare CRS and HIPEC versus surgery alone, but the comparator was systemic chemotherapy [50]. This preliminary US multicentric study compared seven patients treated by intravenous chemotherapy (FOFIRINOX) alone with nine patients who were treated by intravenous FOLFIRINOX associated with CRS and HIPEC with oxaliplatin. Patients had gastric cancer metastatic to liver and lung and PM. Median overall survival was 11.3 months in the test group (CRS and HIPEC plus systemic chemotherapy) versus 4.3 months in the control group (chemotherapy alone). This study has methodological limitations. First, this is a small sized, preliminary study and the size sample was not large enough to draw solid conclusions; enrolment to complete a larger planned trial was discontinued due to slow accrual. Second, two patients of the surgery group had liver resection for metastasis and two patients of the chemotherapy group refused the allocated treatment after randomization. Interestingly, survival in the test group was similar with the Chinese study and median survival after CRS and HIPEC remained below 1 year in both studies, a disappointing result.

The only ongoing RCT identified in the therapeutic indication in gastric cancer is the German GASTRIPEC trial [51]. At least 65 patients have been recruited so far (November 2016) for an intended accrual of 180 [52]. This study is analyzing perioperative chemotherapy and CRS with HIPEC versus without HIPEC in gastric cancer patients with limited PM. All patients receive preoperative chemotherapy. Patients with negative or unknown HER-2 status are administered EOX combination chemotherapy (Epirubicin, Oxaliplatin and Capecitabine). Patients with positive HER-2 status are treated with Cisplatin, Capecitabine and Trastuzumab (CCT). Neoadjuvant chemotherapy is then followed by gastrectomy and surgical cytoreduction. After intraoperative randomization, the tested group receive additional HIPEC with MMC and CDDP; this group may also get a HIPEC intervention without CRS. In the postoperative period, all patients receive three cycles of chemotherapy within 4–12 weeks and are followed up for 30 months. If tumor progression is documented, then the protocol is terminated. The primary outcome measure is overall survival at 2.5 years. Survival results of this trial are not expected before 2023.