Update of 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)

Three RCTs have been identified in patients with PM of colorectal origin, with a planned accrual patient of 544. Two trials were closed and results have been published. One other RCT is active and still recruiting patients.

Results of the French PRODIGE 7 trial [10] were recently published in 2021. In this study, 265 patients were randomly assigned intraoperatively after CRS to receive oxaliplatin based-HIPEC or not. Patients with extraperitoneal metastases, previous HIPEC or high PCI (>25) were excluded. In both groups, complete CRS (CC-0 or CC-1) was performed. In the experimental group, oxaliplatin based-HIPEC was administered by open or closed abdominal techniques over 30 min. After a median follow-up of 63.8 months, Quenet et al. showed no difference in OS between CRS alone and CRS plus HIPEC, respectively, 41.2 and 41.7 months (p=0.99). In the same way, no evidence of a relapse-free survival benefit was demonstrated between both groups (11.1 vs 13.1 months, respectively, p=0.43). In contrast, in a post-hoc subgroup analysis, patients with a PCI between 11 and 15 had longer OS in the CRS + HIPEC group than in the CRS alone group (41.6 vs. 32.7 months, p=0.02). The trial analyzed safety outcomes with a similar 30-day MM between groups. However, at 60 days, MM occurred more frequently in the CRS plus HIPEC group compared to the CRS group (respectively, 26% vs 15%, p=0.035). These results were in accordance with those previously published in the literature [7]. The most important intra-abdominal complications were digestive fistulae and abscesses. Although the frequency of extra-abdominal complications was comparable between groups, hemorrhagic complications were higher in HIPEC group, probably related to the use of oxaliplatin drug.

This RCT was the first trial to investigate the specific role of HIPEC in patients with PM of colorectal origin undergoing CRS. Nevertheless, PRODIGE 7 did not demonstrate the overall survival benefit of oxaliplatin based-HIPEC following CRS, thus challenging the clinical practice.

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

Ten RCTs were identified evaluating the prophylactic role of HIPEC in 1,983 randomized patients with colon cancer at high risk of PM. Six trials have already been analyzed in the previous review by Eveno et al. [8]. Four new trials are presented in Table 2.

The French PROPHYLOCHIP (or PRODIGE 15) trial [11] investigated a potential favorable effect of a second surgical look combined with HIPEC on disease-free survival (DFS) vs. surveillance in patients at high risk of developing colorectal PM. Accrual patient was 130 but 150 patients were included. Eligible patients had histological proven primary colorectal cancer with synchronous and localized PM, or resected ovarian metastases or a perforated tumor. Moreover, all patients received adjuvant chemotherapy for six months. In absence of disease recurrence on abdominal CT-scan, patients were randomly assigned to standard surveillance only vs. a second-look surgery with oxaliplatin based-HIPEC. After a median follow-up of 50.8 months, 3-year DFS did not differ between second-look surgery group and surveillance group (respectively, 44% vs 53%, p=0.82). Recurrence was located in order of frequency in peritoneum, liver and nodes. Three-year peritoneal recurrence-free survival (RFS) was similar in both groups (respectively, 59% vs 61%). However, grade III/IV complications in the second-look surgery were 41% and the most common complications were intra-abdominal complications (17%) and hematological toxicity (18%).

COLOPEC is an open-label, Dutch randomized multicenter trial [12] and aimed to analyze the peritoneal-free survival benefit of adjuvant HIPEC after curative resection of T4N0-2M0 stage or perforated colon cancer. 204 patients (with a planned accrual patient of 176) were randomized to adjuvant oxaliplatin based-HIPEC or standard treatment. Randomization was carried out before curative surgery of the primary tumor or after histological confirmation (T4 stage or perforation). HIPEC was performed simultaneously or 5–8 weeks after surgery. In both groups, all patients were treated with systemic chemotherapy within 12 weeks after curative resection of the primary tumor. In absence of radiological peritoneal recurrence during surveillance, diagnostic laparoscopy was performed at 18 months. No difference in peritoneal-free survival at 18 months was demonstrated: 80.9% for the HIPEC group compared to 76.2% for the control group (p=0.28). PM was diagnosed in 19% of patients in the HIPEC group and 11% of whom were diagnosed at 18-month laparoscopy (vs. 23% and 30%, respectively, in the control group). DFS and OS were comparable between groups (respectively, p=0.99 and p=0.82).

In Italy, a further RCT (NCT03914820) called CHECK study is currently recruiting 330 patients with colon cancer at high risk of developing PM (stage T4, perforated tumor, ovarian metastases or limited peritoneal disease). Exclusion criterion is presence of distant metastases. This phase III trial randomizes patients into adjuvant mitomycin based-HIPEC or not during surgery, provided that a complete R0 resection was achieved. The primary endpoint is the local RFS defined as the time between randomization and recurrence of PM or death for any cause. Secondary endpoints are DFS, OS, morbidity and mortality rate at 30 and 90-day from surgery.

Therapeutic indication

Four trials analyzed the role of HIPEC in patients with synchronous PM of gastric origin. RCTs are ongoing with a total accrual patient of 430.

The GASTRIPEC trial has already been presented in the previous review [8]. Despite a low recruitment with only 105 patients enrolled for 180 scheduled, the results were recently presented in ESMO [13] and ESSO 2021. A large amount of drop-out (50%) was observed between the first laparoscopy (after IV chemotherapy) and the laparoscopy for CRS leading to a small number of patients in CRS alone group (n=22) compared to CRS + HIPEC (n=28). While median OS did not differ between CRS alone group and CRS + HIPEC group (p=0.16), PFS and other distant metastasis free survival were significantly improved in CRS + HIPEC group compared to CRS alone group (7.1 months vs. 3.5 months, p=0.04 and 10.2 months vs. 9.2 months, p=0.02, respectively).

Two Chinese trials (NCT03179579 and NCT03604614) opened in 2017 [14, 15]. The first one [14] aimed to evaluate median 3-year OS in patients with PM of gastric cancer treated either with CRS and HIPEC or with CRS alone. PCI score of patients had to be less than 20. HIPEC was performed with paclitaxel, cisplatin and raltitrexed. The accrual patient was 88. The current recruitment status is unknown with a last update in 2017. In the second one [15] the experimental and control group were similar but the drug used for HIPEC was Oxaliplatin. Primary outcome measure was PFS. Safety results were identified as secondary endpoints. The recruitment status is unknown and the last update was in 2018.

The Dutch PERISCOPE II study [16] is a controlled two-arm multicenter randomized study comparing CRS and HIPEC vs. palliative systemic chemotherapy. Patients with T3-T4 gastric tumor, limited PM (PCI<7) and/or positive cytology without extraperitoneal metastases are eligible for inclusion. All patients receive systemic chemotherapy prior to inclusion and all regimens are acceptable. In the absence of disease progression, patients are included and then randomized. In the experimental group, a gastrectomy with D2 lymphadenectomy is performed. HIPEC procedure is using an open abdominal technique with oxaliplatin during 30 min followed by Docetaxel for 90 min. Adjuvant treatment is not detailed in the protocol. Primary endpoint is 5-year OS. PFS, toxicity, costs and health benefits are also evaluated 5 years postoperatively. One hundred and six patients have been enrolled for an accrual patient of 182. Estimated study completion date is October 2022.

Prophylactic indication

Since the review published in 2016 [8] new promising trials have emerged and are mostly recruiting.

The GOETH study [17] led by Mario Negri was opened in June 2019. The aim is to analyze the efficacy of mitomycin and cisplatin-HIPEC combined with CRS in patients with gastric cancer at high risk of developing PM (T3-T4N0-N+ stage, perforated tumor or cytology positive). Patients with gastroesophageal junction cancer, distant metastases or with synchronous PM are excluded. Randomization is performed intraoperatively if complete resection can be reached. Adjuvant chemotherapy has to be administrated in both groups. The primary objective of the study is 3-year DFS. Secondary end points are 3-year OS, 3-year local RFS, morbidity and mortality.

The Dutch PREVENT trial [18] aims to compare PFS/DFS in patients with locally advanced adenocarcinoma of the stomach (T3-T4, any N, M0) but also gastroesophageal junction (type II/III) with exclusion of distant metastases. After receiving neoadjuvant FLOT-chemotherapy, the experimental group undergoes surgery and HIPEC. In the control group, surgery alone is performed. Curative resection (gastrectomy or transhiatal extended gastrectomy) is planned within 4–6 weeks and drug administered intraperitoneally is cisplatin. All patients receive adjuvant FLOT-chemotherapy (docetaxel, oxaliplatin, leucovorin and 5-fluorouracil) from 6 to 12 weeks maximum after surgery. The number of accrual patients is 200 and the trial is recruiting.

The CHIMERA trial [19], was recently opened in April 2021 in Poland and submitted a similar protocol. CHIMERA is a randomized, multicenter clinical trial with a large accrual patient of 600. Patients with gastric cancer at high risk of developing PM are enrolled. After receiving 4 cycles of FLOT4 chemotherapy, patients are randomly allocated to receive either HIPEC with irinotecan plus surgery or surgery alone, followed by adjuvant chemotherapy with FLOT4 in both groups. Primary outcome criterion is peritoneal recurrence at 6 months postoperative. Patients will be followed for 5 years or until death. Survival results are not expected until 2026.

The most awaited and advanced study is the French GASTRICHIP study conducted by Olivier Glehen [20]. This prospective, randomized, multicenter phase III trial included 367 out of 322 accrual patients. Inclusion criteria were patients with histologically proven resectable gastric adenocarcinoma for which a curative gastrectomy was scheduled, with invasion into the serosa and/or lymph node metastasis and/or positive peritoneal cytology and/or perforated gastric adenocarcinoma and/or Siewert III adenocarcinoma of the cardia for which a gastrectomy by exclusive abdominal laparotomy is scheduled. Patients were treated with a curative gastrectomy with or without Oxaliplatin-based HIPEC. The main objective of the study was 5-year OS. The study is closed to inclusion and the results are expected.

Finally, results of a Chinese study were recently published in 2021 [21]. This prospective phase II study analyzed the survival benefit and toxicity of prophylactic HIPEC in the same type of population than in other studies. The trial was stopped after inclusion of 50 patients (with an initial need of 116 patients). After radical gastrectomy, patients were randomized (2:1) with or without HIPEC. HIPEC was administered with cisplatin drug during 30 min. All patients received adjuvant chemotherapy with SOX regime. Survival results did not show a survival advantage for the experimental group. After a median follow-up of 37 months, 3-year RFS rate was 84.2% in the experimental group compared with 88.2% in the control group (p=0.986). Overall, 3-year survival of patients with or without HIPEC was 87.9% and 100%, respectively (p=0.142). Safety results demonstrated however that HIPEC was well tolerated with no significant difference in postoperative complications rate (p>0.05).

Front-line therapy

Currently, there are still no published trials on the impact of HIPEC in front-line treatment of ovarian cancer for primary surgery. Twelve RCTs have been initiated with a planned total of 2,441 randomized patients: six trials are ongoing; one is completed and results have not yet been presented. The statuses of three studies previously described by Eveno et al. are unknown at this time [22, 23].

The multicentric Dutch OVHIPEC trial [24], published in 2018, analyzed 245 patients with stage III epithelian ovarian, fallopian tube, or peritoneal cancer. Patients eligible for secondary debulking were women with an incomplete primary cytoreduction (one or more residual tumors >1 cm diameter were present) or those who were unable to have cytoreduction because of extensive abdominal disease. Randomization was performed intraoperatively if complete cytoreductive (CC0 or CC1) was achieved. After undergoing interval surgery, patients were randomized with or without cisplatin-HIPEC. Adjuvant chemotherapy was mandatory in both groups with three cycles of carboplatin and paclitaxel. Recurrence survival was defined by increase of CA125 level and Response Evaluation Criteria in Solid Tumors (RECIST) in CT scan, as recommended by Gynecological Cancer InterGroup (GCIG) [25]. At a median follow-up of 4.7 years, the median RFS in the surgery group was 10.7 months compared to 14.2 months in the surgery-HIPEC group. The median OS was higher in patients who underwent CRS/HIPEC than patients who underwent CRS alone (45.7 vs 33.9 months). Adverse events of grade 3 or 4 were similar in both group (respectively, 25 and 27%, p=0.76). The most grade III/IV complications were abdominal pain, infection and ileus. This study is one of the first to demonstrate the survival benefit of combining HIPEC to secondary CRS in patients with ovarian cancer.

Campos et al. published recently a randomized, prospective phase 3 trial for patients with PM from epithelial ovarian or fallopian tube cancer [26]. All patients received at least three cycles of systemic neoadjuvant chemotherapy with carboplatin and paclitaxel. Surgery was performed 4 weeks after systemic chemotherapy and 71 patients were randomized to undergo CRS alone (36 patients in the control group) or CRS combined with HIPEC (35 patients in the experimental group). The primary outcome was DFS, defined as the time from surgery to disease recurrence or death and based on the serologic determination of CA 125 and radiological tests. With a median follow-up of 32 months, DFS and OS were better in the experimental group (18 vs 12 months and 52 vs 45 months, respectively). Morbidity and mortality did not differ in both groups (p>0.05).

The OVHIPEC-2 study [27], which opened in November 2019 by Willemien Van Driel, is a multicenter phase III trial designed to prove the benefit of adjoining HIPEC with CRS in ovarian cancer patients with acceptable morbidity. This large trial with an accrual patient of 538 includes women with FIGO III epithelian ovarian cancer and eligible for primary CRS with no residual disease (CC0) or residual disease up to 2.5 mm (CC-1). Eligible patients are randomized into primary CRS with or without cisplatin-based HIPEC. Six cycles of carboplatin–paclitaxel as adjuvant chemotherapy with or without PARP inhibition or bevacizumab according to international recommendations is administrated in both groups. With a follow-up of 5 years, overall survival as primary criteria is analyzed by CA125 and CT-scan and defined as the time from randomization to the date of death from any cause. Secondary endpoints are RFS, treatment-related toxicity and morbidity.

The French CHIPPI trial [28], another large trial, which opened the same year in France, also investigates the addition of HIPEC to primary or interval surgery in ovarian cancer patients. Accrual patients were 432. After surgery, patients were randomly assigned to receive HIPEC or not. Interval debulking surgery is performed after an interval of 3–5 weekends (4–6 weeks if bevacizumab is added to chemotherapy). HIPEC were administered for 90 min using cisplatin. DFS is assessed up to 5 years. Secondary objectives of the study included OS, morbidity, mortality and quality of life. The primary completion date is estimated for 2023.

Three trials are ongoing in China and consecutively opened in 2018, 2019 and 2020 [29], [30], [31]. Three trials analyze oncologic outcomes of adjuvant HIPEC following CRS in patients with ovarian cancer. CRS is performed if Fagotti score is less than 6 during laparoscopic exploration. Drugs and protocols of HIPEC differ between studies.

Recurrence

Five trials are designed in recurrent ovarian cancer with a planned total of 1,054 randomized patients.

The CHIPOR study, opened in April 2011, is a phase III randomized study and evaluate the impact on OS of adjunction of HIPEC to CRS in patients with first relapsed ovarian and platinum-sensitive ovarian cancer. Over May 2021, over 400 patients have been included and results are awaited.

The HIPOVA-01 study, a French trial led by Naoual Bakrin, which is currently not yet open, aims to evaluate the effectiveness of adding surgery and HIPEC to the systemic treatment of platinium-resistant recurrence [32]. After receiving chemotherapy and bevacizumab, patients will be randomly assigned to the cytoreductive surgery and cisplatin-HIPEC followed by adjuvant systemic therapy or chemotherapy with bevacizumab alone (called “Aurelia arm”). Oncological outcomes will be analyzed over a 36-month follow-up period. The trial is not yet recruiting with an accrual patient of 132.