Outcomes Research in Review

HIPEC for Ovarian Cancer: Standard of Care or Experimental Approach?

van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med 2018;378:230–40.



Study Overview

Objective. To evaluate whether the addition of hyperthermic intraperotoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer.

Design. Phase 3 prospective randomized clinical trial.

Setting and participants. The trial was conducted at 8 hospitals in the Netherlands and Belgium at which medical personnel had experience in administering HIPEC in patients with peritoneal disease from colon cancer or from pseudomyxoma perotinei. Eligible patients had newly diagnosed stage III epithelial ovarian, fallopian tube, or peritoneal cancer and were referred for neoadjuvant chemotherapy because of extensive abdominal disease or incomplete cytoreductive surgery (one or more residual tumors measuring > 1 cm in diameter). Eligibility criteria also including performance status score of 0 to 2, normal blood counts, and adequate renal function.

Intervention. At the time of surgery, patients were randomly assigned in a 1:1 ratio to undergo interval cytoreductive surgery either with HIPEC (surgery-plus-HIPEC group) or without HIPEC (surgery group). HIPEC was administered at the end of the cytoreductive surgical procedure. The abdomen was filled with saline that circulated continuously with the use of a roller pump through a heat exchanger. Perfusion with cisplatin at a dose of 100 mg per square meter and at a flow rate of 1 liter per minute was then initiated. The procedure took 120 minutes in total. To prevent nephrotoxicity, sodium thiosulphate was administered at the start of perfusion as an intravenous bolus (9 g per square meter in 200 mL), followed by a continuous infusion (12 g per square meter in 1000 mL) over 6 hours. Patient received in addition 3 cycles of carboplatin and paclitaxel after surgery. During follow-up, physical examinations and measurement of CA-125 level were repeated every 3 months for 2 years and then every 6 months until 5 years after the completion of chemotherapy. Computed tomography was performed at 1, 6, 12, and 24 months after the last cycle of chemotherapy.

Main outcome measure. The primary endpoint was recurrence-free survival in the intent-to-treat population. Secondary endpoints included overall survival, the side-effect profile, and health-related quality of life.

Main results. A total of 245 women were randomized between April 2007 and April 2016. The median follow-up at the time of recurrence-free survival analysis was 4.7 years. Recurrence-free survival events occurred in 81% of the HIPEC group vs 89% of the control group; median recurrence-free survival was 14.2 months vs 10.7 months, respectively (hazard ratio [HR] 0.66, P = 0.003). The benefit of HIPEC was consistent across stratification factors and post hoc subgroups. Hazard ratios (none reaching statistical significance) were 0.63 and 0.72 for those aged ≥ 65 and < 65 years; 0.69 and 0.56 for those with high-grade serous and other histology; 0.71 and 0.47 for those with no previous surgery and previous surgery; 0.64 and 0.66 for those with 0 to 5 and 6 to 8 involved regions; and 0.69 and 0.61 for those with no laparoscopy vs laparoscopy before surgery. Death occurred in 50% of the hyperthermic intraperitoneal chemotherapy group vs 62% of the control group; median overall survival was 45.7 vs 33.9 months (HR 0.67, P = 0.02).

No significant differences between the HIPEC and control groups were observed in the incidence of adverse events of any grade. The most common adverse events of any grade in the HIPEC group were nausea (63% vs 57%), abdominal pain (60% vs 575), and fatigue (37% vs 30%). Grade ≥ 3 adverse events occurred in 27% vs 25% of patients (P = 0.76). The most common grade 3 or 4 adverse events in the HIPEC group were infection (6% vs 2%), abdominal pain (5% vs 6%), and ileus (4% vs 2%). Among the patients who underwent bowel resection, a colostomy or ileostomy was performed more commonly among patients in the surgery-plus-HIPEC group (21 of 29 patients [72%]) than among those in the surgery group (13 of 30 patients [43%]) (P = 0.04).

Conclusion. Among patients with stage III epithelial ovarian cancer, the addition of hyperthermic intraperitoneal chemotherapy to interval cytoreductive surgery resulted in longer recurrence-free survival and overall survival than surgery alone and did not result in higher rates of side effects.

Next Article: