Willemien J. van Driel, MD, PhD

In a Dutch/Belgian phase III trial reported in The New England Journal of Medicine by Willemien J. van Driel, MD, PhD, of the Netherlands Cancer Institute, and colleagues, the addition of hyperthermic intraperitoneal chemotherapy (aka HIPEC) to interval cytoreductive surgery following neoadjuvant chemotherapy was associated with significantly improved recurrence-free and overall survival in patients with newly diagnosed advanced epithelial ovarian cancer.¹

Study Details

In the open-label trial, 245 women with stage III disease from 8 sites in the Netherlands and Belgium were randomized between April 2007 and April 2016 to undergo interval cytoreductive surgery with (n = 122) or without (n = 123) hyperthermic intraperitoneal chemotherapy with cisplatin at 100 mg/m². Patients had to have at least stable disease after three cycles of carboplatin (AUC = 5–6 mg/mL/min) and paclitaxel (175 mg/m²).

Randomization was performed at the time of surgery for cases in which it was believed surgery would result in no visible disease (complete cytoreduction) or in one or more residual tumors measuring ≤ 10 mm in diameter (optimal cytoreduction). Patients were randomized with stratification by previous surgery, hospital in which surgery was performed, and number of involved regions in the abdominal cavity (0–5 vs 6–8). They received three additional cycles of carboplatin and paclitaxel after surgery.

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….

— WILLEMIEN J. VAN DRIEL, MD, PhD, AND COLLEAGUES

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The primary endpoint was recurrence-free survival in the intent-to-treat population. The minimum number of events required for recurrence-free survival analysis was reached in April 2016, and efficacy data were updated in March 2017.

Most baseline characteristics were similar in the hyperthermic intraperitoneal chemotherapy and control groups. Although the number of patients who had a colostomy or ileostomy was expected for this kind of surgical procedure, among patients who underwent bowel resection, colostomy or ileostomy was more common in the hyperthermic intraperitoneal chemotherapy group (21/29 patients = 72%) vs the control group (13/30 patients = 43%; P = .04).

Efficacy Outcomes

Median follow-up at the time of recurrence-free survival analysis was 4.7 years. Recurrence-free survival events occurred in 81% of the hyperthermic intraperitoneal chemotherapy group vs 89% of the control group. Median recurrence-free survival was 14.2 months vs 10.7 months (hazard ratio [HR] = 0.66. P = .003).

The benefit of hyperthermic intraperitoneal chemotherapy was consistent across stratification factors and post hoc subgroups. Hazard ratios (none reaching statistical significance) were 0.63 and 0.72 for age ≥ 65 and < 65 years; 0.69 and 0.56 for high-grade serous and other histology; 0.71 and 0.47 for no previous surgery and previous surgery; 0.64 and 0.66 for 0 to 5 and 6 to 8 involved regions; and 0.69 and 0.61 for 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 months vs 33.9 months (HR = 0.67, P = .02).

Adverse Events

No significant differences between the hyperthermic intraperitoneal chemotherapy and control groups were observed in the incidence of adverse events of any grade. The most common adverse events of any grade in the hyperthermic intraperitoneal chemotherapy group were nausea (63% vs 57%), abdominal pain (60% vs 57%), and fatigue (37% vs 30%).

Grade ≥ 3 adverse events occurred in 27% vs 25% of patients (P = .76). The most common grade 3 or 4 adverse events in the hyperthermic intraperitoneal chemotherapy group were infection (6% vs 2%), abdominal pain (5% vs 6%), and ileus (4% vs 2%). One patient in the control group died within 30 days after surgery.

The investigators concluded: “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.”

DISCLOSURE: The study was funded by the Dutch Cancer Society. For full disclosures of the study authors, visit www.nejm.org.

REFERENCE

1. van Driel WJ, Koole SN, Sikorska K, et al: Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med 378:230-240, 2018.