Addition of Hyperthermic Intraperitoneal Chemotherapy to Cytoreductive Surgery in Advanced Ovarian Cancer


Key Points

  • Median recurrence-free survival was 14.2 months with hyperthermic intraperitoneal chemotherapy vs 10.7 months without it.
  • Median overall survival was 45.7 vs 33.9 months, respectively.

In a Dutch/Belgian phase III trial reported in The New England Journal of Medicine by van Driel et al, the addition of hyperthermic intraperitoneal chemotherapy 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.

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). Randomization was stratified by previous surgery, hospital in which surgery was performed, and number of involved regions in the abdominal cavity (0–5 vs 6–8). Patients received three additional cycles of carboplatin and paclitaxel after surgery.

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.

In the hyperthermic intraperitoneal chemotherapy vs control groups: the median age was 61 vs 63 years; histology was high-grade serous in 92% vs 87%; 10% in both groups had received prior surgery; the number of regions affected at the start of cytoreductive surgery was 0 to 5 in 68% vs 67%; residual disease after surgery was R-1 in 69% vs 67%, R-2a in 18% vs 20%, and R-2b in 11% in both; 76% in both had no bowel resection; median duration of surgery was 338 vs 192 minutes; median duration of hospitalization was 10 vs 8 days; median time between surgery and the start of adjuvant chemotherapy was 33 vs 30 days; and 94% vs 90% completed 3 cycles of adjuvant chemotherapy. Among patients who underwent bowel resection, colostomy or ileostomy was more common in the hyperthermic intraperitoneal chemotherapy group (21 of 29 patients = 72%) vs the control group (13 of 30 patients = 43%; P = .04).

Efficacy Outcomes

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 hyperthermic intraperitoneal chemotherapy 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 = .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 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 = .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.”

The study was funded by the Dutch Cancer Society.

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