Treatment of newly diagnosed advanced-stage ovarian cancer typically involves cytoreductive surgery and systemic chemotherapy. We conducted a trial to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer.

Background The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery improves recurrence-free and overall survival in patients with FIGO stage III ovarian cancer who are ineligible for primary cytoreductive surgery. The effect of HIPEC remains undetermined in patients who are candidates for primary cytoreductive surgery. Primary objective The primary objective is to evaluate the effect of HIPEC on overall survival in patients with FIGO stage III epithelial ovarian cancer who are treated with primary cytoreductive surgery resulting in no residual disease, or residual disease up to 2.5 mm in maximum dimension. Study hypothesis We hypothesize that the addition of HIPEC to primary cytoreductive surgery improves overall survival in patients with primary FIGO stage III epithelial ovarian cancer. Trial design This international, randomized, open-label, phase III trial will enroll 538 patients with newly diagnosed FIGO stage III epithelial ovarian cancer. Following complete or near-complete (residual disease ≤2.5 mm) primary cytoreduction, patients are randomly allocated (1:1) to receive HIPEC or no HIPEC. All patients will receive six courses of platinum-paclitaxel chemotherapy, and maintenance PARP-inhibitor or bevacizumab according to current guidelines. Major eligibility criteria Patients with FIGO stage III primary epithelial ovarian, fallopian tube, or primary peritoneal cancer are eligible after complete or near-complete primary cytoreductive surgery. Patients with resectable umbilical, spleen, or local bowel lesions may be included. Enlarged extra-abdominal lymph nodes should be negative on FDG-PET or fine-needle aspiration/biopsy. Primary endpoint The primary endpoint is overall survival. Sample size To detect a HR of 0.67 in favor of HIPEC, 200 overall survival events are required. With an expected accrual period of 60 months and 12 months additional follow-up, 538 patients need to be randomized. Estimated dates for completing accrual and presenting results The OVHIPEC-2 trial started in January 2020 and primary analyses are anticipated in 2026. Trial registration ClinicalTrials.gov:NCT03772028

PURPOSE: In the randomized open-label phase III OVHIPEC trial, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery (CRS) improved recurrence-free and overall survival in patients with stage III ovarian cancer. We studied the cost effectiveness of the addition of HIPEC to interval CRS in patients with ovarian cancer. PATIENTS AND METHODS: We constructed a Markov health-state transition model to measure costs and clinical outcomes. Transition probabilities were derived from the OVHIPEC trial by fitting survival distributions. Incremental cost-effectiveness ratio (ICER), expressed as euros per quality-adjusted life-year (QALY), was calculated from a Dutch societal perspective, with a time horizon of 10 years. Univariable and probabilistic sensitivity analyses were conducted to evaluate the decision uncertainty. RESULTS: Total health care costs were €70,046 (95% credibility interval [CrI], €64,016 to €76,661) for interval CRS compared with €85,791 (95% CrI, €78,766 to €93,935) for interval CRS plus HIPEC. The mean QALY in the interval CRS group was 2.12 (95% CrI, 1.66 to 2.64 QALYs) and 2.68 (95% CrI, 2.11 to 3.28 QALYs) in the interval CRS plus HIPEC group. The ICER amounted to €28,299/QALY. In univariable sensitivity analysis, the utility of recurrence-free survival and the number of days in the hospital affected the calculated ICER most. CONCLUSION: On the basis of the trial data, treatment with interval CRS and HIPEC in patients with stage III ovarian cancer was accompanied by a substantial gain in QALYs. The ICER is below the willingness-to-pay threshold in the Netherlands, indicating interval CRS and HIPEC is cost effective for this patient population. These results lend additional support for reimbursing the costs of treating these patients with interval CRS and HIPEC in countries with comparable health care systems.

Patients with advanced epithelial ovarian cancer have a high incidence of peritoneal disease recurrence despite maximal efforts to surgically remove all visible tumor plus intravenous chemotherapy. The administration of intraperitoneal chemotherapy that specifically targets the peritoneal surface has been investigated in previous trials, but questions about the design of these studies has prevented this treatment from being widely adopted in clinical practice. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a single intraoperative approach that also targets the peritoneal surface. A randomized phase 3 trial showed significant benefit in recurrence‐free and overall survival when HIPEC was added to interval cytoreductive surgery (CRS) in patients who were not eligible for primary surgery because of the extent of their disease (OVHIPEC trial; NCT00426257). The trial showed no important differences in toxicity or patient‐reported outcomes between the study groups. The extent of surgery and the number of bowel resections were also similar between the 2 study groups, and the effect of HIPEC was homogeneous across the levels of predefined and post hoc subgroups. Nevertheless, the design and the results of the OVHIPEC trial were critically assessed, and this resembles the reluctance to adopt the positive results of the earlier intraperitoneal chemotherapy studies. This overview discusses the design and results of the OVHIPEC trial. The evidence that is currently available points to a clinically relevant and cost‐effective benefit of HIPEC added to interval CRS for patients with stage III ovarian cancer who are not eligible for primary surgery. Ongoing collaborative research will provide further evidence regarding the role of HIPEC in ovarian cancer.