Myong Cheol Lim, MD, PhD^1,2,3,4; Suk-Joon Chang, MD, PhD⁵; Boram Park, PhD^6,7; Heon Jong Yoo, MD, PhD^1,8; Chong Woo Yoo, MD, PhD¹; Byung Ho Nam, PhD^6,9; Sang-Yoon Park, MD, PhD¹; for the HIPEC for Ovarian Cancer Collaborators

¹Center for Gynecologic Cancer, National Cancer Center, Goyang, South Korea
²Center for Clinical Trial, National Cancer Center, Goyang, South Korea
³Division of Rare and Refractory Cancer, Research Institute, National Cancer Center, Goyang, South Korea
⁴Department of Cancer Control and Policy, National Cancer Center, Goyang, South Korea
⁵Department of Obstetrics and Gynecology, Ajou University School of Medicine, Suwon, South Korea
⁶Biostatistics Collaboration Team, National Cancer Center, Goyang, South Korea
⁷Biomedical Statistics Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea
⁸Chungnam National University School of Medicine, Dajeon, South Korea
⁹HERINGS, Seoul, South Korea

Corresponding Author: Sang-Yoon Park, MD, PhD

Importance
Ovarian cancer has the highest mortality rate among gynecologic malignant tumors. Data are lacking on the survival benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in women with ovarian cancer who underwent primary or interval cytoreductive surgery.

Objective
To assess the clinical benefit of HIPEC after primary or interval maximal cytoreductive surgery in women with stage III or IV primary advanced ovarian cancer.

Design, Setting, and Participants
In this single-blind randomized clinical trial performed at 2 institutions in South Korea from March 2, 2010, to January 22, 2016, a total of 184 patients with stage III or IV ovarian cancer with residual tumor size less than 1 cm were randomized (1:1) to a HIPEC (41.5 °C, 75 mg/m² of cisplatin, 90 minutes) or control group. The primary end point was progression-free survival. Overall survival and adverse events were key secondary end points. The date of the last follow-up was January 10, 2020, and the data were locked on February 17, 2020.

Exposures
Hyperthermic intraperitoneal chemotherapy after cytoreductive surgery.

Main Outcomes and Measures
Progression-free and overall survival.

Results
Of the 184 Korean women who underwent randomization, 92 were randomized to the HIPEC group (median age, 52.0 years; IQR, 46.0-59.5 years) and 92 to the control group (median age, 53.5 years; IQR, 47.5-61.0 years). After a median follow-up of 69.4 months (IQR, 54.4-86.3 months), median progression-free survival was 18.8 months (IQR, 13.0-43.2 months) in the control group and 19.8 months (IQR, 13.7-55.4 months) in the HIPEC group (P = .43), and median overall survival was 61.3 months (IQR, 34.3 months to not reported) in the control group and 69.5 months (IQR, 45.6 months to not reported) in the HIPEC group (P = .52). In the subgroup of interval cytoreductive surgery after neoadjuvant chemotherapy, the median progression-free survival was 15.4 months (IQR, 10.6-21.1 months) in the control group and 17.4 months (IQR, 13.8-31.5 months) in the HIPEC group (hazard ratio for disease progression or death, 0.60; 95% CI, 0.37-0.99; P = .04), and the median overall survival was 48.2 months (IQR, 33.8-61.3 months) in the control group and 61.8 months (IQR, 46.7 months to not reported) in the HIPEC group (hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04). In the subgroup of primary cytoreductive surgery, median progression-free survival was 29.7 (IQR, 17.2-90.1 months) in the control group and 23.9 months (IQR, 12.3-71.5 months) in the HIPEC group, and the median overall survival was not reached in the control group and 71.3 months (IQR, 45.6 months to not reported) in the HIPEC group.

Conclusions and Relevance
The addition of HIPEC to cytoreductive surgery did not improve progression-free and overall survival in patients with advanced epithelial ovarian cancer. Although the results are from a subgroup analysis, the addition of HIPEC to interval cytoreductive surgery provided an improvement of progression-free and overall survival.