Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or Interval Cytoreductive Surgery in Ovarian Cancer: A Randomized Clinical Trial

Abstract

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.

Trial registration: ClinicalTrials.gov Identifier: NCT01091636.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lim reported having a consulting or advisory role for AstraZeneca, Boryung, CKD Pharm, Genexine, Hospicare, GI Innovation, and Takeda and receiving research funding from AbbVie, Amgen, Astellas, AstraZeneca, BeiGene, Cellid, CKD Pharm, Clovis, Eisai, Genexine, GSK, Incyte, Merck, MSD, OncoQuest, Pfizer, and Roche outside the submitted work. Dr Chang reported receiving research funding from AstraZeneca and Clovis outside the submitted work. Dr S.-Y. Park reported having a consulting or advisory role for Boryung and Takeda and receiving research funding from AbbVie, Amgen, Astellas, AstraZeneca, BeiGene, Cellid, CKD Pharm, Clovis, Eisai, Genexine, GSK, Incyte, Merck, MSD, OncoQuest, Pfizer, and Roche outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flowchart of Enrollment and Randomization

HIPEC indicates hyperthermic intraperitoneal chemotherapy.

Figure 2.. Kaplan-Meier Estimates of Progression-Free Survival and Overall Survival as Preplanned Intention to Treat

A, Events of progression or death were observed in 74 patients (80.4%) in the control group and in 71 patients (77.2%) in the hyperthermic intraperitoneal chemotherapy (HIPEC) group. The Kaplan-Meier estimate of patients who were without progression and alive at 24 months was 36.3% in the control group and 41.3% in the HIPEC group. B, A total of 47 patients (51.1%) in the surgery group and 45 (48.9%) patients in the HIPEC group died. The Kaplan-Meier estimate of patients who were alive at 60 months was 52.3% in the control group and 57.5% in the HIPEC group.

Figure 3.. Kaplan-Meier Estimates of Progression-Free Survival and Overall Survival According to the Primary Treatment as Preplanned Intention to Treat

Among the patients undergoing primary cytoreductive surgery prespecified subgroup analysis, the Kaplan-Meier estimate of patients who were free of progression and death at 24 months was 57.1% in the control group and 50% in the hyperthermic intraperitoneal chemotherapy (HIPEC) group (A), and the Kaplan-Meier estimate of patients who were alive at 60 months was 68.7% in the control group and 61% in the HIPEC group (B). Among the patients undergoing interval cytoreductive surgery after neoadjuvant chemotherapy prespecified subgroup analysis, the Kaplan-Meier estimate of patients who were free of progression and death at 24 months was 11.9% in the control group and 26.5% in the HIPEC group (C), and the Kaplan-Meier estimate of patients who were alive at 60 months was 32.2% in the control group and 52% in the HIPEC group (D).