HIPEC Plus Surgery Prolongs PFS and OS in Stage III Ovarian Cancer

Lot Aronson, MD

The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery improved progression-free survival (PFS) and overall survival (OS) compared with surgery alone in patients with stage III epithelial ovarian cancer who were not eligible for primary cytoreduction, according to results from the final survival analysis of the phase 3 OVHIPEC-1 trial (NCT00426257) published in Lancet Oncology.¹

At a data cutoff date of March 31, 2022, and a median follow-up of 10.4 years (95% CI, 9.5-13.3), 89% of patients who received HIPEC plus surgery (n = 122) experienced recurrence, progression, or death, with a median PFS of 14.3 months (95% CI, 12.0-18.5). In contrast, at a median follow-up of 10.1 years (95% CI, 8.4-12.9), recurrence, progression, or death occurred in 93% of patients who received surgery alone (n = 123), with a median PFS of 10.7 months (95% CI, 9.6-12.0; HR, 0.63; 95% CI, 0.48-0.83; stratified log-rank P = .0008). The 5-year PFS rates in these arms were 12.3% (95% CI, 7.7%-19.7%) and 6.6% (95% CI, 3.4%-13.0%), respectively. The respective 10-year PFS rates were 10.1% (95% CI, 5.8%-17.5%) and 6.6% (95% CI, 3.4%-13.0%).

“International guidelines on the use of HIPEC in primary ovarian cancer vary and reflect the ongoing controversy surrounding this treatment method,” lead study author Lot Aronson, MD, PhD candidate, of the Department of Gynaecologic Oncology at Nederlands Kanker Instituut-Antoni van Leeuwenhoek in Amsterdam, North Holland, Netherlands, and coauthors, wrote in the paper. “Available data provide supportive evidence to combine HIPEC with interval cytoreduction for patients with advanced ovarian carcinoma who were ineligible for primary cytoreduction.”

This randomized, open-label trial enrolled patients with histologically confirmed International Federation of Gynecology and Obstetrics stage III epithelial ovarian, fallopian tube, or peritoneal cancer across 8 HIPEC centers in Belgium and the Netherlands. Eligible patients included those between the ages of 18 and 76 years whose disease had not progressed during 3 or more cycles of neoadjuvant carboplatin plus paclitaxel. Patients were also required to have a World Health Organization performance score of 0 to 2, adequate renal function, and normal blood counts. Patients needed to be deemed ineligible for primary cytoreductive surgery by a multidisciplinary team or have previously undergone suboptimal primary cytoreductive surgery. They were excluded if they had previous malignancies within 5 years before trial enrollment.

PFS served as the primary end point of this trial, with OS in the intention-to-treat population serving as a key secondary end point. All other secondary end points have been previously reported.

Before surgery, patients received at least 3 cycles of IV carboplatin at an area under the curve of 5 to 6 mg/mL/min and IV paclitaxel at 175 mg/m2, with 1 cycle administered every 3 weeks. Investigators assessed response to neoadjuvant chemotherapy through physical examination, CA125 concentration measurement, and pelvic and abdominal CT scans. Patients who did not progress during neoadjuvant chemotherapy were deemed eligible for interval cytoreductive surgery with or without HIPEC.

Between April 1, 2007, and April 30, 2016, 245 patients were randomly assigned 1:1 to receive interval cytoreductive surgery with or without HIPEC. Randomization was conducted at the time of surgery, typically 13 to 15 weeks after initiating neoadjuvant chemotherapy, in patients who had complete cytoreduction or residual disease anticipated to be smaller than 10 mm in diameter. Patients were stratified by institution, prior suboptimal cytoreductive surgery (yes vs no), and number of involved abdominal regions (0 to 5 vs 6 to 8).

Patients in the HIPEC arm received HIPEC at the end of cytoreduction using the open abdomen technique. Briefly heated saline was circulated through the abdominal cavity for 90 minutes, and cisplatin was added at 100 mg/m2 in 3 stages: 50% of the dose at the beginning, 25% of the dose at 30 minutes, and 25% of the dose at 60 minutes. Patients received sodium thiosulfate (Pedmark) during and after HIPEC to prevent nephrotoxicity. After surgery, patients were given an additional 3 cycles of carboplatin plus paclitaxel.

During follow-up, patients were expected to receive repeated physical examinations and undergo CA125 serum concentration measurement every 3 months for 2 years and every 6 months until 5 years after completing chemotherapy.

In the initial analysis of this trial, which had a data cutoff date of March 31, 2017, at a median follow-up of 4.7 years, OVHIPEC-1 showed that adding cisplatin-based HIPEC to interval cytoreductive surgery significantly improved PFS (HR, 0.66; 95% CI, 0.50-0.87; stratified P = .0031) and OS (HR, 0.67; 95% CI, 0.48-0.94; stratified P = .019) compared with cytoreductive surgery alone. Moreover, the proportions of patients who experienced severe adverse effects (AEs) were not significantly different between the 2 arms (P = .76). In total, 27% and 25% of patients in the HIPEC and surgery-alone arms, respectively, experienced serious AEs, the most common including infection, abdominal pain, and ileus. One patient in the trial, who was enrolled in the surgery arm, died within 30 days of surgery.

“Following the initial publication of OVHIPEC-1, guidelines have been adjusted variably, ranging from advocating for the use of HIPEC in a select group of patients to no inclusion or consensus on the use of HIPEC for the treatment of [patients with] primary ovarian cancer,” the authors noted. “Long-term survival outcomes are therefore crucial to the ongoing debate and, together with the results of many international randomized trials that are evaluating the efficacy of HIPEC, will contribute to a consensus being reached on the acceptability of this treatment.”

In the updated survival analysis, among the 13 patients in the HIPEC arm who did not experience a PFS event, 12 had high-grade serous disease and 1 had low-grade endometrioid disease. Among the 9 patients in the surgery-alone arm who did not have a PFS event, 7, 1, and 1 had high-grade serous, clear cell, and unknown disease subtypes, respectively.

A total of 82% and 88% of patients in the HIPEC and surgery-alone arms died, respectively, with respective median OS of 44.9 months (95% CI, 38.6-55.1) and 33.3 months (95% CI, 29.0-39.1; HR, 0.70; 95% CI, 0.53-0.92; stratified log-rank P = .011). In these arms, the 5-year OS rates were 36.9% (95% CI, 29.2%-46.5%) and 19.7% (95% CI, 13.7%-28.0%), respectively. The respective 10-year PFS rates were 16.1% (95% CI, 10.3%-25.2%) and 10.9% (95% CI, 6.5%-18.0%).

Although the effects of HIPEC were consistent across prespecified patient populations and the findings from exploratory post-hoc subgroup analyses, PFS and OS with HIPEC were significantly influenced by BRCA1/2 mutation status. Patients with germline or somatic BRCA1/2 mutations in the HIPEC and surgery-alone arms had a median PFS of 15.54 months (95% CI, 11.70-not reached [NR]) and 14.70 months (95% CI, 10.84-NR), respectively (HR, 1.31; 95% CI, 0.51-3.39; Pinteraction = .015). In the homologous recombination–deficient (HRD) wild-type population, these values were 17.66 months (95% CI, 10.81-46.23) and 8.38 months (95% CI, 6.97-13.80), respectively (HR, 0.41; 95% CI, 0.20-0.85). In the homologous recombination–proficient (HRP) wild-type population, these values were 10.28 months (95% CI, 8.97-17.77) and 9.66 (95% CI, 7.79-13.80), respectively (HR, 0.78; 95% CI, 0.46-1.32).

Patients with germline or somatic BRCA1/2 mutations in the HIPEC and surgery-alone arms had a median OS of 46.52 months (95% CI, 30.72-NR) and 51.91 months (95% CI, 37.59-NR), respectively (HR, 1.73; 95% CI, 0.64-4.72; Pinteraction = .016). In the HRD wild-type population, these values were 55.64 months (95% CI, 37.06-NR) and 28.48 months (95% CI, 23.43-44.94), respectively (HR, 0.43; 95% CI, 0.21-1.23). In the HRP wild-type population, these values were 38.70 months (95% CI, 27.76-63.34) and 29.37 (95% CI, 16.79-43.96), respectively (HR, 0.72; 95% CI, 0.42-1.23).

“These findings suggest that patients with HRD tumors without pathogenic BRCA1/2 mutations might benefit more from HIPEC than patients with BRCA1/2[-mutated] tumors,” the authors postulated.

In total, 82% and 85% patients in the HIPEC and surgery-alone arms received subsequent anticancer therapies, respectively. Patients with platinum-resistant disease comprised 26% and 40% of patients in the HIPEC and surgery-alone arms, respectively. In both arms, patients who received new treatment for progressive or recurrent disease received a median of 2 lines (interquartile range, 1 to 3) of subsequent therapy, the most common being platinum-based and non–platinum-based chemotherapy. Ten percent of patients each in the HIPEC and surgery-alone arms who had recurrent or progressive disease received maintenance PARP inhibitors. Furthermore, 1 patient in the HIPEC arm and 2 patients in the surgery-alone arm received frontline maintenance olaparib (Lynparza) in the phase 3 SOLO-1 trial (NCT01844986).

“No imbalance in subsequent therapy after disease recurrence was found that would explain the improved OS in the study,” the authors noted.

One limitation of this follow-up analysis was that beyond 5 years of follow-up, the investigators conducted no further laboratory tests or standardized imaging.

Following the findings from OVHIPEC-1, investigators initiated the international phase 3 OVHIPEC-2 study (NCT03772028), which is examining primary cytoreductive surgery with or without HIPEC in patients with stage III epithelial ovarian cancer.²

“There is an opportunity to enhance the efficacy of HIPEC by optimizing the HIPEC regimen, which warrants further research,” the authors concluded.¹

References

1. Aronson SL, Lopez-Yurda M, Koole SN, et al. Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial. Lancet Oncol. 2023;24(10):1109-1118. doi:10.1016/S1470-2045(23)00396-0
2. Primary cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC) (OVHIPEC-2). ClinicalTrials.gov. Updated September 9, 2023. Accessed February 6, 2024. https://clinicaltrials.gov/study/NCT03772028