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Contains fulltext : 282977.pdf (Publisher’s version ) (Closed access) The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence-free (RFS) and overall survival (OS) in patients with stage III ovarian cancer. Homologous recombination deficient (HRD) ovarian tumors are usually more platinum sensitive. Since hyperthermia impairs BRCA1/2 protein function, we hypothesized that HRD tumors respond best to treatment with HIPEC. We analyzed the effect of HIPEC in patients in the OVHIPEC trial, stratified by HRD status and BRCAm status. Clinical data and tissue samples were collected from patients included in the randomized, phase III OVHIPEC-1 trial. DNA copy number variation (CNV) profiles, HRD-related pathogenic mutations and BRCA1 promotor hypermethylation were determined. CNV-profiles were categorized as HRD or non-HRD, based on a previously validated algorithm-based BRCA1-like classifier. Hazard ratios (HR) and corresponding 99% confidence intervals (CI) for the effect of RFS and OS of HIPEC in the BRCAm, the HRD/BRCAwt and the non-HRD group were estimated using Cox proportional hazard models. Tumor DNA was available from 200/245 (82%) patients. Seventeen (9%) tumors carried a pathogenic mutation in BRCA1 and 14 (7%) in BRCA2. Ninety-one (46%) tumors classified as BRCA1-like. The effect of HIPEC on RFS and OS was absent in BRCAm tumors (HR 1.25; 99%CI 0.48-3.29), and most present in HRD/BRCAwt (HR 0.44; 99%CI 0.21-0.91), and non-HRD/BRCAwt tumors (HR 0.82; 99%CI 0.48-1.42), interaction P value: 0.024. Patients with HRD tumors without pathogenic BRCA1/2 mutation appear to benefit most from treatment with HIPEC, while benefit in patients with BRCA1/2 pathogenic mutations and patients without HRD seems less evident.

Additional file 1: Supplementary Table 1. Knowledge of patients in the intervention and control group. For all statements patients could choose between ‘true’, ‘false’, and ‘don’t know’. *p ≤ 0.05.

The majority of patients with ovarian cancer (OC) receive an initial diagnosis of advanced disease that has spread from the ovaries to the peritoneal surface. The most effective treatment for patients with advanced disease is cytoreductive surgery followed by systemic chemotherapy. As an alternative, interval cytoreductive surgery is performed after 3 cycles of chemotherapy. Following these treatments, the primary site of disease recurrence is the peritoneal surface. Delivery of chemotherapy by the intraperitoneal (IP) route enhances drug delivery at the peritoneal surface and eliminates residual microscopic peritoneal disease more efficiently than intravenous administration. Previous trials have shown that after primary cytoreductive surgery combined use of intravenous and IP chemotherapy results in longer overall survival among patients with stage III OC compared with intravenous administration alone. Combined intravenous/IP chemotherapy has several drawbacks that have hampered its adoption inmany countries. These include catheter-related problems, increased demands on the patient, and gastrointestinal and renal adverse effects. Most of these drawbacks can be circumvented by delivery of the IP chemotherapy at the end of surgery. Delivery of IP chemotherapy during surgery under hyperthermic conditions-termed hyperthermic IP chemotherapy (HIPEC)-increases the penetration of chemotherapy at the peritoneal surface. Although addition of HIPEC to interval cytoreductive surgery is feasible in women with OC, efficacy data from randomized trials are lacking. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of interval cytoreductive surgery with HIPEC as compared with interval cytoreductive surgery without HIPEC in patients with stage III epithelial OC. Subjects were patients receiving neoadjuvant chemotherapy who had at least stable disease after 3 cycles of carboplatin (area under the curve of 5-6 mg/mL per minute) and paclitaxel (175 mg/m(2) of body surface area). Of these patients, 245 were randomized: 122 to the surgery-plus-HIPEC group and 123 to the surgery-without-HIPEC group. Randomization was performed at the time of surgery in cases in which surgery that would result in complete cytoreduction (no visible disease) or optimal cytoreduction (>= 1 residual tumors measuring Among patients who underwent cytoreductive surgery, disease recurrence or death occurred in 89%(110/123) of patients in the surgery-without-HIPEC group and 81%(99/122) of patients in the surgery-plus-HIPEC group; the hazard ratio for disease recurrence or death was 0.66, with a 95% confidence interval of 0.50 to 0.87, P = 0.003. The median recurrence-free survival was 3.5 months longer in the surgery-plus-HIPEC group than in the surgery-without-HIPEC group (14.2 vs 10.7 months). At a median follow-up of 4.7 years, 62% (76/123) of patients in the surgery-without-HIPEC group and 50% (61/122) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% confidence interval, 0.48-0.94; P = 0.02). There were no significant differences in the incidence of adverse events of any grade between the 2 groups (25% in the surgery-withoutHIPEC group and 27% in the surgery-plus-HIPEC group, P = 0.76). These data indicate that among patients with stage III epithelial OC addition of HIPEC to interval cytoreductive surgery provides longer recurrence-free survival and overall survival compared with surgery alone and no higher rates of adverse effects.

The majority of patients with ovarian cancer (OC) receive an initial diagnosis of advanced disease that has spread from the ovaries to the peritoneal surface. The most effective treatment for patients with advanced disease is cytoreductive surgery followed by systemic chemotherapy. As an alternative, interval cytoreductive surgery is performed after 3 cycles of chemotherapy. Following these treatments, the primary site of disease recurrence is the peritoneal surface. Delivery of chemotherapy by the intraperitoneal (IP) route enhances drug delivery at the peritoneal surface and eliminates residual microscopic peritoneal disease more efficiently than intravenous administration. Previous trials have shown that after primary cytoreductive surgery combined use of intravenous and IP chemotherapy results in longer overall survival among patients with stage III OC compared with intravenous administration alone. Combined intravenous/IP chemotherapy has several drawbacks that have hampered its adoption in many countries. These include catheter-related problems, increased demands on the patient, and gastrointestinal and renal adverse effects. Most of these drawbacks can be circumvented by delivery of the IP chemotherapy at the end of surgery. Delivery of IP chemotherapy during surgery under hyperthermic conditions—termed hyperthermic IP chemotherapy (HIPEC)—increases the penetration of chemotherapy at the peritoneal surface. Although addition of HIPEC to interval cytoreductive surgery is feasible in women with OC, efficacy data from randomized trials are lacking. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of interval cytoreductive surgery with HIPEC as compared with interval cytoreductive surgery without HIPEC in patients with stage III epithelial OC. Subjects were patients receiving neoadjuvant chemotherapy who had at least stable disease after 3 cycles of carboplatin (area under the curve of 5–6 mg/mL per minute) and paclitaxel (175 mg/m2 of body surface area). Of these patients, 245 were randomized: 122 to the surgery-plus-HIPEC group and 123 to the surgery-without-HIPEC group. Randomization was performed at the time of surgery in cases in which surgery that would result in complete cytoreduction (no visible disease) or optimal cytoreduction (≥1 residual tumors measuring ≤10 mm in diameter) was deemed to be feasible. Patients received an additional 3 cycles of carboplatin and paclitaxel postoperatively. Recurrence-free survival was the primary study end point. Key secondary end points were overall survival and the side effect profile. Data for recurrence-free and overall survival were analyzed according to intention to treat. Among patients who underwent cytoreductive surgery, disease recurrence or death occurred in 89% (110/123) of patients in the surgery-without-HIPEC group and 81% (99/122) of patients in the surgery-plus-HIPEC group; the hazard ratio for disease recurrence or death was 0.66, with a 95% confidence interval of 0.50 to 0.87, P = 0.003. The median recurrence-free survival was 3.5 months longer in the surgery-plus-HIPEC group than in the surgery-without-HIPEC group (14.2 vs 10.7 months). At a median follow-up of 4.7 years, 62% (76/123) of patients in the surgery-without-HIPEC group and 50% (61/122) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% confidence interval, 0.48–0.94; P = 0.02). There were no significant differences in the incidence of adverse events of any grade between the 2 groups (25% in the surgery-withoutHIPEC group and 27% in the surgery-plus-HIPEC group, P = 0.76).