Perioperative systemic therapy for resectable colorectal peritoneal metastases: A multicenter randomized phase 3 trial (CAIRO6).

3505 Background: In patients with resectable colorectal peritoneal metastases who qualify for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), there is no prospective data comparing the efficacy of perioperative systemic therapy with CRS-HIPEC alone. Methods: In this multicenter phase 3 superiority trial, patients with resectable colorectal peritoneal metastases without extraperitoneal metastases who did not receive systemic therapy within six months prior to enrollment were randomly assigned (1:1) to receive perioperative CAPOX, FOLFOX, or FOLFIRI with neoadjuvant addition of bevacizumab (perioperative systemic therapy group) or CRS-HIPEC alone (surgery alone group). The primary outcome was overall survival. Key secondary outcomes were progression-free survival and 90-day major postoperative morbidity and mortality. The trial needed 179 patients in each arm to detect a superior 3-year overall survival of 65% in the perioperative systemic therapy group versus 50% in the surgery alone group (corresponding hazard ratio [HR] for death 0.62) with 80% power, 5% drop-out, and a two-sided log rank test of p<0.05. The primary overall survival analysis was done after 171 events (88% power). Results: Of 358 randomized patients, 351 were eligible for primary analysis: 173 in the perioperative systemic therapy group and 178 in the surgery alone group. At a median follow-up of 41 months, median and 3-year overall survival were 44 months and 54% in the perioperative systemic therapy group and 39 months and 53% in the surgery alone group, respectively (HR for death 0.85, 95% CI 0.62-1.15, p=0.28). Median and 3-year progression-free survival were 13.5 months and 20% in the perioperative systemic therapy group and 7.0 months and 5% in the surgery alone group, respectively (HR for progression or death 0.51, 95% CI 0.41-0.65). In the per-protocol population of 292 patients who underwent macroscopic complete CRS-HIPEC, median and 3-year overall survival were 54 months and 64% in the perioperative systemic therapy group (138 patients) and 45 months and 59% in the surgery alone group (154 patients), respectively (HR for death 0.73, 95% CI 0.51-1.05). Ninety-day major postoperative morbidity rates were 36% in the perioperative systemic therapy group and 26% in the surgery alone group, with a 90-day postoperative mortality of 1% in both groups. Conclusions: Among patients with resectable colorectal peritoneal metastases, perioperative systemic therapy did not result in superior overall survival as compared to CRS-HIPEC alone. Clinical trial information: NCT02758951 .