Perioperative systemic therapy versus surgery alone for resectable colorectal peritoneal-only metastases (CAIRO6): a randomised, open-label, phase 3 trial

Abstract

Background Data are sparse on the value of perioperative systemic therapy in patients with resectable colorectal peritoneal-only metastases. This trial aimed to compare the efficacy of perioperative systemic therapy versus surgery alone in this population. Methods This randomised, open-label, phase 3 trial was done at all nine Dutch tertiary centres and one Belgian tertiary centre. Eligible patients were aged 18 years or older with a WHO performance status of 0 or 1 and pathologically proven resectable peritoneal-only metastases of a colorectal adenocarcinoma who did not receive systemic therapy for at least 6 months. Enrolled patients were randomly assigned (1:1) to perioperative systemic therapy and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC; perioperative systemic therapy group) or upfront CRS-HIPEC alone (surgery alone group) using a web-based system with minimisation stratified by previous systemic therapy, synchronous or metachronous peritoneal metastases, peritoneal cancer index 0-10 or 11-20, and mitomycin C-based or oxaliplatin-based HIPEC. At investigator's choice, perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (intravenous oxaliplatin 130 mg/m(2) followed by oral capecitabine 1000 mg/m(2) twice per day on days 1-14), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (intravenous oxaliplatin 85 mg/m(2) with intravenous leucovorin 400 mg/m(2), followed by bolus intravenous 5-fluorouracil 400 mg/m(2), and continuous intravenous 5-fluorouracil 2400 mg/m(2) for 48 h), or six 2-week neoadjuvant cycles of FOLFIRI (intravenous irinotecan 180 mg/m(2) with intravenous leucovorin 400 mg/m(2), followed by bolus intravenous 5-fluorouracil 400 mg/m(2), and continuous intravenous 5-fluorouracil 2400 mg/m(2) for 48 h) followed by either four 3-week adjuvant cycles of oral capecitabine (1000 mg/m(2) twice per day on days 1-14) or six 2-week adjuvant cycles of 5-fluorouracil and leucovorin (intravenous leucovorin 400 mg/m(2), followed by bolus intravenous 5-fluorouracil 400 mg/m(2), and continuous intravenous 5-fluorouracil 2400 mg/m(2) for 48 h). Intravenous bevacizumab was added to the first three neoadjuvant cycles of CAPOX (7 & centerdot;5 mg/kg) or the first four neoadjuvant cycles of FOLFOX or FOLFIRI (5 mg/kg). The primary outcome was overall survival assessed in a prespecified modified intention-to-treat population, excluding patients who withdrew consent before treatment or violated major eligibility criteria. Major postoperative morbidity was defined as Clavien-Dindo grade 3-5 and assessed up to 90 days postoperatively. Major systemic therapy-related toxicity was defined as Common Terminology Criteria for Adverse Events (CTCAE) grade 3-5 and assessed up to 30 days after its last administration. The Dutch patient organisation for colorectal cancer was involved in the trial design. The trial is registered with Clinicaltrials.gov (NCT02758951) and is active but not recruiting. Findings Between June 15, 2017, and April 29, 2024, 1922 patients were screened for eligibility. Of these, 358 patients were enrolled and randomly assigned to perioperative systemic therapy (n=180) or surgery alone (n=178). 351 patients were included in the modified intention-to-treat population (173 patients randomly assigned to perioperative systemic therapy and 178 patients to surgery alone; 181 [52%] male and 170 [48%] female). After a median follow-up of 41 months (IQR 21-62), median overall survival was 44 months (95% CI 30-54) in the perioperative systemic therapy group versus 39 months (95% CI 31-46) in the surgery alone group (hazard ratio [HR] 0 & centerdot;85, 95% CI 0 & centerdot;62-1 & centerdot;15; p=0 & centerdot;28). In 292 patients who underwent macroscopic complete or near complete CRS-HIPEC, major 90-day postoperative morbidity occurred in 49 (36%) of 138 patients in the perioperative systemic therapy group and in 40 (26%) of 154 patients in the surgery alone group. The most common Clavien-Dindo grade 3-4 postoperative adverse events were intra-abdominal abscess (16 [12%] of 138 patients in the perioperative systemic therapy group vs 16 [10%] of 154 patients in the surgery alone group), anastomotic leakage (12 [9%] vs six [4%]), and fascia dehiscence (13 [9%] vs six [4%]). 90-day postoperative mortality occurred in two (1%) patients in the perioperative systemic therapy group (anastomotic leakage and cerebrovascular accident) and in one (1%) patient in the surgery alone group (anastomotic leakage). Major systemic therapy-related toxicity occurred in 92 (57%) of 161 patients who started perioperative systemic therapy. The most common CTCAE grade 3-4 systemic therapy-related adverse events were hypertension (13 [8%] patients), diarrhoea (12 [7%] patients), neutropenia (11 [7%] patients), and thromboembolic events (ten [6%] patients). Systemic therapy-related death occurred in one (1%) patient (hyperglycaemia). Interpretation Perioperative systemic therapy cannot be recommended in all patients with resectable colorectal peritoneal-only metastases.