August’s Paper of the Month examines whether perioperative systemic therapy improves overall survival compared with upfront surgery in patients with resectable colorectal peritoneal-only metastases.
Perioperative systemic therapy versus surgery alone for resectable colorectal peritoneal-only metastases (CAIRO6): a randomised, open-label, phase 3 trial
Koen P Rovers, Checca Bakkers, Teun B M van den Heuvel, et al. Published in The Lancet Oncology. 2026. doi: 10.1016/S1470-2045(26)00085-9.
What is known about the subject?
Peritoneal metastases from colorectal cancer are associated with a poor prognosis. For patients whose disease is confined to the peritoneum, complete cytoreductive surgery, usually combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), can achieve prolonged survival.
However, the role of systemic therapy before CRS-HIPEC remains uncertain. It may control micrometastatic disease and help to identify patients with aggressive tumour biology prior to major surgery. However, it can also result in significant toxicity, delay surgery, and exclude some patients from undergoing complete cytoreduction.
Until now, most of the available evidence has come from retrospective studies, which have shown considerable heterogeneity in terms of patient selection, systemic treatment and surgical strategies.
What this study adds
The CAIRO6 trial was a phase 3, open-label, randomised study conducted in nine Dutch and one Belgian tertiary centres. Patients with resectable colorectal peritoneal metastases and no extraperitoneal disease, were randomised to receive either perioperative systemic therapy and CRS-HIPEC or upfront CRS-HIPEC alone.
Systemic therapy consisted of CAPOX, FOLFOX or FOLFIRI, with bevacizumab added during the neoadjuvant component. The length of overall survival was the primary outcome, which was defined as the time between enrolment and death.The primary analysis included 351 patients: 173 in the systemic therapy group and 178 in the surgery-alone group.
After a median follow-up period of 41 months, the median overall survival was 44 months with perioperative systemic therapy and 39 months with upfront surgery. The three-year overall survival rates were 54% and 53%, respectively.
The median overall survival was 44 months with perioperative systemic therapy and 39 months with upfront surgery.
No significant overall survival benefit was observed (HR 0.85; 95% CI 0.62–1.15; p=0.28).
The median progression-free survival was 13.5 months following perioperative chemotherapy compared to 7.0 months following upfront surgery (HR 0.51; 95% CI 0.41–0.65).
Among patients undergoing complete or near-complete CRS-HIPEC, major 90-day postoperative morbidity was 36% after perioperative systemic therapy and 26% after upfront surgery. Anastomotic leakage occurred in 9% and 4%, respectively. Postoperative mortality was 1% in both groups.
Grade 3 or worse treatment-related toxicity occurred in 57% of patients who started systemic therapy.
Implications for colorectal practice
CAIRO6 did not show an overall survival benefit from adding perioperative systemic therapy (doublet chemotherapy with neoadjuvant bevacizumab) to CRS-HIPEC.
Progression-free survival improved, but this came at the cost of significant toxicity and a numerically higher rate of major postoperative complications. Better disease control did not result in longer survival.
Of note, a post-hoc subgroup analysis showed longer overall survival after perioperative systemic therapy than after surgery alone in patients with right-sided colon cancer and synchronous peritoneal metastases. This finding has not been previously reported in this particular subgroup
Nevertheless, perioperative systemic therapy should not be recommended for all patients with resectable colorectal peritoneal-only metastases.