CAIRO6 Randomised Controlled Trial
Title: Perioperative systemic therapy and surgery with HIPEC versus upfront surgery with HIPEC alone for resectable colorectal peritoneal metastases: a randomised controlled trial.
Background: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) and systemic therapy are increasingly used for the treatment of colorectal peritoneal metastases. Subsequently, combined treatment strategies have been introduced, with widespread use of perioperative systemic therapy, either neoadjuvant and/or adjuvant, in patients who undergo CRS + HIPEC for colorectal peritoneal metastases. However, current literature on perioperative systemic therapy in this setting is based on observational studies of low methodological quality, thereby not allowing for evidence based conclusions regarding its benefit, timing, and risks.
Objective: The primary objective of this study is to compare overall survival of perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone in patient with resectable colorectal peritoneal metastases.
Study design: This is a multicentre, parallel group, randomised controlled, phase II-III study with randomisation to perioperative systemic therapy and cytoreductive surgery with HIPEC (experimental arm) or upfront cytoreductive surgery with HIPEC alone (control arm). The study starts as a randomised phase II study to investigate the safety of patients in the experimental arm. If safety criteria are met, the study continues as a phase III study.
Study population: Patients with histologically proven non-signet cell synchronous or metachronous colorectal peritoneal metastases, without systemic metastases, who are candidate for major surgery, and in whom a (nearly) complete cytoreduction (CC-0 or CC-1) seems feasible.
Intervention: Three (CAPOX) or four (FOLFOX) cycles of neoadjuvant doublet chemotherapy with bevacizumab, followed by restaging with at least a thoracoabdominal CT-scan:
- In case of systemic disease progression, patients undergo second line or palliative treatment.
- In case of intraperitoneal disease progression without systemic disease progression, patients undergo laparotomy at least 6 weeks after the last administration of bevacizumab, intentionally followed by cytoreductive surgery in case of resectable disease, intentionally followed by HIPEC in case of a complete cytoreduction.
- In case of response or stable disease, patients receive one (CAPOX) or two (FOLFOX) cycles of combination chemotherapy without bevacizumab. Subsequently, patients undergo laparotomy at least 6 weeks after the last administration of bevacizumab, intentionally followed by cytoreductive surgery in case of resectable disease, intentionally followed by HIPEC in case of a complete cytoreduction. Only in case of sufficiently good postoperative clinical condition, these patients intentionally receive four (CAPOX) or six (FOLFOX) cycles of adjuvant doublet chemotherapy in order to maximise the tumour response.
Study parameters: The primary endpoints of the phase II study are (1) the number of patients with a complete cytoreduction and (2) the number of patients with grade III-V postoperative complications at 90 days postoperatively. The primary endpoint of the phase III study is 3-year overall survival measured from randomisation. Secondary endpoints are progression-free survival, procedure related characteristics, extent of peritoneal disease, number of complete cytoreductions, grade III-V postoperative complications at 90 days postoperatively, quality of life, cost effectiveness, and blood and tissue collection for future translational research purposes. In the experimental arm, additional secondary endpoints are grade III-V systemic therapy-related toxicity and the number of patients with progression, stable disease, and response upon neoadjuvant treatment.
Sample size: The phase II study includes 80 patients, with 40 patients in each arm. The subsequent phase III study is designed as a superiority study. The expected 3-year overall survival after cytoreductive surgery with HIPEC is 50%. The investigators hypothesize that the experimental treatment results in a 15% increase in overall survival rate according to an intention-to-treat principle. With a 0.05 two-sided significance level, 80% power and a drop-out of 5%, a sample size of 179 patients in each arm is needed, resulting in a total of 358 patients, including the 80 patients from the phase II study.
Time schedule: In 2016, the expected number of patients referred for cytoreductive surgery with HIPEC for colorectal peritoneal metastases in the Netherlands was 420. With an expected accrual rate of 20%, accrual should be completed in 4 years.
Dutch Cancer Society