Last updated on February 2019

Perioperative Systemic Therapy and Surgery Versus Surgery Alone for Resectable Colorectal Peritoneal Metastases.

Brief description of study

Patients with potentially resectable peritoneal metastases arising from colorectal cancer are randomised to (1) cytoreductive surgery with HIPEC and perioperative systemic therapy versus (2) cytoreductive surgery with HIPEC without perioperative systemic therapy.

Detailed Study Description

Rationale: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) and systemic therapy are increasingly used for the treatment of peritoneal metastases of colorectal cancer (PMCRC). Subsequently, combined treatment strategies have been introduced, with the use of perioperative systemic therapy, either neoadjuvant or adjuvant, as adjunct to CRS + HIPEC. However, current literature on perioperative systemic therapy as adjunct to CRS + HIPEC is based on observational studies of low methodological quality, thereby leading to worldwide controversy on its benefit. A neoadjuvant treatment strategy that potentially downstages intraperitoneal tumour load, limits extensiveness of CRS, and predicts the biological behaviour of the tumour, appears to be of potential benefit. In patients who proved to respond to neoadjuvant treatment with sufficiently good clinical condition, adjuvant systemic therapy in the same regimen may be of value by further treating micro-metastases.

Objective: The primary objective of this study is to compare overall survival of CRS + HIPEC with perioperative systemic therapy versus upfront CRS + HIPEC alone in patient with potentially resectable PMCRC.

Study design: This is a prospective, multicentre, randomised, parallel group, phase II-III study with randomisation between CRS + HIPEC with perioperative systemic therapy (experimental arm) and upfront CRS + HIPEC alone (control arm). The study starts as a randomised phase II study to investigate the feasibility of accrual and the safety of neoadjuvant systemic therapy prior to CRS + HIPEC. If criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint.

Study population: Patients with histologically proven non-signet cell synchronous or metachronous PMCRC, without systemic metastases, who are candidate for CRS + HIPEC (PCI score 20), and in whom (nearly) complete cytoreduction (CC-0 or CC-1) seems feasible.

Intervention: Neoadjuvant combination chemotherapy plus bevacizumab for three 3-weekly (CAPOX + BEV) or four 2-weekly (FOLFOX + BEV) cycles, followed by restaging with thoraco-abdominal CT-scan. In case of progressive systemic disease (e.g. liver or lung metastases), the best possible palliative treatment is offered. In case of progressive peritoneal disease without progressive systemic disease, patients undergo explorative laparotomy, followed by CRS in case of resectable disease, and HIPEC in case of a CC0/1 cytoreduction. In case of responsive or stable disease, one 3-weekly (CAPOX) or two 2-weekly (FOLFOX) neoadjuvant cycles of combination chemotherapy without bevacizumab are administered. Subsequently, not earlier than 3 weeks after the last day of the last cycle of combination chemotherapy, patients undergo explorative laparotomy, followed by CRS in case of resectable disease, and HIPEC in case of a CC0/1 cytoreduction. Only in patients with stable disease/response upon neoadjuvant treatment, and a sufficiently good clinical condition, adjuvant combination chemotherapy is administered according to the neoadjuvant regimen, but without bevacizumab, for four 3-weekly cycles (CAPOX) or six 2-weekly cycles (FOLFOX).

Study parameters: Regarding feasibility and safety, endpoints of the phase II study are the number of randomised patients 1 year after the start of accrual at the last participating centre, major postoperative complications (Clavien-Dindo grade III-V) at 3 months postoperatively, and the number of patients receiving CRS + HIPEC. Secondary endpoints are minor postoperative complications (Clavien-Dindo grade II) and systemic therapy related toxicity (NCICTCAE v4.0 Grade II-V). The phase II study is deemed unfeasible if <80 patients are randomised, and deemed unsafe if:

  • There is a more than 7 patients difference in major postoperative complications in disadvantage of the experimental arm compared to the control arm.
  • less than 50% (20/40) of included patients in the experimental arm are able to proceed to CRS + HIPEC.

The primary endpoint of the phase III study is 3-year overall survival measured from randomisation. Secondary endpoints are 5-year overall survival, progression-free survival, procedure related characteristics (i.e. operative time, blood loss), peritoneal cancer index (PCI) score, completeness of cytoreduction (CC) score, major postoperative complications (Clavien-Dindo grade III-V) at 90-days postoperatively, hospital stay, quality of life, cost-effectiveness, and blood and tissue collection for future translational research purposes. In the experimental arm, additional secondary endpoints are severe systemic therapy-related toxicity (NCICTCAE v4.0 grade III-V), and the number of patients with progression, stable disease, and response to neoadjuvant combination chemotherapy plus bevacizumab.

Sample size: The phase II study includes 80 patients, with 40 patients in each arm. After fulfilling the criteria of feasibility and safety criteria, the study continues as a phase III superiority study with 3 year overall survival as primary endpoint. The expected 3-year overall survival after CRS + HIPEC is 50%. We hypothesize that the experimental treatment results in a 15% increase in overall survival rate if analysed 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 CRS + HIPEC for PMCRC in the Netherlands was 420. With an expected participation rate of 20%, accrual should be completed in 4 years.

Nature and extent of the burden and risks: In the experimental arm, the risk of this study primarily consists of treatment-related toxicity and morbidity of combination chemotherapy and bevacizumab, which should be weighed against potential survival benefit. Furthermore, some patients in the experimental arm may have disease progression upon neoadjuvant treatment to an extent that does not allow CRS + HIPEC. However, it is highly questionable whether these patients would have derived a benefit from upfront CRS + HIPEC at all, and the investigators hypothesise that a neoadjuvant treatment strategy allows for better patient selection and spares the morbidity of this intervention to patients who are unlikely to benefit.

Clinical Study Identifier: NCT02758951

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