Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: protocol of a multicentre, open-label, parallel-group, phase II-III, randomised, superiority study (CAIRO6)

Abstract

Background Upfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes. Methods This open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0–10 or 11–20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician’s discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates. Discussion This is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM. Trial registration Clinicaltrials.gov/ NCT02758951 , NTR/ NTR6301 , ISRCTN/ ISRCTN15977568 , EudraCT/ 2016–001865-99 .

Impact of Neoadjuvant Chemotherapy on the Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: A Multi-Institutional Retrospective Review

“…Based on seven studies that met inclusion criteria, they concluded that the role of NAC could not be determined by the current evidence [15]. A multicenter Dutch randomized controlled trial is currently underway to test the role of NAC prior to CRS-HIPEC for CR-PM [28].…”

Prognostic factors influencing survival in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for isolated colorectal peritoneal metastases: a systematic review and meta‐analysis

“…A recent study reported that in patients suffering recurrence after CRS and HIPEC, 31% of recurrences are at distant sites [46]. The use of adjuvant chemotherapy may help Test for overall effect: Z = 4.57 (P < 0.00001) Heterogeneity: τ 2 = 0.10; χ 2 = 13.04, df = 7 (P = 0.07); I 2 = 46% Test for overall effect: Z = 4.38 (P < 0.0001) Heterogeneity: τ 2 = 0.00; χ 2 = 31.24, df = 7 (P < 0.0001); I 2 = 78% currently recruiting, aims to evaluate the role of perioperative systemic chemotherapy with CRS and HIPEC versus upfront CRS and HIPEC alone [48]. It is to be hoped that results will better guide the future use of systemic chemotherapy.…”

A population‐based study on the prognostic impact of primary tumor sidedness in patients with peritoneal metastases from colon cancer

“…This study will provide the OS data to determine which treatment is superior. 33 Unfortunately, the majority of patients (>90%) with PM from colon cancer are not eligible for treatment with curative intent. This study shows that patients with PM from right-sided colon cancer who are treated in a palliative setting have a worse OS after diagnosis as compared to patients with PM from left-sided tumors.…”