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)
Authors: Rovers Koen P. , Bakkers Checca , Simkens Geert A. A. M. , Burger Jacobus W. A. , Nienhuijs Simon W. , Creemers Geert-Jan M. , Thijs Anna M. J. , Brandt-Kerkhof Alexandra R. M. , Madsen Eva V. E. , Ayez Ninos , de Boer Nadine L. , van Meerten Esther , Tuynman Jurriaan B. , Kusters Miranda , Sluiter Nina R. , Verheul Henk M. W. , van der Vliet Hans J. , Wiezer Marinus J. , Boerma Djamila , Wassenaar Emma C. E. , Los Maartje , Hunting Cornelis B. , Aalbers Arend G. J. , Kok Niels F. M. , Kuhlmann Koert F. D. , Boot Henk , Chalabi Myriam , Kruijff Schelto , Been Lukas B. , van Ginkel Robert J. , de Groot Derk Jan A. , Fehrmann Rudolf S. N. , de Wilt Johannes H. W. , Bremers Andreas J. A. , de Reuver Philip R. , Radema Sandra A. , Herbschleb Karin H. , van Grevenstein Wilhelmina M. U. , Witkamp Arjen J. , Koopman Miriam , Haj Mohammad Nadia , van Duyn Eino B. , Mastboom Walter J. B. , Mekenkamp Leonie J. M. , Nederend Joost , Lahaye Max J. , Snaebjornsson Petur , Verhoef Cornelis , van Laarhoven Hanneke W. M. , Zwinderman Aeilko H. , Bouma Jeanette M. , Kranenburg Onno , van ‘t Erve Iris , Fijneman Remond J. A. , Dijkgraaf Marcel G. W. , Hemmer Patrick H. J. , Punt Cornelis J. A. , Tanis Pieter J. , de Hingh Ignace H. J. T. ,   Dutch Peritoneal Oncology Group (DPOG),   Dutch Colorectal Cancer Group (DCCG)
Published: April 2019

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.