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)
Dutch Peritoneal Oncology Group (DPOG)
(2019) BMC Cancer, volume 19, issue 1
(Article)
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
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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 .
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Keywords: Colorectal neoplasms, Peritoneal neoplasms, Cytoreduction surgical procedures, Hyperthermia, induced, Neoadjuvant therapy, Adjuvant chemotherapy, Bevacizumab, Randomized control trial, Mortality, Progression-free survival, Randomized controlled trial, Bevacizumab/administration & dosage, Humans, Middle Aged, Peritoneal Neoplasms/drug therapy, Male, Neoplasm Metastasis, Adult, Cytoreduction Surgical Procedures/adverse effects, Female, Leucovorin/administration & dosage, Chemotherapy, Adjuvant/adverse effects, Combined Modality Therapy, Peritoneum/drug effects, Colorectal Neoplasms/drug therapy, Disease-Free Survival, Perioperative Period, Oxaliplatin/administration & dosage, Progression-Free Survival, Fluorouracil/administration & dosage, Quality of Life, Genetics, Oncology, Cancer Research, Journal Article, Randomized Controlled Trial, Clinical Trial, Phase II, Clinical Trial, Phase III
ISSN: 1471-2407
Publisher: BioMed Central
Note: Funding Information: This study is funded by the Dutch Cancer Society (KWF), Catharina Research Fund, and Hoffman-La Roche. Hoffman-La Roche awarded an unrestricted scientific grant for this investigator-initiated study. The funding bodies have no role in the design of the study, in the collection, analysis, and interpretation of data, and in writing the manuscripts. Publisher Copyright: © 2019 The Author(s).
(Peer reviewed)