Abstract
BackgroundAfter curative-intent surgery for colorectal liver metastases (CRLM), liver recurrence occurs in more than 60% of patients, despite the administration of perioperative or adjuvant chemotherapy. This risk is even higher after resection of more than three CRLM. As CRLM are mostly supplied by arterial blood flow, hepatic arterial infusion (HAI) of chemotherapeutic agents after resection of CRLM is an attractive approach. Oxaliplatin-based HAI chemotherapy, in association with systemic fluoropyrimidines, has been shown to be safe and highly active in patients with CRLM. In a retrospective series of 98 patients at high risk of hepatic recurrence (≥4 resected CRLM), adjuvant HAI oxaliplatin combined with systemic chemotherapy was feasible and significantly improved disease-free survival compared to adjuvant, ‘modern’ systemic chemotherapy alone.Methods/DesignThis study is designed as a multicentre, randomized, phase II/III trial. The first step is a non-comparative randomized phase II trial (power, 95%; one-sided alpha risk, 10%). Patients will be randomly assigned in a 1:1 ratio to adjuvant systemic FOLFOX (control arm) or adjuvant HAI oxaliplatin plus systemic LV5FU2 (experimental arm). A total 114 patients will need to be included. The main objective of this trial is to evaluate the potential survival benefit of adjuvant HAI with oxaliplatin after resection of at least 4 CRLM (primary endpoint: 18-month hepatic recurrence-free survival rate). We also aim to assess the feasibility of delivering at least 4 cycles of HAI (or i.v.) oxaliplatin after surgical treatment of at least 4 CRLM, the toxicity (NCI-CTC v4.0) of adjuvant HAI plus systemic chemotherapy, including HAI catheter-related complications, compared to systemic chemotherapy alone, and the efficacy of adjuvant HAI on hepatic and extra-hepatic recurrence-free (survival and overall survival).DiscussionIf 18-month hepatic recurrence-free survival is greater than 50% in the experimental arm, the study will be pursued in phase III, for which the primary endpoint will be 3-year recurrence-free survival rate. Patients randomized in the phase II will be included in the phase III, with an additional number of 106 patients.Trial registrationClinicalTrials.gov, NCT02494973. Trial registration date: July 10, 2015.
Highlights
If 18-month hepatic recurrence-free survival is greater than 50% in the experimental arm, the study will be pursued in phase III, for which the primary endpoint will be 3-year recurrence-free survival rate
This study is important as it provides proof of concept for the potential role of adjuvant chemotherapy with hepatic arterial infusion (HAI) oxaliplatin in patients who have undergone curative resection of liver metastatic disease
All the available data in the literature and the observed disease-free survival (DFS) benefit in the previous retrospective study [51] suggest that it could be interesting to evaluate adjuvant hepatic arterial infusion with oxaliplatin plus systemic 5-FU after resection of at least 4 colorectal liver metastases (CRLM), in order to decrease the rate of hepatic recurrence
Summary
This study is important as it provides proof of concept for the potential role of adjuvant chemotherapy with HAI oxaliplatin in patients who have undergone curative resection of liver metastatic disease. All the available data in the literature and the observed DFS benefit in the previous retrospective study [51] suggest that it could be interesting to evaluate adjuvant hepatic arterial infusion with oxaliplatin plus systemic 5-FU after resection of at least 4 CRLM, in order to decrease the rate of hepatic recurrence. Increasing local delivery of chemotherapy to the liver via the HAI route after resection of CRLM in patients at high risk of hepatic recurrence appears to be an attractive and promising option. There is no controlled phase 3 trial comparing HAI to the “modern” (i.e. oxaliplatin- or irinotecan-based) systemic chemotherapy, and we have enough arguments in the literature to evaluate the potential benefit of adjuvant HAI in a randomized trial focused on patients at high risk of hepatic recurrence
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