Irreversible Electroporation to Treat Unresectable Colorectal Liver Metastases (COLDFIRE-2): A Phase 2, Two-Center, Single-Arm Clinical Trial

Background: Irreversible electroporation (IRE), an ablative technique using high-voltage electrical pulses, has shown promise to eradicate tumors nearby critical structures like blood vessels and bile ducts. The aim was to investigate the efficacy and safety of IRE for colorectal liver metastases (CRLM) anatomically unsuitable for resection and thermal ablation. Methods: In this single-arm, two-center phase 2 clinical trial, patients with 18F-FDG PET-avid CRLM ≤5·0 cm unsuitable for partial hepatectomy and thermal ablation according to a multidisciplinary expert panel, were treated with IRE (ClinicalTrials.gov NCT02082782). For the primary endpoint to be met, at least 50% of treated patients had to be alive without local tumor progression (LTPFS) at 12 months. Secondary aims were safety, technical success, local control following repeat procedures, disease-free and overall survival. Findings: Between June 2014 and November 2018, 50/51 patients with a total of 76 CRLM were successfully treated with IRE in 62 procedures; in 1 patient treatment was stopped prematurely due to a pulsed-induced cardiac arrhythmia. With a per-patient and per-tumor 1-year LTPFS of 68·8% (95%-CI 55·4-81·4%) and 76·0% (95%-CI 64·8-85·8%) respectively, the primary endpoint was met. Including repeat procedures local control was realized in 74·0% (37/50) of patients. Local tumor progression in the first 5 versus the following 45 patients was 80% versus 33·3% (p=0·062). One patient, with an infected biloma post-IRE and an autopsy confirmed pre-existing cardiomyopathy, infected atrial thrombus, massive pulmonary artery embolism and acute myocardial infarction died <90 days (grade 5; 1·6%). Overall, 19 serious adverse events (SAE) were encountered (SAE rate 30·6%), of which 16 (25·8%) were grade 3 and 2 (3·2%) were grade 4. Interpretation: This trial supports the use of IRE for patients with CRLM ≤5·0 cm considered permanently unsuitable for partial hepatectomy and thermal ablation. Trial Registration: The trial was investigator-sponsored, independent of industry and registered at clinicaltrials.gov (NCT02082782). Funding Statement: Amsterdam UMC, Angiodynamics, Adessium Foundation. Declaration of Interests: MRM and KvL were paid consultants to Angiodynamics during the conduct of the study. MRM received an unrestricted research grant from Angiodynamics for a different project during the conduct of the study. All other authors declare no competing interests. Ethics Approval Statement: The study was approved by the Institutional Review Board of the Amsterdam UMC location VUmc. The trial was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent.