COLDFIRE-III Trial: Efficacy of Irreversible Electroporation and Stereotactic Body Radiotherapy for Perivascular and Peribiliary Colorectal Liver Metastases

Rationale: Currently, the gold standard for perivascular and peribiliary colorectal liver metastases (CRLM), that are not amenable for surgical resection or thermal ablation, is undetermined. Two non-thermal treatment modalities could provide a solution for these anatomically challenging CRLM: irreversible electroporation (IRE) and stereotactic body radiotherapy (SBRT).

IRE is a new, minimal-invasive image-guided treatment method for tumors not amenable for surgical resection or thermal ablation, due to vicinity near vital structures such as vessels and bile ducts. With IRE, multiple electrical pulses are applied to tumorous tissue. These pulses alter the existing transmembrane potential of the cell membranes, and create 'nanopores', after which the cell dies through loss of homeastasis. SBRT is another non-thermal ablation modality and has important advantages over conventional radiotherapy such as a more precise and greater biological dose delivery and hence less toxicity and presumably better outcome.

Study design: The COLDFIRE-III trial is a phase IIB/III, prospective randomized clinical trial. The primary conducting center will be the Amsterdam UMC (Amsterdam, the Netherlands). The purpose of this study is to assess and compare the efficacy of IRE and SBRT for perivascular or peribiliary CRLM in terms of local control at 2 years. Other objectives are overall survival, additional efficacy endpoints, safety, pain assessments and costs. For the sample size calculations, the log-rank test is used. The (2-year survival) proportion in group 1 (a treatment group) is 0.80. The proportion in group 2 (the alternative treatment group) is 0.55. The significance level of the test is 0.10. A total number of 78 patients will be randomized into one of two arms: arm A (IRE, n = 39) and arm B (SBRT, n = 39).

Study population: 78 patients with 1-3 perivascular and peribiliary lesions of 0-5 cm, ineligible for surgical resection and thermal ablation, suitable for both IRE and SBRT and no or limited extrahepatic disease (1 extrahepatic lesion is allowed, not including positive para-aortic lymph nodes, celiac lymph nodes, adrenal metastases, pleural carcinomatosis or peritoneal carcinomatosis) can be included. Supplementary resections for resectable lesions and thermal ablations for unresectable CRLM are allowed. A maximum number of 10 CRLM are allowed for patients with no extrahepatic disease and a maximum number of 5 lesions are allowed for patients with limited extrahepatic disease. Eligible patients will be stratified according to tumor size (≤3cm vs. 3-5 cm) and (induction) chemotherapy prior to local treatment.

Intervention: Patients will be randomized into one of two arms, arm A (IRE) and arm B (SBRT). The expert panel, consisting of at least two interventional radiologists, two radiation oncologists and two hepatobiliary surgeons, will appoint lesions that are ineligible for surgery of thermal ablation, and suitable for both IRE and SBRT, as target lesions.

• Overall survival (OS) per patient [Срок оценки: Assessed up to 5 years]
• Local tumor progression-free survival (LTPFS) per patient and per tumor. [Срок оценки: Assessed up to 5 years]
• Distant tumor progression-free survival (DPFS) per patient [Срок оценки: Assessed up to 5 years]
• Time to progression (TTP) per patient [Срок оценки: Assessed up to 5 years]
• Safety per procedure and per patient [Срок оценки: Assessed up to 5 years]
• Assessment of pain per patient [Срок оценки: Assessed up to 1 year]
• Quality of life (QoL) per patient as assessed by EORCT QLQ-C30 questionnaires [Срок оценки: Assessed up to 1 year]
• Quality of life (QoL) per patient as assessed by EQ-5D questionnaires [Срок оценки: Assessed up to 1 year]
• Quality of life (QoL) per patient as assessed by PRODISQ questionnaires [Срок оценки: Assessed up to 1 year]
• Cost-effectiveness ratio (ICER) per patient [Срок оценки: Assessed up to 5 years]