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

The primary objective of this phase IIb/III, prospective, randomized clinical trial is to compare the efficacy of irreversible electroporation (IRE) with stereotactic body radiotherapy (SBRT) in patients with perivascular or peribiliary colorectal liver metastases (CRLM), that are not amenable for surgical resection or thermal ablation. Efficacy is assessed in terms of local control at 2 years.

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.

Eligibility Criteria:
Inclusion Criteria:

* Histological documentation of primary colorectal tumor is available;
* 1-3 CRLM visible on ceCT and/or MRI, size 0-5 cm and not eligible for resection or thermal ablation due to location close to a vessel or bile duct;
* Additional CRLM are allowed if considered either resectable or ablatable with a maximum of 10 CRLM. In patients with extrahepatic disease, a maximum of 5 additional CRLM is allowed;
* No or limited extrahepatic disease (1 extrahepatic lesion is allowed, with some exclusions mentioned in the exclusion criteria);
* Prior focal liver treatment is allowed;
* Subjects should preferably be treated with neo-adjuvant systemic therapy;
* Subjects with recurrent (either local or distant-hepatic) CRLM after previous focal treatment who are unsuitable for (further) systemic therapy (further downsizing or conversion to resectable disease improbable);
* Adequate bone marrow, liver and renal function as assessed by laboratory requirements to be conducted within 7 days prior to definite inclusion;
* ASA classification 0 - 3;
* Age \>18 years;
* Written informed consent;

Exclusion Criteria:

* Radical treatment unfeasible or unsafe (e.g. insufficient FLR);
* \>10 CRLM; \>5 CRLM when extra-hepatic disease is present;
* Positive para-aortal lymph nodes, celiac lymph nodes, adrenal metastases, pleural carcinomatosis or peritoneal carcinomatosis;
* Subjects who have progressive disease after neo-adjuvant systemic therapy;
* History of epilepsy;
* History of cardiac disease:
* Uncontrolled hypertension. Blood pressure must be ≤160/95 mmHg at the time of screening on a stable antihypertensive regimen;
* Compromised liver function (e.g. signs of portal hypertension, INR \> 1,5 without use of anticoagulants, ascites);
* Pregnant or breast-feeding subjects;
* Immunotherapy ≤ 2 weeks prior to the procedure;
* Chemotherapy and/or targeted therapy ≤ 2 weeks prior to the procedure;
* Severe allergy to contrast media not controlled with premedication;
* Any condition that is unstable or that could jeopardize the safety of the subject and their compliance in the study.