Efficacy of Irreversible Electroporation (IRE) for Central Colorectal Liver Metastases (COLDFIRE-2)

Colorectal Metastatic Liver Disease: Efficacy of Irreversible Electroporation (IRE) - a Phase II Clinical Trial (COLDFIRE-2 Study)

Irreversible electroporation (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.

The purpose of this study is to investigate the efficacy of percutaneous and open IRE in the treatment of patients with colorectal liver metastases (CRLM) that are unsuitable for resection or thermal ablation due to vicinity to vulnerable structures such as vessels and bile ducts. Other objectives are safety, feasibility (technical success) and imaging characteristics on follow-up (PET-)CT and PET-MRI and the value of these imaging modalities in dianosing local site recurrence (LSR) or residual disease (RD).

29 patients with histologically confirmed colorectal carcinoma who present with unresectable and not thermally ablative CRLM< 3.5cm suitable for IRE will undergo percutaneous or open irreversible electroporation of the tumor using CT and ultrasound guidance. All (serious) adverse events are registered. One day post-IRE MRI is performed to assess technical success. Follow-up will consist of frequent (PET-)CT and (PET-)MRI scanning to localize residual or recurrent disease. Overall technique effectiveness is determined 1 year after treatment.

The investigators hypothesize that IRE for central CRLM will lead to good tumor control without causing severe complications.

Study Overview

• Status: Completed
• Conditions: Colorectal Liver Metastases
• Intervention / Treatment: Procedure: Irreversible electroporation (IRE)

• Study Type: Interventional
• Enrollment (Anticipated): 51
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hester J Scheffer, MD; Phone Number: +31204444533; Email: hj.scheffer@vumc.nl
• Study Contact Backup: Name: Martijn R Meijerink, MD, PhD; Phone Number: +314444444; Email: mr.meijerink@vumc.nl

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081 HV
      • VU University Medical Center
    • Amsterdam, Noord-Holland, Netherlands, 1105 AZ
      • Academic Medical Center
  • Zuid-Holland
    • Leiden, Zuid-Holland, Netherlands, 2333 ZA
      • Leiden University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histological or cytological documentation of primary colorectal tumor;
• Previous induction chemotherapy due to unresectability; no intra- or extrahepatic disease progression under induction chemotherapy; OR
• Previous chemotherapy for other CRLM, now presenting with renewed CRLM unsuitable for resection or thermal ablation;
• Liver metastases F-18-FDG PET avid and visible on ceCT, size ≤ 3,5 cm and not eligible for resection or thermal ablation due to location close to a vessel or bile duct;
• Age more than 18 years;
• ASA classification 0 - 3;

• Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to definite inclusion:

  • Hemoglobin ≥ 5.6 mmol/L;
  • Absolute neutrophil count (ANC) ≥ 1,500/mm3;
  • Platelet count ≥ 100*109/l;
  • Total bilirubin ≤ 1.5 times the upper limit of normal (ULN);
  • ALT and AST ≤ 2.5 x ULN
  • Serum creatinine ≤ 1.5 x ULN or a calculated creatinine clearance > 50 ml/min;
  • Prothrombin time or INR < 1.5 x ULN;
  • Activated partial thromboplastin time < 1.25 x ULN (therapeutic anticoagulation therapy is allowed if this treatment can be interrupted as judged by the treating physician)
• Written informed consent

Exclusion Criteria:

• Lesion > 3,5 cm size;
• History of epilepsy;
• Extrahepatic metastases rendering local therapy unfeasible;

• History of cardiac disease:

  • Congestive heart failure >NYHA class 2;
  • Active Coronary Artery Disease (defined as myocardial infarction within 6 months prior to screening);
  • Cardiac arrhythmias requiring anti-arrhythmic therapy or pacemaker (beta blockers are permitted);
• 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 ≤ 6 weeks prior to the procedure;
• Chemotherapy ≤ 6 weeks prior to the procedure;
• Concomitant use of anti-convulsives and anti-arrhythmic drugs other than beta blockers for antiepileptic or antiarrhythmic purpose;
• Allergy to contrast media;
• Any implanted stimulation device;
• Any condition that is unstable or that could jeopardize the safety of the subject and their compliance in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: irreversible electroporation (IRE); Single arm study: percutaneous or open irreversible electropration of CRLM	Procedure: Irreversible electroporation (IRE); Percutaneous (CT-guided) or open (US-guided) irreversible electroporation of central colorectal liver metastasis.; Other Names: NanoKnife

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy	The primary objective of this project is to evaluate the efficacy (percentage of lesions that show no sign of recurrence 12 months after the initail IRE procedure) of IRE for CRLM on cross-sectional imaging performed after respectively 6 weeks, and after 3, 6, 9 and 12 months. Research has shown that 95% of all recurrences after RFA of CRLM are diagnosed within one year after treatment. Therefore, one year follow-up will allow for accurate calculation of efficacy. Exact secondary efficacy rate may require follow-up longer than 12 months since this includes lesions that have been re-treated due to local site recurrence/local tumor residue (which will be individualized for each patient after re-treatment of LSR/LTR).	12 months

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: Martijn R Meijerink, MD, PhD, VU University Medical Center (VUMC); Principal Investigator: Krijn P van Lienden, MD, PhD, Academic Medical Center Amsterdam (AMC); Principal Investigator: Arian R van Erkel, MD, PhD, Leiden University Medical Center (LUMC)

Publications and helpful links

General Publications

• Meijerink MR, Ruarus AH, Vroomen LGPH, Puijk RS, Geboers B, Nieuwenhuizen S, van den Bemd BAT, Nielsen K, de Vries JJJ, van Lienden KP, Lissenberg-Witte BI, van den Tol MP, Scheffer HJ. Irreversible Electroporation to Treat Unresectable Colorectal Liver Metastases (COLDFIRE-2): A Phase II, Two-Center, Single-Arm Clinical Trial. Radiology. 2021 May;299(2):470-480. doi: 10.1148/radiol.2021203089. Epub 2021 Mar 16.
• Scheffer HJ, Vroomen LG, Nielsen K, van Tilborg AA, Comans EF, van Kuijk C, van der Meijs BB, van den Bergh J, van den Tol PM, Meijerink MR. Colorectal liver metastatic disease: efficacy of irreversible electroporation--a single-arm phase II clinical trial (COLDFIRE-2 trial). BMC Cancer. 2015 Oct 24;15:772. doi: 10.1186/s12885-015-1736-5.

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): May 1, 2017
• Study Completion (Actual): May 1, 2020

Study Registration Dates

• First Submitted: March 6, 2014
• First Submitted That Met QC Criteria: March 7, 2014
• First Posted (Estimate): March 10, 2014

Study Record Updates

• Last Update Posted (Actual): December 20, 2022
• Last Update Submitted That Met QC Criteria: December 18, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Irreversible electroporation (IRE); Colorectal liver metastases (CRLM); Tumor ablation; Interventional oncology; NanoKnife; Colorectal liver metastasis, unresectable and not-thermally ablative due to location near vulnerable structures like vessels or bile ducts
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Neoplastic Processes; Neoplasm Metastasis; Liver Neoplasms
• Other Study ID Numbers: COLDFIRE-2 study