Irreversible electroporation in the liver

Introduction: Malignant tumours in the liver are divided into primary liver cancers and liver metastases. Among primary liver cancers, hepatocellular carcinoma (HCC) accounts for 75-85% and is globally the fourth most common cause of cancer related death. Colorectal cancer (CRC) is the second most common cause of cancer related death. As many as 25-50% of all CRC-patients will be diagnosed with liver metastases, either at the time of diagnosis of their primary cancer, or later during progression of their disease. Surgery is the primary treatment option for colorectal liver metastases (CRCLM). When surgery is not a possible, either due to an insufficient future liver remnant (FLR), or that the patient is not fit for extensive surgery, ablation therapies can be an alternative. Thermal ablation strategies can widen treatment options for extensive liver disease, for oligometastatic disease and for small, potentially resectable tumours, to spare liver parenchyma. The most common thermal ablation techniques for liver tumours are radio-frequency ablation (RFA) and microwave ablation (MWA). The goal is to induce heat within the tumour including a surrounding margin of normal liver to create coagulative necrosis. Irreversible electroporation (IRE) is a non-thermal ablation technique that uses multiple electrodes to administer short pulses of direct current at high voltage to induce permanent pores in the lipid bilayer of the cell walls, disrupting the homeostasis and making the cells go into apoptosis. Since there is only a small amount of heat created just around the electrodes, IRE can be used to treat tumours close to heat-sensitive structures such as major bile ducts and larger hepatic vessels. The placement of the applicators in ablative treatment is one of the main parameters for success, even more so in IRE where several electrodes are placed around the tumour. For optimal treatment effect, they need to be as parallel as possible and at equal depth around the tumour. Different radiological guiding methods are used, ultrasound being the most common. To improve accuracy of applicator placement, stereotactic CT-based navigation systems have been developed.

Aims: The aim of Study I was to report the outcome and complications of the first 50 IRE treatments of liver tumours at a national referral centre. Study II compared the accuracy of multiple IRE-electrode placements with ultrasound guidance versus a stereotactic CT-based navigation system. In Study III the accuracy of multiple IRE-electrode placements with stereotactic CT-based navigation was evaluated in clinical practice. Study IV is a national multicentre study assessing complications and survival after IRE treatment of liver tumours. In Study V the aim was to investigate the relationship between decrease in tissue resistance and local tumour progression after IRE treatment of liver tumours.

Materials and methods: In Study I the 50 first patients treated with IRE of liver tumours at a national referral centre were included. Retrospective data on patient characteristics, guidance methods and treatment data were collected as well as all relevant radiological follow ups. For Study II, a liver phantom was used, containing an artificial liver with tumours as well as structures mimicking a rib cage, lungs, and large vessels. Around each of five tumours the interventionists placed four IRE-electrodes in a two-by-two-centimetre pattern using either US guidance or stereotactic CT-based navigation and the accuracy was compared between the two groups. In Study III 60 patients that had been treated with IRE for liver tumours using stereotactic CT-based navigation were included. All procedural CT-scans were retrospectively analysed and comparisons between the planned electrode placements and the actual placements were done regarding lateral and angular error, both for every single electrode and for all electrode pairs. Study IV and Study V are nationwide multi centre studies including all patients treated with IRE of liver tumours in Sweden from the first case in 2011 until the end of 2018. In Study IV patient-, tumour-, and treatment characteristics were collected through a retrospective search of patient records. Short- and long-term data were collected. Sub-group analyses were made for HCC- and CRCLM-patients. In Study V the recurrence patterns were compared to data collected from the IRE hardware regarding delivered currents and changes in tissue resistance.

Results: Study I analysed 60 tumours in 50 treatments and showed that IRE treatment of liver tumours is safe and with acceptable recurrence rates, 37% local tumour progression at 12 months in the whole group and 20% complications within 30 days, with two of them being Clavien-Dindo grade 3b-4b, and no 30-day mortality. Study II showed greater accuracy both in the pairwise electrode distances and angles in the stereotactic CT-based navigation group compared to US navigation, at the cost of longer procedural times. Study III found a good accuracy regarding stereotactic CT-based navigation with a median lateral error of 3.6 mm (range 0.2-13.6 mm) and a median angular error of 3.1 degrees (range 0.2-18.9 degrees) comparing planned and validated electrode placement. No electrode placement-related complications were recorded. Study IV analysed all 183 patients treated with IRE for 257 liver tumours in Sweden between 2011 and 2018, the majority with CRCLM or HCC. Median follow-up time was 59 months, and 30-day complications were reported in 18% of the patients with 1.2% being Clavien-Dindo grade 3b-5. Overall survival for the whole cohort was 32.6 months (95% CI 28.3-42.6), longer for HCC than CRCLM, 42.3 months (95% CI 27.8-65.7 months) compared to 27.9 months (95% CI 20.4-35.6 months). For CRCLM the time to local tumour progression was significantly longer for tumours smaller than 20 mm compared to larger tumours and it was also longer for patients with IRE as their primary treatment in the liver compared to patients previously treated with other modalities. Study V used the same cohort as study IV and data from 132 patients with 203 tumours that was complete regarding delivered energy during the IRE treatments. The analysis showed that impaired change in resistance over at least one electrode pair was correlated with the time to local tumour progression for liver metastases, but not for HCC.

Discussion: Study I, presenting the initial experiences of IRE of liver tumours, and study IV, a nationwide multicentre study, further establish IRE as a safe and efficient ablation method for primary and secondary hepatic tumours. The complication rates in these studies are lower compared to previously published papers, especially for major complications. The overall survival and time to local tumour progression are comparable to previous studies. Study II and III demonstrate that a stereotactic CT-based navigation system is safe to use and gives good accuracy in electrode placement with no electrode placement related complications. The navigation system is superior to US in placing IRE electrodes in a liver phantom regarding parallelism and lateral deviation of electrodes. Study V demonstrates a relationship between change in tissue resistance and time to local tumour progression in CRCLM and NCRCLM, but not for HCC. There are multiple factors affecting tissue resistance during IRE, the formation of nanopores and altered electrical properties around the cells is one, the change in temperature in the ablation zone is another. Further studies are needed to find the optimal electrode placement and energy settings in IRE treatment of liver tumours. Real-time measurement of tissue resistance could be one factor to investigate in the future.

List of scientific papers

I. Initial experience with irreversible electroporation of liver tumours. Stillström D, Beermann M, Engstrand J, Freedman J, Nilsson H. Eur J Radiol Open. 2019 Jan 22;6:62-67.
https://doi.org/10.1016/j.ejro.2019.01.004

II. Stereotactic navigation versus ultrasound guidance in placing IRE applicators in a liver phantom. Stillström D, Eigl B. Freedman J Scientific Reports. (2021) 11:21031.
https://doi.org/10.1038/s41598-021-00505-1

III. Accuracy of Electrode Placement in IRE Treatment with Navigated Guidance. Stillström D, Sandu RM, Freedman J. Cardiovasc Intervent Radiol. 2021 Jun;44(6):968-975.
https://doi.org/10.1007/s00270-020-02762-5

IV. Irreversible electroporation of liver tumours: A nation-wide multicenter study with long term follow-up. Stillström D, Frühling P, Holmquist F, Nilsson A, Freedman J. [Manuscript]

V. Change in tissue resistance during IRE of liver tumours as an indicator of treatment success, a multicentre analyse with long term follow-up. Stillström D, Frühling P, Holmquist F, Nilsson A, Freedman J. [Manuscript]