The efficacy and safety of irreversible electroporation for the ablation of renal masses: a prospective, human, in-vivo study protocol

The past two decades have shown a steady increase in the incidence of small renal masses (SRM) up to 4 cm [1,2]. Nephron sparing surgery, in the form of partial nephrectomy, is considered to be the gold standard for treatment of SRMs [3]. Currently thermal focal therapies such as cryoablation and radiofrequency ablation (RFA) are primarily recommended in patients who are poor surgical candidates or have a genetic predisposition for developing multiple tumours [4-6]. However, promising long-term results combined with little or no loss in renal function have created interest in thermal focal therapies as a future treatment option for a broader range of patients [7-10].

Focal treatment of kidney tumour requires precisely dosed and accurate targeting of the tissue to be ablated while preserving surrounding healthy tissue and vital structures such as blood vessels, nerves, the renal collecting system and neighbouring organs [11]. The unselective destruction of currently practiced thermal ablation techniques can result in damage to vital structures in the vicinity of the tumour and undesired excessive ablation of normal parenchyma [12]. Thermal ablation intensity can be impaired due to ‘heat sink’ in the vicinity of large vessels and the renal collecting system [4].

Electroporation or electropermeabilisation is a technique in which electric pulses, traveling between two or more electrodes, are used to create ‘nanopores’ in the cell membrane. These pores allow for molecules to pass into the cell. The process can be temporary (reversible electroporation, RE), however above a certain threshold the ‘nanopores’ become permanent causing cell death due to the inability to maintain homeostasis (irreversible electroporation, IRE) [13-15]. It has been hypothesized that IRE is not dependent on temperature and is therefore not influenced by ‘heat sink’ promising consistent ablation results [11]. In theory IRE is defined to damage of the cell membrane, sparing tissue architecture and minimizing damage to blood vessels, nerves and the renal collecting system [16]. Recent literature however, has predicted [17] and measured [18,19] a large increase of temperature in healthy porcine kidney using currently practiced equipment and settings. As a result, it remains unclear to which extent the thermal effect or the electroporation contribute to the IRE ablation effect. Histopathology using viability staining of renal IRE lesions shows a sharp demarcation between ablated and non-ablated tissue allowing for precise targeting while sparing the surrounding healthy tissue [20,21].

Animal trials have assessed the use of MRI and CT imaging for the intermediate follow-up of IRE lesions. Contrast enhanced CT imaging directly after IRE ablation of porcine kidney showed a hypodense non-enhancing lesion, persisting at 1 week post IRE. At 3 weeks, 4 out of 6 IRE lesions had disappeared completely [22]. Thomson et al. performed in human IRE in 10 renal tumours with subsequent follow-up by CT imaging. At 3 months post IRE incomplete ablation was diagnosed in 2 patients on the basis of CT-imaging. However, the authors provide little information on the imaging characteristics of the residual lesion. MRI directly after IRE of porcine kidney showed a localized oedema at the region of IRE ablation. At 7 days after IRE a hypo-intense necrosis-like lesion in the renal parenchyma at the region of IRE was visualised. Finally, at 28 days a sharply delineated, non-intense, scar-like lesion with cortical shrinkage and without contrast enhancement was visualised [20]. These results provide an insight in the use of imaging for the follow-up of renal IRE. However, a study where follow-up imaging, specifically assessment of ablation volume and residual enhancing tumour, is correlated to histopathology of the resected specimen has not yet been performed.

Procedural safety of renal IRE in humans has been tested and confirmed [15]. The electric pulses administered during IRE have the potential of causing cardiac arrhythmias; by synchronising the IRE pulses with the ECG this complication can be avoided [23]. In a study by Pech et al., ablated tumours were resected directly after IRE and they observed swelling of cells but no actual cell death. However, histological staining to assess cell viability was not performed [15].

Before progressing to a long-term IRE follow-up study it is vital to have pathological confirmation of the efficacy of the technique. Furthermore, follow-up of IRE ablation requires an accurate imaging modality. This trial will investigate IRE ablation efficacy by correlating 3D histopathology of a resected IRE lesion with: 1) 3D reconstructed imaging using MRI and contrast enhance ultrasound (CEUS), and 2) the 3D predicted ablation volume as provided by the manufacturer. The objectives of the study are assessing the safety and efficacy of IRE of renal masses (primary objectives), and assessing the efficacy of MRI and CEUS for the initial evaluation and short-term (4 weeks) follow-up of IRE lesions (secondary objectives). This study conforms to the recommendations of the IDEAL Collaboration and can be categorised as a phase 2A development trial [24].

Before progressing to follow-up studies of IRE in renal masses it is vital to perform tissue specific testing of IRE ablation efficacy and safety. This trial will investigate IRE ablation efficacy by comparing 3D histopathological examination of a (partially) resolved IRE lesion, through radical nephrectomy with 1) examination of 3D imaging using MRI and CEUS and 2) 3D prediction of ablation volume as given by the manufacturer. IRE ablation volume and shape is influenced by many variables such as needle number, needle configuration, and device/pulse settings. With only 10 IRE ablations it is not within in the scope of this study to experiment with a wide variety of IRE settings. We aim to test 2 needle electrode configurations, while keeping the device settings constant. In clinical practice contrast enhanced CT scanning is most widely used modality for follow-up after renal mass treatment. In this study however it was decided not to investigate CT imaging in order to limit the cumulative radiation exposure. Study participants are already receiving an estimated 32 mSv of ionizing radiation due to the CT guided IRE procedure. Adding CT follow-up to the research protocol would result in 2–3 additional 4 phase CT scans, besides any CT scans that are necessary after the final treatment. Another limitation of this study is the follow-up period, which is limited at 4 weeks. Animal trials have shown renal IRE lesions to be partially resolved at 3–4 weeks [20-22]. Preferably radical nephrectomy would be postponed longer than 4 weeks, giving the IRE lesion more time to mature, allowing for better analysis of intermediate ablation results. However, further prolonging the final treatment is unethical at this early phase of the research. A final limitation is the tumour size. Patients who are candidate for radical nephrectomy, except for patients with ERDS, will have tumours larger than 4 cm. Ablative therapies are indicated for tumours ≤ 4 cm, which means that we not testing renal IRE in the intended population. The choice for radical nephrectomy was made out of the concern that IRE ablation might complicate a subsequent partial nephrectomy leading to impaired surgical outcome. In our opinion this trial will provide essential knowledge on IRE of renal masses, guiding future research of this promising ablative technique.