The Safety and Efficacy of Nanosecond Pulsed Electric Field in Patients With Hepatocellular Carcinoma: A Prospective Phase 1 Clinical Study Protocol

Min Xu, Danxia Xu, Gang Dong, Zhigang Ren, Wu Zhang, Tuerganaili Aji, Qiyu Zhao, Xinhua Chen, Tian'an Jiang, Min Xu, Danxia Xu, Gang Dong, Zhigang Ren, Wu Zhang, Tuerganaili Aji, Qiyu Zhao, Xinhua Chen, Tian'an Jiang

Abstract

Background: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy. Irreversible electroporation (IRE) is an ablative modality that uses high-voltage electrical pulses to permeabilize the cell membrane leading to cell necrosis. Unlike traditional thermal ablation, IRE is hardly affected by the "heat-sink" effect and can prevent damage of the adjacent vital structures. Nanosecond pulsed electric field (nsPEF) is a new IRE technique using ultra-short pulses (nanosecond duration), can not only penetrate the cell membranes, but also act on the organelles. Sufficient preclinical researches have shown that nsPEF can eliminate HCC without damaging vital organs, and elicit potent anti-tumor immune response.

Objective: This is the first clinical study to evaluate feasibility, efficacy, and safety of nsPEF for the treatment of HCC, where thermal ablation is unsuitable due to proximity to critical structures.

Methods and analysis: We will conduct an open-labeled, single-arm, prospective, multicenter, and objective performance criteria trial. One hundred and ninety-two patients with HCC, in which the tumor is located immediately (<0.5 cm) adjacent to the portal vein, hepatic veins, bile duct, gastrointestinal tract, or diaphragm, will be enrolled among 4 academic medical centers. The primary outcomes are the rate of complete ablation at 1 month and adverse events. Secondary outcomes include technical success, technique efficacy, nsPEF procedural characteristics, local tumor progression, and local progression-free survival.

Ethics and dissemination: The trial will be conducted according to the ethical principles of the Declaration of Helsinki and has been approved by the ethics committee of all participating centers. The results of this study will be published in peer-reviewed scientific journals and presented at relevant academic conferences.

Conclusions: This study is the Phase 1 clinical trial to evaluate the efficacy and safety of nsPEF in patients with HCC at high-risk locations where thermal ablation is contra-indicated. The results may expand the options and offer an alternative therapy for HCC.

Clinical trial registration: ClinicalTrials.gov, identifier NCT04309747.

Keywords: ablation; hepatocellular carcinoma (HCC); irreversible electroporation (IRE); nanosecond pulsed electric field (nsPEF); protocol.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Xu, Xu, Dong, Ren, Zhang, Aji, Zhao, Chen and Jiang.

Figures

Figure 1
Figure 1
The mechanisms of high-voltage electric pulses with microsecond or nanosecond duration.
Figure 2
Figure 2
Flow chart of study. *Contrast-enhanced MRI will be performed 1 month after the procedures to evaluate technique efficacy. In the event of incomplete ablation, an additional nsPEF procedure will be conducted with the same technique. If the residual tumor is still viable after the second session, then nsPEF is considered failed, and the patient will be excluded from the trial and referred to other therapies. HCC, hepatocellular carcinoma; nsPEF, nanosecond pulsed electric field; MRI, magnetic resonance imaging.
Figure 3
Figure 3
Nanosecond pulsed electric field equipment (Hangzhou Ruidi Biotech Ltd, Hangzhou, Zhejiang, China) (A) console. (B) displayer. (C, D) 19G monopolar needle electrodes.
Figure 4
Figure 4
The nsPEF procedure strategy. Depending on the individual tumor size and shape, 2 to 6 19-gauge unipolar electrodes with an appropriate active tip length of 1.0 to 2.0 cm will be placed 1.0 to 2.5 cm apart using ultrasound guidance. The nsPEF will be conducted with 800 pulses of 300ns duration, and an electric field of 15 to 30 kV. nsPEF, nanosecond pulsed electric field.
Figure 5
Figure 5
Ultrasound-guided nsPEF procedure for HCC adjacent to gallbladder. (A) Pre-ablation contrast-enhanced MRI revealed a hepatocellular carcinoma adjacent to gallbladder. (B) Ultrasound showed a hypoecho tumor located in close contact with gallbladder and right portal branch (arrow). (C) Ultrasound-guided nsPEF with a two-electrode configuration, and the head and tail end of the active tip of the electrodes can have punctuated enhancements (arrow). (D) The contrast-enhanced ultrasound image revealed no enhancement after ablation. (arrow).

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