Simple SummaryElectroporation is a method of treatment in which electrical pulses are generated and applied to a cell, resulting in temporary (reversible electroporation, RE) or permanent (irreversible electroporation, IRE) changes to the structure of the cell, depending on the pulse parameters applied. There has been increasing interest in manipulating the pulse parameters used to deliver successful electroporation for cutaneous malignancies in order to reduce muscle contractions and pain associated with traditional low-frequency electrochemotherapy (LF-ECT), which often requires general anaesthesia. Higher-frequency electroporation with biphasic waves successfully permeabilises the cell membrane, usually without causing these side effects, thus allowing treatment to be delivered under local anaesthetic. This permits a wide range of patients to be safely treated, including those for which general anaesthetic is a contra-indication. This article aims to demonstrate the safety and efficacy of high-frequency electroporation, as well as equivalence and good tolerability in comparison to traditional electrochemotherapy.AbstractHigh-frequency electroporation (HF-EP) with chemotherapy is a novel therapy proposed for both curative and palliative treatment of cutaneous malignancies. The use of high-frequency biphasic pulses is thought to reduce the painful muscle contractions associated with traditional electrochemotherapy (ECT), allowing treatment administration under local anaesthesia. This proof-of-concept study investigated the efficacy and tolerability of HF-EP protocols on a variety of cutaneous malignancies. A total of 97 lesions of five different histological subtypes were treated across 25 patients. At 12 weeks post-treatment, a 91.3% overall lesion response rate was observed (complete response: 79%; partial response: 12.3%), with excellent intraprocedural patient tolerability under local anaesthetic. HF-EP with chemotherapy shows promising results regarding tumour response rates for cutaneous malignancies of varying histological subtypes when compared to traditional ECT protocols. Improved patient tolerability is important, increasing the possibility of treatment delivery under local anaesthesia and potentially broadening the treatment envelope for patients with cutaneous malignancies.