Electrochemotherapy: technological advancements for efficient electroporation-based treatment of internal tumors

Abstract

Electrochemotherapy, a combination of high voltage electric pulses and of an anticancer drug, has been demonstrated to be highly effective in treatment of cutaneous and subcutaneous tumors. Unique properties of electrochemotherapy (e.g., high specificity for targeting cancer cells, high degree of localization of treatment effect, capacity for preserving the innate immune response and the structure of the extracellular matrix) are facilitating its wide spread in the clinics. Due to high effectiveness of electrochemotherapy in treatment of cutaneous and subcutaneous tumors regardless of histological origin, there are now attempts to extend its use to treatment of internal tumors. To advance the applicability of electrochemotherapy to treatment of internal solid tumors, new technological developments are needed that will enable treatment of these tumors in daily clinical practice. New electrodes through which electric pulses are delivered to target tissue need to be designed with the aim to access target tissue anywhere in the body. To increase the probability of complete tumor eradication, the electrodes have to be accurately positioned, first to provide an adequate extent of electroporation of all tumor cells and second not to damage critical healthy tissue or organs in its vicinity. This can be achieved by image guided insertion of electrodes that will enable accurate positioning of the electrodes in combination with patient-specific numerical treatment planning or using a predefined geometry of electrodes. In order to be able to use electrochemotherapy safely for treatment of internal tumors located in relative proximity of the heart (e.g., in case of liver metastases), the treatment must be performed without interfering with the heart's electrical activity. We describe recent technological advances, which allow treatment of liver and bone metastases, soft tissue sarcomas, brain tumors, and colorectal and esophageal tumors. The first clinical experiences in these novel application areas of electrochemotherapy are also described.

Fig. 1

Basic concept of electrochemotherapy: a after injection drug surrounds the cells; b formation of pores after pulse delivery, drug enters the cells; c membrane resealing, drug entrapped inside the cells; d drug kills the cells

Fig. 2

Electrodes with trocar tip for direct insertion by drilling into the bone or bone metastasis. The tip is bare allowing electrical contact whereas the rest of the electrode is insulated. The holder provides parallelism of electrodes and facilitates insertion of electrodes at predefined distances to each other

Fig. 3

Image of an EndoVE prototype (left) that is then attached to the endoscope head: 1 the electrodes, 2 holder for attachment to the head of an endoscope, 3 cable connection. Middle and right view through the endoscope head of esophageal tissue being drawn into the device chamber. On the right the tissue under pressure has entered the electrode chamber and is being injected with a drug via the endoscope biopsy port. The two electrodes are placed in parallel on the walls inside the chamber. Electric pulses are delivered to the tissue captured between the two electrodes

Fig. 4

Electrodes inserted into brain through a drilled hole

Fig. 5

Specific patient treatment plan is prepared based on medical images. The plan is prepared using numerical modeling and provides number of electrodes, their placement with respect to the tumor tissue, and amplitudes of pulses to be delivered and between which electrodes. It serves the surgeon to insert the electrodes into and around target tissue

Fig. 6

Breast metastatic carcinoma of the proximal femur at presentation (a) and reduction of the metastasis 5 weeks after electrochemotherapy (b). Red line a guide to the eye (colour figure online)

Fig. 7

Soft tissue sarcomas, representative model of the electrochemotherapy treatment of a deep soft tissue tumor by means of a plastic stabilization holder (a) that is fixed on the patient’s skin surface and has several holes through which long needle electrodes (b, c) can be inserted percutaneously and thus held parallel. The electrodes consist from insolated (b) and active (c) part. Their arrangement (i.e., distance in between, asterisk) depends on the choice of the operator, based on the data of the pre-treatment planning (colour figure online)