Towards treatment planning and treatment of deep-seated solid tumors by electrochemotherapy

Abstract

Background: Electrochemotherapy treats tumors by combining specific chemotherapeutic drugs with an intracellular target and electric pulses, which increases drug uptake into the tumor cells. Electrochemotherapy has been successfully used for treatment of easily accessible superficial tumor nodules. In this paper, we present the first case of deep-seated tumor electrochemotherapy based on numerical treatment planning.

Methods: The aim of our study was to treat a melanoma metastasis in the thigh of a patient. Treatment planning for electrode positioning and electrical pulse parameters was performed for two different electrode configurations: one with four and another with five long needle electrodes. During the procedure, the four electrode treatment plan was adopted and the patient was treated accordingly by electrochemotherapy with bleomycin. The response to treatment was clinically and radiographically evaluated. Due to a partial response of the treated tumor, the metastasis was surgically removed after 2 months and pathological analysis was performed.

Results: A partial response of the tumor to electrochemotherapy was obtained. Histologically, the metastasis showed partial necrosis due to electrochemotherapy, estimated to represent 40-50% of the tumor. Based on the data obtained, we re-evaluated the electrical treatment parameters in order to correlate the treatment plan with the clinical response. Electrode positions in the numerical model were updated according to the actual positions during treatment. We compared the maximum value of the measured electric current with the current predicted by the model and good agreement was obtained. Finally, tumor coverage with an electric field above the reversible threshold was recalculated and determined to be approximately 94%. Therefore, according to the calculations, a small volume of tumor cells remained viable after electrochemotherapy, and these were sufficient for tumor regrowth.

Conclusions: In this, the first reported clinical case, deep-seated melanoma metastasis in the thigh of the patient was treated by electrochemotherapy, according to a treatment plan obtained by numerical modeling and optimization. Although only a partial response was obtained, the presented work demonstrates that treatment of deep-seated tumor nodules by electrochemotherapy is feasible and sets the ground for numerical treatment planning-based electrochemotherapy.

Trial registration: EudraCT:2008-008290-54.

Figure 1

Size of the melanoma metastasis determined by ultrasound. The figure shows the tumor size shortly before the treatment, at the time of the treatment itself and during the follow-up. Regrowth of the tumor was observed at day 31 and the tumor was excised at day 52.

Figure 2

Anatomical model consisting of adipose tissue (pink), muscle tissue (blue), melanoma metastasis (green) and inserted electrodes. Note that only the closest two muscles were considered in the model, as the other muscle groups lying further away would not contribute to the model accuracy and would only increase the computational cost.

Figure 3

Electrode positions according to the treatment plan. Electrode positions for four (dashed line circles) and five (solid line circles) electrodes are shown. The presented tumor cross-section is a parallel projection of the tumor on a plane parallel to the skin surface. Note that electrode 2 is in the same location in both treatment plans.

Figure 4

Actual positioning of the electrodes relative to the treatment plan. Electrode positions according to the treatment plan (dashed line circles) and actual electrode positions during treatment as determined by ultrasonography and photo documentation (solid line circles). The presented tumor cross-section is a parallel projection of the tumor on a plane parallel to the skin surface.

Figure 5

Combinations of electric pulse delivery between the electrodes as well as voltages between each pair.

Figure 6

Cross-section of the excised melanoma metastasis (in toto).

Figure 7

Histology of melanoma metastasis treated by electrochemotherapy. The tumor (A) shows partial necrosis (short arrows). In the surrounding tissue (B), fat necrosis (long arrow) and obliterated blood vessels (double arrow) are visible (H&E, original magnification 20×).

Figure 8

Prediction of tumor permeabilization. The figure shows the numerical prediction of tumor permeabilization after application of all electric pulses in a plane parallel to the skin surface, passing through the centre of the tumor. The green color represents unpermeabilized tumor tissue, while shades of brown represent tissue permeabilized by one or more pulse sequences (from a lighter to a darker shade). The cross-section is made through the centre of mass of the tumor. At this location, the tumor has the largest cross-section area and therefore coverage is less than 94%.