Management of cutaneous metastases using electrochemotherapy

Abstract

Background: Cutaneous metastases may cause considerable discomfort as a consequence of ulceration, oozing, bleeding and pain. Electrochemotherapy has proven to be highly effective in the treatment of cutaneous metastases. Electrochemotherapy utilises pulses of electricity to increase the permeability of the cell membrane and thereby augment the effect of chemotherapy. For the drug bleomycin, the effect is enhanced several hundred-fold, enabling once-only treatment. The primary endpoint of this study is to evaluate the efficacy of electrochemotherapy as a palliative treatment.

Methods: This phase II study is a collaboration between two centres, one in Denmark and the other in the UK. Patients with cutaneous metastases of any histology were included. Bleomycin was administered intratumourally or intravenously followed by application of electric pulses to the tumour site.

Results: Fifty-two patients were included. Complete and partial response rate was 68% and 18%, respectively, for cutaneous metastases <3 cm and 8% and 23%, respectively, for cutaneous metastases >3 cm. Treatment was well-tolerated by patients, including the elderly, and no serious adverse events were observed.

Conclusions: ECT is an efficient and safe treatment and clinicians should not hesitate to use it even in the elderly.

Figure 1

The electroporation procedure: A. Electroporation occurs when an applied external field exceeds the capacity of the cell membrane. The formation of permeable areas happens in the frame of less than a second whereas resealing happens over minutes. As the resting transmembrane potential is negative on the inside respective to the outside, the first part of the membrane that will be permeabilised is the pole facing the positive electrode. The positive electrode should be imagined in the left of the picture and the negative electrode on the right. Pulses were delivered to a cell suspended in medium containing propidium iodide and after the pulses propidium iodide is trapped within the cells [9]. B. The application of pulses to skin tumours must be preceded by local or general anaesthesia, in local anaesthesia the lidocain is injected around the metastasis. C. The cliniporator equipment allows monitoring of voltage and current during the pulse. D. A treatment situation is shown where a patient is receiving local injection of bleomycin followed by application of pulses under local anaesthesia. The application of pulses lasts only a few minutes in total.

Figure 2

Electrochemotherapy. In the right panel, bleomycin is injected at the tumour site, at a concentration of 1000 IU/ml (1 U/ml). In the middle panel the electric pulses are subsequently applied, cells are permeabilised and the drug enters. In the left panel the cells reseal after a few minutes and the extracellular drug is washed out while the internalised molecules remain trapped intracellularly.

Figure 3

Results. Top: ECT treatment of a 75-year-old woman with metastatic breast cancer. Previously the patient underwent surgery and received endocrine therapy, chemotherapy and radiotherapy. The patient was treated with one single treatment of ECT in local anaesthesia with intratumoural injection of bleomycin. A. before treatment, B. two weeks after treatment, C. four weeks after treatment. A crust formed and after four weeks showed signs of falling of. The patient was very satisfi ed with the treatment and had no side-effects. Middle: ECT treatment of an 82-year-old woman with malignant melanoma. The patient was diagnosed in 2007, since had local spread on the lower limb and metastasis to the lungs. The patient was not suited for temozolamide, immunotherapy or isolated limb perfusion. The patient was treated with ECT in general anaesthesia and intravenous injection of bleomycin. A. before treatment, B. 24 days after treatment and C. three months after treatment. After three months the metastasis is in partial response. Bottom: ECT treatment of a 38-year-old woman with metastatic breast cancer. Previously the patient underwent mastectomy, radiotherapy and chemotherapy. The patient was treated with one single treatment of ECT in general anaesthesia with i.v. injection of bleomycin. A. before treatment, B. 10 weeks after treatment, C. two years and two months after treatment with complete resolution despite ongoing systemic disease.