2 The procedure
2.1.1 Cutaneous and subcutaneous metastases of non-skin origin and melanoma often occur in the setting of disseminated disease and cause significant clinical problems including bleeding, pain and ulceration. The primary aim of treatment is therefore palliative and includes modalities such as regional chemotherapy, curettage, cryotherapy and radiotherapy.
2.2.1 Electrochemotherapy aims to enhance the effects of chemotherapy and can be performed as an outpatient procedure. It can be used for local control of cancers that are unsuitable for surgery and resistant to radiotherapy or chemotherapy.
2.2.2 The procedure is performed with the patient under general or local anaesthesia with or without sedation. Chemotherapy drugs are given first, either intravenously or directly into the tumour. Drug dose is individualised based on either body surface area or tumour volume. Shortly after drug administration, brief and intense electric pulses are delivered around or directly into the tumour using either surface plates or needle electrodes. This makes the cell membranes more permeable to the chemotherapy drugs so that their cytotoxic effect is increased. Different-shaped electrodes or plates are used depending on the tumour size, extent, shape and location. Treatment duration may vary depending on the number and size of tumours. Larger tumours may need several applications to cover the entire surface. Repeated treatments can be performed if necessary (within the lifetime dose limits of the chemotherapy drugs).
Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overviews on electrochemotherapy for metastases in the skin (of non-skin origin) and electrochemotherapy for melanoma metastases in the skin.
2.3.1 A randomised controlled trial of 19 patients with melanoma metastases comparing intratumoural electrochemotherapy (in 18 tumours) with intratumoural chemotherapy alone (in 19 tumours) reported complete response in 72% (13/18) of tumours treated with electrochemotherapy at end of follow-up ('average' of 21 months). On an intention-to-treat basis, objective response for electrochemotherapy was significantly greater than for chemotherapy alone (64% versus 29%, p=0.02).
2.3.2 A non-randomised comparative study of 61 patients that evaluated electrochemotherapy efficacy in 21 patients (73 tumours) with mixed non-melanoma metastases and 20 patients (98 tumours) with melanoma metastases reported an 85% objective tumour response and a 74% complete tumour response at a median follow-up of 133 days regardless of tumour histology, drug used (bleomycin or cisplatin) or route of drug administration (intravenous or intratumoural). Numbers were not reported.
2.3.4 A non-randomised study of 52 patients (608 tumours) including 18 patients with non-melanoma metastases of mainly breast cancer (95 tumours) and 34 patients with malignant melanoma (171 tumours) reported a significant inverse correlation between maximum tumour diameter and complete response rate: 66% for diameters less than 1.5 cm, 36% for diameters between 1.6 cm and 3 cm and 28% for diameters greater than 3 cm (p=0.0035).
2.3.5 The same study of 52 patients reported that 9% (3/34) of patients with melanoma developed recurrence in the areas treated with electrochemotherapy. One patient developed recurrence at 7 months following an initial complete response.
2.3.6 A non-randomised comparative study of 6 patients with 26 cutaneous metastases of breast cancer origin, 12 of which were treated with electrochemotherapy, reported a median duration of response of 10 weeks in 33% (4/12) of tumours that had a complete response and 5 weeks in 67% (8/12) of tumours that had a partial response at up to 26 weeks of follow-up.
2.3.7 In the randomised controlled trial of 19 patients, 26% (5/19) of patients were alive at follow-up of 37 months. The average survival of the 14 out of 19 patients (74%) who died before this follow-up was 14 months.
2.3.8 The study of 52 patients reported improvements in overall quality of life score (assessed in 36 patients) from a mean pretreatment score of 46 to mean scores of 52 and 55 at 1 and 2 months respectively (p<0.005). These were measured using a non-validated questionnaire with scores of 0 to 60, higher scores indicating better quality of life. In the study, 94% (34/36) of responding patients reported an improvement in 1 or more of the 6 parameters assessed in the questionnaire (bleeding, ulceration, aesthetics, activities of daily living, social relations and pain control).
2.3.9 The Specialist Advisers listed additional key efficacy outcomes as the number of procedures needed, control of bleeding and reduction in odour from fungating tumours.
2.4.1 Muscle spasms with myoclonus secondary to electric pulses were reported in 25% (3/12) of patients treated by electrochemotherapy in a randomised controlled trial of 12 patients. These stopped immediately after the electric pulses were discontinued.
2.4.2 An inflammatory reaction leading to superficial necrosis and an eschar occurred in all tumours treated with electrochemotherapy in the randomised controlled trial of 19 patients. These all healed completely by 16 weeks.
2.4.3 Electrode marks and superficial erosions occurred in all patients after electrochemotherapy in the case series of 14 patients. The marks healed within 1 month. A mild injection site rash of grade I–II according to common toxicity criteria was reported in 8% (4/52) of patients treated with electrochemotherapy in the study of 52 patients with metastatic cancer (34 of whom had malignant melanoma).
2.4.4 Erythema and oedema at treated areas that resolved in a 'few' days was reported in 2% (3/14) of individuals in the case series of 14 patients.
2.4.5 'Minimal scarring and depigmentation' of the treatment site as a late effect was reported in the non-randomised comparative study of 6 patients. This persisted for the duration of follow-up (up to 26 weeks). No further details were reported.
2.4.6 Other side effects attributed to the chemotherapy agent such as slight nausea, transient increase in heart rate and transient dyspnoea were also reported.
2.4.7 The Specialist Advisers listed additional key safety outcomes as increase in wound exudate after the procedure and chemotherapy toxicity, specifically pulmonary fibrosis.