Interventional procedure consultation document

Electrochemotherapy for metastases in the skin (of non-skin origin and melanoma)

Treating metastases in the skin (of non-skin origin and melanoma) using pulses of electricity together with chemotherapy

Cancer that starts in one part of the body can spread (metastasise) and form tumours on or below the skin elsewhere in the body, especially when the cancer is severe and widespread. These skin tumours can cause problems such as bleeding, pain or ulceration.

In electrochemotherapy an anticancer drug is given by injection either into a vein or directly into a tumour. Short, powerful pulses of electricity are then applied to the tumour. The electrical energy opens the membranes (outer coverings) of the tumour cells, allowing the anticancer drug to pass through into the cells and have a more damaging effect.

The National Institute for Health and Clinical Excellence (NICE) is examining electrochemotherapy for metastases in the skin (of non-skin origin and melanoma) and will publish guidance on its safety and efficacy to the NHS in England, Wales, Scotland and Northern Ireland. NICE’s Interventional Procedures Advisory Committee has considered the available evidence and the views of Specialist Advisers, who are consultants with knowledge of the procedure. The Advisory Committee has made provisional recommendations about electrochemotherapy for metastases in the skin (of non skin-origin and melanoma).

This document summarises the procedure and sets out the provisional recommendations made by the Advisory Committee. It has been prepared for public consultation. The Advisory Committee particularly welcomes:

• comments on the provisional recommendations
• the identification of factual inaccuracies
• additional relevant evidence, with bibliographic references where possible.

Note that this document is not NICE’s formal guidance on this procedure. The recommendations are provisional and may change after consultation.

The process that NICE will follow after the consultation period ends is as follows.

• The Advisory Committee will meet again to consider the original evidence and its provisional recommendations in the light of the comments received during consultation.
• The Advisory Committee will then prepare draft guidance which will be the basis for NICE’s guidance on the use of the procedure in the NHS in England, Wales, Scotland and Northern Ireland.

For further details, see the Interventional Procedures Programme manual, which is available from the NICE website (www.nice.org.uk/ipprogrammemanual).

Through its guidance NICE is committed to promoting race and disability equality, equality between men and women, and to eliminating all forms of discrimination. One of the ways we do this is by trying to involve as wide a range of people and interest groups as possible in the development of our interventional procedures guidance. In particular, we aim to encourage people and organisations from groups who might not normally comment on our guidance to do so.

In order to help us promote equality through our guidance, we should be grateful if you would consider the following question:

Are there any issues that require special attention in light of NICE’s duties to have due regard to the need to eliminate unlawful discrimination and promote equality and foster good relations between people with a characteristic protected by the equalities legislation and others?

Please note that NICE reserves the right to summarise and edit comments received during consultations or not to publish them at all where in the reasonable opinion of NICE, the comments are voluminous, publication would be unlawful or publication would otherwise be inappropriate.

Closing date for comments: 20 November

Target date for publication of guidance: February 2013

1   Provisional recommendations

1.1   There is sufficient evidence of efficacy of electrochemotherapy for treating metastases in the skin (of non-skin origin and melanoma) to support its use as a palliative treatment. There are no major safety concerns. Therefore, the procedure can be used with normal arrangements for clinical governance, consent and audit.

1.2   Patient selection should be carried out by a specialist skin multidisciplinary team experienced in managing the condition and including an oncologist.

1.3   This procedure should only be carried out by a clinician with specific training in the technique.

1.4   Clinicians should collect data on all patients undergoing electrochemotherapy (including details of case selection, methods of follow-up and outcomes) for submission to the InspECT registry and review clinical outcomes locally.

2   The procedure

2.1   Indications and current treatments

2.1.1   Cutaneous and subcutaneous metastases from primary cancers (including 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 chemotherapy, curettage, cryotherapy and radiotherapy.

2.2   Outline of the procedure

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 intratumourally. 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).

2.2.3   The European Standard Operating Procedures for Electrochemotherapy (ESOPE) provides a set of guidelines for this procedure.

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 overview, available at www.nice.org.uk/guidance/IP/984 & 1041/overview

2.3   Efficacy

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.

2.3.3   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).

2.3.4   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.

2.3.5   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 follow-up.

2.3.6   A case series of 14 patients with 233 malignant melanoma metastases reported that local tumour control was 75% 2 years after treatment. The median time to treatment failure was 18 months.

2.3.7   In the 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). This was 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 in the questionnaire assessed before and after treatment (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 optimal number of procedures to perform, control of bleeding and reduction in odour from fungating tumours.

2.4   Safety

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   A transient increase in heart rate and blood pressure during treatment was reported in 1 patient in a case series of 7 patients. This returned to normal ‘in a few seconds’.

2.4.3   Transient dyspnoea 5 days after electrochemotherapy treatment was reported in 1 patient in the case series of 7 patients. This was attributed to the chemotherapy drug. No further details were reported.

2.4.4   Slight nausea for up to 48 hours thought to be associated with the chemotherapeutic drug was reported in 6% (2/34) of patients in a non-randomised comparative study of 34 patients (no further details reported).

2.4.5   Muscle fatigue in treated limbs after electrochemotherapy, lasting for 24 hours, was reported by a ‘few’ patients in the same study of 34 patients (no further details reported).

2.4.6   Electrode marks and superficial erosions occurred in all patients after electrochemotherapy in the case series of 14 patients. The marks healed within 1 month.

2.4.7   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).

2.4.8   Erythema and oedema at treated areas which resolved in a ‘few’ days was reported in 2% (3/14) of individuals in the case series of 14 patients.

2.4.9   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.

2.4.10   ‘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.

2.4.11   The Specialist Advisers listed additional key safety outcomes as increase in wound exudate after the procedure and chemotherapy toxicity, specifically pulmonary fibrosis.

2.5   Other comments

2.5.1   The Committee noted that this procedure might provide palliation and improved of quality of life for patients with disease unsuitable for, or resistant to, other treatments.

2.5.2   The Committee noted that patients may experience pain and ulceration following treatment.

3   Further information

3.1   For related NICE guidance see www.nice.org.uk

Barrie White

Vice Chairman, Interventional Procedures Advisory Committee

October 2012