Update on Electro-Chemo-Therapy in Bristol Antonio Orlando Department of Plastic Surgery Southmead Hospital – North Bristol Trust SWAG Skin SSG meeting, 17th May 2016

Electroporation of the cellular membrane: 11/10/2017 Electroporation of the cellular membrane: The application of electric pulses induces cells to form a transient pore in the cell membrane Pores formation Cell membrane before electroporation Electroporation: physical phenomenon that affects cells when applying short and high intensity electric pulses which increase the permeability of cell membrane. This permits anti-cancer drugs which are normally poorly permeant, to enter the cytosol and increase the intrinsic cytotoxicity and anti-tumoral effect. Well-defined number, amplitude and length of the pulses allows this physically reversible phenomenon of increasing in cell membrane permeability to occur in a transient fashion. Low dosage chemotherapeutic drug can enter the cell e.g. Bleomycin / Cisplatin (non/ poorly permeable anticancer drug possessing a high intrinsic cytotoxicity).

ELECTROCHEMOTHERAPY The efficacy of bleomycin in the treatment of melanoma is increased by over 100% when associated with electroporation TUMOR RESPONSE In few words: The application of electric pulses to the tumour tissue induces the formation of pores across the plasma membrane, and this phenomenon is called electroporation. The pores allow the diffusion into the cell of poorly or not permeant drugs, significantly increasing the drug intracellular concentration and thus its cytotoxicity. The efficacy of bleomycin in the treatment of melanoma is increased by over 100% when associated with electroporation compared to bleomycin alone. MEDICAL DEVICE AND CHEMOTHERAPEUTIC DRUG COMBINATION: LOCALLY ENHANCED CHEMOTHERAPY

CLINIPORATOR EPSO2, ECT, CE Mark, Class IIa Elettric field amplitude: 1000V/cm Electric field distribution: omogeneous Pulse number: 8 Pulse lenght: 100s

STANDARD OPERATING PROCEDUReS

CLINIPORATOR ELECTRODES PLATE: P-30-8B HEXAGONAL NEEDLE: N–10/20/30-HG FINGER ELECTRODE: F–05/10-LG Cliniporator is very flexible. It allows physicians to use three different kind of electrodes: plates, linear needle and hexagonal needle electrodes. Plates; blue handle The plate electrode hosting two 10x30 mm stainless steel plates with rounded corners, 6 and 8 mm apart. The electric field flows between the two plates uniformly. Linear needle electrodes; blue handle They are needle electrodes hosting 8 needles, distributed on two rows of 4 needles each, 0.7 mm thick. Rows are 4 mm apart from each other. In N-20-4B electrode needles are 20 mm long, while in N-30-4B electrode needles are 30 mm long. It is possible to use needle 18 mm long and 0.6 mm thick in order to make easier the penetration into tissues. During treatment all the electrodes of the same row are short-circuited together and a voltage difference is applied between the needle rows. Hexagonal needle electrodes; green handle The N-20-HG and N-30-HG are needle electrodes hosting 7 needles. Six needles are at the vertices of a hexagon and the seventh is at its centre. In N-20-HG electrode needles are 20 mm long, while in N-30-HG electrode needles are 30 mm long. It is possible to use needle 18 mm long and 0.6 mm thick in order to make easier the penetration into tissues. During treatment, pulsed voltage differences are applied between couples of adjacent needles, reversing voltage polarity as well. LINEAR NEEDLE: N-10/20/30-HG FINGER ELECTRODE: F–05/10-OR Handles

Adjustable leght exagonal electrode

Indications ECT is an effective treatment of neoplastic lesions located in the skin or subcutaneous tissue, both primary and metastatic, regardless of the histological type of the neoplasm or previous treatments. It can be used as an adjunct to normal treatment options or as an additional option for patients unresponsive or unfit for normal treatment regimes

Indications melanoma basal cell carcinoma squamous cell carcinoma kaposi sarcoma local recurrences or cutaneous metastases from breast cancer, head and neck cancers

Intra-tumoral administration: BLM and CDDP 11/10/2017 STANDARD OPERATING PROCEDURES: DRUG ADMINISTRATION Intra-tumoral administration: BLM and CDDP Volume ab2/6 V < 0.5 cm3 0.5 cm3 < V < 1 cm3 V > 1 cm3 BLM 1000IU/ml 1ml/cm3 (> 0,1ml) 0.5ml/cm3 0,25 ml/cm3 CDDP 2mg/ml 1ml (2 mg)/cm3 0.5ml (1 mg)/cm3 0,25 ml (0.5mg)/cm3 Intravenous administration: Bleomycin Standard dose 15.000 IU/m2 in bolus; Electric pulses delivered after 8 minutes of the drug administration to allow optimized diffusion; Window timing for electric pulses: 30-40 minutes.

ECT centres in Europe Country Centres Italy 28 Germany 12 Austria 1 Portugal Spain 3 Sweden Greece 5 Great Britain 7 (6*) Hungary Poland The Netherlands Lithuania ESOPE 4 Research Total 80 4 7 12 28 3 5 * A further 6 UK Trusts have applied for new CLINIPORATOR set up

ECT in North Bristol Trust Total of 70 ECT procedures on 52 patients January 2012 – May 2016 (see bar chart) Most commonly used for melanoma (pie chart), but also successfully used for breast cancer, SCC, BCC (including 2 Gorlin’s cases), Merkel cell, angiosarcoma and T-cell lymphoma

ECT – Southmead experience 52 patients: 30 females, 22 males Age range: 29-98yrs Mean age: 73.7yrs Median age: 77.5yrs

Diagnosis

Annual Breakdown

ECT Pathway - Referral to the SSMDT - Consultation with plastic surgeon - Lung function test/pre op assessment for GA - Oncology referral - Day case GA - Follow up 6/weeks - Re-treat not before 8-12 weeks

ECT +Lesional Excision % ECT cases Yes 56% No 44%

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