Electrochemotherapy treatment of multiple Basal Cell Carcinomas in a patient with Gorlin syndrome Dr Beth Emily Wright, ST4 Dermatology on behalf of Dr Adam Bray Mr Antonio Orlando & Dr Chris Herbert

Electrochemotherapy – how it works https://vimeopro.com/vismedia/pelham-bell-pottinger-video-examples/video/51431187 So how does electrochemotherapy work? Electrochemotherapy combines the use of pulses of electricity (electropulsation) via needle array electrodes, with chemotherapy As demonstrated by our intraoperative photographs, - The first stage involves administering the cytotoxic drug to the patient. This can be done directly in to the tumour as in our case, or it can be given intraveneously. Both cisplatin & bleomycin have been used for this process. Studies in mice & rats have demonstrated that bleomycin is an effective antitumor agent when used for electrocheotherapy in a variety of tumor types, including melanoma, hepatocellular carcinoma, lung carcinoma, breast carcinoma, fibrosarcoma, and glio- ma. - An electroporator device is then used, to apply pulses of electricity into the tumour. This transiently increases the cell membrane permeability and increases the itra cellular access to cytotoxic drugs by up to 100 fold. This called electroporation - The cytotoxic drug then has direct access to cytosol and causes mitotic catastrophe through DNA damage within the tumour cells. Without electroporation these chemotherapeutic agents don’t effectively permeate tumour cells. NB IF intravenously (and electrical pulses delivered to tumour 8-28 minutes after IV administration during during it’s pharmacokinetic peak)

Electrochemotherapy – the evidence Author Number of patients treated Intra venous (IV) OR Intra tumour (IT) Tumour treated Complete response rate Follow up period Kis et al 2012 3 with Gorlin (99 tumours) IV bleomycin BCC (all subtypes) 87% 10-28 months Glass et al 1997 20 (54 tumours) IT bleomycin Nodular BCC 94% 14 months Heller et al 2001 34 SCC, Kaposi, BCC and Melanoma Mets 80-95% 20 months ESOPE study 2006 42 patients IV / IT bleomycin & cisplatin Any cutaneous / subcutaneous malignancy 73-88% 2-12 months (median 4) Evidence There are few studies that review the use of electrochemotherapy for primary curative therapy and there are several case reports and a small case series of the successful use of ECT in patients with Gorlin syndrome (given both intraveneously and directly in to the tumour) A selection of relevant are outlined in this table. They are all case reports or observational studies, and are difficult to compare due to differing methodology, tumour types (including primary, recurrent tumours , and different tumour sutypes of BCC and other cutaneous malignancy). They all used multiple treatments of ECT and varied in their follow up period. No randomised control trials have been performed looking at the effectiveness of electrochemotherapy for cutaneous malignancy, and no longer term outcomes have been described in the literature to date However, these clinical studies have shown the potential of ECT as an antitumor treatment for cutaneous malignancies and have demonstrated promising results, with complete response rates for basal cell carcinoma of up to 94% over a 14 month follow up period.

Discussion - Electrochemotherapy Discontiguous areas of tumour, possibly reduce effectiveness of Mohs surgery Prolonged secondary intension healing & post operative swelling Long term effects not known Treat multiple areas Repeat treatments Reduce systemic effects of cytotoxic agent if administered into tumour directly May reduce number & size of surgical excisions Minimise facial disfigurement Whilst we are concerned that electrochemotherapy might create discontiguous areas of tumour that could reduce the effectiveness of subsequent Mohs surgery, we propose that clinicians could still consider this adjunct to surgical treatment in Gorlin syndrome, as some tumours may fully respond. Possible benefits include the ability to treat multiple areas, repeat treatments. Intralesional ECT reduces the systemic effect of the cytotoxic agents. Effectively treating the BCCs, and possibly reducing the number and size of surgical excisions in order to minimise facial disfigurement were both paramount to our patient. We are grateful to our plastic surgery and oncology colleagues who have helped us with the joint management of this challenging case.

Thank you for listening We invite any questions or discussion of similar experience

References Kis, E., Baltás, E., Kinyó, Á., Varga, E., Nagy, N., Gyulai, R., Kemény, L. and Oláh, J., 2012. Successful treatment of multiple basaliomas with bleomycin-based electrochemotherapy: a case series of three patients with Gorlin-Goltz syndrome. Acta dermato-venereologica, 92(6), pp.649-652. Glass LF, Jaroszeski M, Gilbert R, Reintgen DS, Heller R. Intralesional bleomycin-mediated electrochemotherapy in 20 patients with basal cell carcinoma. J Am Acad Dermatol 1997; 37: 596–599. Heller R, Jaroszeski MJ, Reintgen DS, Puleo CA, DeConti RC, Gilbert RA, et al. Treatment of cutaneous and subcuta- neous tumors with electrochemotherapy using intralesional bleomycin. Cancer 1998; 83: 148–157. Rodriguez-Cuevas S, Barroso-Bravo S, Almanza-Estrada J, Cristobal-Martinez L, Gonzalez-Rodriguez E. Electroche- motherapy in primary and metastatic skin tumors: phase II trial using intralesional bleomycin. Arch Med Res 2001; 32: 273–276 Landström FJ, Nilsson CO, Crafoord S, Reizenstein JA, Adamsson GB, Löfgren LA. Electroporation therapy of skin cancer in the head and neck area. Dermatol Surg 2010; 36: 1245–1250 Mir, L.M., Gehl, J., Sersa, G., Collins, C.G., Garbay, J.R., Billard, V., Geertsen, P.F., Rudolf, Z., O’Sullivan, G.C. and Marty, M., 2006. Standard operating procedures of the electrochemotherapy: instructions for the use of bleomycin or cisplatin administered either systemically or locally and electric pulses delivered by the Cliniporator TM by means of invasive or non-invasive electrodes. European Journal of Cancer Supplements, 4(11), pp.14-25.