Evaluation of Calcium Electroporation for the Treatment of Cutaneous Metastases: A Double Blinded Randomised Controlled Phase II Trial

Dóra Ágoston, Eszter Baltás, Henriette Ócsai, Sándor Rátkai, Péter Gy Lázár, Irma Korom, Erika Varga, István Balázs Németh, Éva Dósa-Rácz Viharosné, Julie Gehl, Judit Oláh, Lajos Kemény, Erika Gabriella Kis, Dóra Ágoston, Eszter Baltás, Henriette Ócsai, Sándor Rátkai, Péter Gy Lázár, Irma Korom, Erika Varga, István Balázs Németh, Éva Dósa-Rácz Viharosné, Julie Gehl, Judit Oláh, Lajos Kemény, Erika Gabriella Kis

Abstract

Calcium electroporation (Ca-EP) is a new anticancer treatment providing similar features to electrochemotherapy (ECT). The aim of our study is to compare the efficacy of Ca-EP with bleomycin-based ECT. This double-blinded randomized controlled phase II study was conducted at the Medical University of Szeged, Hungary. During this once only treatment up to ten measurable cutaneous metastases per patient were separately block randomized for intratumoral delivery of either calcium or bleomycin, which was followed by reversible electroporation. Tumour response was evaluated clinically and histologically six months after treatment. (ClinicalTrials.gov: NCT03628417, closed). Seven patients with 44 metastases (34 from malignant melanoma, 10 from breast cancer) were included in the study. Eleven metastases were taken for biopsies, and 33 metastases were randomised and treated once. The objective response rates were 33% (6/18) for Ca-EP and 53% (8/15) for bleomycin-based ECT, with 22% (4/18) and 40% (6/15) complete response rates, respectively. The CR was confirmed histologically in both arms. Serious adverse events were not registered. Ulceration and hyperpigmentation, both CTCA criteria grade I side effects, were observed more frequently after bleomycin-based ECT than for Ca-EP. Ca-EP was non-inferior to ECT, therefore, it should be considered as a feasible, effective and safe treatment option.

Keywords: biopsy; bleomycin-based electrochemotherapy; breast cancer; calcium electroporation; cutaneous metastases; melanoma malignum; non-inferiority; randomization.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Trial profile. Illustration of trial profile. Further results are described in detail.
Figure 2
Figure 2
Histology from biopsies before and 7 days after treatment. Biopsies before and one week after treatment. (A–C) Patient nr. 5 with MM. A: Pre-treatment biopsy: Extensive tumour infiltration, mild fibrosis, moderate lymphocytic inflammation, no necrosis. The tumour cells show diffuse MelanA positivity. (B) Day 7. Post-treatment with Ca-EP: Partly ulcerated skin, moderate tumour infiltration and fibrosis, mild inflammation, no necrosis. Only scattered MelanA positive tumour cells. (C) Day 7. Post treatment with bleomycin-based ECT: Partly fragmented, ulcerated skin with pseudoepitheliomatous hyperplasia of the epidermis, moderate fibrosis and inflammation, no necrosis. Focal MM nests with MelanA positivity. (D–F) Patient nr. 2 with breast cancer. (D) Pre-treatment biopsy: Extensive breast cancer infiltration without fibrosis, inflammation and necrosis. The tumour cells are CKAE1/AE3 positive. (E) Day 7. Post-treatment with Ca-EP: Focal tumour infiltration, very mild inflammation no fibrosis or necrosis. (F) Day 7. Post treatment with bleomycin-based ECT: Dispersed tumour cells with CKAE1/AE3 positivity, mild inflammation, no fibrosis or necrosis. MM: malignant melanoma, CK: cytokeratin. Histological photos: digital scanning with magnification approximately 5–20×.
Figure 3
Figure 3
Change in tumour size over time. Metastases were treated at day = 0 with either i.t. calcium and or i.t. bleomycin in a randomized double-blinded study design. Patients received only one treatment and response was evaluated 6 months after treatment, after the randomization code was revealed. Change in size over time; the graph illustrates the percent change in tumour size recorded 6 months after treatment. The two non-measurable metastases treated with calcium-chloride and bleomycin were irradiated, and are not included in the graph, but were included in the response analysis as PD.
Figure 4
Figure 4
Histologically confirmed complete remission 6 months after Ca-EP. Tumour cells were not identified 6 months after Ca-EP neither in malignant melanoma (A) nor in breast cancer metastases (B). A: patient no 3, Ca-EP treated clinically CR melanoma malignum cutaneous metastasis. B: patient no 2, Ca-EP treated clinically CR breast cancer cutaneous metastasis. Histological photos: digital scanning with low magnification.
Figure 5
Figure 5
Clinical response. Clinical response after Ca-EP; clinical response after bleomycin-based ECT. The lesions are from patient no.2 with cutaneous metastases from breast cancer in the same region (trunk). Lesion no. 2: Ca-EP treated cutaneous metastasis. Lesion no. 5: bleomycin-based ECT treated cutaneous metastasis. (A,E) Before treatment. (B,F) Two weeks after treatment; typical crust appearance. (C,G) Two months after treatment; clear hyperpigmentation in the areas treated with calcium and bleomycin. (D,H) Six months after treatment; complete disappearance of metastases.

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