Introduction. The principle of cell electroporation (EP) (the temporary permeabilization of the cytoplasmatic membrane by means of electric fields) has been applied to the treatment of tumors with the intent of increasing the concentration of anticancer drugs (cisplatin and bleomycin) within the tumor cell and hence their cytotoxic effect. Until 2006, the year of standardization of the electrochemotherapy (ECT) procedure, clinical experience was limited to small heterogeneous series, mainly focused on local activity data in patients with superficial metastases.
Aims. The aim of this project was to investigate the efficacy of ECT in homogeneous populations of cancer patients of different histotypes (patients with skin metastases from malignant melanoma, recurrent breast cancer on the chest wall, recurrent soft tissue sarcomas and tumors of the head and neck area). Furthermore, it was investigated the feasibility and efficacy of a new device (electric pulse generator and dedicated needle electrodes), capable of applying homogeneous electric fields also to deep tumors. Finally, we investigated, both at clinical and preclinical level, the possibility of improving the effectiveness of ECT by, respectively, the evaluation of some immune effect of treatment (i.e., the induction of the Toll-like receptors, TLRs) and the evaluation of the tumor sensitizing action to ECT of buthionine sulfoximine (BSO), an inhibitor of glutathione biosynthesis.
Methods. Overall, four prospective, phase-II, clinical trials were designed, three of them have been concluded and a fourth is still ongoing and patientsâ enrollment is open. Moreover, a retrospective study was performed on head and neck cancer patients. In some patients, tissue samples were analyzed before and after ECT, to evaluate the expression of TLRs. Finally, some in vitro tests were conducted on tumor cell lines to assess the sensitizing effect of BSO pre-treatment to BLM + EP administration.
Results. All the histotypes showed high local response rates and ECT activity was more pronounced than standard chemotherapy regimens employed in current oncology practice. Local response translated in an appreciable local control of the treated tumors, while toxicity was limited and mainly local.
TLRs levels in post-ECT tumor biopsies was not significantly different, compared with pre-ECT samples. However, the immune reaction seems to play a role since a high lymphocytic infiltrate into the electroporated lesions was associated with higher response rates. In vitro tests, BSO pretreatment enhanced the cytotoxicity of BLM + EP. Of note, we also found an increased toxicity of melphalan, a drug currently used in the treatment of locoregional melanoma, in association with EPs. Thanks to the multi-disciplinary collaboration and clinical case management, we have individuated some technical aspects that deserve further improvement in order to increase the effectiveness of treatment application and the number of patients who can benefit from it.
Conclusions. ECT has proved a highly active treatment in recurrent melanoma, breast cancer, soft tissue sarcomas and cancers of the head and neck region. The preliminary clinical experience with a new device and dedicated electrodes indicates the feasibility to treat percutaneously even large, deep-seated tumors. Although ECT treatment do not seem to raise the levels of TLRs in the electroporated tumors, however the levels of lymphocytic infiltration were associated with better local response. In vitro, BSO pre-treatment is able to sensitize tumor cells to the combined treatment of BLM and EP.
Electroporation deserves further investigation also in combination with melphalan, which is currently used in locoregional chemotherapy of in transit metastases from melanoma.
In conclusion, ECT has the potential to be implemented in the oncology field through the multidisciplinary collaboration of oncologists, surgeons, radiation oncologists, biologists and engineers
