Electrochemotherapy: from the drawing board into medical practice

Electrochemotherapy is a local treatment of cancer employing electric pulses to improve transmembrane transfer of cytotoxic drugs. In this paper we discuss electrochemotherapy from the perspective of biomedical engineering and review the steps needed to move such a treatment from initial prototypes into clinical practice. In the paper also basic theory of electrochemotherapy and preclinical studies in vitro and in vivo are briefly reviewed. Following this we present a short review of recent clinical publications and discuss implementation of electrochemotherapy into standard of care for treatment of skin tumors, and use of electrochemotherapy for other targets such as head and neck cancer, deep-seated tumors in the liver and intestinal tract, and brain metastases. Electrodes used in these specific cases are presented with their typical voltage amplitudes used in electrochemotherapy. Finally, key points on what should be investigated in the future are presented and discussed.

[1]  L. Mir,et al.  Electrochemotherapy: variable anti-tumor effect on different tumor models , 1994 .

[2]  Mounir Tarek,et al.  Membrane electroporation: a molecular dynamics simulation. , 2005, Biophysical journal.

[3]  Julie Gehl,et al.  Direct therapeutic applications of calcium electroporation to effectively induce tumor necrosis. , 2012, Cancer research.

[4]  Damijan Miklavcic,et al.  Towards treatment planning and treatment of deep-seated solid tumors by electrochemotherapy , 2010, Biomedical engineering online.

[5]  Damijan Miklavcic,et al.  Antivascular effects of electrochemotherapy: implications in treatment of bleeding metastases , 2010, Expert review of anticancer therapy.

[6]  R. Heller,et al.  Delivery of Interleukin-15 to B16 Melanoma by Electroporation Leads to Tumor Regression and Long-term Survival , 2014, Technology in cancer research & treatment.

[7]  Richard Heller,et al.  In vivo electroporation for gene therapy. , 2006, Human gene therapy.

[8]  Martin L. Yarmush,et al.  Nonthermal Irreversible Electroporation: Fundamentals, Applications, and Challenges , 2013, IEEE Transactions on Biomedical Engineering.

[9]  C. Arena,et al.  Advances in Therapeutic Electroporation to Mitigate Muscle Contractions , 2012 .

[10]  Aaron S Kesselheim,et al.  Regulation of medical devices in the United States and European Union. , 2012, The New England journal of medicine.

[11]  D Miklavcic,et al.  Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma , 2008, British Journal of Cancer.

[12]  J. Malvehy,et al.  Desmoplastic melanoma on the nose: electrochemotherapy as an alternative treatment to local advanced disease , 2014, Journal of the European Academy of Dermatology and Venereology : JEADV.

[13]  L. Löfgren,et al.  Electroporation Therapy of Skin Cancer in the Head and Neck Area , 2010, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[14]  M. Čemažar,et al.  Limb sparing treatment of bleeding melanoma recurrence by electrochemotherapy. , 2009, Tumori.

[15]  Damijan Miklavcic,et al.  Kinetics of transmembrane transport of small molecules into electropermeabilized cells. , 2008, Biophysical journal.

[16]  A. Testori,et al.  Local and intralesional therapy of in‐transit melanoma metastases , 2011, Journal of surgical oncology.

[17]  M. Weichenthal,et al.  Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma” , 2013, Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG.

[18]  Ozlem Birgul,et al.  In vivo MRI electrical impedance tomography (MREIT) of tumors. , 2006, Technology in cancer research & treatment.

[19]  D Miklavcic,et al.  Electrochemotherapy with cisplatin: potentiation of local cisplatin antitumour effectiveness by application of electric pulses in cancer patients. , 1998, European journal of cancer.

[20]  Saptarshi Basu,et al.  Patient access to medical devices--a comparison of U.S. and European review processes. , 2012, The New England journal of medicine.

[21]  G. Botti,et al.  Feasibility of neoadjuvant electrochemotherapy for a large metastatic lesion of the cheek in a patient with melanoma , 2012 .

[22]  Damijan Miklavcic,et al.  Tumor size and effectiveness of electrochemotherapy , 2013, Radiology and oncology.

[23]  D Miklavcic,et al.  Electrochemotherapy with cisplatin: clinical experience in malignant melanoma patients. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[24]  D. Miklavčič,et al.  Electrochemotherapy with bleomycin. The first clinical experience in malignant melanoma patients , 1995 .

[25]  M Cemazar,et al.  Improvement of combined modality therapy with cisplatin and radiation using electroporation of tumors. , 2000, International journal of radiation oncology, biology, physics.

[26]  Damijan Miklavčič,et al.  Advantages and Disadvantages of Different Concepts of Electroporation Pulse Generation , 2011 .

[27]  D. Miklavcic,et al.  Effective treatment of cutaneous and subcutaneous malignant tumours by electrochemotherapy. , 1998, British Journal of Cancer.

[28]  M. Jaroszeski,et al.  Treatment of B16 mouse melanoma with the combination of electropermeabilization and chemotherapy. Bioelectrochem , 1995 .

[29]  D. Miklavčič,et al.  Cell membrane electroporation- Part 1: The phenomenon , 2012, IEEE Electrical Insulation Magazine.

[30]  D. Winter,et al.  P80. Endoscopically targeted electrochemotherapy for the treatment of colorectal cancer , 2012 .

[31]  L. Prosen,et al.  Potentiation of electrochemotherapy by intramuscular IL-12 gene electrotransfer in murine sarcoma and carcinoma with different immunogenicity , 2012, Radiology and oncology.

[32]  M. Čemažar,et al.  Successful sphincter-saving treatment of anorectal malignant melanoma with electrochemotherapy, local excision and adjuvant brachytherapy. , 2005, Anti-cancer drugs.

[33]  Gregor Sersa,et al.  The state-of-the-art of electrochemotherapy before the ESOPE study; advantages and clinical uses , 2006 .

[34]  E. Neumann,et al.  Gene transfer into mouse lyoma cells by electroporation in high electric fields. , 1982, The EMBO journal.

[35]  D Miklavcic,et al.  Electrochemotherapy with cisplatin: the systemic antitumour effectiveness of cisplatin can be potentiated locally by the application of electric pulses in the treatment of malignant melanoma skin metastases , 2000, Melanoma research.

[36]  M J Jaroszeski,et al.  Toxicity of anticancer agents mediated by electroporation in vitro , 2000, Anti-cancer drugs.

[37]  G. Botti,et al.  Use of neoadjuvant electrochemotherapy to treat a large metastatic lesion of the cheek in a patient with melanoma , 2012, Journal of Translational Medicine.

[38]  Antonella Vecchiato,et al.  Bleomycin-Based Electrochemotherapy: Clinical Outcome from a Single Institution’s Experience with 52 Patients , 2008, Annals of Surgical Oncology.

[39]  Teissié,et al.  Electropermeabilization of cell membranes. , 1999, Advanced drug delivery reviews.

[40]  J. Gehl,et al.  Electroporation enhances mitomycin C cytotoxicity on T24 bladder cancer cell line: a potential improvement of intravesical chemotherapy in bladder cancer. , 2012, Bioelectrochemistry.

[41]  K. Schoenbach,et al.  Simulations of transient membrane behavior in cells subjected to a high-intensity ultrashort electric pulse. , 2005, Physical review. E, Statistical, nonlinear, and soft matter physics.

[42]  M. Rols,et al.  Electrochemotherapy: progress and prospects. , 2012, Current pharmaceutical design.

[43]  Osamu Yamaguchi,et al.  Potentiation of effects of anticancer agents by local electric pulses in murine bladder cancer , 2000, Urological Research.

[44]  M. Tangney,et al.  Successful application of targeted electrochemotherapy using novel flexible electrodes and low dose bleomycin to solid tumours. , 2006, Cancer letters.

[45]  C. Cabula Neoadjuvant electrochemotherapy of breast cancer: our experience on first case treated in Italy , 2013, Updates in Surgery.

[46]  D Miklavcic,et al.  Antitumor effectiveness of electrochemotherapy: a systematic review and meta-analysis. , 2013, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[47]  P. Capasso,et al.  Electrochemotherapy for Non-Melanoma Head and Neck Cancers: Clinical Outcomes in 25 Patients , 2012, Annals of surgery.

[48]  M. Jaroszeski,et al.  Treatment of cutaneous and subcutaneous tumors with electrochemotherapy using intralesional bleomycin , 1998, Cancer.

[49]  J. Reizenstein,et al.  Electroporation therapy for T1 and T2 oral tongue cancer , 2011, Acta oto-laryngologica.

[50]  Jens Ricke,et al.  Irreversible Electroporation of Renal Cell Carcinoma: A First-in-Man Phase I Clinical Study , 2011, CardioVascular and Interventional Radiology.

[51]  S. O'sullivan,et al.  Electrochemotherapy for the treatment of ocular basal cell carcinoma; a novel adjunct in the disease management. , 2014, Journal of plastic, reconstructive & aesthetic surgery : JPRAS.

[52]  D Miklavcic,et al.  Electrochemotherapy in veterinary oncology. , 2008, Journal of Veterinary Internal Medicine.

[53]  Boris Rubinsky,et al.  Irreversible Electroporation in Medicine , 2007, Technology in cancer research & treatment.

[54]  M Fini,et al.  Ablation of bone cells by electroporation. , 2010, The Journal of bone and joint surgery. British volume.

[55]  L. Mir,et al.  Antitumor electrochemotherapy: New advances in the clinical protocol , 1996, Cancer.

[56]  Chad R. Tracy,et al.  Irreversible electroporation (IRE): a novel method for renal tissue ablation , 2011, BJU international.

[57]  J. Gehl,et al.  Electrochemotherapy for large cutaneous recurrence of breast cancer: A phase II clinical trial , 2012, Acta oncologica.

[58]  B. Benway Irreversible Electroporation of Renal Cell Carcinoma: A First-in-Man Phase I Clinical Study: Pech M, Janitzky A, Wendler JJ, et al (Univ of Magdeburg, Germany) Cardiovasc Intervent Radiol 34:132-138, 2011§ , 2011 .

[59]  L. Mir,et al.  Transient electropermeabilization of cells in culture. Increase of the cytotoxicity of anticancer drugs. , 1988, Biochemical pharmacology.

[60]  M. Čemažar,et al.  Radiosensitising effect of electrochemotherapy with bleomycin in LPB sarcoma cells and tumors in mice , 2005, BMC Cancer.

[61]  D. Peter Tieleman,et al.  Electroporating Fields Target Oxidatively Damaged Areas in the Cell Membrane , 2009, PloS one.

[62]  Damijan Miklavčič,et al.  Planning of Electroporation-Based Treatments Using Web-Based Treatment-Planning Software , 2013, The Journal of Membrane Biology.

[63]  Damijan Miklavčič,et al.  Patient-specific treatment planning of electrochemotherapy: procedure design and possible pitfalls. , 2012, Bioelectrochemistry.

[64]  D Miklavcic,et al.  Increasing the repetition frequency of electric pulse delivery reduces unpleasant sensations that occur in electrochemotherapy. , 2007, Neoplasma.

[65]  C. Collins,et al.  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 CliniporatorTM by means of invasive or non-invasive electrodes , 2006 .

[66]  D. Miklavčič,et al.  Anti-tumor effectiveness of electrochemotherapy with bleomycin is increased by TNF-alpha on SA-1 tumors in mice. , 1997, Cancer letters.

[67]  H. Naganuma,et al.  Enhancing effect of electric stimulation on cytotoxicity of anticancer agents against rat and human glioma cells , 2000, Brain Research Bulletin.

[68]  G. Botti,et al.  Long-lasting response to electrochemotherapy in melanoma patients with cutaneous metastasis , 2013, BMC Cancer.

[69]  N. Pimpinelli,et al.  Dendritic cells recruitment in melanoma metastasis treated by electrochemotherapy , 2012, Clinical & Experimental Metastasis.

[70]  D Miklavcic,et al.  Electrochemotherapy in treatment of tumours. , 2008, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[71]  J. Teissié,et al.  Generation of reactive-oxygen species induced by electropermeabilization of Chinese hamster ovary cells and their consequence on cell viability. , 1994, European journal of biochemistry.

[72]  B. Rubinsky,et al.  Tissue Ablation with Irreversible Electroporation , 2005, Annals of Biomedical Engineering.

[73]  R. Heller Treatment of cutaneous nodules using electrochemotherapy. , 1995, The Journal of the Florida Medical Association.

[74]  S. Mocellin,et al.  Electrochemotherapy for disseminated superficial metastases from malignant melanoma , 2012, The British journal of surgery.

[75]  Damijan Miklavčič,et al.  Electrochemotherapy – An easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: Results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study , 2006 .

[76]  P. Rutkowski,et al.  Effective treatment of recurrent, advanced dermatofibrosarcoma protuberans by electrochemotherapy. , 2013, European journal of dermatology : EJD.

[77]  T. Jarm,et al.  Electrochemotherapy , 2011, Technology in cancer research & treatment.

[78]  H. Schwan Electrical properties of tissue and cell suspensions. , 1957, Advances in biological and medical physics.

[79]  A. Finazzi Agro',et al.  Role of lipid peroxidation in electroporation-induced cell permeability. , 1995, Biochemical and biophysical research communications.

[80]  Helen Kavnoudias,et al.  Irreversible Electroporation: A New Challenge in “Out of Operating Theater” Anesthesia , 2010, Anesthesia and analgesia.

[81]  D Miklavcic,et al.  Antitumor effectiveness of electrochemotherapy with cis-diamminedichloroplatinum(II) in mice. , 1995, Cancer research.

[82]  Damijan Miklavcic,et al.  Electrochemotherapy: technological advancements for efficient electroporation-based treatment of internal tumors , 2012, Medical and Biological Engineering and Computing.

[83]  Luigi Corti,et al.  The activity and safety of electrochemotherapy in persistent chest wall recurrence from breast cancer after mastectomy: a phase-II study , 2012, Breast Cancer Research and Treatment.

[84]  Damijan Miklavcic,et al.  Treatment planning of electroporation-based medical interventions: electrochemotherapy, gene electrotransfer and irreversible electroporation , 2012, Physics in medicine and biology.

[85]  M. Okino,et al.  Optimal Electric Conditions in Electrical Impulse Chemotherapy , 1992, Japanese journal of cancer research : Gann.

[86]  M. Gargiulo,et al.  Electrochemotherapy: actual considerations and clinical experience in head and neck cancers. , 2010, Annals of surgery.

[87]  L. Borgognoni,et al.  Enhancing anti-melanoma immunity by electrochemotherapy and in vivo dendritic-cell activation , 2012, Oncoimmunology.

[88]  Damijan Miklavčič,et al.  Importance of tumour coverage by sufficiently high local electric field for effective electrochemotherapy , 2006 .

[89]  Elisabetta Sieni,et al.  Electrochemotherapy Treatment of Locally Advanced and Metastatic Soft Tissue Sarcomas: Results of a Non-Comparative Phase II Study , 2014, World Journal of Surgery.

[90]  Boris Rubinsky,et al.  Irreversible electroporation near the heart: ventricular arrhythmias can be prevented with ECG synchronization. , 2011, AJR. American journal of roentgenology.

[91]  Julie Gehl,et al.  Calcium electroporation in three cell lines: a comparison of bleomycin and calcium, calcium compounds, and pulsing conditions. , 2014, Biochimica et biophysica acta.

[92]  L. Mir,et al.  Electrochemotherapy with CDDP on LPB sarcoma: comparison of the anti-tumor effectiveness in immunocompotent and immunodeficient mice , 1997 .

[93]  J Teissié,et al.  Control by ATP and ADP of voltage-induced mammalian-cell-membrane permeabilization, gene transfer and resulting expression. , 1998, European journal of biochemistry.

[94]  Richard Heller,et al.  Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[95]  Boris Rubinsky,et al.  Non Thermal Irreversible Electroporation: Novel Technology for Vascular Smooth Muscle Cells Ablation , 2009, PloS one.

[96]  Carlo Bartolozzi,et al.  Targeting Liver Lesions for Radiofrequency Ablation: An Experimental Feasibility Study Using a CT–US Fusion Imaging System , 2008, Investigative radiology.

[97]  T. Jarm,et al.  An algorithm for synchronization of in vivo electroporation with ECG , 2005, Journal of medical engineering & technology.

[98]  A. Testori,et al.  Electrochemotherapy for cutaneous and subcutaneous tumor lesions: a novel therapeutic approach , 2010, Dermatologic therapy.

[99]  S. Bagla,et al.  Percutaneous irreversible electroporation of surgically unresectable pancreatic cancer: a case report. , 2012, Journal of vascular and interventional radiology : JVIR.

[100]  M. Tangney,et al.  Electrochemotherapy: Aspects of Preclinical Development and Early Clinical Experience , 2007, Annals of surgery.

[101]  A. Eggermont,et al.  Surgical management of melanoma: an EORTC Melanoma Group survey , 2013, Ecancermedicalscience.

[102]  Lucie Delemotte,et al.  Molecular Dynamics Simulations of Lipid Membrane Electroporation , 2012, The Journal of Membrane Biology.

[103]  M J Jaroszeski,et al.  In vivo antitumor effects of electrochemotherapy in a hepatoma model. , 1997, Biochimica et biophysica acta.

[104]  Stuart K. Roberts,et al.  Irreversible Electroporation for Unresectable Hepatocellular Carcinoma: Initial Experience and Review of Safety and Outcomes , 2013, Technology in cancer research & treatment.

[105]  D Miklavcic,et al.  The importance of electric field distribution for effective in vivo electroporation of tissues. , 1998, Biophysical journal.

[106]  Faisal Mahmood,et al.  Optimizing clinical performance and geometrical robustness of a new electrode device for intracranial tumor electroporation. , 2011, Bioelectrochemistry.

[107]  L. Mir,et al.  Cost-effectiveness analysis of electrochemotherapy with the Cliniporator™ vs other methods for the control and treatment of cutaneous and subcutaneous tumors , 2008, Therapeutics and clinical risk management.

[108]  J. Gehl,et al.  Efficient palliation of haemorrhaging malignant melanoma skin metastases by electrochemotherapy , 2000, Melanoma research.

[109]  M. Okino,et al.  Effects of a high-voltage electrical impulse and an anticancer drug on in vivo growing tumors. , 1987, Japanese journal of cancer research : Gann.

[110]  M. Čemažar,et al.  Cytotoxicity of different platinum (II) analogues to human tumour cell lines in vitro and murine tumour in vivo alone or combined with electroporation. , 2006, Anticancer research.

[111]  M. Čemažar,et al.  Differential Mechanisms Associated with Vascular Disrupting Action of Electrochemotherapy: Intravital Microscopy on the Level of Single Normal and Tumor Blood Vessels , 2013, PloS one.

[112]  M. Jaroszeski,et al.  Electrically enhanced drug delivery for the treatment of soft tissue sarcoma , 1999, Cancer.

[113]  S. Calvieri,et al.  Electrochemotherapy in the Treatment of Kaposi Sarcoma Cutaneous Lesions: A Two-Center Prospective Phase II Trial , 2011, Annals of Surgical Oncology.

[114]  D. Miklavčič,et al.  Intrinsic Sensitivity of Tumor Cells to Bleomycin as an Indicator of Tumor Response to Electrochemotherapy , 1998, Japanese journal of cancer research : Gann.

[115]  Damijan Miklavcic,et al.  Robustness of Treatment Planning for Electrochemotherapy of Deep-Seated Tumors , 2010, The Journal of Membrane Biology.

[116]  Helle K. Iversen,et al.  Multiple brain metastases - current management and perspectives for treatment with electrochemotherapy , 2012, Radiology and oncology.

[117]  L. Mir,et al.  Electrochemotherapy potentiation of antitumour effect of bleomycin by local electric pulses. , 1991, European journal of cancer.

[118]  V. Sondak,et al.  Phenotypic and functional analysis of dendritic cells and clinical outcome in patients with high-risk melanoma treated with adjuvant granulocyte macrophage colony-stimulating factor. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[119]  J. Gehl,et al.  Enhancement of cytotoxicity by electropermeabilization: an improved method for screening drugs , 1998, Anti-cancer drugs.

[120]  Damijan Miklavcic,et al.  The effect of electroporation pulses on functioning of the heart , 2008, Medical & Biological Engineering & Computing.

[121]  Juergen F Kolb,et al.  Membrane permeabilization and cell damage by ultrashort electric field shocks. , 2007, Archives of biochemistry and biophysics.

[122]  J. Gehl,et al.  Management of cutaneous metastases using electrochemotherapy , 2011, Acta oncologica.

[123]  L. Mir,et al.  Electrochemotherapy of tumours resistant to cisplatin: a study in a murine tumour model. , 2001, European journal of cancer.

[124]  M. Jaroszeski,et al.  In vivo electroporation of plasmids encoding GM-CSF or interleukin-2 into existing B16 melanomas combined with electrochemotherapy induces long-term antitumour immunity , 2000, Melanoma research.