ReviewAntitumor effectiveness of electrochemotherapy: A systematic review and meta-analysis
Introduction
Electrochemotherapy (ECT) is an antitumor therapy in which administration of a chemotherapeutic drug is followed by local application of electroporation pulses. Electroporation transiently permeabilizes tumor cell membranes, thus enabling diffusion of a chemotherapeutic drug (bleomycin or cisplatin) into the cells and increasing its cytotoxicity.1, 2 Other secondary mechanisms of ECT were also recognized.3, 4, 5, 6, 7 Since the first clinical study in 1990,8, 9 ECT has been reported as highly effective, with complete response rates between 60 and 70% and objective response rates of about 80%,10, 11, 12, 13, 14, 15, 16, 17 especially when the standard operating procedures (SOP) for ECT were followed.18 ECT is routinely used in treatment of cutaneous and subcutaneous tumors due to high effectiveness, safety, limited toxicity, simplicity, cost-effectiveness, organ-sparing effect, and suitability for repetitive and neoadjuvant treatment.1, 10, 11, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 New ECT approaches are currently being developed for treatment of deep seated tumors.29, 30, 31, 32, 33
Effectiveness of ECT depends on extracellular drug concentration at the time of electroporation pulse delivery and on distribution of electric field inside tumor.34, 35, 36 Other influential parameters related to patient, tumor and treatment characteristics (such as age; gender; tumor type, size and location; drug type, dose and route of administration; electrode type; protocol of electroporation pulse delivery) probably contribute to variability in tumor response to ECT, but their role has not been sufficiently explored.11, 24, 37
The aim of this systematic review was to consolidate current experience with clinical ECT of cutaneous or subcutaneous tumors from the effectiveness point of view and to provide a transparent and objective framework for discussion on differences in effectiveness of clinical ECT. The main objectives were to evaluate: (a) overall effectiveness of ECT; (b) effectiveness of ECT in comparison to chemotherapeutic alone; (c) differences in effectiveness of ECT with respect to drug type and route of administration; (d) differences in effectiveness of ECT with respect to histological type of tumors.
Section snippets
Search strategy
A systematic search of 16 bibliographic databases was performed to obtain articles regarding clinical ECT (Fig. 1), using search terms “electrochemotherapy” and “clinical” and time range between 1st January 1991 and 18th October 2011. Language restriction to English was applied. Some references cited in these articles were screened to identify additional potentially eligible studies. Unpublished studies, abstracts, posters, reviews, editorials, lectures and commentaries were not included in
Search results
The initial search identified 1181 records after removal of duplicates. The study selection procedure is shown in Fig. 1. Finally, 44 studies were appropriate for systematic review and data analysis (Table 1A). A much smaller subset of these studies was eligible for meta-analysis therefore the results of meta-analysis were treated as supplementary to the results of other statistical methods (Fig. 1, Table 1B, Table 1C).
Characteristics of the eligible studies
Characteristics of the studies used for systematic review are listed in
Discussion
Several clinical reviews have reported on effectiveness of ECT, but no systematic and comprehensive summary of effectiveness of clinical ECT has been published to date. In this systematic review, local effectiveness of a single-session ECT across all eligible studies was estimated as complete and objective response rate (denoted as CR% and OR% respectively) of 59.4% and 84.1% respectively (Table 2). The reviews of studies conducted before publication of the SOP for ECT reported similar values
Conclusions
The overall effectiveness of ECT in clinical setting and the differences in effectiveness of ECT of cutaneous and subcutaneous tumors due to heterogeneous treatment conditions (i.e. tumor type, drug type, route of drug administration) were systematically addressed for the first time. The identified differences could be used for a refined prediction of response to ECT of different tumor types, drug used and route of drug administration. This information should be taken into account for
Conflict of interest
The authors declare no potential conflicts of interest. Damijan Miklavcic holds patents of which some have been licensed to IGEA SpA; the producer of a clinical device used in some of the studies considered in this systematic review.
Role of the funding source
This work was supported by the Research Agency of the Republic of Slovenia (P2-0249 and P3-0003).
Acknowledgements
The authors thank prof. dr. Andrej Kosir from Faculty of Electrical Engineering, Ljubljana for helping with discussions on statistical analysis of the data included in this review. This work was conducted within the scope of the EBAM European Associated Laboratory (LEA).
References (92)
- et al.
Electrochemotherapy potentiation of antitumour effect of bleomycin by local electric pulses
Eur J Cancer
(1991) - et al.
Electrochemotherapy with CDDP on LPB sarcoma: comparison of the anti-tumor effectiveness in immunocompetent and immunodeficient mice
Bioelectrochem Bioenerg
(1997) - et al.
Electrochemotherapy in treatment of tumours
Eur J Surg Oncol
(2008) - 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
Eur J Cancer Suppl
(2006) The state-of-the-art of electrochemotherapy before the ESOPE study; advantages and clinical uses
Eur J Cancer Suppl
(2006)- et al.
Electrochemotherapy of chest wall breast cancer recurrence
Cancer Treat Rev
(2012) - 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 Cliniporator™ by means of invasive or non-invasive electrodes
Eur J Cancer Suppl
(2006) - et al.
Importance of tumour coverage by sufficiently high local electric field for effective electrochemotherapy
Eur J Cancer Suppl
(2006) - et al.
Successful application of targeted electrochemotherapy using novel flexible electrodes and low dose bleomycin to solid tumours
Cancer Lett
(2006) - et al.
Optimizing clinical performance and geometrical robustness of a new electrode device for intracranial tumor electroporation
Bioelectrochemistry
(2011)
The importance of electric field distribution for effective in vivo electroporation of tissues
Biophys J
A validated model of in vivo electric field distribution in tissues for electrochemotherapy and for DNA electrotransfer for gene therapy
Biochim Biophys Acta
Positron emission tomography (PET) for assessment of axillary lymph node status in early breast cancer: a systematic review and meta-analysis
Eur J Surg Oncol
Systematic review of radioguided surgery for non-palpable breast cancer
Eur J Surg Oncol
A systematic review and meta-analysis of the volume-outcome relationship in the surgical treatment of breast cancer. Are breast cancer patients better of with a high volume provider?
Eur J Surg Oncol
The role of intratumour therapy with electroporation and bleomycin in the management of advanced squamous cell carcinoma of the head and neck
Eur J Surg Oncol
Successful repetitive treatments by electrochemotherapy of multiple unresectable Kaposi sarcoma nodules
Eur J Cancer Suppl
Palliation of haemorrhaging and ulcerated cutaneous tumours using electrochemotherapy
Eur J Cancer Suppl
Successful treatment of metastatic skin lesions with electrochemotherapy
J Urol
Electrochemotherapy with cisplatin: potentiation of local cisplatin antitumour effectiveness by application of electric pulses in cancer patients
Eur J Cancer
Electrochemotherapy for digital chondrosarcoma
J Orthop Sci
Long lasting complete response in melanoma treated by electrochemotherapy
Eur J Cancer Suppl
Effective treatment of an extensive recurrent breast cancer which was refractory to multimodal therapy by multiple applications of electrochemotherapy
Eur J Cancer Suppl
Bleomycin: revival of an old drug
Gen Pharmacol
Bases and rationale of the electrochemotherapy
Eur J Cancer Suppl
Transient electropermeabilization of cells in culture. Increase of the cytotoxicity of anticancer drugs
Biochem Pharmacol
Electrochemotherapy: variable anti-tumor effect on different tumor models
Bioelectrochem Bioenerg
Electrochemotherapy in primary and metastatic skin tumors: phase II trial using intralesional bleomycin
Arch Med Res
Antitumor effectiveness of electrochemotherapy with cis-diamminedichloroplatinum(II) in mice
Cancer Res
Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma
Br J Cancer
Antivascular effects of electrochemotherapy: implications in treatment of bleeding metastases
Expert Rev Anticancer Ther
Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma
J Clin Oncol
Cancer electrogene therapy with Interleukin-12
Curr Gene Ther
Electrochemotherapy, a novel antitumor treatment – 1st clinical-trial (in French: L’electrochimiotherapie, un nouveau traitement antitumoral: premier essai clinique)
C R Acad Sci III
Electrochemotherapy, a new antitumor treatment – 1st clinical phase-I–II trial
Cancer
Electroporation therapy of skin cancer in the head and neck area
Dermatol Surg
Electrochemotherapy of cutaneous metastases of melanoma – a case series study and systematic review of the evidence
Dermatol Surg
Management of cutaneous metastases using electrochemotherapy
Acta Oncol
Electric pulses help with chemotherapy, may open new paths for other agents
JAMA
Electrochemotherapy as an adjunct or alternative to other treatments for unresectable or in-transit melanoma
Expert Rev Anticancer Ther
Local and intralesional therapy of in-transit melanoma metastases
J Surg Oncol
Cost-effectiveness analysis of electrochemotherapy with the Cliniporator™ vs other methods for the control and treatment of cutaneous and subcutaneous tumors
Ther Clin Risk Manag
Electrochemotherapy with intravenous bleomycin in the local treatment of skin melanoma metastases
Ann Surg Oncol
Bleomycin-based electrochemotherapy: clinical outcome from a single institution’s experience with 52 patients
Ann Surg Oncol
Electrochemotherapy: clinical outcome and predictive factors from a single institution experience on 50 melanoma patients
Ann Surg Oncol
Electrochemotherapy for cutaneous and subcutaneous tumor lesions: a novel therapeutic approach
Dermatol Ther
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