Review
Antitumor effectiveness of electrochemotherapy: A systematic review and meta-analysis

https://doi.org/10.1016/j.ejso.2012.08.016Get rights and content

Abstract

Background

This systematic review has two purposes: to consolidate the current knowledge about clinical effectiveness of electrochemotherapy, a highly effective local therapy for cutaneous and subcutaneous tumors; and to investigate the differences in effectiveness of electrochemotherapy with respect to tumor type, chemotherapeutic drug, and route of drug administration.

Methods

All necessary steps for a systematic review were applied: formulation of research question, systematic search of literature, study selection and data extraction using independent screening process, assessment of risk of bias, and statistical data analysis using two-sided common statistical methods and meta-analysis. Studies were eligible for the review if they provided data about effectiveness of single-session electrochemotherapy of cutaneous or subcutaneous tumors in various treatment conditions.

Results

In total, 44 studies involving 1894 tumors were included in the review. Data analysis confirmed that electrochemotherapy had significantly (p < .001) higher effectiveness (by more than 50%) than bleomycin or cisplatin alone. The effectiveness was significantly higher for intratumoral than for intravenous administration of bleomycin (p < .001 for CR%, p = .028 for OR%). Bleomycin and cisplatin administered intratumorally resulted in equal effectiveness of electrochemotherapy. Electrochemotherapy was more effective in sarcoma than in melanoma or carcinoma tumors.

Conclusions

The results of this review shed new light on effectiveness of electrochemotherapy and can be used for prediction of tumor response to electrochemotherapy with respect to various treatment conditions and should be taken into account for further refinement of electrochemotherapy protocols.

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)

  • D. Miklavcic et al.

    The importance of electric field distribution for effective in vivo electroporation of tissues

    Biophys J

    (1998)
  • D. Miklavcic et al.

    A validated model of in vivo electric field distribution in tissues for electrochemotherapy and for DNA electrotransfer for gene therapy

    Biochim Biophys Acta

    (2000)
  • K.L. Cooper et al.

    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

    (2011)
  • P.J. Lovrics et al.

    Systematic review of radioguided surgery for non-palpable breast cancer

    Eur J Surg Oncol

    (2011)
  • G.A. Gooiker et al.

    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

    (2010)
  • D.C. Bloom et al.

    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

    (2005)
  • J.R. Garbay et al.

    Successful repetitive treatments by electrochemotherapy of multiple unresectable Kaposi sarcoma nodules

    Eur J Cancer Suppl

    (2006)
  • J. Gehl et al.

    Palliation of haemorrhaging and ulcerated cutaneous tumours using electrochemotherapy

    Eur J Cancer Suppl

    (2006)
  • Y. Kubota et al.

    Successful treatment of metastatic skin lesions with electrochemotherapy

    J Urol

    (1998)
  • G. Sersa et al.

    Electrochemotherapy with cisplatin: potentiation of local cisplatin antitumour effectiveness by application of electric pulses in cancer patients

    Eur J Cancer

    (1998)
  • T. Shimizu et al.

    Electrochemotherapy for digital chondrosarcoma

    J Orthop Sci

    (2003)
  • M. Snoj et al.

    Long lasting complete response in melanoma treated by electrochemotherapy

    Eur J Cancer Suppl

    (2006)
  • M.C. Whelan et al.

    Effective treatment of an extensive recurrent breast cancer which was refractory to multimodal therapy by multiple applications of electrochemotherapy

    Eur J Cancer Suppl

    (2006)
  • L.M. Mir et al.

    Bleomycin: revival of an old drug

    Gen Pharmacol

    (1996)
  • L.M. Mir

    Bases and rationale of the electrochemotherapy

    Eur J Cancer Suppl

    (2006)
  • S. Orlowski et al.

    Transient electropermeabilization of cells in culture. Increase of the cytotoxicity of anticancer drugs

    Biochem Pharmacol

    (1988)
  • G. Sersa et al.

    Electrochemotherapy: variable anti-tumor effect on different tumor models

    Bioelectrochem Bioenerg

    (1994)
  • S. Rodriguez-Cuevas et al.

    Electrochemotherapy in primary and metastatic skin tumors: phase II trial using intralesional bleomycin

    Arch Med Res

    (2001)
  • G. Sersa et al.

    Antitumor effectiveness of electrochemotherapy with cis-diamminedichloroplatinum(II) in mice

    Cancer Res

    (1995)
  • G. Sersa et al.

    Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma

    Br J Cancer

    (2008)
  • T. Jarm et al.

    Antivascular effects of electrochemotherapy: implications in treatment of bleeding metastases

    Expert Rev Anticancer Ther

    (2010)
  • A.I. Daud et al.

    Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma

    J Clin Oncol

    (2008)
  • M. Cemazar et al.

    Cancer electrogene therapy with Interleukin-12

    Curr Gene Ther

    (2010)
  • L.M. Mir et al.

    Electrochemotherapy, a novel antitumor treatment – 1st clinical-trial (in French: L’electrochimiotherapie, un nouveau traitement antitumoral: premier essai clinique)

    C R Acad Sci III

    (1991)
  • M. Belehradek et al.

    Electrochemotherapy, a new antitumor treatment – 1st clinical phase-I–II trial

    Cancer

    (1993)
  • F.J. Landstrom et al.

    Electroporation therapy of skin cancer in the head and neck area

    Dermatol Surg

    (2010)
  • E. Kis et al.

    Electrochemotherapy of cutaneous metastases of melanoma – a case series study and systematic review of the evidence

    Dermatol Surg

    (2011)
  • L.W. Matthiessen et al.

    Management of cutaneous metastases using electrochemotherapy

    Acta Oncol

    (2011)
  • T. Hampton

    Electric pulses help with chemotherapy, may open new paths for other agents

    JAMA

    (2011)
  • M.G. Moller et al.

    Electrochemotherapy as an adjunct or alternative to other treatments for unresectable or in-transit melanoma

    Expert Rev Anticancer Ther

    (2009)
  • A. Testori et al.

    Local and intralesional therapy of in-transit melanoma metastases

    J Surg Oncol

    (2011)
  • G.L. Colombo et al.

    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

    (2008)
  • P. Quaglino et al.

    Electrochemotherapy with intravenous bleomycin in the local treatment of skin melanoma metastases

    Ann Surg Oncol

    (2008)
  • L.G. Campana et al.

    Bleomycin-based electrochemotherapy: clinical outcome from a single institution’s experience with 52 patients

    Ann Surg Oncol

    (2009)
  • L.G. Campana et al.

    Electrochemotherapy: clinical outcome and predictive factors from a single institution experience on 50 melanoma patients

    Ann Surg Oncol

    (2010)
  • A. Testori et al.

    Electrochemotherapy for cutaneous and subcutaneous tumor lesions: a novel therapeutic approach

    Dermatol Ther

    (2010)
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