Electrochemotherapy: Aspects of Preclinical Development and ... : Annals of Surgery (original) (raw)

Original Articles

Aspects of Preclinical Development and Early Clinical Experience

Larkin, John O. MB, AFRCSI*; Collins, Christopher G. PhD, AFRCSI*; Aarons, Simon PhD*; Tangney, Mark PhD*; Whelan, Maria MB, AFRCSI*; O'Reily, Seamus BSc, MD, PhD, FRCPI†; Breathnach, Oscar MB, MRCPI†; Soden, Declan M. BSc, PhD*; O'Sullivan, Gerald C. MCh, FRCSI, FRCSG (Hons), FACS*

From the *Cork Cancer Research Centre, Leslie C. Quick Jr. Cancer Laboratory, Biosciences Institute & Mercy University Hospital, National University of Ireland, Cork, Ireland; and the †Department of Oncology, Mercy University Hospital, Cork, Ireland.

Supported in part by ESOPE, Irish Cancer Society, Science Foundation Ireland, Health Research Board, Mercy University Hospital, and the Leslie Quick family.

Reprints: Gerald C. O'Sullivan, MCh, FRCSI, Cork Cancer Research Centre, Mercy University Hospital, National University of Ireland, Cork, Ireland. E-mail: [email protected].

Objective:

To develop an optimized, reproducible system of electrochemotherapy, and to investigate its clinical application in patients with cutaneous or subcutaneous recurrences of inoperable or progressive disease recalcitrant to current anticancer treatments.

Background:

Electrochemotherapy is the application of electric pulses to tumor tissue, rendering the cell membranes permeable to otherwise impermeant or poorly permeant anticancer drugs. This facilitates a potent local cytotoxic effect.

Study Design:

The optimal parameters for electrical pulses and bleomycin concentration were obtained in vitro and then applied to tumors derived from 4 histologically distinct human cancer cell lines (7860, PC3, OE19, MCF-7) established in athymic nude mice. Comparison was made with tumors that received bleomycin alone, electric pulses alone, and untreated controls. The optimized electrochemotherapy was then applied to patients with cutaneous or subcutaneous tumors, of any histologic type, recurrent or metastatic and unresponsive to standard chemotherapy and/or radiotherapy regimens. Tumors were assessed at monthly intervals to determine response to the treatment.

Results:

In vivo: Using the optimal parameters ascertained in vitro, all tumors treated by electrochemotherapy with bleomycin (n = 24) had significantly regressed (P < 0.001, all 4 lines) compared with control tumors (n = 72). Twelve tumors completely regressed (50%) following a single application, with 12 partial regressions (50%). Clinical: In 30 patients (111 tumors), none of the treated tumors progressed. Sixty percent of tumors (66 of 111) showed complete regression, 22% (24 of 111) partial response, and 18% (21 of 111) no change. Electrochemotherapy was more effective in smaller tumors (<3 cm), 71% (64 of 90) showing complete regression, 20% (18 of 90) partial response, and 9% (8 of 90) no change.

Conclusions:

Electrochemotherapy parameters optimized in vitro are applicable in vivo. This treatment is effective in athymic nude mice for all histologic types indicating a nonimmunologic mode of action. In clinical application, electrochemotherapy is an effective, safe, and reproducible therapy. Patients with cutaneous or subcutaneous tumors previously refractory to surgical intervention, systemic chemotherapy, and/or radiotherapy responded successfully irrespective of histologic type.