Recent reports show progress in the use of altered trans-membrane electrical fields to increase the efficiency of drug – and possibly, therapeutic gene – delivery into cells. Electroporation is also under investigation as a non-thermal tumor ablation modality.
The idea behind electroporation is simple: increase cells’ trans-membrane voltage to transiently disrupt the molecular organization of membranes (creating new pores, as the name suggests), and you’ll increase membranes’ permeability to therapeutic agents – allowing anticancer drug molecules to diffuse more rapidly and efficiently into tumor cells, for example.
Pulsed electroporation to facilitate tumor cell uptake of bleomycin or cisplatin was first tried with patients in Europe in the 1990s. Two decades later, thousands of cancer patients have undergone these electrochemotherapies. While most studies have involved electrochemotherapy for melanomas, Kaposi sarcomas, and Merkel cell carcinomas, open-surgery, endoscopic and percutaneous modalities now allow electrochemotherapy for subcutaneous tumors, as well.
According to a September 2012 meta-analysis of data from 44 clinical studies, published online in the European Journal of Surgical Oncology, electroporation increases bleomycin’s and cisplatin’s antitumor efficacy “by more than 50%” (P<0.001) compared to chemotherapy alone – particularly for bleomycin delivered directly into the tumor instead of administered intravenously (for complete response [CR] rates, P<0.001; for objective response rate, P=0.028). Overall, electrochemotherapy “was more effective in sarcoma than in melanoma or carcinoma tumors,” the authors noted.
Few adverse events have been reported for this modality – primarily tolerable, transient discomfort or pain during treatment. However, electroporation near the heart can induce transient arrhythmias during treatment if pulse delivery is not synchronized with heart rhythm. Clinical trials published this year have reported safety and tolerability of bleomycin electrochemotherapy for cutaneous-recurrence of breast cancer and recurrent head and neck cancer.
Efficacy trials are under way in the United States. OncoSec, a San Diego, CA-based company, recently reported that its NeoPulse intratumoral melanoma electrochemotherapy system achieved complete response in >90% of patients with basal cell carcinoma and 70% of patients with squamous cell carcinoma at 6-month follow-up.
Electroporation shows preclinical promise as a component of multimodality anticancer regimens, as well. A recent mouse-model study of invasive ductal breast carcinomas of sizes “comparable to clinical lesions” found that combined radioelectrochemotherapy, involving a single low radiation dose of 3 Gy – 5 Gy plus cisplatin electrochemotherapy, was more effective than electrochemotherapy alone; in addition, electrochemotherapy was more effective at achieving remission at 100 days than was either electroporation or cisplatin chemotherapy alone.
Meanwhile, efforts to use electroporation to vector gene-therapy products to target cells – an effort initially undertaken in part as an attempt to circumvent the immune response and other challenges involved in virally-vectored gene delivery – appear to be paying off. OncoSec’s ImmunoPulse DNA IL-12 system uses electroporation to enhance immunotherapy. A recently-reported phase 2 trial found the system, which involves intratumoral administration of DNA IL-12 during electroporation, is safe and well-tolerated, and might induce tumor regression and stabilization in metastatic melanoma.
Irreversible Electroporation Also Shows Promise
Cytotoxic irreversible electroporation (IRE) is also under development as a non-thermal ablation modality. IRE uses powerful, static electric fields of up to 1,000 volts/cm to permanently disrupt membrane integrity, killing tumor cells. Because it does not use heat, this modality might be particularly promising for ablation of primary and metastatic liver tumors near portal pedicles and hepatic veins. A recent retrospective review of IRE ablation of perivascular liver tumors among 28 patients (79% in open surgery and 21% percutaneously) found the procedure to be safe. Lead author Peter T. Kingham, MD, of the Memorial Sloan Kettering Cancer Center in New York, NY, reported that there were no treatment-associated deaths and an overall morbidity rate of 3% — although he was quick to note that “larger studies and longer follow-ups are necessary to determine long-term efficacy.”
“Complications included 1 intraoperative arrhythmia and 1 postoperative portal vein thrombosis,” Dr. Kingham and his coauthors noted.
A study of 27 patients with unresectable, locally-advanced pancreatic adenocarcinoma similarly found IRE to be safe, with one patient death and no evidence of clinical pancreatitis or fistula 3 months after treatment. After 90-day follow-up, “there has been 100% ablation success,” the authors reported.
The percutaneous NanoKnife System (AngioDynamics, Latham, NY) has received FDA clearance for surgical ablation of soft tissues but not any specific disease.