By: Dan Sperling, MD

This is the second of a series of five articles on Irreversible Electroporation (IRE) for prostate cancer. This article discusses the scientific methods used to test its effectiveness.

The hypothesis that IRE can evenly destroy individual cells within a group grew from subjecting cells to microseconds of pulsed electrical energy, which was already known to force open tiny holes, called nanopores, in the cell membrane. Up to a certain voltage threshold, the cells will survive, and the pores close (reversible electroporation). Researchers used reversible electroporation to create electro-chemotherapy, a cancer treatment in which anticancer drugs (chemotherapy) are first injected into a tumor, which is then subjected to reversible electroporation. The opening of the pores allows a drug to penetrate the cell in very tiny amounts. When the pores close, the drug exerts a toxic effect from within the cell, and it dies. (Cell death is called apoptosis, a phenomenon that naturally occurs due to the ongoing programmed death of countless cells in living creatures).

In the case of IRE, no chemotherapeutic drugs are needed because electrical current over above the threshold used in reversible electroporation causes the pores to remain open. Essentially, the protective membrane has been breached, and the delicate liquid environment within the cell, essential for the cell to function, is contaminated with the external liquid environment that seeps in. The blending of fluids is hostile to the inner components of the cell, and it simply dies off. Normal clean-up mechanisms of the body dispose of the dead cell and its components, so it poses no future threat.

In 2007, a team of researchers published their experiment using dogs to test both the safety and effectiveness of IRE in prostate tissue.[i] The same team, as well as others, had contributed scientific information that established cryotherapy (freezing) as a thermal ablation method that had gained clearance for Medicare reimbursement in 1999, so an important feature of their 2007 publication was defining the differences between ablation using extreme temperatures vs. the apoptosis caused by IRE.

The experiment was conducted with six male beagle dogs, and was performed in full compliance with federal regulations governing good laboratory practice when animals are involved. All IRE procedures were performed under general anesthesia as well as an injectable muscle relaxant to avoid involuntary contractions (movement) during treatment. Five of the dogs were subjected to treatment directed to the prostate (two of them were directed to just one side of the gland, or the equivalent of a “hemi-ablation” if done by cryotherapy); in the sixth dog, the electrode probes were placed at the urethra, rectum, and neurovascular bundle (NVB) to observe the effect of the treatment on these sensitive structures. The researchers note that they varied the number of probes used and the access pathways for placing the probes; with such a small number of subjects, they admit this is a limitation of the study. Another limitation is that the observations were gained from treating normal prostates; it’s possible that prostate cancer tumors will require adjustments to the electrical field to effectively open cell pores.

Following treatment, the prostates were removed for pathology analysis. The first gland, removed at day one after treatment, revealed gross hemorrhage (bleeding) on the treated side of the gland. Tissue analysis under the microscope showed no living prostate tissue. The margin between the area of treatment and untreated prostate tissue was abrupt, unlike the more gradual transition observed with thermal treatments. In other words, IRE created a very clean margin. In the areas where the urethra, rectum and neurovascular bundles had been directly treated, aside from evidence of minor effect in the tissues directly adjacent, the ability of these structures to quickly recover and perform normally appeared intact, including the nerves themselves.

At two weeks following treatment, the remaining 5 glands were removed and examined. The hemorrhagic changes had mostly resolved, and the treated area was greatly reduced in size and composed of collagenous tissue consistent with the beginning scar tissue. The urethral wall adjacent to the treated area showed no evidence of cell death and appeared to be capable of normal function. According to the authors, “The nerves and vessels within the NVB on the side of the lesion were intact and patent.” In other words, on the treated side of the gland, the nerves and blood vessels appeared functional. Regarding the effect of treatment on the rectal wall, those tissues also appeared functional with no evidence of fistula (hole) in the wall itself.

The authors point out the advantages of IRE by comparing it with thermal ablation (extreme heat or cold). They note that IRE produces relatively clean treatment margins and is not subject to the “heat sink” effect of blood vessels that can compromise thermal treatments by the physics of heat transfer due to blood flow, such that warm temperatures are cooled or cold temperatures are warmed. The heat sink effect possibly accounts for the failure of thermal ablation to destroy all cancer cells within or at the edge of a thermal ablation lesion. A distinct advantage of IRE is manner in which the cells that make up glands and organs are more susceptible to the voltage than are the nerves, blood vessels and mucosal tissues that line the urethra and rectal walls. This allows sensitive structures to be spared, avoiding the risks to urinary, sexual and bowel function that accompany thermal ablation and radiation therapies. Additional features include:

a)      Treatment is efficient due to microsecond bursts of electrical energy. Accurate probe placement constitutes the majority of the treatment time, and this can be done very efficiently under image guidance.

b)      The size of the electrode probe can be very small and still generate a sufficient field.

c)       IRE is ideal for hemi-ablations or focal treatment; however, the entire prostate could be treated using an array formed with a greater number of electrode probes.

d)      IRE is amenable to mathematical and physics calculations that can predict the size and shape of the treatment area. This has implications both for re-treatment, should that prove necessary, and also for reproducible research studies.

e)      Theoretically, a positive immunologic effect may occur after treatment, since proteins that “inform” the immune system are not denatured as they are by extreme heat.

The authors conclude that IRE can be a safe and effective treatment for use in the prostate.

[i] Onik G, Mikus P, Rubinsky B. Irreversible electroporation: implications for prostate ablation. Technical Cancer Res Treat. 2007 Aug; 6(4):295-300.