By David Yeager
Vol. 12 No. 12 P. 32
This IR oncology procedure may prove a more precise alternative to radio-frequency ablation in some cancer patients.
The extreme mutability of cancer requires a variety of treatments. While radiation therapy, chemotherapy, and surgery are most often employed, adjunct therapies can be valuable additions to the cancer treatment arsenal. One such adjunct therapy that has shown promise is irreversible electroporation (IRE).
IRE is a type of ablation but, rather than destroying cancer cells with heat or cold, it uses electrical impulses to create permanent nanopores in cancer cells, hastening cell death. Unlike thermal ablation or cryoablation techniques, where the ablation tool is inserted in the center of a treatment site and the therapeutic effects radiate outward and can affect healthy tissue, IRE creates an electrical field around the tumor. The tissue within the field receives the treatment, and there is minimal damage to surrounding tissue.
Because the therapy can be delivered with great precision and causes less damage to interstitial structures, such as collagen, and surrounding healthy cells, it has piqued some researchers’ interest. Not long after AngioDynamics’ NanoKnife IRE tool received 510(k) approval in 2008, Ziv Haskal, MD, vice chair and a professor of diagnostic radiology and surgery at the University of Maryland School of Medicine and chief of vascular and interventional radiology at the University of Maryland Medical Center (UMMC), and his institution found that IRE was a worthwhile investment. So far, results with the therapy have been encouraging, but there is much that is not yet known about its benefits and limitations.
“It is an exciting, early, and new technology in interventional oncology,” says Haskal. “We do embrace new technologies and new strategies in hopes of better understanding the limit of each therapy, as well as how and why we might extract a technical or improved clinical outcome or minimization of complications by using these new tools. And that, for me, is the primary reason why I worked hard to get the unit here.”
Old Dog, New Trick
Although IRE is fairly new, the process of electroporation was developed in the late 1960s to facilitate gene therapies. At lower electrical intensities, pores can be temporarily created in cells to allow gene delivery. The researchers who first described the phenomenon noted that higher intensities can permanently porate cells. Haskal, who is also the editor-in-chief of the Journal of Vascular and Interventional Radiology, says an upcoming article in the journal is the first to describe what IRE looks like through an electron microscope and provides clues to its mechanics.
During a typical IRE treatment, clinicians place two or three pairs of electrodes that emit 3,000-volt pulses of direct current at low amperage around the tumor. The pulses are delivered in groups of 10, usually for nine cycles. Each 10-pulse cycle takes about one second, and the electrodes pause briefly before starting the next cycle. A nine-cycle ablation takes around 90 seconds to deliver, as long as the patient’s heart rate is stable.
As with any cancer treatment, precise planning is necessary to achieve the desired effect. Proper placement of the electrodes requires detailed 3D mapping of the tumor, which is done in a two-step process. First, the tumor is reconstructed in 3D on a CT workstation. Then the 3D data are imported into the NanoKnife system. Based on the CT data, the system allows the clinician to see how the number and placement of electrodes affect the ablation zone. Depending on the tumor’s location, it can take between 20 and 45 minutes to place the electrodes.
“It’s not really a replacement for standard ablation techniques [such as] RFA [radio-frequency ablation], cryo, or microwave,” says Rahul Patel, MD, an assistant professor of diagnostic radiology and nuclear medicine at the University of Maryland School of Medicine and an interventional radiologist at UMMC. “And the reason for that is it is somewhat more expensive, and it is also somewhat time consuming. Once the ablation gets going, it does take a little more time than an RFA. It also requires general anesthesia.”
The anesthesia is required to keep patients still, and a short-acting paralytic agent is administered to prevent the involuntary movements associated with electrical stimulation, which can cause difficulties with patient positioning. In addition, practitioners use the system’s gating software to sync the electrical impulses to the heartbeat to avoid heart misstimulation, although Patel says gating is less of a concern in treatment sites that are not close to the heart. Including planning time, anesthesia administration, and patient transport to and from the operating room, it takes three to four hours to complete an IRE treatment for a 4- to 5-cm tumor. Patel says UMMC’s doctors have treated tumors as large as 12 cm, but it takes nearly an entire day to do this. For this reason, he considers time to be a limiting factor for treating larger tumors with IRE.
For smaller tumors, IRE can be performed as an outpatient procedure, but more often the patient is kept overnight for observation. Most of the necessary recovery time is due to the effects of the anesthesia, and there is relatively little pain associated with the procedure. Follow-up for treatment efficacy is similar to other ablation procedures, with patients being seen after the procedure to assess the clinical outcome and several weeks later for repeat imaging to reassess.
(Not) Feeling the Heat
One potential benefit of IRE is that it generates less heat than RFA. While RFA typically produces temperatures between 70˚ and 80˚C, or higher, IRE temperatures are usually in the 50˚ to 60˚C range—not high enough to kill cells. Although heat effects can be seen on MRI the day after an IRE treatment, the thermal effects travel only 1 to 1.5 mm from the electrode, leaving the surrounding healthy cells intact. Also, because the heat is generated during the pulses but dissipates while the electrode rests, there isn’t a constant cooking effect, as with RFA.
Extreme heat or cold from other ablation procedures destroys not only cancer cells but also the collagen skeleton that underlies the cancer tissue. IRE leaves that scaffolding intact. As a result, rather than the so-called black hole phenomenon that is seen with other types of ablation, healthy tissue often grows over the remaining scaffolding. With smaller lesions, healthy tissue may completely fill the ablation zone in about one month. With larger lesions, clinicians typically observe a shrinking scar over time.
“We may characterize it as having, perhaps, more of a neutron bomb effect, rather than a total area of destruction, by leaving some of the structures intact,” Haskal says.
Whether the reduced scarring is clinically beneficial is an open question: As far as clinicians are concerned, a dead tumor is a dead tumor. One possible advantage of IRE and other nonthermal treatments, though, is that the technique may prove useful for treating areas where tumors abut structures that dissipate heat, such as large arteries or veins. These structures can act as heat sinks, moderating the temperature in an ablation zone before the treatment can achieve its maximum cancer-killing effect.
For example, the proximity of the liver and the pancreas to the hepatic portal vein and other large blood vessels makes them extremely difficult to treat with thermal ablation. The prostate gland also presents difficulty because the flow of urine through the urethra acts as a heat sink. Since IRE doesn’t rely on temperature, researchers hypothesize that it may be more effective in these areas than thermal ablation procedures. If they are correct, IRE may become a valuable adjunct treatment for pancreas, liver, and prostate cancers, among others. However, Patel says the technology is new enough that its limits have yet to be defined. UMMC currently is developing an experimental protocol for IRE treatment of the pancreas.
From Theory to Practice
Doctors at UMMC have treated approximately 20 patients with IRE, with a total of 25 to 30 ablations being done. Patients have been treated for pancreatic, adrenal, prostate, liver, and head and neck tumors. So far, the results have been generally positive, particularly with liver tumors. Patel says, in one case, doctors were able to clear a tumor from a patient’s blocked portal vein, allowing that patient to be posted for a liver transplant. However, the medical center hasn’t yet undertaken a review of IRE’s overall efficacy.
In an effort to learn more about IRE’s potential, UMMC applied for and received a seed grant from the Society of Interventional Radiology (SIR) for small animal research that will examine IRE’s use in neural applications. Patel is the lead principal investigator. The SIR grant will allow researchers to study the effects of IRE in neural tissue to find out if tissue sparing occurs. Patel says there is anecdotal evidence from spine and prostate patients that some nerve damage occurs with IRE, resulting in temporary parasthesia, but that the damage heals.
“Our plan is to test that effect on both peripheral and central nerves and see exactly how much really comes back,” Patel says, “with the idea being maybe we can treat epidural tumors of the spine or tumors of the spinal canal that are closer to the cord, where patients will be willing to accept that they’ll have some parasthesia—there’s some leg weakness—for a few weeks, but they won’t necessarily have the debilitating problems of a true spinal surgery.”
Haskal says this type of research is vital to establish the technology’s capabilities and limits. He is excited about IRE’s possibilities and welcomes clinical and research opportunities to move IRE in new directions. Even so, he believes IRE and other interventional oncology treatments should be supported by the same type of research-based evidence that supports chemotherapy and surgical options. He is interested in moving the field of interventional radiology in that direction, particularly in the treatment of peripheral arterial disease and oncology. While he doesn’t view IRE or any other interventional treatment as a replacement for traditional therapies, he does believe that interventional therapies offer effective treatment options.
“External beam radiation is an excellent tool, but a lot of this is a zone defense, not man to man,” Haskal says. “The clinical question is how do you bring adjunctive therapies to bear on a tumor? For example, when we treat liver tumors in our multidisciplinary group, at the table we have radiation oncology, surgical oncology, pathology, interventional radiology, and several other disciplines, and we often use multipronged therapies, including external beam radiation on top, before or after some of our ablations. So I don’t view any interventional oncology treatment as a replacement or standalone for other tools. I view these as tools that work together. You need a knife and a fork.”
— David Yeager is a freelance writer and editor based in Royersford, Pa. He is a frequent contributor to Radiology Today.