DIRECT Study Focuses on NanoKnife Technology

New drugs, new combinations of drugs, targeted treatments, and immunotherapies are all being studied in the hopes of improving the lives of people with pancreatic cancer.

Besides medications, researchers are also looking at how medical devices can potentially play a role. One such device is the NanoKnife irreversible electroporation (IRE) system. It’s a minimally invasive technology that uses multiple needle probes to deliver pulsed, low-current, high-voltage electrical energy to destroy tumor cells. In 2008, the technology was approved by the FDA for the surgical ablation of soft tissue. Now it’s being studied in a multi-site trial called DIRECT for the treatment of locally advanced stage III pancreatic cancer.

There are limited treatment options for stage III pancreatic cancer. Currently, chemotherapy alone or in combination with radiation therapy is the standard of care. Both approaches have seen some advancement, but treatments can be difficult for patients and toxicity is a problem. “As an interventional radiologist I take care of patients with many types of cancer and at all different stages, and pancreatic cancer is indeed one of the deadliest cancers, but in addition, the symptoms people develop can really impact their quality of life,” explains vascular and interventional radiologist Daniel J. Holzwanger, M.D., Assistant Professor of Radiology at Weill Cornell Medicine and an Assistant Attending Radiologist at the NewYork-Presbyterian Hospital-Weill Cornell Campus (New York). Dr. Holzwanger is leading the DIRECT study at Weill Cornell. “I really feel for these patients and their family members since receiving this diagnosis is life-altering. This is why it is critical to continue to develop treatments that improve survival and also their quality of life,” he says.

A Different Type of Ablation

Ablation is a method of destroying diseased tissue that has typically applied either temperature extremes or chemical substances to the tissues. Unlike traditional thermal ablation techniques that kill cancer cells with heat or cold, NanoKnife, technically called NanoKnife IRE, uses electrical impulses to create tiny holes called nanopores in malignant cells. These pores then cause the cancer cells to malfunction and die.

This key technical difference is why IRE could be well-suited for treating pancreatic cancer. “Pancreatic tumors grow in one of the most challenging areas of the body to treat,” Holzwanger says. “These tumors will often neighbor and even directly involve multiple, critically important blood vessels and the common bile duct. Other forms of ablation such as radiofrequency, microwave, and cryo-ablation will heat or freeze the target area to kill the tumor, and in doing so, are at a high risk of injuring these nearby blood vessels and the bile duct.”

“Targeting the cell membrane to specifically kill the cells in the area helps preserve the surrounding collagen and extracellular matrix which are key components for maintaining the structure of the vessels and bile ducts,” he adds. “A complication to a nearby blood vessel could still happen but it is less likely compared with any of the thermal ablation techniques.”

“IRE can be done during surgery or in a completely needle-based fashion—essentially with no incision. The reason for either choice is decided on a case-by-case basis,” says Holzwanger. “As an interventional radiologist, I am most interested in the needle-only procedure, but at the end of the day what matters most is that we do what is best and safest for each patient.”

“In my opinion, no procedure is straightforward. However, we are always weighing the risks and benefits of the procedure against the risks and benefits of any alternative options that may exist for someone, such as not doing the procedure. For some of these people, that may not leave them many options at all.”

While undergoing IRE, the patient is placed under general anesthesia, “and then using advanced imaging techniques we guide the needle probes into position around the tumor to start delivering the electrical pulses,” he explains. “Once the procedure is complete the needles are removed, and the patient is returned to recovery. Patients are usually hospitalized for a couple of days so we can monitor and manage any side effects or issues related to the treatment,” he adds.

The DIRECT Study

DIRECT stands for “Direct IRE Cancer Treatment.” The study comprises a randomized controlled trial at up to 15 sites, as well as a “real-world evidence, next-generation registry at up to 30 sites,” each with a NanoKnife system treatment arm and a control arm, according to biomedical company AngioDynamics, the provider of the NanoKnife system and trial sponsor. Each NanoKnife arm is expected to consist of approximately 250 patients with an equal number of control patients. The primary endpoint of the study is overall survival.

The study design is well thought out, Holzwanger believes. “The DIRECT study is really two studies looking at the safety and efficacy of IRE in patients with locally advanced pancreatic cancer,” he explains. “It consists of a randomized controlled trial of a FOLFIRINOX regimen plus IRE versus the FOLFIRINOX regimen only, as well as a ‘real-world’ observational registry study comparing standard of care therapy plus IRE versus standard of care only.”

“I think this is great since the randomized trial will provide a rigorous, highly-controlled evaluation of the efficacy of IRE, while the real-world registry will provide additional information about how the procedure performs outside of the confines of a randomized controlled trial.”

In January 2018, the FDA granted the NanoKnife System a Breakthrough Device designation under the 21st Century Cures Act. In April 2019, the FDA approved AngioDynamics’s investigational device exemption application for the DIRECT trial.

Based on accumulated evidence in treating stage III patients, including both borderline resectable and unresectable tumors, the approach leads to improvements in median overall survival from 15.3 to 27 months following treatment. Nonetheless, more research like that of the DIRECT study is absolutely necessary.

“I believe based off the existing data that you can say that IRE has a reasonable safety profile and that there is a potential for real clinical benefit, however, it definitely needs to be studied further to truly evaluate the efficacy of the procedure and to identify what groups of patients will benefit most from the procedure,” Holzwanger says.