NanoKnife, Liposomal Doxorubicin Show Efficacy Against Liver Cancer

Becky McCall

March 16, 2011

March 16, 2011 (Vienna, Austria) — Two advanced technologies — irreversible electroporation (IRE; NanoKnife, AngioDynamics) and a thermally sensitive liposomal doxorubicin (ThermoDox, Celsion) — used in conjunction with radiofrequency ablation (RFA), are the investigational subjects of clinical trials that could potentially transform the treatment of hepatocellular carcinoma (HCC), according to a presentation here at the European Congress of Radiology 2011.

The presentation by Ricardo Lencioni, MD, associate professor of radiology at the University of Pisa, and director of the Division of Diagnostic Imaging and Intervention at Pisa University Hospital, Italy, covered a variety of approaches to improving HCC ablation outcomes. Unfortunately, long-term outcomes using conventional RFA remain unsatisfactory because new tumors emerge in about 80% of cases within 5 years.

"Recently, there was a randomized clinical trial comparing RFA and surgery, and it showed that surgery was better in terms of overall survival and tumor-free survival," said Dr. Lencioni.

Image-guided percutaneous RFA with ultrasound or computed tomography guidance is the standard of care in early-stage HCC when resection is not recommended. It is also often used for patients awaiting transplantation.

Dr. Lencioni said that in recent years, there has been a focus on optimizing RFA to kill tumors; this is usually achieved by combining therapies (e.g., combining RFA with drug-eluting beads).

This combination takes advantage of the transcatheter intraarterial administration of drug-eluting beads. "RFA is applied first, when we try to expose the tumor to lethal temperatures, but this may not always be enough to kill the tumor, particularly if it is greater than 3 cm, in which case the periphery might not reach the desired temperature," Dr. Lencioni said.

Cells that do not reach the lethal temperature are exposed to a sublethal temperature, which leaves them vulnerable to the effects of the cytotoxic drugs delivered by the drug-eluting beads. Dr. Lencioni explained that the standard dose of cytotoxic drug is effectively very potent because it applies to small volumes of peripheral tumor tissue.

However, added Dr. Lencioni, "there are limitations with this because of the need for RFA, followed by administration of the drugs, which involves a sequence of timely and complex procedures."

Dr. Lencioni presented the most recent findings from 2 clinical trials; he is principal investigator of both. First, the HEAT trial investigates a new carrier for doxorubicin called ThermoDox. This is a phase 3 randomized double-blinded placebo-controlled efficacy and safety study of thermally sensitive liposomal doxorubicin plus RFA vs RFA plus placebo infusion. Six hundred patients are being enrolled worldwide.

"The thermally sensitive liposomal doxorubicin is injected intravenously, avoiding a double procedure involving catheters. At the time of the RFA, the patient receives [intravenous] ThermoDox, which circulates in the body until it reaches tissue at or above 39 °C, [at which point] the membrane breaks down and the doxorubicin is released," Dr. Lencioni explained.

He noted that the concept of RFA has been revolutionized by its combination with the new carrier because it no longer relies on a lethal temperature. "So far in the trial, there are no safety concerns."

The second clinical trial currently recruiting participants relates to IRE. IRE is expected to kill tumors by irreversibly opening tumor cells with a series of short intense electric pulses from small electrodes placed in the tumor. "IRE is a completely new form of ablation unrelated to heat. The concept is the same, in that the needle is placed on the target, but instead of burning to 100 °C, as in RFA, the electrodes release a DC current that breaks open the cell membrane, and . . . the cell dies," Dr. Lencioni reported.

Currently, ablation with IRE low-energy direct current has clearance by the US Food and Drug Administration for the surgical ablation of soft tissue. In this phase 1/2 trial, Dr. Lencioni and colleagues aim to measure treatment efficacy within 30 days of treatment and safety.

"Experimental animal studies have suggested that some of the drawbacks related to the heat of RFA are no longer relevant with IRE, and definition of the area to treat is more predictable. Here . . ., I am presenting the design of the first phase 1/2 multicenter prospective international trial, involving 7 centers in Europe," Dr. Lencioni told Medscape Medical News.

Stephen B. Solomon, MD, chief of the Interventional Radiology Service at Memorial Sloan-Kettering Cancer Center, New York City, attested to the fact that both trials are important to the world of interventional oncology. He explained that although RFA has been an excellent tool for destroying localized tumors, efforts to improve results are welcome.

"ThermoDox is a very cleverly designed encapsulated version of the chemotherapy drug doxorubicin. The goal in combining ThermoDox with RFA is to expand the effects of RFA by allowing doxorubicin to be released in the elevated-temperature environment created by the RFA. This can help expand the kill zone to areas that might not be hot enough to kill cells, but are hot enough to release the drug," he said.

Dr. Solomon said that the trial of IRE in a clinical setting will be valuable to our understanding of the role of IRE in the future. He also pointed out that there are distinct advantages to using IRE over RFA.

"IRE can be advantageous over RFA, when nearby blood vessels that essentially cool down the area that is being heated by RFA prevent [the achievement of] sufficient temperatures to kill the tumor cells. IRE is independent of these 'cooling vessels' that create the 'heat sink'," Dr. Solomon explained.

"Furthermore, IRE kills through a mechanism that targets cells and may be able to preserve the protein infrastructure of organs," he added.

Celsion is sponsoring the study on ThermoDox. AngioDynamics is sponsoring the NanoKnife study. Dr. Lencioni has disclosed no relevant financial relationships. Dr. Solomon reports receiving research support from AngioDynamics, Johnson & Johnson, and GE.

European Congress of Radiology (ECR) 2011. Presented March 7, 2011.


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