Chemotherapy, RFA may treat tumors up to 7 cm in diameter

Combination therapy involving radiofrequency ablation and transarterial administration of doxorubicin-eluting beads (DEB) may successfully extend interventional treatment to patients with few other options: those with large hepatocellular (HCC) tumors.

According to initial findings from a pilot study of 20 patients with tumors between 3 cm and 7 cm, the combination therapy elicited an impressive 74% objective tumor response rate, Prof. Ricardo Lencioni, a professor in the radiology department at the University of Pisa in Italy told attendees at the 2007 annual meeting of the Cardiovascular and Interventional Radiology Society of Europe (CIRSE), held in Athens in September.

"I think this study provides evidence that there could be synergy between RFA and a different way of using intra-arterial therapy," he said. "By using the sustained local release of [a chemotherapeutic] agent provided by [drug-eluting] microspheres, the effect of the treatment is increased."

RFA is a well-established option for treating patients with early-stage HCC. The technology has shown great promise over the past few years, with a comprehensive spectrum of devices becoming available that allow ablation spheres of up to 7 cm to be created with a single probe, Lencioni said.

However, the survival benefit from localized ablation techniques has been restricted to small tumors, those in the range of 2 cm or less, said Josep Llovet, head of the HCC Translational Research Lab and the liver unit of the Barcelona Clinic Liver Cancer (BCLC) Group in Spain.

The overall five-year survival rate following localized ablation was 42% and the survival rate for those with tumors smaller than 2 cm was 63% in a study of 282 patients cited by Llovet. In other studies, a tumor size of 2 cm has been critical for achieving favorable five-year survival rates after localized ablation, he said.

The choice of interventional technique does not appear to influence survival. In four head-to-head comparison trials, RFA and percutaneous ethanol injection significantly reduced the probability of local recurrence, but data supporting a survival advantage for RFA were not robust, Llovet said.

The effectiveness of RFA, particularly in the treatment of large HCC tumors, has been limited by perfusion-mediated cooling due to vascular flow. When a tumor is adjacent to a vessel, there is a chance that the portal or hepatic vein will lower the temperature by convection, according to Lencioni. And the larger the tumor size, the greater the chance that the mass will come in contact with a large vessel.

RFA is also limited by the propensity of HCC to penetrate the capsule and produce microsatellites in close proximity to the main tumor. The difference in tissue reactivity between tumor material and surrounding cirrhotic liver causes a dramatic drop in temperature and sublethal tissue heating.

Local exposure to a chemotherapeutic agent such as doxorubicin offers a possible answer for the treatment of large HCC tumors by acting directly on cells that have been damaged but not destroyed by RFA, he said.

In the pilot study, Lencioni took advantage of the introduction into clinical practice of DEB microspheres that release the agent in a controlled fashion.

"We hypothesized that the administration of doxorubicin-eluting beads to HCC tumors that were incompletely cured by RFA would result in an increase in tumor necrosis, hopefully improving tumor response," he said.

Administration of DEB did increase the mean area of RFA necrosis by 61%, which resulted in complete or partial ablation of tumors as large as 7 cm in diameter. Fifteen of the 20 patients (74%) had a complete or partial response to treatment, including 10 who had a complete response in the target lesion. Although survival was not an endpoint of the analysis, 92% of the patients were still alive 13 months after treatment.

Though he called for a randomized trial to determine a clear-cut survival benefit from combined RFA and DEB administration, Lencioni has faith in the technique.

"I do believe that combination therapy will be a way for the future," he said.