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Phase II trial aims to extend ablation to larger liver tumors

This computed tomography (CT) image shows a nearly 6 cm ablation of a liver tumor of a patient who received RFA following either sorafenib or placebo in the double-blind study. Image courtesy of Salomao Faintuch.

Hepatocellular (HCC) cancer generally has a poor prognosis and, in contrast to other cancers in the United States, mortality is increasing. Unfortunately, less than one-third of patients are eligible for the potentially curative liver resection or liver transplant. Even then, the transplant wait list can be long—about one year in the New England region—and in many patients, cancer progresses while waiting for a donor.

Rebecca Miksad, MD, MPH (BIDMC), and her colleagues are leading the effort to expand treatment options for patients with larger HCC tumors who are on the transplant list or who are not surgical candidates. Miksad developed a randomized clinical trial to determine if the anti-angiogenic effects of the multi-kinase inhibitor sorafenib can make larger tumors susceptible to destruction by radiofrequency ablation (RFA).

“Studies have shown in humans and mice that if you can decrease the blood supply to the tumor, you can increase the size of the RFA coagulation zone, a measurement of the amount of the dead tumor,” Miksad says.

Objectives and importance of this trial

This phase II randomized, double-blind, placebo-controlled trial of 20 patients is designed to test if a short course of sorafenib prior to RFA increases the size of the RFA coagulation zone for tumors sized 3.5 to 7 cm.

RFA directly destroys tumor tissue with the heat generated from radiofrequency waves passing through a probe placed within the tumor under image guidance. This minimally invasive technique boasts a published 80 percent complete response rate in tumors measuring less than 3 cm across, with 80 to 90 percent one-year survival rates for patients with small tumors. For larger tumors, RFA efficacy falls off, plummeting to less than 25 percent complete response for tumors larger than 5 cm in diameter. Efforts to increase the size of tumors that RFA can effectively treat, such as those investigated in this trial, may greatly improve treatment options for patients with larger tumors.

In larger tumors, blood flow dissipates the heat generated by the radiofrequency probe, limiting the size and uniformity of the coagulation zone. Computer models suggest that blocking tumor blood flow can increase the coagulation zone up to 6.4 cm. Other groups have confirmed the concept in humans. Although improved RFA efficacy can be obtained by stopping blood flow during surgery (with balloons or with chemoemobilization), these procedures are relatively more invasive and add risks, said co-principal investigator Salomao Faintuch, MD (BIDMC), an interventional radiologist at BIDMC who performs the 12-minute ablation procedure in the study.

The trial builds on published pre-clinical work by Miksad’s colleagues at BIDMC to harness the antiangiogenic properities of anti-cancer therapies to limit tumor blood flow and, by doing so, increase RFA efficacy. A team led by Nahum Goldberg, MD (BIDMC), found that sorafenib increased the zone of RF heating and tumor destruction in mice transplanted with human renal cell carcinoma.

For a secondary objective, Miksad is evaluating a novel magnetic resonance imaging (MRI) technique to assess changes in blood flow in the liver tumor. These imaging techniques may provide a marker of antiangiogenic activity and may predict tumor response to antiangiogenic agents and to RFA. Miksad plans additional correlative studies for tumor tissue obtained during the RFA procedure.

Like all targeted therapies, sorafenib has potential side effects. However, most are usually mild, especially during the short treatment course of this trial. This study also collects safety data for combined antiangiogenic therapy and RFA.

Patients with liver tumors, including those referred for this trial, are evaluated in the BIDMC weekly liver tumor conference by a multidisciplinary team of physicians from hepatobiliary surgery, transplant surgery, hepatology, transplant hepatology, interventional radiation, radiology, pathology, oncology, and radiation oncology. This conference considers and assesses all treatment options and recommends the optimal individualized treatment plan. “Multidisciplinary assessment and care is particularly important for liver cancer,” Miksad says, "because there are so many treatment options available to patients at multiple times during the course of their disease."

Official title
Sorafenib Therapy Prior to Radiofrequency Ablation for Intermediate Sized Hepatocellular Cancer

Principal investigator
Rebecca Miksad, MD, MPH (BIDMC)
Co-Principal investigators:
Salomao Faintuch, MD (BIDMC)
Muneeb Ahmed, MD (BIDMC)

More information
For eligibility criteria go to NCT00813293 on ClinicalTrials.gov. To refer a patient to the trial, contact Dr. Rebecca Miksad at 617-667-4827 or rmiksad@bidmc.harvard.edu. Referral for evaluation of all liver masses can be facilitated by calling 1-877-LIVER-90.

— Carol Cruzan Morton