BOSTON – A concurrent combination of the targeted agent sorafenib and stereotactic body radiotherapy showed promising efficacy against advanced liver cancer in a phase I clinical trial, but investigators found toxicity was unacceptable for clinical use.
Only 3 of 16 patients completed the study evaluating the safety of concurrent sorafenib (Nexavar) and stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC), Dr. Anthony Brade reported at the annual meeting of the American Society for Radiation Oncology.
Dr. Anthony Brade
"We found delivery concurrently of sorafenib and radiotherapy was challenging and likely limited by the volume of tumor and liver that’s irradiated, as well as drug dose," Dr. Brade, a radiation oncologist at the University of Toronto, said at a news briefing.
"Despite the advanced tumor burden and toxicity, the response rates we observed were encouraging," he added. "Sorafenib alone has a response rate under 2%, so to see response rates in the 36%-50% range was very encouraging."
Two of four patients with small tumors involving less than 40% of the liver had a partial response to the combined therapy, and the other two had stable disease over 8-12 weeks of follow-up. Among 11 patients with tumors involving 40%-60% of the liver, four had a partial response and 7 had stable disease. One patient died of tumor rupture before receiving radiation.
The investigators reported a 50% response rate for the smaller-tumor group and 36% for the larger-tumor group.
Promise and Peril
Sorafenib, a tyrosine kinase inhibitor, is standard of care for locally advanced HCC. In a 2008 study it was shown to improve overall survival and time to radiologic progression in patients with advanced HCC who were ineligible for local therapies but had good liver function (Child-Pugh Class A), Dr. Brade noted (N. Engl. J. Med. 2008;359:378-90). Preclinical data also suggest that the combination of sorafenib and radiotherapy may improve outcomes, he said.
Similar in concept to stereotactic radiosurgery with a cyberknife, SBRT is a technique for precise high-dose targeting of tissues from multiple angles and planes, allowing delivery of much larger doses by fraction than conformal three-dimensional or intensity-modulated radiation therapy. With SBRT, radiation therapy sessions can often be compressed into as little as four to six fractions delivered over 2-2.5 weeks, compared with 8-9 weeks of daily fractions for other techniques.
The current phase I study enrolled patients with good performance status, good liver function (Child-Pugh Class A), more than 800 cc of liver without tumor involvement, adequate hematologic parameters and liver and kidney function, and minimal extrahepatic disease.
The participants had a median age of 61.5 years, and 10 patients each had the significant adverse prognostic features of tumor thrombus and multiple lesions, Dr. Brade noted.
Patients with smaller tumors (stratum 1) were assigned to receive low effective liver volume irradiation at less than 30% of volume, with doses ranges from 39-54 Gy in six fractions over 2 weeks.
Patients with larger tumors had high effective volume (30%-60%) irradiation, with doses ranging from 39-54 Gy, also in six fractions. The maximum permitted doses to the gastrointestinal lumen was 31-34 Gy.
Patients received sorafenib 1 week prior to, during, and 4 weeks post SBRT, at which point escalation to full-dose sorafenib was allowed. Although the protocol called for escalating from an initial dose of 200 mg b.i.d. (400 mg daily) to 600 mg daily delivered in a 400-mg morning and a 200-mg evening dose and finally to 800 mg (400 mg b.i.d.), the study was closed before the maximum was reached in stratum 1. In stratum 1 patients, the 200 mg b.i.d. dose appeared to be tolerable, Dr. Brade said.
Four patients discontinued the drug at less than 4 weeks either because of tumor progression (2) or toxicity (2). There were three dose-limiting toxicities in the larger tumor cohort: a grade-4 small bowel obstruction, a grade-3 lower gastrointestinal tract bleed, and a death from an upper gastrointestinal bleed and tumor rupture. These toxicities led to dose reductions to 200 mg sorafenib daily (compared with a standard oral dose of 400 mg b.i.d.).
"We do not recommend concurrent sorafenib and SBRT outside the context of clinical trials," Dr. Brade said.
Sequential Trial Being Planned
Dr. Catherine Park
He noted that the outcomes of this trial have influenced the design of the Radiation Therapy Oncology Group (RTOG) 1112 phase III trial, which will compare sorafenib with sorafenib following stereotactic radiotherapy. The trial is still in its planning stages and the protocol has not been made public.
"The use of biologic targeting for radiosensitization in the context of SBRT is both a novel and promising approach," commented Dr. Catherine Park, a radiation oncologist at the University of California, San Francisco.