Daniel M. Keller, PhD

May 10, 2013

AMSTERDAM, the Netherlands — For patients with unresectable intermediate-stage hepatocellular carcinoma, selective internal radioembolization and standard transarterial chemoembolization provide equivalent outcomes, new research shows. The advantage of radioembolization is that it can be administered in a single treatment.

"Our small pilot study suggests that a single session of radioembolization is as safe and effective as multiple sessions of chemoembolization. There are no differences between radioembolization and chemoembolization in terms of health-related quality of life, progression-free survival, or severity of adverse events," said Frank Kolligs, MD, from the University of Munich in Germany.

Dr. Kolligs presented the study results here at the International Liver Congress 2013.

Although both approaches can result in downstaging of the disease, possibly allowing for curative surgery or transplantation, chemoembolization is considered the treatment of choice for inoperable intermediate-stage hepatocellular carcinoma in guidelines from the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases. However, chemoembolization is often associated with postembolization syndrome.

Dr. Kolligs and his team conducted an open-label, randomized, prospective study of 28 evaluable patients from 2 university centers. This sample size allowed them to compare the different approaches for health-related quality of life.

They screened patients with liver angiography and then randomized them to radioembolization or chemoembolization. Study participants were 18 years or older, had a performance status of 0 or 1, Child–Pugh class B-7 cirrhosis or lower, and a bilirubin level of 2 mg/dL or less. Exclusion criteria were previous chemoembolization treatment, extrahepatic disease or portal vein occlusion, more than 5 lesions, any lesion 10 cm or larger, a cumulative lesion diameter of 20 cm or larger, and anticipated liver resection or transplantation.

At baseline, 85% of participants were men, mean age was 65.6 years, and time since diagnosis ranged from 0.8 to 1.1 months. Most had a Child–Pugh score of 5; the rest (31% in the radioembolization group and 40% in the chemoembolization group) had a score of 6 or 7. Six of 13 patients in the radioembolization group and 4 of 15 in the chemoembolization group had Barcelona Clinic Liver Cancer stage A disease; the rest of the patients had stage B disease.

Patients in the radioembolization group received a single brachytherapy treatment as a whole-liver, lobar, or segmental procedure (n = 13) using yttrium-90 radionuclide microspheres (32 µm; median, 1.6 Gbq). Patients in the chemoembolization group (n = 15) were treated with epirubicin 50 mg in Lipiodol 5 mL (iodized oil) and Embosphere microspheres (150 to 300 µm or 300 to 500 µm) every 6 weeks. Chemoembolization patients were assessed before each procedure, and underwent a mean of 3.5 sessions.

Treatment response was assessed by local and independent central examiners using RECIST (Response Evaluation Criteria in Solid Tumors). Patients were followed for a minimum of 12 months or until death.

Quality of Life Maintained With Either Therapy

We found "no detectable difference in health-related quality of life" between the 2 treatments over the first 12 weeks, Dr. Kolligs reported. Quality-of-life measures included dimensions of physical, social, emotional, and functional well being, as well as health concerns assessed on a hepatobiliary scale.

There was no difference between radioembolization and chemoembolization in progression-free survival, determined by intention-to treat-analysis (3.6 vs 3.7 months; log-rank P = .374).

There was also no difference in objective response rates between radioembolization and chemoembolization (23.1% vs 33.3%), and no difference in disease control rates (69.2% vs 67.7%).

At follow-up, 1 radioembolization patient and 2 chemoembolization patients were downstaged for liver transplantation. In addition, 1 radioembolization patient was downstaged for radiofrequency ablation, and that patient "has had no evidence of disease for the past 3 years," Dr. Kolligs reported.

Kaplan–Meier analysis showed no difference in survival between the radioembolization and chemoembolization groups at 6-month follow-up (69.2% vs 86.7%) or at 12-month follow-up (46.2% vs 66.7%; P = .244).

After progression, 4 patients in the chemoembolization group underwent additional treatment and 2 underwent radioembolization. One patient in the radioembolization group had additional treatment and 1 underwent additional chemoembolization.

There were 4 serious adverse events (grade 3 or 4) in each group. The most common adverse events were ascites, fatigue, and infection in the radioembolization group, and infection in the chemoembolization group.

There were only minor changes in liver function tests from baseline, and only in the radioembolization group, where total bilirubin elevations of grade 3 or higher were seen in 2 patients at 3 months and in 1 patient at 6 months.

For radioembolization, patient selection is important. "If you don't pay attention to liver function, and I guess the best parameter is bilirubin, then the patient has a risk of developing radiation-induced liver disease, which is a further impairment of liver function, ascites, and other symptoms," Dr. Kolligs told Medscape Medical News. A bilirubin level of 2 mg/dL should be the cutoff, he said.

Treatment decisions are made by an interdisciplinary tumor board. "We usually perform chemoembolization in patients with a limited number of tumor nodules that are usually not larger than 6 to 8 cm. If patients have very many nodules or very large nodules, if patients have a portal vein thrombosis, then we discuss performing radioembolization," he explained.

In response to an audience question about whether the 32 µm radioactive microspheres could end up in the systemic circulation, he said that all patients are screened with magnetic resonance angiography before initiating therapy to rule out significant shunting. In fact, 2 patients were excluded from the study for this reason.

In my opinion, these findings "show that it would be very reasonable and timely to have a large phase 3 study conducted to compare these 2 treatments in patients with intermediate [hepatocellular carcinoma] to really show where the place of this treatment could be," said Markus Peck-Radosavljevic, MD, from the Medical University of Vienna in Austria, and the new EASL secretary general.

Dr. Kolligs added a caveat: "There is definitely a place for radioembolization in the treatment algorithm. However, because of the lack of randomized clinical studies, we can't tell exactly where this place is." Unfortunately, a noninferiority trial would require 1500 patients, and a trial with adequate power to show the superiority of one treatment over the other would require 60,000 patients, Dr. Kolligs explained.

"This underscores the problem of designing a randomized controlled study for intermediate-stage hepatocellular carcinoma," he noted, but added that there are 3 trials in progress for more advanced disease.

In general, some intermediate-stage patients do quite well with chemoembolization, but others do not, Dr. Peck-Radosavljevic pointed out. "The problem is that when you do a transarterial treatment, you block the arterial blood supply to the liver. That kills the tumor but is not always good for the liver," he explained. "What you see when you're treating those patients is that some have very, very, very long survival, whereas others, who you think are in quite good condition, deteriorate very fast after this kind of treatment."

Dr. Kolligs reports being a speaker for Sirtex Medical, Bayer, and Pfizer, and a member of the advisory board for Bayer. Dr. Peck-Radosavljevic reports being a consultant to AbbVie, Roche, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Janssen, Eli Lilly, Jennerex, Merz, MSD, and Novartis.

International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 114. Presented April 27, 2013.