More Toxicity Associated With Addition of Sorafenib to Yttrium-90 Radioembolization Prior to Liver Transplantation
The addition of sorafenib (Nexavar) to yttrium-90 radioembolization was associated with higher rates of biliary complications and potentially more acute rejections prior to transplantation in patients with hepatocellular carcinoma, according to the results of a prospective randomized pilot study. These findings, reported by Kulik et al in the Journal of Hepatology, support the continued use of locoregional therapies in the bridge to transplantation, although ongoing sorafenib research may be of clinical interest earlier in the course of liver disease.
Traditionally, the best chance of long-term survival for patients with hepatocellular carcinoma has been liver transplantation. However, limited access to organs and the standard wait time for such organs have led researchers to search for other possible measures to prevent tumor progression in potential transplant candidates.
Liver-directed therapies such as yttrium-90 radioembolization typically serve as a bridge to transplantation for many patients with advanced hepatocellular carcinoma whose waiting time to transplant may exceed 6 months. With yttrium-90 radioembolization, microspheres are injected into the hepatic artery, and high doses of radiation are given locally through the tumor vasculature.
The researchers investigated the safety of adding sorafenib to yttrium-90 radioembolization vs yttrium-90 radioembolization alone in patients awaiting liver transplantation, focusing primarily on clinical tolerance, adverse events, and peritransplant complications. In an initial imaging analysis of this combination therapy, the investigators reported and published preliminary data showing that sorafenib did not increase the antitumoral effect of yttrium-90 radioembolization.
Study Details
In this single-center, prospective pilot study, 20 patients with hepatocellular carcinoma were randomized to receive yttrium-90 radioembolization alone (group A, 10 patients) or yttrium-90 radioembolization with sorafenib (group B, 10 patients). These patients were recruited through hepatology, hepatocellular carcinoma, interventional radiology, and pretransplantation clinics.
Study inclusion criteria included hepatocellular carcinoma confirmed by histology or imaging measures, Child-Pugh score ≤ B8, and potential candidacy for liver transplantation. Most of the patients (70%) had Child-Pugh A disease, and 90% had portal hypertension. Excluded from the study were patients who had extrahepatic disease, vascular invasion, or a performance status > 2. The median age of the entire study group was 59 years, and there were 13 men and 7 women.
Sorafenib was given 14 days prior to yttrium-90 radioembolization. The dose (800 mg/d) was adjusted based on the occurrence of toxicities. Patients were seen by a dermatologist before and after administration of sorafenib to monitor skin side effects, and fluocinonide 0.05% cream was prescribed for all patients.
Half of Patients Discontinued Sorafenib Due to Side Effects
Overall, the most common grade 3/4 biologic adverse effects were absolute lymphocyte toxicity (55%) and total bilirubin toxicity (45%). Patients in group A were found to have lymphocyte toxicity more frequently than those in group B, whereas the total bilirubin toxicity was well balanced between the two treatment groups.
Patients in group A had more fatigue, abdominal pain, and nausea than did those in group B. All patients in group B experienced sorafenib-related clinical side effects, mostly grade 1/2. However, 20% of patients in group B experienced grade 3/4 toxicities, which included hand-foot skin reaction.
All patients given sorafenib required permanent half-daily dose reduction. Sorafenib was discontinued in 50% of patients due to side effects (among them severe dermatologic toxicities such as erythroderma and worsening psoriasis). Finally, sorafenib was withheld in two patients as a result of hypertension and gastrointestinal side effects, and both of these patients declined to restart the drug after resolution of these symptoms.
Liver transplantation was performed in 17 patients (9 from group A and 8 from group B). In group B, there were three biliary anastomotic strictures and one leak followed by anastomotic stricture post transplantation. In contrast, there were no biliary complications in group A over the same period. Similarly, three transplanted patients from group B developed acute cellular rejection, compared with no patients from group A (P = .082).
Closing Thoughts
Although other retrospective studies are investigating sorafenib, this is reportedly the first prospective randomized design of neoadjuvant sorafenib prior to transplantation. Similar to the findings in other reports, the investigators found that the addition of sorafenib to yttrium-90 radioembolization was linked to a higher incidence of biliary complications and a strong trend toward more acute cellular rejection. The investigators admitted, however, that their limited patient sample size at a single institution made it difficult to reach definitive conclusions regarding the impact of sorafenib in conjunction with locoregional therapies and whether it provided a protective effect in bridging patients to liver transplantation.
“Caution should be exercised when considering sorafenib prior to orthotopic liver transplantation, and further studies are needed,” they concluded.
Riad Salem, MD, MBA, of the Department of Radiology, Northwestern University, Chicago, is the corresponding author for the article in the Journal of Hepatology.
Partial support of this study was provided by Bayer/Onyx. Dr. Kulik is an advisor to Bayer/Onyx. Dr. Salem and Mary F. Mulcahy, MD, are principal investigators for trials involving glass microspheres.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
