If sorafenib (Nexavar) and local ablation techniques are both effective in the treatment of metastatic hepatocellular carcinoma, could they deliver an even greater punch when combined? The concurrent use of interventional radiology approaches and sorafenib for metastatic hepatocellular carcinoma is being evaluated at major cancer centers, with research presented at the Society of Interventional Radiology 38th Annual Scientific Meeting.
Sorafenib plus Chemoembolization
Potential benefit for sorafenib plus doxorubicin-eluting bead-transarterial chemoembolization (DEB-TACE) was demonstrated in the final analysis of a phase II trial presented at the meeting by Jean-Francois (Jeff) H. Geschwind, MD, Professor of Radiology, Surgery, and Oncology and Director of the Division of Vascular and Interventional Radiology at Johns Hopkins University, Baltimore.1 The study’s first author was Allen Feng, a medical student at Hopkins.
Dr. Geschwind explained the rationale for the combination, noting that large clinical trials have established the survival benefit of sorafenib, while DEB-TACE is considered superior to conventional TACE, a common approach to metastatic hepatocellular carcinoma. “This is why we used DEB-TACE and sorafenib together,” he said.
The first prospective study of this combination included 50 patients with Child Pugh A to B7, Barcelona Clinic Liver Cancer (BCLC) class A to C, and good performance status. Patients with partial portal vein thrombosis and asymptomatic extrahepatic disease were allowed to enroll (whereas they were excluded in the SPACE trial, which evaluated this strategy and showed a statistically significant, though clinically small, benefit).2
“These were the typical patients we see in a tertiary care center,” Dr. Geschwind noted.
Patients received sorafenib at 800 mg/d beginning 1 week prior to DEB-TACE and underwent as many as four DEB-TACE treatments over 6 months. Aside from safety, the primary endpoint was time to untreatable progression, defined as the interval from the initiation of sorafenib until the patient was unable to receive further intra-arterial therapy. Outcomes were stratified according to whether patients were classified as BCLC A/B or BCLC C.
Key Results
The DEB-TACE/sorafenib concurrent treatment yielded a disease control rate of 98% at 1 month and 100% at 6 months, by both Response Evaluation Criteria in Solid Tumors (RECIST) and European Association for the Study of the Liver (EASL) criteria. “We were able to achieve a 100% disease control rate at 6 months, which is quite promising,” Dr. Geschwind commented.
Median time to untreatable progression was 15.4 months for the overall population. For BCLC A/B patients, median time to untreatable progression reached 29.1 months, whereas it decreased to 6.2 months for BCLC C patients (P < .001). “We viewed this as encouraging, even in the C group,” he commented.
Median overall survival was 20.4 months for the study population, including 32.4 months for BCLC A/B patients and 8.0 months for BCLC C patients (P < .001). When BCLC C patients were stratified by portal vein thrombosis, median overall survival was 17.1 months in those without this complication, and 7.2 months in those with thrombosis (P = .03).
Interestingly, median overall survival, stratified according to the duration of sorafenib use, showed that BLCL C patients who received at least 6 months of the drug lived much longer than those who received less than 6 months (21.0 vs. 6.8 months; P < .01). However, duration of sorafenib was inconsequential for BLCL A/B patients (28.2 vs 24.6 months; P = .52).
“These are promising survival outcomes,” Dr. Geschwind observed. “The addition of DEB-TACE to sorafenib for BCLC C patients may lead to improvements in survival.”
Safety was acceptable, and the “vast majority” of patients were able to stay on sorafenib, he said. The incidence of dose cessation requiring exit from the study was 27%.
“The imaging data support this combination,” Dr. Geschwind said. “Safety was established, and the efficacy data are promising, but we acknowledge that this is a single-arm, single-center trial with no comparator. Nevertheless, it appears that the addition of DEB-TACE to sorafenib may improve survival, especially in BLCL C patients.”
Sorafenib plus Radioembolization
Sorafenib is also being studied in combination with yttrium-90 radioembolization. Results from a retrospective analysis of this approach in a study led by Armeen Mahvash, MD, Associate Professor, and Ravi Murthy, MD, Professor, at The University of Texas MD Anderson Cancer Center, Houston, were reported at the meeting by Sameer Gadani, MD, an interventional oncology fellow at MD Anderson.3
Dr. Mahvash and colleagues asked whether the addition of yttrium-90 resin microspheres to sorafenib could improve tumor response without adding toxicity in patients with advanced or multifocal hepatocellular carcinoma. They retrospectively examined 19 patients with BCLC class B/C and Child Pugh class A0 to B7 treated between 2008 and 2010. Most patients were Child Pugh class A (n = 16) and BCLC C (n = 13).
All patients were on sorafenib prior to and following yttrium-90 treatment. Sorafenib was stopped 1 week prior to radioembolization and restarted after 1 week. Median follow-up was 19 months.
“We found that a local response (partial response, stable disease) was achieved in all patients, and overall survival and progression-free survival were increased as compared to prior studies of sorafenib alone in patients with similar disease status,” Dr. Gadani reported.
The partial response rate was 19% by RECIST criteria and 42% by EASL criteria; stable disease was observed in 81% and 58%, by these respective assessments.
Median overall survival was 19.5 months for the overall population, 54.9 months for BCLC B patients and 12.1 months for BCLC C patients. Median hepatic disease progression-free survival was 7.8, 9.3, and 6.9 months, respectively, for the above population, while extrahepatic disease progression-free survival was 8.9, 38.0, and 7.5 months, respectively.
The addition of yttrium-90 in patients receiving standard- or reduced-dose sorafenib did not increase the incidence of grade 4 adverse events (none were observed). There were four grade 3 adverse events (21%), including gastrointestinal ulcer, lymphopenia without life-threatening infection, mucositis, and abdominal pain/nausea/vomiting.
Looking Ahead
During the presentation, Dr. Gadani acknowledged the limitations of the study: It was a retrospective evaluation of a small number of patients, the treatment effect could be confounded by multiple other treatments the patients received before and after this approach, and selection bias was possible, since patients were already on sorafenib before the yttrium-90 treatment. Nevertheless, he said, the encouraging results warrant future prospective studies.
Robert K.W. Ryu, MD, of Northwestern University, Chicago, who moderated the radioembolization session, commented that the combined drug/embolization strategy is an active research area. “There are a number of ongoing studies. At Northwestern, we are sponsoring a single-center study of yttrium-90 with or without sorafenib,” he noted. Much of the current data come from retrospective studies, and prospective data are necessary to confirm the efficacy of this approach, he said. “It’s too early to tell, but the general feeling is one of optimism about the potential synergy between these two treatment modalities.” ■
Disclosure: Dr. Geschwind received grant support from NIH/NCI (RO1, KL2, R21), Abdulrahman Abdulmalik Research Fund Charles W. Pratt Foundation for Liver Cancer Research RSNA, SIR Foundation, and the Department of Defense, and pharmaceutical support from Genentech, Biocompatibles/BTG, Philips Healthcare, Nordion, Guerbet, and Bayer Healthcare. He is also a consultant for Bayer Healthcare, Genentech, Biocompatibles/BTG, Nordion, and Guerbet, and is CEO and founder of PreScience Labs. Dr. Gadani reported no potential conflicts of interest. Dr. Ryu is a consultant for IORAD.
References
1. Feng A, Reyes D, Kamel I, et al: Prospective phase II trial of sorafenib combined with doxorubicin eluting bead-transarterial chemoembolization for patients with unresectable hepatocellular carcinoma: Efficacy analysis. Society of Interventional Radiology Annual Scientific Meeting. Abstract 134. Presented April 16, 2013.
2. Lencioni R, Llovet JM, Han G, et al: Sorafenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediate-stage hepatocellular carcinoma (HCC): Phase II, randomized, double-blind SPACE trial. 2012 Gastrointestinal Cancers Symposium. Abstract LBA154. Presented January 20, 2012.
3. Gadani S, Mahvash A, Avritscher R, et al: Yttirum-90 resin microspheres as an adjunct to sorafenib in patients with unresectable HCC: A retrospective study for evaluation of survival benefit and adverse events. Society of Interventional Radiology Annual Scientific Meeting. Abstract 62. Presented April 15, 2013.
