Current status of studies combining sorafenib with TACE
Multiple clinical trials in the United States and around the world are examining this novel approach in treating patients with HCC (Table 1). Chung and colleagues presented the interim analysis of a phase II trial using the combination of sorafenib and TACE in patients with unresectable HCC at the 2010 American Society of Clinical Oncology meeting.17 Eligibility criteria included intermediate stage of HCC (BCLC stage B) and a Child-Pugh score ≤ 7 in candidates for TACE therapy. The objective of the study was to evaluate the safety and efficacy of sorafenib after TACE.
Patients were treated with sorafenib (400 mg twice daily initiated on day 4) after the first TACE treatment (day 1). Sorafenib was interrupted 4 days before TACE and 4 days after the next TACE treatment. TACE was performed using lipiodol and doxorubicin (30–60 mg), for a maximum of 6 cycles. A computed tomography (CT) scan of the abdomen and serum alpha-fetoprotein (AFP) measurements were performed 4 weeks after each TACE procedure. Patients remained on sorafenib and underwent CT and AFP analysis every 3 months.
Preliminary data suggest that this approach is feasible, with expected side effects including hand-foot syndrome, fatigue, and neutropenia. Among the 50 patients who had at least two tumor assessments and were available for efficacy analysis, 18 patients (36%) achieved a complete response (CR), 30 patients (60%) had a partial response (PR) or stable disease (SD), and 2 patients (4%) had progressive disease.12
Another multicenter, phase II study was conducted by Erhardt and colleagues. 18 This study also investigated the combination of sorafenib and TACE for the treatment of HCC. Eligibility criteria were similar to the previous study. The primary study endpoint was TTP. Enrolled in the study were 44 patients, with a mean age of 67 years. The majority of patients had Child-Pugh A status (87%) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (79%). Disease etiology included hepatitis C (21%) and hepatitis B (23%), respectively.
Patients were treated with sorafenib (400 mg twice daily continuously), starting 2 weeks before the first TACE procedure. Sorafenib was stopped at least 3 days prior to TACE and could be resumed 1 day after improvement in liver function. TACE was performed using lipiodol and 50 mg of doxorubicin and was repeated at 6-week intervals if necessary. Patients received a mean of two TACE procedures (range, 1–10) and were treated for 6 cycles (range, 1–20).
TTP was estimated to be 491 days, progression-free survival was 242 days, and overall survival was estimated to be 356 days.18 Thirty-one patients received at least one TACE procedure and were evaluable for response. The disease control rate was 90% (28 of 31 patients), according to RECIST (Response Evaluation Criteria In Solid Tumors) criteria.
A large phase III study of sorafenib in patients who had responded to prior TACE was reported by Okita et al.19 A total of 552 patients with advanced HCC received TACE and were assessed by CT scan for response. Those who responded to TACE were stratified according to the type of response (CR vs non-CR), ECOG perperformance status (0 vs 1), and number of prior TACE procedures (1 vs 2) and randomized in a 1:1 ratio to receive either sorafenib (n = 229) or placebo (n = 229). The median time from TACE to receiving sorafenib was 9.3 weeks. The most common adverse events were hand-foot syndrome and elevated lipase levels.
In the analysis of the data, the median TTP was 5.4 months in the sorafenib group versus 3.7 months in the placebo group (hazard ratio [HR] = 0.87; P = 0.252). The median overall survival was 29.7 months in the sorafenib group and had not been reached (due to immaturity of the data) in the placebo group (HR = 1.06; P = 0.790).19 Hence, the addition of sorafenib did not significantly prolong the median TTP or overall survival in patients with HCC who had previously responded to TACE. The study was criticized on a number of accounts, including the delay in initiation of sorafenib and the relatively short duration of its use in most patients. Exploratory subgroup analysis showed that clinical benefit was noted in a younger Korean population.
More to learn from ongoing clinical trials
Currently, there are several multicenter clinical trials investigating the benefit of adding sorafenib to chemoembolization in patients with advanced HCC. SPACE is a multinational, randomized, double-blind, placebo-controlled study in patients with intermediate- stage HCC (BCLC stage B; defined as the presence of asymptomatic, unresectable, multinodular tumors without vascular invasion or extrahepatic spread). Major eligibility also includes Child-Pugh class A status without ascites. Eligible patients undergoing TACE with doxorubicin-eluting beads (loaded with 150 mg of doxorubicin) are randomized 1:1 to receive sorafenib (400 mg twice daily) or matching placebo orally on a continuous basis. Treatment cycles are repeated every 4 weeks until disease progression. TACE is performed on day 1 of cycles 1, 3, 7, and 13 and every 6 cycles thereafter. All endpoints will be assessed on an intent-to-treat analysis. The primary study endpoint is TTP. Secondary endpoints are overall survival, time to untreatable tumor progression, time to vascular invasion/extrahepatic tumor spread, and safety. Estimated overall accrual is 300 patients.