Sorafenib + TACE for Advanced HCC
ABSTRACT & COMMENTARY
By William B. Ershler, MD
Synopsis: In an observational cohort of 222 hepatocellular cancer patients treated in China, transarterial chemoembolization (TACE) combined with sorafenib resulted in outcomes in terms of response rates and survival that compare favorably with prior series of sorafenib used alone. Although TACE is not typically used in U.S. patients with advanced disease, this series would indicate that it may prove an effective and safe adjunct to sorafenib and is worthy of exploration by prospective clinical trial.
Source:Zhao Y, et al. Sorafenib combined with transarterial chemoembolization for the treatment of advanced hepatocellular carcinoma:
A large-scale multicenter study of 222 patients. Ann Oncol 2013;24:1786-1792.
Worldwide, hepatocellular carcinoma (HCC) remains a major cause of cancer-related deaths and its incidence is increasing in the United States.1,2 Surgical excision remains the best chance for cure but unfortunately patients frequently present with advanced, unresectable disease. Patients with intermediate-stage disease are frequently treated with transarterial chemoembolization (TACE), and studies have indicated angiogenesis inhibitors such as sorafenib provide additional response rate and survival advantage.3,4 Until recently, TACE was considered inappropriate for patients with advanced disease. However, there has been a rationale presented that combining systemic and localized therapy (e.g., TACE) would improve outcomes even for patients with advanced disease.5 To investigate this hypothesis, Zhao and colleagues at seven treatment centers in China reviewed their collective experience with TACE plus sorafenib in patients with advanced HCC. For this study, data on 222 consecutive patients with advanced HCC treated from June 2008 through July 2011 were retrospectively analyzed.
HCC was diagnosed according to the criteria from the European Association for the Study of Liver Disease/American Association for the Study of Liver Disease and staging was per Barcelona Clinic Liver Cancer criteria.6 The inclusion criteria for the study population were as follows: an ECOG performance status of ≤ 2, Child-Pugh class A or B, HCC stage B or C, a baseline CT obtained just prior to therapy, an elapsed time of < 60 days between the beginning of sorafenib treatment and the first TACE procedure, and treatment and follow-up in one of the seven participating centers. All consecutive patients who met these criteria were included unless they had any of the following conditions: main portal vein obstruction, second primary malignancy, sorafenib discontinuation due to patient compliance, or a known transjugular intrahepatic portosystemic shunt. Chronic hepatitis B was causally related in 86% of enrolled subjects. Eighty percent of patients were at stage C, and 86% patients were in Child-Pugh class A.
In all cases, TACE consisted of an injection containing a mixture of chemotherapeutic agents followed by embolization with gelatin foam until complete stasis was achieved in the tumor-feeding vessels. The chemotherapeutic agents used concurrently included doxorubicin (10-50 mg), epirubicin (10-50 mg), cisplatin (10-110 mg), and/or mitomycin (2-10 mg); they were selected according to the preferred practices at each center. Tumor-feeding vessels were selected whenever possible. TACE was repeated as tolerated and indicated by radiological response. Sorafenib treatment was initiated at a dose of 400 mg twice daily and was administered continuously with no breaks before or after TACE. Standard follow-up evaluations (including CT) were carried out during weeks 4 and 8 after initiation of treatment and every 8 weeks thereafter. Overall survival (OS) was measured from the time treatment started until the time of death from any cause. Time to progression (TTP) was defined as the time from the baseline CT scan to radiological disease progression according to RECIST criteria.
During the study period, 302 patients received combined TACE/sorafenib. Of these, 222 met the inclusion criteria for this analysis. The majority of patients were male (84%) and the mean age was 51 years (range 23-80 years).
The overall median survival was 12 months (95% confidence interval [CI], 10.1-13.9). The rates of CR, PR, SD, and PD were 2%, 25%, 60%, and 14% respectively. The median TTP was 8.5 months (95% CI, 6.4-10.6 months). For patients with stage C disease, factors influencing OS included performance status, the number of nodules, Child-Pugh score, and macrovascular invasion.
The overall incidence of adverse events (AEs) was 87%. Most frequently observed were diarrhea (50%), hand-foot skin reaction (44%), rash (39%), and fatigue (33%). The most frequent grade 3 or 4 AEs were diarrhea (5%), hand-foot skin reaction (5%), and rash (4%).
This was a retrospective, observational series of consecutive HCC patients treated with combined local and systemic therapy at several centers in China. Distinct from HCC in the United States, the great majority (approaching 90%) of included patients had evidence for hepatitis B. However, what makes this study unique and of value is the advanced stage of the majority of patients included. Historically, and most notably in treatment centers outside of Asia, TACE has been generally reserved for those with earlier-stage disease and those with more advanced disease are often treated with single-agent sorafenib or a similar drug.7,8 Yet, there is an evolving rationale that for those with preserved liver function despite advanced stage HCC, TACE might be equal or even superior to sorafenib used alone.9 In fact, although comparisons between series of patients are imprecise, the outcomes for patients included in this study are at least comparable, if not superior to those observed for advanced HCC patients treated with sorafenib alone.7,8 Certainly, we have a long way to go in optimizing care for this group of patients with advanced HCC, but strategies that incorporate the use of TACE with sorafenib should be considered for further study in prospective, randomized trials.
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