Combining sorafenib with chemoembolization for hepatocellular cancer

The incidence of hepatocellular carcinoma (HCC) has increased over the past decade, with an estimated 1 million new cases per year worldwide. In 2010 in the United States alone, it was expected that over 24,000 new cases would be diagnosed, with approximately 19,000 deaths.1 The incidence of HCC in the Western world is expected to rise until 2020 because of the large population of patients infected with the hepatitis C virus. 2 Furthermore, epidemiologic data suggest that many patients with cryptogenic cirrhosis have nonalcoholic steatohepatitis (NASH) as the cause of their chronic liver disease.3 Due to the rise in obese patient populations, NASH could be an important risk factor for patients with cirrhosis.

Surgical resection and liver transplantation are the preferred treatments of HCC, because they both are potentially curative. Unfortunately, only 10%–15% of patients are candidates for either of these approaches.4 Patients with liver-limited disease who are not candidates for liver transplantation or resection may be managed by liver-directed therapies. Common treatment modalities include ablation (eg, microwave ablation, radiofrequency ablation, and cryoablation), chemoembolization, and radioembolization.

Systemic therapy for HCC

HCC is considered a chemotherapy-resistant malignancy. Systemic chemotherapy approaches have been ineffective in patients with HCC, with increased toxicities.5 However, the introduction of sorafenib (Nexavar) has changed the landscape of systemic therapy for HCC and opened up opportunities for development of new drug regimens and multidisciplinary approaches in the treatment of those patients. Sorafenib is a smallmolecule kinase inhibitor that blocks multiple intracellular and cell-surface kinases (KIT, FLT3, RET, VEGFR- 1, VEGFR-2, VEGFR-3, and PDGFR- b) involved in cell signaling, angiogenesis, and apoptosis.6

In two large international studies (SHARP and Asia-Pacific) in patients with advanced HCC, sorafenib showed improvement in time to tumor progression (TTP) as well as in overall survival compared with placebo.7,8 Patients in these two studies had a Child-Pugh classification of A and a favorable performance status. The hypervascularity of HCC and the predominant effect of sorafenib of vascular endothelial growth factor receptor (VEGFR)-related tyrosine kinase activity provided the proof of principle for targeting angiogenesis in this disease.

In the multicenter, phase III, double-blinded, placebo-controlled SHARP trial,7 602 patients with advanced HCC who had not received previous systemic treatment were given either sorafenib (400 mg twice daily) or placebo. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. The median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group.7 In 2007, sorafenib was granted US Food and Drug Administration approval for the treatment of patients with advanced HCC.

Overview of chemoembolization

Transarterial chemoembolization (TACE) is the most widely used approach in the palliative setting and in some patients considered for liver transplantation. Embolization of the hepatic artery and its branches causes ischemic necrosis in the tumor cells that derive their blood supply predominantly from the hepatic artery. In contrast, the normal liver parenchyma is fed primarily by the portal system. The additional mechanism of action of chemoembolization is the trapping of cytotoxic agents within the embolized tissue. This process occurs because the lipiodol, which is used in most regimens, flows through the malignant tissues and parenchyma to obstruct portal vein inflow and hepatic vein washout, whereas particulate material employed near the end of the embolization procedure acts by entrapping the agents through blocking the hepatic arterial supply inflow.

Doxorubicin is the most commonly used cytotoxic drug in conjunction with embolization. Other agents used include mitomycin C and cisplatin. Partial responses in the range of 20%– 50% have been reported in the literature. 9,10 Two randomized trials and meta-analyses of chemoembolization in approximately 500 patients showed clinical benefit of this approach when compared with conservative management in patients with HCC.9,10 These patients were not candidates for either resection or transplantation.

Mild systemic toxicity continues to be an advantageous part of chemoembolization. Although upward of 90% of patients experience the symptoms of postembolization syndrome, which include fever, nausea, vomiting, and abdominal pain, they are generally self-limited and confined to the immediate acute postprocedure period. More serious toxicities such as anemia, liver decompensation, and infection (including cholecystitis) are rare and mostly encountered in patients with more advanced disease.11

Rationale for combining sorafenib with TACE

Treatment with TACE alone causes necrosis of tumor tissue, with transient elevations of levels of many angiogenic growth factors (such as VEGF and plasma insulin-like growth factor 2 [IGF-2]).12,13 High expression of stem cell likeness and tumor angiogenesis results in a poor prognosis. 14,15 Emerging clinical data also suggest that increased VEGF levels post TACE may be associated with an increased chance of disease progression. 16 These angiogenic factors may be responsible for the limited longterm benefit of TACE seen in patients with HCC. Therefore, the combination of sorafenib with TACE may have the potential to improve clinical outcomes in patients with HCC by blocking this angiogenic signaling activated by the chemoembolization.

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.

The HeiLivCa study,20 ECOG 1208, and the TACE-2 study are also addressing similar questions with slightly different patient populations. For example, the open ECOG 1208 study randomizes patients to receive sorafenib or placebo in conjunction with TACE and allows the interventionalist to choose one of a few different chemoembolization methods. Liver-directed therapy can take the form of conventional TACE, using the mixture of doxorubicin, mitomycin, and cisplatin described previously. However, embolization may also be completed by employing conventional Ethiodol (ethiodized oil) TACE, using only doxorubicin or doxorubicin-loaded beads. This varied approach may provide an analytic advantage, because the design better mirrors what is happening at institutions around the world.

The optimal scheduling of sorafenib in relation to TACE has yet to be determined, but with these trials, the elucidation of combination therapy will be discovered. For instance, the TACE-2 trial is not only comparing drug-eluting beads with and without sorafenib but is also additionally randomizing patients into two arms. One arm starts sorafenib or placebo at day 0, whereas the other arm begins with sorafenib or placebo at day 7 after TACE (2–5 weeks post randomization). This study will help to clarify the timing of combination therapy for HCC.

Conclusion

With increased angiogenic factors following embolization and the emergence of specific agents to target those factors, a potential benefit of targeting angiogenesis as an adjunct to TACE may be expected. Although the rationale is sound and safety has been demonstrated in preliminary studies,21,22 using sorafenib in patients with HCC receiving chemoembolization is not yet recommended outside the clinical trial setting. Over the coming years, efficacy data from ongoing randomized studies will be available. It is best to support the current ongoing clinical trials so we may reach a definitive answer. With the increasing awareness among community oncologists and their participation in clinical trials, we should be able to optimize the use of sorafenib in combination with TACE and extend its use in conjunction with other locoregional therapies.

References

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300.
2. El-Serag HB, Mason AC. Risk factors for the rising rates of primary liver cancer in the United States. Arch Intern Med 2000;160:3227–3230.
3. Caldwell SH, Oelsner DH, Iezzoni JC, et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999;29:664–669.
4. Llovet JM. Treatment of hepatocellular carcinoma. Curr Treat Options Gastroenterol 2004;7:431–441.
5. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907– 1917.
6. Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/ PRF/5. Cancer Res 2006;66:11851–11858.
7. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinomacarcinoma. N Engl J Med 2008;359:378–390.
8. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, doubleblind, placebo-controlled trial. Lancet Oncol 2009;10:25–34.
9. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003;37:429–442.
10. Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002;224:47–54.
11. Leung DA, Goin JE, Sickles C, Raskay BJ, Soulen MC. Determinants of postembolization syndrome after hepatic chemoembolization. J Vasc Interv Radiol 2001;12:321–326.
12. Sergio A, Cristofori C, Cardin R, et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol 2008;103:914–921.
13. Li X, Feng GS, Zheng CS, Zhuo CK, Liu X. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 2004;10:2878–2882.
14. Yang XR, Xu Y, Yu B, et al. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut 2010;59:953–962.
15. Hu J, Xu Y, Shen ZZ, et al. High expressions of vascular endothelial growth factor and platelet-derived endothelial cell growth factor predict poor prognosis in alpha-fetoprotein- negative hepatocellular carcinoma patients after curative resection. J Cancer Res Clin Oncol 2009;135:1359–1367.
16. Xiong ZP, Yang SR, Liang ZY, et al. Association between vascular endothelial growth factor and metastasis after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2004;3:386–390.
17. Chung Y, Kim B, Chen C, et al. Study in Asia of the combination of transarterial chemoembolization (TACE) with sorafenib in patients with hepatocellular carcinoma trial (START): second interim safety and efficacy analysis. J Clin Oncol 2010;28[15S]:4026.
18. Erhardt A, Kolligs FT, Dollinger MM, et al. First-in-men demonstration of sorafenib plus TACE for the treatment of advanced hepatocellular carcinoma (SOCRATES trial). Presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases; October 30–November 3, 2009; Boston, MA.
19. Okita K, Imanaka K, Chida N, et al. Phase III study of sorafenib in patients in Japan and South Korea with advanced hepatocellular carcinoma (HCC) treated after transarterial chemoembolization (TACE). Presented at the 2010 Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, FL. Abstract LBA128.
20. Hoffmann K, Glimm H, Radeleff B, et al. Prospective, randomized, double-blind, multi-center, phase III clinical study on transarterial chemoembolization (TACE) combined with sorafenib versus TACE plus placebo in patients with hepatocellular cancer before liver transplantation–HeiLivCa [ISRCTN24081794]. BMC Cancer 2008;8:349.
21. Reyes DK, Azad NS, Koteish A, et al. Phase II trial of sorafenib combined with doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) for patients with unresectable hepatocellular carcinoma (HCC): interim safety and efficacy analysis. Presented at the 2010 Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, FL. Abstract 254.
22. Valenti DA, Cabrera T, Khankan A, et al. Combined sorafenib and yttrium-90 radioembolization in the treatment of advanced HCC: preliminary results. J Vasc Interv Radiol 2009;20(suppl):S65–S66. Abstract 169.

ABOUT THE AUTHORS

Affiliations: Dr. Choi is Assistant Professor of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI. Dr. Critchfield is Assistant Professor of Radiology and Chief of Interventional Oncology, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI. Dr. Philip is Professor of Medicine, Wayne State University School of Medicine, and Clinical Professor of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI. Conflicts of interest: The authors have no conflicts of interest to disclose.

The incidence of hepatocellular carcinoma (HCC) has increased over the past decade, with an estimated 1 million new cases per year worldwide. In 2010 in the United States alone, it was expected that over 24,000 new cases would be diagnosed, with approximately 19,000 deaths.1 The incidence of HCC in the Western world is expected to rise until 2020 because of the large population of patients infected with the hepatitis C virus. 2 Furthermore, epidemiologic data suggest that many patients with cryptogenic cirrhosis have nonalcoholic steatohepatitis (NASH) as the cause of their chronic liver disease.3 Due to the rise in obese patient populations, NASH could be an important risk factor for patients with cirrhosis.

Surgical resection and liver transplantation are the preferred treatments of HCC, because they both are potentially curative. Unfortunately, only 10%–15% of patients are candidates for either of these approaches.4 Patients with liver-limited disease who are not candidates for liver transplantation or resection may be managed by liver-directed therapies. Common treatment modalities include ablation (eg, microwave ablation, radiofrequency ablation, and cryoablation), chemoembolization, and radioembolization.

Systemic therapy for HCC

HCC is considered a chemotherapy-resistant malignancy. Systemic chemotherapy approaches have been ineffective in patients with HCC, with increased toxicities.5 However, the introduction of sorafenib (Nexavar) has changed the landscape of systemic therapy for HCC and opened up opportunities for development of new drug regimens and multidisciplinary approaches in the treatment of those patients. Sorafenib is a smallmolecule kinase inhibitor that blocks multiple intracellular and cell-surface kinases (KIT, FLT3, RET, VEGFR- 1, VEGFR-2, VEGFR-3, and PDGFR- b) involved in cell signaling, angiogenesis, and apoptosis.6

In two large international studies (SHARP and Asia-Pacific) in patients with advanced HCC, sorafenib showed improvement in time to tumor progression (TTP) as well as in overall survival compared with placebo.7,8 Patients in these two studies had a Child-Pugh classification of A and a favorable performance status. The hypervascularity of HCC and the predominant effect of sorafenib of vascular endothelial growth factor receptor (VEGFR)-related tyrosine kinase activity provided the proof of principle for targeting angiogenesis in this disease.

In the multicenter, phase III, double-blinded, placebo-controlled SHARP trial,7 602 patients with advanced HCC who had not received previous systemic treatment were given either sorafenib (400 mg twice daily) or placebo. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. The median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group.7 In 2007, sorafenib was granted US Food and Drug Administration approval for the treatment of patients with advanced HCC.

Overview of chemoembolization

Transarterial chemoembolization (TACE) is the most widely used approach in the palliative setting and in some patients considered for liver transplantation. Embolization of the hepatic artery and its branches causes ischemic necrosis in the tumor cells that derive their blood supply predominantly from the hepatic artery. In contrast, the normal liver parenchyma is fed primarily by the portal system. The additional mechanism of action of chemoembolization is the trapping of cytotoxic agents within the embolized tissue. This process occurs because the lipiodol, which is used in most regimens, flows through the malignant tissues and parenchyma to obstruct portal vein inflow and hepatic vein washout, whereas particulate material employed near the end of the embolization procedure acts by entrapping the agents through blocking the hepatic arterial supply inflow.

Doxorubicin is the most commonly used cytotoxic drug in conjunction with embolization. Other agents used include mitomycin C and cisplatin. Partial responses in the range of 20%– 50% have been reported in the literature. 9,10 Two randomized trials and meta-analyses of chemoembolization in approximately 500 patients showed clinical benefit of this approach when compared with conservative management in patients with HCC.9,10 These patients were not candidates for either resection or transplantation.

Mild systemic toxicity continues to be an advantageous part of chemoembolization. Although upward of 90% of patients experience the symptoms of postembolization syndrome, which include fever, nausea, vomiting, and abdominal pain, they are generally self-limited and confined to the immediate acute postprocedure period. More serious toxicities such as anemia, liver decompensation, and infection (including cholecystitis) are rare and mostly encountered in patients with more advanced disease.11

Rationale for combining sorafenib with TACE

Treatment with TACE alone causes necrosis of tumor tissue, with transient elevations of levels of many angiogenic growth factors (such as VEGF and plasma insulin-like growth factor 2 [IGF-2]).12,13 High expression of stem cell likeness and tumor angiogenesis results in a poor prognosis. 14,15 Emerging clinical data also suggest that increased VEGF levels post TACE may be associated with an increased chance of disease progression. 16 These angiogenic factors may be responsible for the limited longterm benefit of TACE seen in patients with HCC. Therefore, the combination of sorafenib with TACE may have the potential to improve clinical outcomes in patients with HCC by blocking this angiogenic signaling activated by the chemoembolization.

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.

The HeiLivCa study,20 ECOG 1208, and the TACE-2 study are also addressing similar questions with slightly different patient populations. For example, the open ECOG 1208 study randomizes patients to receive sorafenib or placebo in conjunction with TACE and allows the interventionalist to choose one of a few different chemoembolization methods. Liver-directed therapy can take the form of conventional TACE, using the mixture of doxorubicin, mitomycin, and cisplatin described previously. However, embolization may also be completed by employing conventional Ethiodol (ethiodized oil) TACE, using only doxorubicin or doxorubicin-loaded beads. This varied approach may provide an analytic advantage, because the design better mirrors what is happening at institutions around the world.

The optimal scheduling of sorafenib in relation to TACE has yet to be determined, but with these trials, the elucidation of combination therapy will be discovered. For instance, the TACE-2 trial is not only comparing drug-eluting beads with and without sorafenib but is also additionally randomizing patients into two arms. One arm starts sorafenib or placebo at day 0, whereas the other arm begins with sorafenib or placebo at day 7 after TACE (2–5 weeks post randomization). This study will help to clarify the timing of combination therapy for HCC.

Conclusion

With increased angiogenic factors following embolization and the emergence of specific agents to target those factors, a potential benefit of targeting angiogenesis as an adjunct to TACE may be expected. Although the rationale is sound and safety has been demonstrated in preliminary studies,21,22 using sorafenib in patients with HCC receiving chemoembolization is not yet recommended outside the clinical trial setting. Over the coming years, efficacy data from ongoing randomized studies will be available. It is best to support the current ongoing clinical trials so we may reach a definitive answer. With the increasing awareness among community oncologists and their participation in clinical trials, we should be able to optimize the use of sorafenib in combination with TACE and extend its use in conjunction with other locoregional therapies.

References

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300.
2. El-Serag HB, Mason AC. Risk factors for the rising rates of primary liver cancer in the United States. Arch Intern Med 2000;160:3227–3230.
3. Caldwell SH, Oelsner DH, Iezzoni JC, et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999;29:664–669.
4. Llovet JM. Treatment of hepatocellular carcinoma. Curr Treat Options Gastroenterol 2004;7:431–441.
5. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907– 1917.
6. Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/ PRF/5. Cancer Res 2006;66:11851–11858.
7. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinomacarcinoma. N Engl J Med 2008;359:378–390.
8. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, doubleblind, placebo-controlled trial. Lancet Oncol 2009;10:25–34.
9. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003;37:429–442.
10. Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002;224:47–54.
11. Leung DA, Goin JE, Sickles C, Raskay BJ, Soulen MC. Determinants of postembolization syndrome after hepatic chemoembolization. J Vasc Interv Radiol 2001;12:321–326.
12. Sergio A, Cristofori C, Cardin R, et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol 2008;103:914–921.
13. Li X, Feng GS, Zheng CS, Zhuo CK, Liu X. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 2004;10:2878–2882.
14. Yang XR, Xu Y, Yu B, et al. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut 2010;59:953–962.
15. Hu J, Xu Y, Shen ZZ, et al. High expressions of vascular endothelial growth factor and platelet-derived endothelial cell growth factor predict poor prognosis in alpha-fetoprotein- negative hepatocellular carcinoma patients after curative resection. J Cancer Res Clin Oncol 2009;135:1359–1367.
16. Xiong ZP, Yang SR, Liang ZY, et al. Association between vascular endothelial growth factor and metastasis after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2004;3:386–390.
17. Chung Y, Kim B, Chen C, et al. Study in Asia of the combination of transarterial chemoembolization (TACE) with sorafenib in patients with hepatocellular carcinoma trial (START): second interim safety and efficacy analysis. J Clin Oncol 2010;28[15S]:4026.
18. Erhardt A, Kolligs FT, Dollinger MM, et al. First-in-men demonstration of sorafenib plus TACE for the treatment of advanced hepatocellular carcinoma (SOCRATES trial). Presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases; October 30–November 3, 2009; Boston, MA.
19. Okita K, Imanaka K, Chida N, et al. Phase III study of sorafenib in patients in Japan and South Korea with advanced hepatocellular carcinoma (HCC) treated after transarterial chemoembolization (TACE). Presented at the 2010 Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, FL. Abstract LBA128.
20. Hoffmann K, Glimm H, Radeleff B, et al. Prospective, randomized, double-blind, multi-center, phase III clinical study on transarterial chemoembolization (TACE) combined with sorafenib versus TACE plus placebo in patients with hepatocellular cancer before liver transplantation–HeiLivCa [ISRCTN24081794]. BMC Cancer 2008;8:349.
21. Reyes DK, Azad NS, Koteish A, et al. Phase II trial of sorafenib combined with doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) for patients with unresectable hepatocellular carcinoma (HCC): interim safety and efficacy analysis. Presented at the 2010 Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, FL. Abstract 254.
22. Valenti DA, Cabrera T, Khankan A, et al. Combined sorafenib and yttrium-90 radioembolization in the treatment of advanced HCC: preliminary results. J Vasc Interv Radiol 2009;20(suppl):S65–S66. Abstract 169.

ABOUT THE AUTHORS

Affiliations: Dr. Choi is Assistant Professor of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI. Dr. Critchfield is Assistant Professor of Radiology and Chief of Interventional Oncology, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI. Dr. Philip is Professor of Medicine, Wayne State University School of Medicine, and Clinical Professor of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI. Conflicts of interest: The authors have no conflicts of interest to disclose.

The incidence of hepatocellular carcinoma (HCC) has increased over the past decade, with an estimated 1 million new cases per year worldwide. In 2010 in the United States alone, it was expected that over 24,000 new cases would be diagnosed, with approximately 19,000 deaths.1 The incidence of HCC in the Western world is expected to rise until 2020 because of the large population of patients infected with the hepatitis C virus. 2 Furthermore, epidemiologic data suggest that many patients with cryptogenic cirrhosis have nonalcoholic steatohepatitis (NASH) as the cause of their chronic liver disease.3 Due to the rise in obese patient populations, NASH could be an important risk factor for patients with cirrhosis.

Surgical resection and liver transplantation are the preferred treatments of HCC, because they both are potentially curative. Unfortunately, only 10%–15% of patients are candidates for either of these approaches.4 Patients with liver-limited disease who are not candidates for liver transplantation or resection may be managed by liver-directed therapies. Common treatment modalities include ablation (eg, microwave ablation, radiofrequency ablation, and cryoablation), chemoembolization, and radioembolization.

Systemic therapy for HCC

HCC is considered a chemotherapy-resistant malignancy. Systemic chemotherapy approaches have been ineffective in patients with HCC, with increased toxicities.5 However, the introduction of sorafenib (Nexavar) has changed the landscape of systemic therapy for HCC and opened up opportunities for development of new drug regimens and multidisciplinary approaches in the treatment of those patients. Sorafenib is a smallmolecule kinase inhibitor that blocks multiple intracellular and cell-surface kinases (KIT, FLT3, RET, VEGFR- 1, VEGFR-2, VEGFR-3, and PDGFR- b) involved in cell signaling, angiogenesis, and apoptosis.6

In two large international studies (SHARP and Asia-Pacific) in patients with advanced HCC, sorafenib showed improvement in time to tumor progression (TTP) as well as in overall survival compared with placebo.7,8 Patients in these two studies had a Child-Pugh classification of A and a favorable performance status. The hypervascularity of HCC and the predominant effect of sorafenib of vascular endothelial growth factor receptor (VEGFR)-related tyrosine kinase activity provided the proof of principle for targeting angiogenesis in this disease.

In the multicenter, phase III, double-blinded, placebo-controlled SHARP trial,7 602 patients with advanced HCC who had not received previous systemic treatment were given either sorafenib (400 mg twice daily) or placebo. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. The median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group.7 In 2007, sorafenib was granted US Food and Drug Administration approval for the treatment of patients with advanced HCC.

Overview of chemoembolization

Transarterial chemoembolization (TACE) is the most widely used approach in the palliative setting and in some patients considered for liver transplantation. Embolization of the hepatic artery and its branches causes ischemic necrosis in the tumor cells that derive their blood supply predominantly from the hepatic artery. In contrast, the normal liver parenchyma is fed primarily by the portal system. The additional mechanism of action of chemoembolization is the trapping of cytotoxic agents within the embolized tissue. This process occurs because the lipiodol, which is used in most regimens, flows through the malignant tissues and parenchyma to obstruct portal vein inflow and hepatic vein washout, whereas particulate material employed near the end of the embolization procedure acts by entrapping the agents through blocking the hepatic arterial supply inflow.

Doxorubicin is the most commonly used cytotoxic drug in conjunction with embolization. Other agents used include mitomycin C and cisplatin. Partial responses in the range of 20%– 50% have been reported in the literature. 9,10 Two randomized trials and meta-analyses of chemoembolization in approximately 500 patients showed clinical benefit of this approach when compared with conservative management in patients with HCC.9,10 These patients were not candidates for either resection or transplantation.

Mild systemic toxicity continues to be an advantageous part of chemoembolization. Although upward of 90% of patients experience the symptoms of postembolization syndrome, which include fever, nausea, vomiting, and abdominal pain, they are generally self-limited and confined to the immediate acute postprocedure period. More serious toxicities such as anemia, liver decompensation, and infection (including cholecystitis) are rare and mostly encountered in patients with more advanced disease.11

Rationale for combining sorafenib with TACE

Treatment with TACE alone causes necrosis of tumor tissue, with transient elevations of levels of many angiogenic growth factors (such as VEGF and plasma insulin-like growth factor 2 [IGF-2]).12,13 High expression of stem cell likeness and tumor angiogenesis results in a poor prognosis. 14,15 Emerging clinical data also suggest that increased VEGF levels post TACE may be associated with an increased chance of disease progression. 16 These angiogenic factors may be responsible for the limited longterm benefit of TACE seen in patients with HCC. Therefore, the combination of sorafenib with TACE may have the potential to improve clinical outcomes in patients with HCC by blocking this angiogenic signaling activated by the chemoembolization.

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.

The HeiLivCa study,20 ECOG 1208, and the TACE-2 study are also addressing similar questions with slightly different patient populations. For example, the open ECOG 1208 study randomizes patients to receive sorafenib or placebo in conjunction with TACE and allows the interventionalist to choose one of a few different chemoembolization methods. Liver-directed therapy can take the form of conventional TACE, using the mixture of doxorubicin, mitomycin, and cisplatin described previously. However, embolization may also be completed by employing conventional Ethiodol (ethiodized oil) TACE, using only doxorubicin or doxorubicin-loaded beads. This varied approach may provide an analytic advantage, because the design better mirrors what is happening at institutions around the world.

The optimal scheduling of sorafenib in relation to TACE has yet to be determined, but with these trials, the elucidation of combination therapy will be discovered. For instance, the TACE-2 trial is not only comparing drug-eluting beads with and without sorafenib but is also additionally randomizing patients into two arms. One arm starts sorafenib or placebo at day 0, whereas the other arm begins with sorafenib or placebo at day 7 after TACE (2–5 weeks post randomization). This study will help to clarify the timing of combination therapy for HCC.

Conclusion

With increased angiogenic factors following embolization and the emergence of specific agents to target those factors, a potential benefit of targeting angiogenesis as an adjunct to TACE may be expected. Although the rationale is sound and safety has been demonstrated in preliminary studies,21,22 using sorafenib in patients with HCC receiving chemoembolization is not yet recommended outside the clinical trial setting. Over the coming years, efficacy data from ongoing randomized studies will be available. It is best to support the current ongoing clinical trials so we may reach a definitive answer. With the increasing awareness among community oncologists and their participation in clinical trials, we should be able to optimize the use of sorafenib in combination with TACE and extend its use in conjunction with other locoregional therapies.

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18. Erhardt A, Kolligs FT, Dollinger MM, et al. First-in-men demonstration of sorafenib plus TACE for the treatment of advanced hepatocellular carcinoma (SOCRATES trial). Presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases; October 30–November 3, 2009; Boston, MA.
19. Okita K, Imanaka K, Chida N, et al. Phase III study of sorafenib in patients in Japan and South Korea with advanced hepatocellular carcinoma (HCC) treated after transarterial chemoembolization (TACE). Presented at the 2010 Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, FL. Abstract LBA128.
20. Hoffmann K, Glimm H, Radeleff B, et al. Prospective, randomized, double-blind, multi-center, phase III clinical study on transarterial chemoembolization (TACE) combined with sorafenib versus TACE plus placebo in patients with hepatocellular cancer before liver transplantation–HeiLivCa [ISRCTN24081794]. BMC Cancer 2008;8:349.
21. Reyes DK, Azad NS, Koteish A, et al. Phase II trial of sorafenib combined with doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) for patients with unresectable hepatocellular carcinoma (HCC): interim safety and efficacy analysis. Presented at the 2010 Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, FL. Abstract 254.
22. Valenti DA, Cabrera T, Khankan A, et al. Combined sorafenib and yttrium-90 radioembolization in the treatment of advanced HCC: preliminary results. J Vasc Interv Radiol 2009;20(suppl):S65–S66. Abstract 169.

ABOUT THE AUTHORS

Affiliations: Dr. Choi is Assistant Professor of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI. Dr. Critchfield is Assistant Professor of Radiology and Chief of Interventional Oncology, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI. Dr. Philip is Professor of Medicine, Wayne State University School of Medicine, and Clinical Professor of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI. Conflicts of interest: The authors have no conflicts of interest to disclose.