Abstract
Purpose
The present multicenter phase II trial investigated the combination of TACE and sorafenib for the treatment of HCC.
Patients and methods
Eligibility criteria included histologically confirmed, unresectable HCC beyond Milan criteria, no extrahepatic spread, Child–Pugh score ≤8 and ECOG PS 0-2. Patients had received no prior therapy for HCC. Sorafenib was given at a dose of 400 mg/bid (interrupted only around TACE). TACE with lipiodol, 50 mg doxorubicin and polyvinyl alcohol (PVA) particles was repeated q6w as long as there was no overall disease progression. Tumor assessment by MRI was performed q6w according to EASL criteria. The primary endpoint was time to progression (TTP).
Results
Patients (n = 43) received a mean of 2.6 ± 2.2 TACE interventions (range 0–10). Median TTP was 16.4 months (95 % CI 10.7–∞). Median overall survival (OS) was 20.1 months (95 % CI 17.6–28.2). Disease control rate according to EASL criteria was 74.4 % (7 % complete responses [CRs] + 41.8 % partial responses [PRs] + 25.6 % stable diseases [SDs]). Four patients (9 %) became amenable to either radiofrequency ablation or liver transplantation; 5 (12 %) patients died during the trial. Overall, there were 360 AEs, including 56 grade 3/4 AEs and 39 SAEs.
Conclusions
Combination treatment of TACE and sorafenib in the present trial was tolerable and associated with an interesting response rate, TTP and OS. Combination therapies will probably close gaps in the present mono therapy driven treatment guidelines for locally advanced HCC.
Similar content being viewed by others
References
Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108
Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP (2006) The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 45:529–538
Altekruse SF, McGlynn KA, Reichman ME (2009) Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 27:1485–1491
Whittaker S, Marais R, Zhu AX (2010) The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 29:4989–5005
Bruix J, Sherman M (2011) Management of hepatocellular carcinoma: an update. Hepatology 53:1020–1022
E- EORTC (2012) EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 56:908–943
Cabibbo G, Latteri F, Antonucci M, Craxi A (2009) Multimodal approaches to the treatment of hepatocellular carcinoma. Nat Clin Pract Gastroenterol Hepatol 6:159–169
Qu XD, Chen CS, Wang JH et al (2012) The efficacy of TACE combined sorafenib in advanced stages hepatocellular carcinoma. BMC Cancer 12:263
Pawlik TM, Reyes DK, Cosgrove D et al (2011) Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma. J Clin Oncol 29:3960–3967
Lencioni R, Llovet JM, Han G et al (2012) Sorafenib (S) or placebo (P) in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediate-stage hepatocellular carcinoma (HCC): phase II, randomized, double-blind, placebo-controlled SPACE trial. J Clin Oncol 30:LBA 154
Sansonno D, Lauletta G, Russi S et al (2012) Transarterial chemoembolization plus sorafenib: a sequential therapeutic scheme for HCV-related intermediate-stage hepatocellular carcinoma: a randomized clinical trial. Oncologist 17:359–366
Pinter M, Hucke F, Graziadei I et al (2012) Advanced-stage hepatocellular carcinoma: transarterial chemoembolization versus sorafenib. Radiology 263:590–599
Park JW, Koh YH, Kim HB et al (2012) Phase II study of concurrent transarterial chemoembolization and sorafenib in patients with unresectable hepatocellular carcinoma. J Hepatol 56:1336–1342
Dufour JF, Hoppe H, Heim MH et al (2010) Continuous administration of sorafenib in combination with transarterial chemoembolization in patients with hepatocellular carcinoma: results of a phase I study. Oncologist 15:1198–1204
Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307
Li X, Feng GS, Zheng CS, Zhuo CK, Liu X (2004) 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 10:2878–2882
Abou-Alfa GK, Johnson P, Knox JJ et al (2010) Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 304:2154–2160
Bruix J, Sherman M (2005) Management of hepatocellular carcinoma. Hepatology 42:1208–1236
Wakabayashi I, Groschner K (2003) Vascular actions of anthracycline antibiotics. Curr Med Chem 10:427–436
Nexavar summary of product characteristics. http://wwwemaeuropaeu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000690/WC500027704pdf. Accessed October 2012
Fu QH, Zhang Q, Bai XL et al (2014) Sorafenib enhances effects of transarterial chemoembolization for hepatocellular carcinoma: a systematic review and meta-analysis. J Cancer Res Clin Oncol 140:1429–1440
Liu L, Chen H, Wang M et al (2014) Combination therapy of sorafenib and TACE for unresectable HCC: a systematic review and meta-analysis. PLoS ONE 9:e91124
Kudo M, Imanaka K, Chida N et al (2011) Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer 47:2117–2127
Hsu C, Po Ching L, Morita S, Hu FC, Cheng AL (2012) Perspectives on the design of clinical trials combining transarterial chemoembolization and molecular targeted therapy. Liver Cancer 1:168–176
Lammer J, Malagari K, Vogl T et al (2010) Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 33:41–52
Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390
Bruix J, Raoul JL, Sherman M et al (2009) Efficacy and safety of sorafenib in patients with hepatocellular carcinoma (HCC): subanalysis of SHARP trial based on Barcelona Clinic Liver Cancer (BCLC) stage. J Hepatol 50:S29 (Abstract 67)
Llovet JM, Real MI, Montana X et al (2002) Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359:1734–1739
Cunningham D, Atkin W, Lenz HJ et al (2010) Colorectal cancer. Lancet 375:1030–1047
Marelli L, Stigliano R, Triantos C et al (2007) Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 30:6–25
Acknowledgments
The Socrates study team is indebted to all study nurses in the participating centers especially Katja Pöggel-Krämer and Carola Blondin. Janette Schindler took care of the data management. Pablo Verde took care of the statistics. The study was supported by a grant of Bayer HealthCare AG, Leverkusen, Germany.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Erhardt, A., Kolligs, F., Dollinger, M. et al. TACE plus sorafenib for the treatment of hepatocellular carcinoma: results of the multicenter, phase II SOCRATES trial. Cancer Chemother Pharmacol 74, 947–954 (2014). https://doi.org/10.1007/s00280-014-2568-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-014-2568-8