The safety and efficacy of transarterial chemoembolization combined with sorafenib and sorafenib mono-therapy in patients with BCLC stage B/C hepatocellular carcinoma

Fei-Xiang Wu, Jie Chen, Tao Bai, Shao-Liang Zhu, Tian-Bo Yang, Lu-Nan Qi, Ling Zou, Zi-Hui Li, Jia-Zhou Ye, Le-Qun Li, Fei-Xiang Wu, Jie Chen, Tao Bai, Shao-Liang Zhu, Tian-Bo Yang, Lu-Nan Qi, Ling Zou, Zi-Hui Li, Jia-Zhou Ye, Le-Qun Li

Abstract

Background: Sorafenib and transarterial chemoembolization (TACE) are recommended therapies for advanced hepatocellular carcinoma (HCC), but their combined efficacy remains unclear.

Methods: Between August 2004 and November 2014, 104 patients with BCLC stage B/C HCC were enrolled at the Affiliated Tumor Hospital of Guangxi Medical University, China. Forty-eight patients were treated with sorafenib alone (sorafenib group) and 56 with TACE plus sorafenib (TACE + sorafenib group). Baseline demographic/clinical data were collected. The primary outcomes were median overall survival (OS) and progression-free survival (PFS). Secondary outcomes were overall response rate (ORR) and sorafenib-related adverse events (AEs). Baseline characteristics associated with disease prognosis were identified using multivariate Cox hazards regression.

Results: The mean age of the 104 patients (94 males; 90.38%) was 49.02 ± 12.29 years. Of the baseline data, only albumin level (P = 0.028) and Child-Pugh class (P = 0.017) differed significantly between groups. Median OS did not differ significantly between the sorafenib and TACE + sorafenib groups (18.0 vs. 22.0 months, P = 0.223). Median PFS was significantly shorter in the sorafenib group than that in the TACE + sorafenib group (6.0 vs. 8.0 months, P = 0.004). Six months after treatments, the ORRs were similar between the sorafenib and TACE + sorafenib groups (12.50% vs. 18.75%, P = 0.425). The rates of grade III-IV adverse events in sorafenib and TACE + sorafenib groups were 29.2% vs. 23.2%, respectively. TACE plus sorafenib treatment (HR = 0.498, 95% CI = 0.278-0.892), no vascular invasion (HR = 0.354, 95% CI = 0.183-0.685) and Child-Pugh class A (HR = 0.308, 95% CI = 0.141-0.674) were significantly associated with better OS, while a larger tumor number was predictive of poorer OS (HR = 1.286, 95% CI = 1.031-1.604). TACE plus sorafenib treatment (HR = 0.461, 95% CI = 0.273-0.780) and no vascular invasion (HR = 0.557, 95% CI = 0.314-0.988) were significantly associated with better PFS.

Conclusions: Compared with sorafenib alone, combining TACE with sorafenib might prolong survival and delay disease progression in patients with advanced HCC.

Keywords: Adverse events; Hepatocellular carcinoma; Portal vein tumor thrombus; Sorafenib; Transarterial chemoembolization.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Guangxi Medical University and was conducted in accordance with the Declaration of Helsinki and internationally accepted ethical guidelines. During their admission for surgery, the patients enrolled in this study provided written informed consent for their information to be stored in hospital databases and used for research.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Comparison of survival outcomes between patients treated with sorafenib mono-therapy (sorafenib group) and those treated with transarterial chemoembolization plus sorafenib combination therapy (TACE + sorafenib group). a Overall survival (OS, months). b Progression-free survival (PFS, months)
Fig. 2
Fig. 2
Comparison of survival outcomes between patients with different tumor diameters. a Overall survival (OS, months) in patients with a tumor diameter < 5 cm and those with a tumor diameter ≥ 5 cm. b Progression-free survival (PFS, months)in patients with a tumor diameter < 5 cm and those with a tumor diameter ≥ 5 cm. c Overall survival (OS, months) in patients with a tumor diameter < 7 cm and those with a tumor diameter ≥ 7 cm. d Progression-free survival (PFS, months)in patients with a tumor diameter < 7 cm and those with a tumor diameter ≥ 7 cm

References

    1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. doi: 10.3322/caac.21262.
    1. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399):1907–1917. doi: 10.1016/S0140-6736(03)14964-1.
    1. Llovet JM, Fuster J, Bruix J. Barcelona-clinic liver cancer G. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. 2004;10(2 Suppl 1):S115–S120. doi: 10.1002/lt.20034.
    1. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245–1255. doi: 10.1016/S0140-6736(11)61347-0.
    1. Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014;63(5):844–855. doi: 10.1136/gutjnl-2013-306627.
    1. Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg. 2002;235(3):373–382. doi: 10.1097/00000658-200203000-00009.
    1. Chen MF, Hwang TL, Jeng LB, Wang CS, Jan YY, Chen SC. Postoperative recurrence of hepatocellular carcinoma. Two hundred five consecutive patients who underwent hepatic resection in 15 years. Arch Surg. 1994;129(7):738–742. doi: 10.1001/archsurg.1994.01420310070012.
    1. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35(5):1164–1171. doi: 10.1053/jhep.2002.33156.
    1. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359(9319):1734–1739. doi: 10.1016/S0140-6736(02)08649-X.
    1. Bruix J, Llovet JM, Castells A, Montana X, Bru C, Ayuso MC, et al. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Hepatology. 1998;27(6):1578–1583. doi: 10.1002/hep.510270617.
    1. Xie ZB, Ma L, Wang XB, Bai T, Ye JZ, Zhong JH, et al. Transarterial embolization with or without chemotherapy for advanced hepatocellular carcinoma: a systematic review. Tumour Biol. 2014;35(9):8451–8459. doi: 10.1007/s13277-014-2340-z.
    1. Xie ZB, Wang XB, Peng YC, Zhu SL, Ma L, Xiang BD, et al. Systematic review comparing the safety and efficacy of conventional and drug-eluting bead transarterial chemoembolization for inoperable hepatocellular carcinoma. Hepatol Res. 2015;45(2):190–200. doi: 10.1111/hepr.12450.
    1. Bao Y, Feng WM, Tang CW, Zheng YY, Gong HB, Hou EG. Endostatin inhibits angiogenesis in hepatocellular carcinoma after transarterial chemoembolization. Hepato-Gastroenterology. 2012;59(117):1566–1568.
    1. Poon RT, Lau C, Yu WC, Fan ST, Wong J. High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma: a prospective study. Oncol Rep. 2004;11(5):1077–1084.
    1. Jia L, Kiryu S, Watadani T, Akai H, Yamashita H, Akahane M, et al. Prognosis of hepatocellular carcinoma with portal vein tumor thrombus: assessment based on clinical and computer tomography characteristics. Acta Med Okayama. 2012;66(2):131–141.
    1. Wang B, Xu H, Gao ZQ, Ning HF, Sun YQ, Cao GW. Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol. 2008;49(5):523–529. doi: 10.1080/02841850801958890.
    1. Strebel BM, Dufour JF. Combined approach to hepatocellular carcinoma: a new treatment concept for nonresectable disease. Expert Rev Anticancer Ther. 2008;8(11):1743–1749. doi: 10.1586/14737140.8.11.1743.
    1. Hu H, Duan Z, Long X, Hertzanu Y, Shi H, Liu S, et al. Sorafenib combined with transarterial chemoembolization versus transarterial chemoembolization alone for advanced-stage hepatocellular carcinoma: a propensity score matching study. PLoS One. 2014;9(5):e96620. doi: 10.1371/journal.pone.0096620.
    1. Pan T, Li XS, Xie QK, Wang JP, Li W, Wu PH, et al. Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus. Clin Radiol. 2014;69(12):e553–e561. doi: 10.1016/j.crad.2014.09.007.
    1. Zhu K, Chen J, Lai L, Meng X, Zhou B, Huang W, et al. Hepatocellular carcinoma with portal vein tumor thrombus: treatment with transarterial chemoembolization combined with sorafenib--a retrospective controlled study. Radiology. 2014;272(1):284–293. doi: 10.1148/radiol.14131946.
    1. Zhong JH, Li H, Xiao N, Ye XP, Ke Y, Wang YY, et al. Hepatic resection is safe and effective for patients with hepatocellular carcinoma and portal hypertension. PLoS One. 2014;9(9):e108755. doi: 10.1371/journal.pone.0108755.
    1. European Association For The Study Of The L. European Organisation For R. Treatment Of C EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–943. doi: 10.1016/j.jhep.2011.12.001.
    1. Zhong JH, Ke Y, Gong WF, Xiang BD, Ma L, Ye XP, et al. Hepatic resection associated with good survival for selected patients with intermediate and advanced-stage hepatocellular carcinoma. Ann Surg. 2014;260(2):329–340. doi: 10.1097/SLA.0000000000000236.
    1. Quirk M, Kim YH, Saab S, Lee EW. Management of hepatocellular carcinoma with portal vein thrombosis. World J Gastroenterol. 2015;21(12):3462–3471. doi: 10.3748/wjg.v21.i12.3462.
    1. Ye JZ, Zhang YQ, Ye HH, Bai T, Ma L, Xiang BD, et al. Appropriate treatment strategies improve survival of hepatocellular carcinoma patients with portal vein tumor thrombus. World J Gastroenterol. 2014;20(45):17141–17147. doi: 10.3748/wjg.v20.i45.17141.
    1. National Cancer Institute. Common terminology criteria for adverse events, version 3.0. 2006. . Accessed 18 June 2009.
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–216. doi: 10.1093/jnci/92.3.205.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45(2):228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012;57(4):821–829. doi: 10.1016/j.jhep.2012.06.014.
    1. Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer. 2012;48(10):1452–1465. doi: 10.1016/j.ejca.2011.12.006.
    1. Rimassa L, Santoro A. Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial. Expert Rev Anticancer Ther. 2009;9(6):739–745. doi: 10.1586/era.09.41.
    1. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34. doi: 10.1016/S1470-2045(08)70285-7.
    1. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. doi: 10.1056/NEJMoa0708857.
    1. Kane RC, Farrell AT, Madabushi R, Booth B, Chattopadhyay S, Sridhara R, et al. Sorafenib for the treatment of unresectable hepatocellular carcinoma. Oncologist. 2009;14(1):95–100. doi: 10.1634/theoncologist.2008-0185.
    1. Yang M, Yuan JQ, Bai M, Han GH. Transarterial chemoembolization combined with sorafenib for unresectable hepatocellular carcinoma: a systematic review and meta-analysis. Mol Biol Rep. 2014;41(10):6575–6582. doi: 10.1007/s11033-014-3541-7.
    1. Zhang L, Hu P, Chen X, Bie P. Transarterial chemoembolization (TACE) plus sorafenib versus TACE for intermediate or advanced stage hepatocellular carcinoma: a meta-analysis. PLoS One. 2014;9(6):e100305. doi: 10.1371/journal.pone.0100305.
    1. Fu QH, Zhang Q, Bai XL, Hu QD, Su W, Chen YW, et al. Sorafenib enhances effects of transarterial chemoembolization for hepatocellular carcinoma: a systematic review and meta-analysis. J Cancer Res Clin Oncol. 2014;140(8):1429–1440. doi: 10.1007/s00432-014-1684-5.
    1. Yao X, Yan D, Zeng H, Liu D, Li H. Concurrent sorafenib therapy extends the interval to subsequent TACE for patients with unresectable hepatocellular carcinoma. J Surg Oncol. 2016;113(6):672–677. doi: 10.1002/jso.24215.
    1. Abdel-Rahman O, Elsayed ZA. Combination trans arterial chemoembolization (TACE) plus sorafenib for the management of unresectable hepatocellular carcinoma: a systematic review of the literature. Dig Dis Sci. 2013;58(12):3389–3396. doi: 10.1007/s10620-013-2872-x.
    1. Muhammad A, Dhamija M, Vidyarthi G, Amodeo D, Boyd W, Miladinovic B, et al. Comparative effectiveness of traditional chemoembolization with or without sorafenib for hepatocellular carcinoma. World J Hepatol. 2013;5(7):364–371. doi: 10.4254/wjh.v5.i7.364.
    1. Erhardt A, Kolligs F, Dollinger M, Schott E, Wege H, Bitzer M, et al. TACE plus sorafenib for the treatment of hepatocellular carcinoma: results of the multicenter, phase II SOCRATES trial. Cancer Chemother Pharmacol. 2014;74(5):947–954. doi: 10.1007/s00280-014-2568-8.
    1. Zhang YQ, Yang JY, Wang Y, Huang YH, Fan WZ, Li JP. The analysis of the efficacy and safety of combined transarterial chemoembolization with sorafenib in patients with large hepatocellular carcinoma. Zhonghua Yi Xue Za Zhi. 2013;93(13):987–991.
    1. Choi GH, Shim JH, Kim MJ, Ryu MH, Ryoo BY, Kang YK, et al. Sorafenib alone versus sorafenib combined with transarterial chemoembolization for advanced-stage hepatocellular carcinoma: results of propensity score analyses. Radiology. 2013;269(2):603–611. doi: 10.1148/radiol.13130150.
    1. Chao Y, Chung YH, Han G, Yoon JH, Yang J, Wang J, et al. The combination of transcatheter arterial chemoembolization and sorafenib is well tolerated and effective in Asian patients with hepatocellular carcinoma: final results of the START trial. Int J Cancer. 2015;136(6):1458–1467. doi: 10.1002/ijc.29126.
    1. Cabrera R, Pannu DS, Caridi J, Firpi RJ, Soldevila-Pico C, Morelli G, et al. The combination of sorafenib with transarterial chemoembolisation for hepatocellular carcinoma. Aliment Pharmacol Ther. 2011;34(2):205–213. doi: 10.1111/j.1365-2036.2011.04697.x.
    1. Geschwind JF, Gholam PM, Goldenberg A, Mantry P, Martin RC, Piperdi B, et al. Use of Transarterial Chemoembolization (TACE) and Sorafenib in patients with Unresectable Hepatocellular carcinoma: US regional analysis of the GIDEON registry. Liver Cancer. 2016;5(1):37–46. doi: 10.1159/000367757.
    1. Zheng J, Shao G, Luo J. Analysis of survival factors in patients with intermediate-advanced hepatocellular carcinoma treated with transcatheter arterial chemoembolization combined with sorafenib. Clin Transl Oncol. 2014;16(11):1012–1017. doi: 10.1007/s12094-014-1189-3.
    1. Uchino K, Obi S, Tateishi R, Sato S, Kanda M, Sato T, et al. Systemic combination therapy of intravenous continuous 5-fluorouracil and subcutaneous pegylated interferon alfa-2a for advanced hepatocellular carcinoma. J Gastroenterol. 2012;47(10):1152–1159. doi: 10.1007/s00535-012-0574-3.
    1. Ohki T, Sato K, Yamagami M, Ito D, Yamada T, Kawanishi K, et al. Erratum to: efficacy of Transcatheter arterial Chemoembolization followed by Sorafenib for intermediate/advanced Hepatocellular carcinoma in patients in Japan: a retrospective analysis. Clin Drug Investig. 2016;36(1):93–96. doi: 10.1007/s40261-015-0363-x.
    1. Martins A, Cortez-Pinto H, Marques-Vidal P, Mendes N, Silva S, Fatela N, et al. Treatment and prognostic factors in patients with hepatocellular carcinoma. Liver Int. 2006;26(6):680–687. doi: 10.1111/j.1478-3231.2006.001285.x.
    1. Lee YH, Hsia CY, Hsu CY, Huang YH, Lin HC, Huo TI. Total tumor volume is a better marker of tumor burden in hepatocellular carcinoma defined by the Milan criteria. World J Surg. 2013;37(6):1348–1355. doi: 10.1007/s00268-013-1978-9.
    1. Fan J, Zhou J, Wu ZQ, Qiu SJ, Wang XY, Shi YH, et al. Efficacy of different treatment strategies for hepatocellular carcinoma with portal vein tumor thrombosis. World J Gastroenterol. 2005;11(8):1215–1219. doi: 10.3748/wjg.v11.i8.1215.
    1. Zhang Y, Fan W, Wang Y, Lu L, Fu S, Yang J, et al. Sorafenib with and without Transarterial Chemoembolization for advanced Hepatocellular carcinoma with main portal vein tumor thrombosis: a retrospective analysis. Oncologist. 2015;20(12):1417–1424. doi: 10.1634/theoncologist.2015-0196.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren