Adjuvant apatinib treatment after resection of hepatocellular carcinoma with portal vein tumor thrombosis: a phase II trial

Hui-Chuan Sun, Xiao-Dong Zhu, Jian Zhou, Qiang Gao, Ying-Hong Shi, Zhen-Bing Ding, Cheng Huang, Shuang-Jian Qiu, Ning Ren, Guo-Ming Shi, Jian Sun, Qing-Hai Ye, Xiao-Wu Huang, Xin-Rong Yang, Jia Fan, Hui-Chuan Sun, Xiao-Dong Zhu, Jian Zhou, Qiang Gao, Ying-Hong Shi, Zhen-Bing Ding, Cheng Huang, Shuang-Jian Qiu, Ning Ren, Guo-Ming Shi, Jian Sun, Qing-Hai Ye, Xiao-Wu Huang, Xin-Rong Yang, Jia Fan

Abstract

Background: Survival after resection of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) still remains poor. Apatinib, a vascular endothelial cell growth factor receptor 2 inhibitor, has been shown to be safe and effective in patients with advanced HCC, so in the present study its efficacy and safety in the adjuvant setting was explored.

Methods: In this single-center, open-label phase II trial, the patients received apatinib (500 mg/day) until they experienced disease recurrence or intolerable toxicity. The primary endpoint was recurrence-free survival (RFS); the secondary endpoints included overall survival (OS) and safety.

Results: From a total of 49 patients who were screened between August 2017 and December 2018, 30 study participants received apatinib. According to the Liver Cancer Study Group of Japan classification of PVTT, there were 7, 11, and 12 participants with Vp1, Vp2, and Vp3, respectively. The median duration of treatment was 4.8 months [interquartile range (IQR): 2.0-8.8], and the median dose of apatinib was 339.7 mg/day (IQR: 267.7-500 mg/day). The median follow-up was 14.3 months (IQR: 12.3-19.3). The median RFS was 7.6 months [95% confidence interval (CI): 5.7-9.5 months]. The 1-year RFS rate and the 1-year OS rate were 36.1% and 93.3%, respectively. A total of 29 (96.7%) patients experienced adverse events, and 14 (46.7%) had grade 3 or 4 adverse events. No treatment-related deaths occurred.

Conclusions: Apatinib was well tolerated in patients after resection of HCC with PVTT. The median RFS in this group was improved compared with that previously reported.

Trial registration: No.: NCT03261791 (ClinicalTrials.gov).

Keywords: Apatinib; hepatocellular carcinoma (HCC); portal vein.

Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-6181). HCS reports personal fees from Bayer, personal fees from Eisai, personal fees from MSD, personal fees from Hengrui Co., Ltd., personal fees from Innovent Biologics, outside the submitted work; XDZ reports personal fees from Eisai, personal fees from MSD, personal fees from Hengrui Co. Ltd., outside the submitted work. The other authors have no conflicts of interest to declare.

2020 Annals of Translational Medicine. All rights reserved.

Figures

Figure 1
Figure 1
Patient flowchart. AFP, alpha-fetoprotein; HBV, hepatitis B virus; TACE, transarterial chemoembolization.
Figure 2
Figure 2
Recurrence-free survival after surgery.

References

    1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. 10.3322/caac.21492
    1. Cheung TT. Management of hepatocellular carcinoma: from bench to bedside and beyond. Transl Gastroenterol Hepatol 2019;4:54. 10.21037/tgh.2019.07.01
    1. Park JW, Chen M, Colombo M, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int 2015;35:2155-66. 10.1111/liv.12818
    1. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998;28:751-5. 10.1002/hep.510280322
    1. Holzwanger DJ, Madoff DC. Role of interventional radiology in the management of hepatocellular carcinoma: current status. Chin Clin Oncol 2018;7:49. 10.21037/cco.2018.07.04
    1. Sun JX, Shi J, Li N, et al. Portal vein tumor thrombus is a bottleneck in the treatment of hepatocellular carcinoma. Cancer Biol Med 2016;13:452-8. 10.20892/j.issn.2095-3941.2016.0059
    1. Zhou J, Sun HC, Wang Z, et al. Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition). Liver Cancer 2018;7:235-60. 10.1159/000488035
    1. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2018;68:723-50. 10.1002/hep.29913
    1. Wei X, Jiang Y, Zhang X, et al. Neoadjuvant Three-Dimensional Conformal Radiotherapy for Resectable Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Randomized, Open-Label, Multicenter Controlled Study. J Clin Oncol 2019;37:2141-51. 10.1200/JCO.18.02184
    1. Sun J, Zhang T, Wang J, et al. Biologically effective dose (BED) of stereotactic body radiation therapy (SBRT) was an important factor of therapeutic efficacy in patients with hepatocellular carcinoma (</=5 cm). BMC Cancer 2019;19:846. 10.1186/s12885-019-6063-9
    1. Scott LJ. Apatinib: A Review in Advanced Gastric Cancer and Other Advanced Cancers. Drugs 2018;78:747-58. 10.1007/s40265-018-0903-9
    1. Liu G, Wang C, He Y, et al. Application effect of apatinib in patients with failure of standard treatment for advanced malignant tumours. BMC Pharmacol Toxicol 2019;20:61. 10.1186/s40360-019-0362-2
    1. Yang D, Dai R, Zhang Q, et al. Apatinib for heavily treated patients with non-small cell lung cancer: Report of a case series and literature review. Saudi J Biol Sci 2018;25:888-94. 10.1016/j.sjbs.2017.12.011
    1. Zhang Y, Fan W, Wang Y, et al. Apatinib for Patients With Sorafenib-Refractory Advanced Hepatitis B Virus Related Hepatocellular Carcinoma: Results of a Pilot Study. Cancer Control 2019;26:1073274819872216. 10.1177/1073274819872216
    1. Kong Y, Sun L, Hou Z, et al. Apatinib is effective for treatment of advanced hepatocellular carcinoma. Oncotarget 2017;8:105596-605. 10.18632/oncotarget.22337
    1. Qin S. Apatinib in Chinese patients with advanced hepatocellular carcinoma: A phase II randomized, open-label trial. J Clin Oncol 2014;32:abstr 4019.
    1. Kudo M, Izumi N, Kokudo N, et al. Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis 2011;29:339-64. 10.1159/000327577
    1. Chen J, Wang J. Efficacy and safety assessment of apatinib in patients with advanced gastric cancer: a meta-analysis. Onco Targets Ther 2018;11:4149-58. 10.2147/OTT.S157466
    1. Cheng H, Sun A, Guo Q, et al. Efficacy and safety of apatinib combined with chemotherapy for the treatment of advanced gastric cancer in the Chinese population: a systematic review and meta-analysis. Drug Des Devel Ther 2018;12:2173-83. 10.2147/DDDT.S170678
    1. Liu Y, Zhou C, Zhang K, et al. The combination of apatinib and S-1 for the treatment of advanced gastric cancer in China: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2018;97:e13259. 10.1097/MD.0000000000013259
    1. Peng L, Ye X, Hong Y, et al. Treatment-related toxicities of apatinib in solid tumors: a meta-analysis. Oncotarget 2018;9:32262-70. 10.18632/oncotarget.24215
    1. Sun D, Hou H, Zhang C, et al. The efficacy and safety of apatinib for refractory malignancies: a review and meta-analysis. Onco Targets Ther 2018;11:6539-54. 10.2147/OTT.S176429
    1. Wei Y, Liu J, Yan M, et al. Effectiveness and Safety of Combination Therapy of Transarterial Chemoembolization and Apatinib for Unresectable Hepatocellular Carcinoma in the Chinese Population: A Meta-Analysis. Chemotherapy 2019;64:94-104. 10.1159/000502510
    1. Xue JM, Astere M, Zhong MX, et al. Efficacy and safety of apatinib treatment for gastric cancer, hepatocellular carcinoma and non-small cell lung cancer: a meta-analysis. Onco Targets Ther 2018;11:6119-28. 10.2147/OTT.S172717
    1. Yu GC, Yang J, Ye B, et al. Apatinib in the treatment of advanced non-small-cell lung cancer: A meta-analysis. Math Biosci Eng 2019;16:7659-70. 10.3934/mbe.2019383
    1. Zhao S, Zhang T, Dou W, et al. A comparison of transcatheter arterial chemoembolization used with and without apatinib for intermediate- to advanced-stage hepatocellular carcinoma: a systematic review and meta-analysis. Ann Transl Med 2020;8:542. 10.21037/atm.2020.02.125
    1. Li Q, Qin S, Gu S, et al. Apatinib as second-line therapy in Chinese patients with advanced hepatocellular carcinoma: A randomized, placebo-controlled, double-blind, phase III study. J Clin Oncol 2020;38:abstr 4507.
    1. Zhu XD, Li KS, Sun HC. Adjuvant therapies after curative treatments for hepatocellular carcinoma: Current status and prospects. Genes Dis 2020;7:359-69. 10.1016/j.gendis.2020.02.002
    1. Peng ZW, Guo RP, Zhang YJ, et al. Hepatic resection versus transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with portal vein tumor thrombus. Cancer 2012;118:4725-36. 10.1002/cncr.26561
    1. Kokudo T, Hasegawa K, Matsuyama Y, et al. Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion. J Hepatol 2016;65:938-43. 10.1016/j.jhep.2016.05.044
    1. Zhang YF, Shang H, Zeng XL, et al. Postoperative adjuvant chemo (embolization) therapy for hepatocellular carcinoma with portal vein tumor thrombosis. Onco Targets Ther 2018;11:5407-17. 10.2147/OTT.S171612
    1. Sherman M, Mazzaferro V, Amadori D, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and vascular invasion or extrahepatic spread: A subanalysis from the SHARP trial. J Clin Oncol 2008;26:abstr 4584.
    1. Cheng AL, Guan Z, Chen Z, 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;48:1452-65. 10.1016/j.ejca.2011.12.006
    1. Li J, Hou Y, Cai XB, et al. Sorafenib after resection improves the outcome of BCLC stage C hepatocellular carcinoma. World J Gastroenterol 2016;22:4034-40. 10.3748/wjg.v22.i15.4034
    1. Bodnar RJ. Anti-Angiogenic Drugs: Involvement in Cutaneous Side Effects and Wound-Healing Complication. Adv Wound Care (New Rochelle) 2014;3:635-46. 10.1089/wound.2013.0496
    1. Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2015;16:1344-54. 10.1016/S1470-2045(15)00198-9

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner