Efficacy and Safety of the Arsenic Trioxide/Lipiodol Emulsion in the Transcatheter Arterial Chemoembolization Combined with Apatinib in the Treatment of Advanced Hepatocellular Carcinoma

Purpose The goal of this study was to assess the clinical efficacy and safety of the arsenic trioxide (ATO)/lipiodol emulsion in the transcatheter arterial chemoembolization (TACE) combined with apatinib in the treatment of advanced hepatocellular carcinoma (HCC). Methods From December 2015 to February 2017, a total of 87 patients were consecutively enrolled and underwent ATO-TACE (aTACE) combined with apatinib in the treatment of advanced HCC. The treatment response and adverse events were assessed at the first month and third month after aTACE therapy. Progression-free survival (PFS), overall survival (OS), and treatment-related adverse events were also analyzed. Results 87 patients (57 men; 30 women) were enrolled in the present study. Compared to that at the pre-aTACE examination, the levels of AST and ALT were elevated at the first week after procedure (65.84 U/L ± 22.93 U/L vs. 54.15 U/L ± 19.60 U/L, p=0.032; 63.44 U/L ± 22.50 U/L vs. 51.60 U/L ± 13.89 U/L, p=0.027, respectively). Most of the adverse events were grade 1 or 2 according to National Cancer Institute Common Terminology Criteria for Adverse Event (CTCAE). Of the exception, 4 persons (2%) did have grade 3 hand-foot skin reactions, 1 (1%) had grade 3 diarrhea, 1 (1%) had grade 3 hypertension, and 3 (3%) had grade 3 proteinuria and forced to reduce the dose of apatinib by half. The survival analysis of the combination with aTACE and apatinib therapy found that the median PFS was 10.2 months (95% CI: 8.543–11.857), and the median OS was 23.300 months (95% CI: 20.833–25.767). Additionally, both univariate and multivariate Cox regression revealed that the tumor burden (≤50%) and the patients without portal vein tumor thrombus (PVTT) significantly impacted the patient's PFS and OS and were related to better survival. Conclusion aTACE combined with apatinib is a safe and promising treatment approach for patients with advanced HCC. Additionally, tumor burden (≤50%) and the patients without PVTT are associated with better PFS and OS.

[1]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[2]  Yun-fei Yuan,et al.  Transarterial chemoembolization (TACE) combined with apatinib versus TACE combined with sorafenib in advanced hepatocellular carcinoma patients: a multicenter retrospective study , 2021, Annals of translational medicine.

[3]  J. González‐Gallego,et al.  Prognostic and clinicopathological significance of hypoxia-inducible factors 1α and 2α in hepatocellular carcinoma: a systematic review with meta-analysis , 2021, Therapeutic advances in medical oncology.

[4]  Z. Wang,et al.  Efficacy and safety of apatinib combined with transarterial chemoembolization (TACE) in treating patients with recurrent hepatocellular carcinoma , 2020, Annals of translational medicine.

[5]  Xinwei Han,et al.  Transcatheter Arterial Chemoembolization Combined with Simultaneous Cone-beam Computed Tomography-guided Microwave Ablation in the Treatment of Small Hepatocellular Carcinoma: Clinical Experiences From 50 Procedures. , 2020, Academic radiology.

[6]  Yun-fei Yuan,et al.  Apatinib versus sorafenib in patients with advanced hepatocellular carcinoma: a preliminary study , 2020, Annals of translational medicine.

[7]  C. Zheng,et al.  Transarterial Chemoembolization Combined With Apatinib for Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis , 2020, Frontiers in Oncology.

[8]  Jianwei Xu,et al.  Safety and Efficacy of Drug-Eluting Bead Transarterial Chemoembolization Combined with Apatinib in Patients with Advanced Hepatocellular Carcinoma. , 2020, Academic radiology.

[9]  Xi-lin Du,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 , 2020, Annals of translational medicine.

[10]  X. Duan,et al.  Arsenic trioxide-eluting Callispheres beads is more effective and equally tolerant compared with arsenic trioxide/lipiodol emulsion in the transcatheter arterial chemoembolization treatment for unresectable hepatocellular carcinoma patients. , 2020, European review for medical and pharmacological sciences.

[11]  Xinwei Han,et al.  Portal Vein Stenting Combined with 125I Particle Chain Implantation Followed by As2O3 in the Treatment of Hepatocellular Carcinoma with Portal Vein Tumour Thrombus , 2020, BioMed research international.

[12]  Xinwei Han,et al.  Assessment of efficacy and safety of the transcatheter arterial chemoembolization with or without apatinib in the treatment of large hepatocellular carcinoma , 2019, Cancer Chemotherapy and Pharmacology.

[13]  W. Fan,et al.  Apatinib Combined With Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma and Portal Vein Tumor Thrombus: A Multicenter Retrospective Study. , 2019, Clinical therapeutics.

[14]  W. Huang,et al.  A candidate for lung cancer treatment: arsenic trioxide , 2019, Clinical and Translational Oncology.

[15]  Jing Zhang,et al.  Skp2 Expression Is Inhibited by Arsenic Trioxide through the Upregulation of miRNA-330-5p in Pancreatic Cancer Cells , 2019, Molecular therapy oncolytics.

[16]  Chaoqian Xu,et al.  Synergistic anti-tumor effects of arsenic trioxide and blue LED irradiation on human osteosarcoma , 2019, International journal of biological sciences.

[17]  Jianping Zhang,et al.  Arsenic trioxide reverses the chemoresistance in hepatocellular carcinoma: a targeted intervention of 14–3-3η/NF-κB feedback loop , 2018, Journal of Experimental & Clinical Cancer Research.

[18]  Wenchang Yu,et al.  Comparison of the efficacy and safety of Transarterial chemoembolization with and without Apatinib for the treatment of BCLC stage C hepatocellular carcinoma , 2018, BMC Cancer.

[19]  X. Yi,et al.  Anti-PD-1 Antibody SHR-1210 Combined with Apatinib for Advanced Hepatocellular Carcinoma, Gastric, or Esophagogastric Junction Cancer: An Open-label, Dose Escalation and Expansion Study , 2018, Clinical Cancer Research.

[20]  Long Jin,et al.  The safety and efficacy of TACE combined with apatinib on patients with advanced hepatocellular carcinoma: a retrospective study , 2018, Cancer biology & therapy.

[21]  J. González‐Gallego,et al.  Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors , 2018, Experimental & Molecular Medicine.

[22]  Zhe Zhang,et al.  Comparison of efficacy between TACE combined with apatinib and TACE alone in the treatment of intermediate and advanced hepatocellular carcinoma: A single-center randomized controlled trial , 2017, Cancer biology & therapy.

[23]  Xu He,et al.  Arsenic trioxide transarterial chemoembolization with and without additional intravenous administration of arsenic trioxide in unresectable hepatocellular carcinoma with lung metastasis: a single-blind, randomized trial , 2015, Journal of Cancer Research and Clinical Oncology.

[24]  Jianping Zhang,et al.  Inhibition of TGF-β/SMAD3/NF-κB signaling by microRNA-491 is involved in arsenic trioxide-induced anti-angiogenesis in hepatocellular carcinoma cells. , 2014, Toxicology letters.

[25]  L. Lou,et al.  YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor‐2 tyrosine kinase with potent activity in vitro and in vivo , 2011, Cancer science.

[26]  M. Fu,et al.  Therapeutic effect of arsenic trioxide (As2O3) on cervical cancer in vitro and In vivo through apoptosis induction , 2007, Cancer biology & therapy.

[27]  Chih-Hung Hsu,et al.  Arsenic trioxide in patients with hepatocellular carcinoma: a phase II trial , 2006, Investigational New Drugs.

[28]  Eun Jung Lee,et al.  Arsenic trioxide (As2O3) sensitivity of carcinoma cell lines and cancer cells from patients with carcinomatosis peritonei. , 2004, Annals of clinical and laboratory science.

[29]  L. Schwartz,et al.  Phase II Trial of Arsenic Trioxide in Patients with Metastatic Renal Cell Carcinoma , 2002, Investigational New Drugs.

[30]  S. Deaglio,et al.  Arsenic Trioxide and Breast Cancer: Analysis of the Apoptotic, Differentiative and Immunomodulatory Effects , 2002, Breast Cancer Research and Treatment.

[31]  Jianping Zhang,et al.  Inhibition of the cancer stem cells-like properties by arsenic trioxide, involved in the attenuation of endogenous transforming growth factor beta signal. , 2015, Toxicological sciences : an official journal of the Society of Toxicology.