Advertisement

Transarterial chemoembolization plus immune checkpoint inhibitor as postoperative adjuvant therapy for hepatocellular carcinoma with portal vein tumor thrombus: A multicenter cohort study

  • Author Footnotes
    1 These authors have contributed equally to this work.
    Luyun Yuan
    Footnotes
    1 These authors have contributed equally to this work.
    Affiliations
    Cancer Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China
    Search for articles by this author
  • Author Footnotes
    1 These authors have contributed equally to this work.
    Jinkai Feng
    Footnotes
    1 These authors have contributed equally to this work.
    Affiliations
    Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
    Search for articles by this author
  • Author Footnotes
    1 These authors have contributed equally to this work.
    Yuqing Zhang
    Footnotes
    1 These authors have contributed equally to this work.
    Affiliations
    Cancer Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China
    Search for articles by this author
  • Author Footnotes
    1 These authors have contributed equally to this work.
    Chongde Lu
    Footnotes
    1 These authors have contributed equally to this work.
    Affiliations
    Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
    Search for articles by this author
  • Liu Xu
    Affiliations
    Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001, Zhejiang, China
    Search for articles by this author
  • Chao Liang
    Affiliations
    Department of Hepatobiliary Surgery, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China
    Search for articles by this author
  • Zonghan Liu
    Affiliations
    Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
    Search for articles by this author
  • Feifei Mao
    Affiliations
    Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
    Search for articles by this author
  • Yanjun Xiang
    Affiliations
    Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
    Search for articles by this author
  • Weijun Wang
    Affiliations
    Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
    Search for articles by this author
  • Kang Wang
    Affiliations
    Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
    Search for articles by this author
  • Shuqun Cheng
    Correspondence
    Corresponding author. Cancer Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Shanghai, 200083, China.
    Affiliations
    Cancer Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China

    Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jiaxing, The First Affiliated Hospital of Jiaxing University, Jiaxing, 314001, Zhejiang, China

    Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200433, China
    Search for articles by this author
  • Author Footnotes
    1 These authors have contributed equally to this work.
Published:January 17, 2023DOI:https://doi.org/10.1016/j.ejso.2023.01.020

      Abstract

      Purpose

      This study aimed to assess the efficacy and safety of postoperative adjuvant transarterial chemoembolization (PA-TACE) plus immune checkpoint inhibitor (ICI) for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT).

      Patients and methods

      This study was conducted on three centers from June 2018 to December 2020. Patients were divided into the PA-TACE (n = 48) and PA-TACE plus ICI groups (n = 42). The recurrence-free survival (RFS) and overall survival (OS) curves were depicted by Kaplan-Meier method, and the differences between the two groups were compared using log-rank test. Univariate and multivariate Cox analyses were performed to identify independent risk factors for RFS and OS. Adverse events (AEs) were assessed according to the Common Terminology Criteria for AEs (CTCAE) version 5.0.

      Results

      The median RFS of the PA-TACE plus ICI group was significantly longer than the PA-TACE group (12.76 months vs. 8.11 months; P = 0.038). The median OS of the PA-TACE plus ICI group was also significanfly better than the PA-TACE group (24.5 months vs. 19.1 months; P = 0.032). PA-TACE plus ICI treatment was an independent prognostic factor for RFS (HR: 0.54, 95% CI: 0.32–0.9, P = 0.019) and OS (HR: 0.47, 95% CI: 0.26–0.86, P = 0.014). Only one patient experienced grade ≥3 immune-related AEs in the PA-TACE plus ICI group.

      Conclusions

      PA-TACE plus ICI treatment had better efficacy in preventing recurrence and prolonging survival than PA-TACE alone for HCC patients with PVTT after R0 resection. This novel treatment modality may be an appropriate option for HCC with PVTT.

      Keywords

      Abbreviations:

      ICI (immune checkpoint inhibitor), PA-TACE (postoperative adjuvant transarterial chemoembolization), PVTT (portal vein tumor thrombus), HCC (hepatocellular carcinoma), OS (overall survival), RFS (recurrence-free survival)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Surgical Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Torre L.A.
        • Bray F.
        • Siegel R.L.
        • Ferlay J.
        • Lortet-Tieulent J.
        • Jemal A.
        Global cancer statistics, 2012.
        CA Cancer J Clin. 2015; 65: 87-108
        • Zhang X.P.
        • Gao Y.Z.
        • Chen Z.H.
        • Chen M.S.
        • Li L.Q.
        • Wen T.F.
        • et al.
        An eastern hepatobiliary surgery hospital/portal vein tumor thrombus scoring system as an aid to decision making on hepatectomy for hepatocellular carcinoma patients with portal vein tumor thrombus: a multicenter study.
        Hepatology. 2019; 69: 2076-2090
        • Cabibbo G.
        • Enea M.
        • Attanasio M.
        • Bruix J.
        • Craxì A.
        • Cammà C.
        A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma.
        Hepatology. 2010; 51: 1274-1283
        • Zhang Z.
        • Lai E.C.
        • Zhang C.
        • Yu H.
        • Liu Z.
        • Wan B.
        • et al.
        The strategies for treating primary hepatocellular carcinoma with portal vein tumor thrombus.
        Int J Surg. 2015; 20: 8-16
        • Bruix J.
        • Reig M.
        • Sherman M.
        Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma.
        Gastroenterology. 2016; 150: 835-853
        • Reig M.
        • Forner A.
        • Rimola J.
        • Ferrer-Fàbrega J.
        • Burrel M.
        • Garcia-Criado Á.
        • et al.
        BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update.
        J Hepatol. 2022; 76: 681-693
        • Cheng A.L.
        • Kang Y.K.
        • Chen Z.
        • Tsao C.J.
        • Qin S.
        • Kim J.S.
        • 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: 25-34
        • Zhang X.P.
        • Wang K.
        • Guo W.X.
        • Chen Z.H.
        • Cheng S.Q.
        Is sorafenib an optimal treatment for hepatocellular carcinoma with macrovascular invasion or metastatic disease?.
        Hepatology. 2018; 68: 786
        • Shi J.
        • Lai E.C.
        • Li N.
        • Guo W.X.
        • Xue J.
        • Lau W.Y.
        • et al.
        A new classification for hepatocellular carcinoma with portal vein tumor thrombus.
        J Hepatobiliary Pancreat Sci. 2011; 18: 74-80
        • Kokudo T.
        • Hasegawa K.
        • Matsuyama Y.
        • Takayama T.
        • Izumi N.
        • Kadoya M.
        • et al.
        Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion.
        J Hepatol. 2016; 65: 938-943
        • Chok K.S.
        • Cheung T.T.
        • Chan S.C.
        • Poon R.T.
        • Fan S.T.
        • Lo C.M.
        Surgical outcomes in hepatocellular carcinoma patients with portal vein tumor thrombosis.
        World J Surg. 2014; 38: 490-496
        • Ye J.Z.
        • Zhang Y.Q.
        • Ye H.H.
        • Bai T.
        • Ma L.
        • Xiang B.D.
        • et al.
        Appropriate treatment strategies improve survival of hepatocellular carcinoma patients with portal vein tumor thrombus.
        World J Gastroenterol. 2014; 20: 17141-17147
      1. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.
        J Hepatol. 2012; 56: 908-943
        • Ishizawa T.
        • Hasegawa K.
        • Aoki T.
        • Takahashi M.
        • Inoue Y.
        • Sano K.
        • et al.
        Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma.
        Gastroenterology. 2008; 134: 1908-1916
        • Belghiti J.
        • Panis Y.
        • Farges O.
        • Benhamou J.P.
        • Fekete F.
        Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis.
        Ann Surg. 1991; 214: 114-117
        • Wang K.
        • Guo W.X.
        • Chen M.S.
        • Mao Y.L.
        • Sun B.C.
        • Shi J.
        • et al.
        Multimodality treatment for hepatocellular carcinoma with portal vein tumor thrombus: a large-scale, multicenter, propensity matching score analysis.
        Medicine (Baltim). 2016; 95e3015
        • Lee J.M.
        • Jang B.K.
        • Lee Y.J.
        • Choi W.Y.
        • Choi S.M.
        • Chung W.J.
        • et al.
        Survival outcomes of hepatic resection compared with transarterial chemoembolization or sorafenib for hepatocellular carcinoma with portal vein tumor thrombosis.
        Clin Mol Hepatol. 2016; 22: 160-167
        • Liu P.H.
        • Lee Y.H.
        • Hsia C.Y.
        • Hsu C.Y.
        • Huang Y.H.
        • Chiou Y.Y.
        • et al.
        Surgical resection versus transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis.
        Ann Surg Oncol. 2014; 21: 1825-1833
        • Inoue Y.
        • Hasegawa K.
        • Ishizawa T.
        • Aoki T.
        • Sano K.
        • Beck Y.
        • et al.
        Is there any difference in survival according to the portal tumor thrombectomy method in patients with hepatocellular carcinoma?.
        Surgery. 2009; 145: 9-19
        • Chen X.P.
        • Qiu F.Z.
        • Wu Z.D.
        • Zhang Z.W.
        • Huang Z.Y.
        • Chen Y.F.
        • et al.
        Effects of location and extension of portal vein tumor thrombus on long-term outcomes of surgical treatment for hepatocellular carcinoma.
        Ann Surg Oncol. 2006; 13: 940-946
        • Ikai I.
        • Hatano E.
        • Hasegawa S.
        • Fujii H.
        • Taura K.
        • Uyama N.
        • et al.
        Prognostic index for patients with hepatocellular carcinoma combined with tumor thrombosis in the major portal vein.
        J Am Coll Surg. 2006; 202: 431-438
        • Lo C.M.
        • Liu C.L.
        • Chan S.C.
        • Lam C.M.
        • Poon R.T.
        • Ng I.O.
        • et al.
        A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma.
        Ann Surg. 2007; 245: 831-842
        • Li J.
        • Xing J.
        • Yang Y.
        • Liu J.
        • Wang W.
        • Xia Y.
        • et al.
        Adjuvant (131)I-metuximab for hepatocellular carcinoma after liver resection: a randomised, controlled, multicentre, open-label, phase 2 trial.
        Lancet Gastroenterol Hepatol. 2020; 5: 548-560
        • Wang Z.
        • Ren Z.
        • Chen Y.
        • Hu J.
        • Yang G.
        • Yu L.
        • et al.
        Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study.
        Clin Cancer Res. 2018; 24: 2074-2081
        • Liu F.
        • Guo X.
        • Dong W.
        • Zhang W.
        • Wei S.
        • Zhang S.
        • et al.
        Postoperative adjuvant TACE-associated nomogram for predicting the prognosis of resectable Hepatocellular Carcinoma with portal vein Tumor Thrombus after Liver Resection.
        Int J Biol Sci. 2020; 16: 3210-3220
        • Liu S.
        • Guo L.
        • Li H.
        • Zhang B.
        • Sun J.
        • Zhou C.
        • et al.
        Postoperative adjuvant trans-arterial chemoembolization for patients with hepatocellular carcinoma and portal vein tumor thrombus.
        Ann Surg Oncol. 2018; 25: 2098-2104
        • Peng B.G.
        • He Q.
        • Li J.P.
        • Zhou F.
        Adjuvant transcatheter arterial chemoembolization improves efficacy of hepatectomy for patients with hepatocellular carcinoma and portal vein tumor thrombus.
        Am J Surg. 2009; 198: 313-318
        • Liang L.
        • Li C.
        • Diao Y.K.
        • Jia H.D.
        • Xing H.
        • Pawlik T.M.
        • et al.
        Survival benefits from adjuvant transcatheter arterial chemoembolization in patients undergoing liver resection for hepatocellular carcinoma: a systematic review and meta-analysis.
        Therap Adv Gastroenterol. 2020; 131756284820977693
        • Zhou J.
        • Sun H.
        • Wang Z.
        • Cong W.
        • Wang J.
        • Zeng M.
        • et al.
        Guidelines for the diagnosis and treatment of hepatocellular carcinoma (2019 edition).
        Liver Cancer. 2020; 9: 682-720
        • Wei W.
        • Jian P.E.
        • Li S.H.
        • Guo Z.X.
        • Zhang Y.F.
        • Ling Y.H.
        • et al.
        Adjuvant transcatheter arterial chemoembolization after curative resection for hepatocellular carcinoma patients with solitary tumor and microvascular invasion: a randomized clinical trial of efficacy and safety.
        Cancer Commun. 2018; 38: 61
        • Huo Y.R.
        • Chan M.V.
        • Chan C.
        Resection plus post-operative adjuvant transcatheter arterial chemoembolization (TACE) compared with resection alone for hepatocellular carcinoma: a systematic review and meta-analysis.
        Cardiovasc Intervent Radiol. 2020; 43: 572-586
        • Duffy A.G.
        • Ulahannan S.V.
        • Makorova-Rusher O.
        • Rahma O.
        • Wedemeyer H.
        • Pratt D.
        • et al.
        Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma.
        J Hepatol. 2017; 66: 545-551
        • Pinato D.J.
        • Murray S.M.
        • Forner A.
        • Kaneko T.
        • Fessas P.
        • Toniutto P.
        • et al.
        Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy.
        J Immunother Cancer. 2021; 9e003311
        • Meder L.
        • Schuldt P.
        • Thelen M.
        • Schmitt A.
        • Dietlein F.
        • Klein S.
        • et al.
        Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer.
        Cancer Res. 2018; 78: 4270-4281
        • Fukumura D.
        • Kloepper J.
        • Amoozgar Z.
        • Duda D.G.
        • Jain R.K.
        Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges.
        Nat Rev Clin Oncol. 2018; 15: 325-340
        • Sun J.
        • Guo R.
        • Bi X.
        • Wu M.
        • Tang Z.
        • Lau W.Y.
        • et al.
        Guidelines for diagnosis and treatment of hepatocellular carcinoma with portal vein tumor thrombus in China (2021 edition).
        Liver Cancer. 2022; 11: 315-328
        • Shi J.
        • Lai E.C.
        • Li N.
        • Guo W.X.
        • Xue J.
        • Lau W.Y.
        • et al.
        Surgical treatment of hepatocellular carcinoma with portal vein tumor thrombus.
        Ann Surg Oncol. 2010; 17: 2073-2080
        • Huang J.
        • Liu F.C.
        • Li L.
        • Yuan S.X.
        • Yang Y.
        • Jiang B.G.
        • et al.
        Prognostic nomogram for hepatitis B virus-related hepatocellular carcinoma with adjuvant transarterial chemoembolization after radical resection.
        Am J Clin Oncol. 2020; 43: 20-27
        • Li Q.
        • Wang J.
        • Sun Y.
        • Cui Y.L.
        • Juzi J.T.
        • Li H.X.
        • et al.
        Efficacy of postoperative transarterial chemoembolization and portal vein chemotherapy for patients with hepatocellular carcinoma complicated by portal vein tumor thrombosis--a randomized study.
        World J Surg. 2006; 30 (discussion 2012-3): 2004-2011
        • Sun H.C.
        • Zhu X.D.
        • Zhou J.
        • Gao Q.
        • Shi Y.H.
        • Ding Z.B.
        • et al.
        Adjuvant apatinib treatment after resection of hepatocellular carcinoma with portal vein tumor thrombosis: a phase II trial.
        Ann Transl Med. 2020; 8: 1301
        • Bruix J.
        • Takayama T.
        • Mazzaferro V.
        • Chau G.Y.
        • Yang J.
        • Kudo M.
        • 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: 1344-1354
        • Zhang X.P.
        • Chai Z.T.
        • Gao Y.Z.
        • Chen Z.H.
        • Wang K.
        • Shi J.
        • et al.
        Postoperative adjuvant sorafenib improves survival outcomes in hepatocellular carcinoma patients with microvascular invasion after R0 liver resection: a propensity score matching analysis.
        HPB. 2019; 21: 1687-1696
        • Lin K.
        • Wei F.
        • Huang Q.
        • Lai Z.
        • Zhang J.
        • Chen Q.
        • et al.
        Postoperative adjuvant transarterial chemoembolization plus tyrosine kinase inhibitor for hepatocellular carcinoma: a multicentre retrospective study.
        J Hepatocell Carcinoma. 2022; 9: 127-140
        • Jin H.
        • Qin S.
        • He J.
        • Xiao J.
        • Li Q.
        • Mao Y.
        • et al.
        New insights into checkpoint inhibitor immunotherapy and its combined therapies in hepatocellular carcinoma: from mechanisms to clinical trials.
        Int J Biol Sci. 2022; 18: 2775-2794
        • Bruix J.
        • Sherman M.
        Management of hepatocellular carcinoma: an update.
        Hepatology. 2011; 53: 1020-1022
        • Schöniger-Hekele M.
        • Müller C.
        • Kutilek M.
        • Oesterreicher C.
        • Ferenci P.
        • Gangl A.
        Hepatocellular carcinoma in Central Europe: prognostic features and survival.
        Gut. 2001; 48: 103-109
        • Xu X.F.
        • Xing H.
        • Han J.
        • Li Z.L.
        • Lau W.Y.
        • Zhou Y.H.
        • et al.
        Risk factors, patterns, and outcomes of late recurrence after liver resection for hepatocellular carcinoma: a multicenter study from China.
        JAMA Surg. 2019; 154: 209-217
        • Eggert T.
        • Greten T.F.
        Tumor regulation of the tissue environment in the liver.
        Pharmacol Ther. 2017; 173: 47-57
        • Jiang Y.
        • Han Q.J.
        • Zhang J.
        Hepatocellular carcinoma: mechanisms of progression and immunotherapy.
        World J Gastroenterol. 2019; 25: 3151-3167
        • Galluzzi L.
        • Buqué A.
        • Kepp O.
        • Zitvogel L.
        • Kroemer G.
        Immunological effects of conventional chemotherapy and targeted anticancer agents.
        Cancer Cell. 2015; 28: 690-714
        • Kroemer G.
        • Galluzzi L.
        • Kepp O.
        • Zitvogel L.
        Immunogenic cell death in cancer therapy.
        Annu Rev Immunol. 2013; 31: 51-72
        • Liao Y.
        • Wang B.
        • Huang Z.L.
        • Shi M.
        • Yu X.J.
        • Zheng L.
        • et al.
        Increased circulating Th17 cells after transarterial chemoembolization correlate with improved survival in stage III hepatocellular carcinoma: a prospective study.
        PLoS One. 2013; 8e60444
        • Liao J.
        • Xiao J.
        • Zhou Y.
        • Liu Z.
        • Wang C.
        Effect of transcatheter arterial chemoembolization on cellular immune function and regulatory T cells in patients with hepatocellular carcinoma.
        Mol Med Rep. 2015; 12: 6065-6071
        • Marinelli B.
        • Kim E.
        • D'Alessio A.
        • Cedillo M.
        • Sinha I.
        • Debnath N.
        • et al.
        Integrated use of PD-1 inhibition and transarterial chemoembolization for hepatocellular carcinoma: evaluation of safety and efficacy in a retrospective, propensity score-matched study.
        J Immunother Cancer. 2022; 10e004205