Review article: systemic treatment of hepatocellular carcinoma

The approval of the tyrosine kinase inhibitor sorafenib in 2007 marked a milestone in the treatment of hepatocellular carcinoma, as sorafenib was the first systemic therapy to show a survival benefit in patients with advanced hepatocellular carcinoma. Since then many drugs failed in the first‐ and second‐line setting and it took almost another decade until further tyrosine kinase inhibitors succeeded in phase III trials.

[1]  T. Greten,et al.  Targets for immunotherapy of liver cancer. , 2017, Journal of hepatology.

[2]  R. Jain,et al.  Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal‐derived factor 1 alpha/C‐X‐C receptor type 4 axis and myeloid differentiation antigen–positive myeloid cell infiltration in mice , 2014, Hepatology.

[3]  B. Naini,et al.  Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma , 2017, Pediatric blood & cancer.

[4]  F. Hucke,et al.  Clinical characteristics of patients with hepatocellular carcinoma in Austria – is there a need for a structured screening program? , 2011, Wiener klinische Wochenschrift.

[5]  R. Jain,et al.  Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy , 2017, Science Translational Medicine.

[6]  A. Chakraborti,et al.  Sorafenib response in hepatocellular carcinoma: MicroRNAs as tuning forks , 2018, Hepatology research : the official journal of the Japan Society of Hepatology.

[7]  M. Kudo,et al.  S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial. , 2017, The lancet. Gastroenterology & hepatology.

[8]  B. Daniele,et al.  Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma , 2008 .

[9]  V. Gebski,et al.  SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  A. Ribas,et al.  Combination cancer immunotherapies tailored to the tumour microenvironment , 2016, Nature Reviews Clinical Oncology.

[11]  E. Van Cutsem,et al.  Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. , 2009, The New England journal of medicine.

[12]  J. Bruix,et al.  SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  J. Bruix,et al.  Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma. , 2016, Gastroenterology.

[14]  D. Munn,et al.  Immune suppressive mechanisms in the tumor microenvironment. , 2016, Current opinion in immunology.

[15]  Dirk Schadendorf,et al.  Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. , 2015, The New England journal of medicine.

[16]  T. Greten,et al.  Immune checkpoint blockade in hepatocellular carcinoma: Current progress and future directions , 2014, Hepatology.

[17]  G. Abou-Alfa,et al.  Immunotherapy in hepatocellular carcinoma: Primed to make a difference? , 2016, Cancer.

[18]  Chih-Hung Hsu,et al.  Early alpha‐fetoprotein response predicts treatment efficacy of antiangiogenic systemic therapy in patients with advanced hepatocellular carcinoma , 2010, Cancer.

[19]  S. Steinberg,et al.  Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. , 2017, Journal of hepatology.

[20]  M. Rela,et al.  Pembrolizumab for metastatic hepatocellular carcinoma following live donor liver transplantation: The silver bullet? , 2018, Hepatology.

[21]  J. Bruix,et al.  Treatment of intermediate-stage hepatocellular carcinoma , 2014, Nature Reviews Clinical Oncology.

[22]  H. Amthauer,et al.  The impact of combining Selective Internal Radiation Therapy (SIRT) with Sorafenib on overall survival in patients with advanced hepatocellular carcinoma: The Soramic trial palliative cohort , 2018 .

[23]  Percy A. Knolle,et al.  Antigen-presenting cell function in the tolerogenic liver environment , 2010, Nature Reviews Immunology.

[24]  Laurence Zitvogel,et al.  Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors , 2018, Science.

[25]  D. Stocken,et al.  Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. , 2017, The lancet. Gastroenterology & hepatology.

[26]  J. Bruix,et al.  Plasma Biomarkers as Predictors of Outcome in Patients with Advanced Hepatocellular Carcinoma , 2012, Clinical Cancer Research.

[27]  M. Trauner,et al.  Epidemiological Trends of Hepatocellular Carcinoma in Austria , 2014, Digestive Diseases.

[28]  M. Trauner,et al.  Cancer and liver cirrhosis: implications on prognosis and management , 2016, ESMO Open.

[29]  N. Enomoto,et al.  Changes in plasma vascular endothelial growth factor at 8 weeks after sorafenib administration as predictors of survival for advanced hepatocellular carcinoma , 2013, Cancer.

[30]  M. Dowsett,et al.  Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. , 2005, The New England journal of medicine.

[31]  P. Schirmacher,et al.  EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. , 2018, Journal of hepatology.

[32]  Derek Y. Chiang,et al.  Pivotal role of mTOR signaling in hepatocellular carcinoma. , 2008, Gastroenterology.

[33]  R. Stauber,et al.  Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib , 2011, Alimentary pharmacology & therapeutics.

[34]  R. Finn,et al.  Personalized Clinical Trials in Hepatocellular Carcinoma Based on Biomarker Selection , 2016, Liver Cancer.

[35]  R. Jain,et al.  CXCR4 inhibition in tumor microenvironment facilitates anti‐programmed death receptor‐1 immunotherapy in sorafenib‐treated hepatocellular carcinoma in mice , 2015, Hepatology.

[36]  V. Mazzaferro,et al.  Heterogeneity of Patients with Intermediate (BCLC B) Hepatocellular Carcinoma: Proposal for a Subclassification to Facilitate Treatment Decisions , 2012, Seminars in Liver Disease.

[37]  Ying Cheng,et al.  Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  S. Fan,et al.  The significance of early alpha-fetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib. , 2011, The oncologist.

[39]  M. Kudo,et al.  A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). , 2018 .

[40]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[41]  R. Flavell,et al.  TGF-β: A Master of All T Cell Trades , 2008, Cell.

[42]  Lieping Chen,et al.  Molecular mechanisms of T cell co-stimulation and co-inhibition , 2013, Nature Reviews Immunology.

[43]  J. Bruix,et al.  Postprogression survival of patients with advanced hepatocellular carcinoma: Rationale for second‐line trial design , 2013, Hepatology.

[44]  H. Yoshiji,et al.  619OJET-HCC: A phase 3 randomized, double-blind, placebo-controlled study of tivantinib as a second-line therapy in patients with c-Met high hepatocellular carcinoma , 2017 .

[45]  Jonathan I. Huz,et al.  Spontaneous regression of hepatocellular carcinoma is most often associated with tumour hypoxia or a systemic inflammatory response. , 2012, HPB : the official journal of the International Hepato Pancreato Biliary Association.

[46]  A. Santoro,et al.  Usefulness of alpha-fetoprotein response in patients treated with sorafenib for advanced hepatocellular carcinoma. , 2012, Journal of hepatology.

[47]  M. Kudo,et al.  MicroRNAs for the Prediction of Early Response to Sorafenib Treatment in Human Hepatocellular Carcinoma , 2016, Liver Cancer.

[48]  F. Cappuzzo,et al.  First-line crizotinib versus chemotherapy in ALK-positive lung cancer. , 2014, The New England journal of medicine.

[49]  Jeffrey W. Clark,et al.  Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma , 2017, Clinical Cancer Research.

[50]  M. Kudo,et al.  Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial , 2017, The Lancet.

[51]  S. Zappavigna,et al.  MicroRNA-423-5p Promotes Autophagy in Cancer Cells and Is Increased in Serum From Hepatocarcinoma Patients Treated With Sorafenib. , 2015, Molecular therapy. Nucleic acids.

[52]  R. Jain,et al.  Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. , 2014, Cancer cell.

[53]  K. Rau,et al.  A Phase II Study of the Efficacy and Safety of the Combination Therapy of the MEK Inhibitor Refametinib (BAY 86-9766) Plus Sorafenib for Asian Patients with Unresectable Hepatocellular Carcinoma , 2014, Clinical Cancer Research.

[54]  T. Reiberger,et al.  The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma – a pilot study , 2012, Alimentary pharmacology & therapeutics.

[55]  Ed Yong,et al.  Cancer biomarkers: Written in blood , 2014, Nature.

[56]  L. Jeng,et al.  Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  M. Kudo,et al.  Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma , 2016, Journal of Gastroenterology.

[58]  A. Gasbarrini,et al.  Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. , 2013, The Lancet. Oncology.

[59]  P. Olinga,et al.  Evaluating the antifibrotic potency of galunisertib in a human ex vivo model of liver fibrosis , 2017, British journal of pharmacology.

[60]  G. Chatellier,et al.  SARAH: a randomised controlled trial comparing efficacy and safety of selective internal radiation therapy (with yttrium-90 microspheres) and sorafenib in patients with locally advanced hepatocellular carcinoma , 2017 .

[61]  Yifan Sun,et al.  Exosomes: small vesicles with big roles in hepatocellular carcinoma , 2016, Oncotarget.

[62]  M. Kudo,et al.  Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. , 2014, JAMA.

[63]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[64]  Reinhard Dummer,et al.  High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy , 2018, Nature Network Boston.

[65]  S. Truant,et al.  Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child‐Pugh score , 2011, Alimentary pharmacology & therapeutics.

[66]  M. Makuuchi,et al.  Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. , 2015, The Lancet. Oncology.

[67]  P. Hofman Liquid Biopsy and Therapeutic Targets: Present and Future Issues in Thoracic Oncology , 2017, Cancers.

[68]  L. Schwartz,et al.  Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance). , 2016 .

[69]  J. Prieto,et al.  A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. , 2013, Journal of hepatology.

[70]  J. Prieto,et al.  Immunological landscape and immunotherapy of hepatocellular carcinoma , 2015, Nature Reviews Gastroenterology &Hepatology.

[71]  M. Kudo,et al.  REACH-2: A randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. , 2018 .

[72]  A. Zhu,et al.  Rationally combining anti-VEGF therapy with checkpoint inhibitors in hepatocellular carcinoma. , 2016, Immunotherapy.

[73]  E. Gostick,et al.  Immunodominance and functional alterations of tumor‐associated antigen‐specific CD8+ T‐cell responses in hepatocellular carcinoma , 2014, Hepatology.

[74]  J. Bruix,et al.  Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. , 2014, Journal of hepatology.

[75]  B. Sangro,et al.  Immunotherapy of Hepatocellular Carcinoma: Facts and Hopes , 2017, Clinical Cancer Research.

[76]  M. Mitterhauser,et al.  Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats. , 2009, Journal of hepatology.

[77]  M. Kudo,et al.  Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[78]  R. Perez-soler,et al.  Treatment of non-small-cell lung cancer with erlotinib or gefitinib. , 2011, The New England journal of medicine.

[79]  P. Jansen,et al.  Diagnostic and therapeutic potential of miRNA signatures in patients with hepatocellular carcinoma. , 2012, Journal of hepatology.

[80]  D. Weaver,et al.  Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy , 2016, Nature Medicine.

[81]  Masatoshi Kudo,et al.  Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial , 2017, The Lancet.

[82]  Joon-Oh Park,et al.  Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. , 2015, The Lancet. Oncology.

[83]  C. Porta,et al.  Second-line tivantinib (ARQ 197) vs placebo in patients (Pts) with MET-high hepatocellular carcinoma (HCC): Results of the METIV-HCC phase III trial. , 2017 .

[84]  M. Rebelatto,et al.  Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses. , 2017 .

[85]  Zemin Zhang,et al.  Variable Intra-Tumor Genomic Heterogeneity of Multiple Lesions in Patients With Hepatocellular Carcinoma. , 2016, Gastroenterology.

[86]  A. Burroughs,et al.  A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[87]  R. Labianca,et al.  MicroRNA‐425‐3p predicts response to sorafenib therapy in patients with hepatocellular carcinoma , 2015, Liver international : official journal of the International Association for the Study of the Liver.

[88]  M. Kudo,et al.  Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study. , 2017 .

[89]  M. Fassan,et al.  Pretreatment MicroRNA Level and Outcome in Sorafenib-treated Hepatocellular Carcinoma , 2014, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[90]  Yoon-Koo Kang,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. , 2009, The Lancet. Oncology.

[91]  M. Kudo,et al.  On‐target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: a multi‐centre, prospective study , 2017, Alimentary pharmacology & therapeutics.

[92]  J. Marrero,et al.  Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study. , 2016, Journal of hepatology.

[93]  H. Heinzl,et al.  The ART of decision making: Retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma , 2013, Hepatology.

[94]  M. Kudo,et al.  Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[95]  Dieter Häussinger,et al.  Sorafenib in advanced hepatocellular carcinoma. , 2008, The New England journal of medicine.

[96]  J. Nemunaitis,et al.  Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). , 2017 .

[97]  D. Ichikawa,et al.  Liquid biopsy in patients with hepatocellular carcinoma: Circulating tumor cells and cell-free nucleic acids , 2017, World journal of gastroenterology.

[98]  M. Pishvaian,et al.  Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC). , 2018 .

[99]  H. Heinzl,et al.  How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma. , 2014, Journal of hepatology.

[100]  M. Kudo,et al.  Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial , 2018, The Lancet.

[101]  M. Kudo,et al.  Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. , 2011, European journal of cancer.

[102]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[103]  M. Dumont,et al.  European Association for the Study of the Liver , 1971 .

[104]  J. Llovet,et al.  Hepatocellular Carcinoma: Reasons for Phase III Failure and Novel Perspectives on Trial Design , 2014, Clinical Cancer Research.

[105]  H. Heinzl,et al.  The ART-strategy: sequential assessment of the ART score predicts outcome of patients with hepatocellular carcinoma re-treated with TACE. , 2014, Journal of hepatology.

[106]  M. Torbenson,et al.  mTOR and P70 S6 Kinase Expression in Primary Liver Neoplasms , 2004, Clinical Cancer Research.

[107]  Riccardo Lencioni,et al.  Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial. , 2016, Journal of hepatology.

[108]  M. Manns,et al.  Fighting the bushfire in HCC trials. , 2011, Journal of hepatology.

[109]  J. Bruix,et al.  Pattern of tumor progression in liver cancer: The missing partner in trial design , 2015, Hepatology.

[110]  X. Wang,et al.  Current concepts of immune based treatments for patients with HCC: from basic science to novel treatment approaches , 2015, Gut.

[111]  O. Mir,et al.  Reversible Decrease of Portal Venous Flow in Cirrhotic Patients: A Positive Side Effect of Sorafenib , 2011, PloS one.

[112]  M. Kudo,et al.  Hand-foot skin reaction (HFSR) and overall survival (OS) in the phase 3 RESORCE trial of regorafenib for treatment of hepatocellular carcinoma (HCC) progressing on sorafenib. , 2018 .