[Skip to Content]
[Skip to Content Landing]

Management of Hepatocellular CarcinomaA Review

To identify the key insights or developments described in this article
1 Credit CME

Importance  Hepatocellular carcinoma (HCC) is the sixth most common malignancy and fourth leading cause of cancer-related death worldwide. Recent advances in systemic and locoregional therapies have led to changes in many guidelines regarding systemic therapy, as well as the possibility to downstage patients to undergo resection. This review examines the advances in surgical and medical therapies relative to multidisciplinary treatment strategies for HCC.

Observations  HCC is a major health problem worldwide. The obesity epidemic has made nonalcoholic fatty liver disease a major risk factor for the development of HCC. Multiple societies, such as the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, the Asian Pacific Association for the Study of the Liver, and the National Comprehensive Cancer Network, provide guidelines for screening at-risk patients, as well as define staging systems to guide optimal treatment strategies. The Barcelona Clinic Liver Cancer staging system is widely accepted and has recently undergone updates with the introduction of new systemic therapies and stage migration.

Conclusions and Relevance  The treatment of patients with HCC should involve a multidisciplinary approach with collaboration among surgeons, medical oncologists, radiation oncologists, and interventional radiologists to provide optimal care. Treatment paradigms must consider both tumor and patient-related factors such as extent of liver disease, which is a main driver of morbidity and mortality. The advent of more effective systemic and locoregional therapies has prolonged survival among patients with advanced disease and allowed some patients to undergo surgical intervention who would otherwise have disease considered unresectable.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: December 3, 2022.

Published Online: February 15, 2023. doi:10.1001/jamasurg.2022.7989

Corresponding Author: Timothy M. Pawlik, MD, PhD, MPH, MTS, MBA, Department of Surgery, The Ohio State University Wexner Medical Center, 395 W 12th Ave, Ste 670, Columbus, OH 43210 (Tim.Pawlik@osumc.edu).

Author Contributions: Dr Pawlik had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Brown, Tsilimigras, Ruff, Kamel, Cloyd, Pawlik.

Acquisition, analysis, or interpretation of data: Brown, Tsilimigras, Mohseni, Kamel, Pawlik.

Drafting of the manuscript: Brown, Tsilimigras, Ruff, Mohseni, Kamel.

Critical revision of the manuscript for important intellectual content: Brown, Tsilimigras, Mohseni, Kamel, Cloyd, Pawlik.

Statistical analysis: Brown, Kamel, Pawlik.

Administrative, technical, or material support: Brown, Mohseni, Kamel.

Supervision: Tsilimigras, Mohseni, Kamel, Cloyd, Pawlik.

Conflict of Interest Disclosures: None reported.

Bray  F , Ferlay  J , Soerjomataram  I , Siegel  RL , Torre  LA , Jemal  A .  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.   CA Cancer J Clin. 2018;68(6):394-424. doi:10.3322/caac.21492PubMedGoogle ScholarCrossref
Fujiwara  N , Friedman  SL , Goossens  N , Hoshida  Y .  Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine.   J Hepatol. 2018;68(3):526-549. doi:10.1016/j.jhep.2017.09.016PubMedGoogle ScholarCrossref
Huang  DQ , El-Serag  HB , Loomba  R .  Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention.   Nat Rev Gastroenterol Hepatol. 2021;18(4):223-238. doi:10.1038/s41575-020-00381-6PubMedGoogle ScholarCrossref
Frenette  CT , Isaacson  AJ , Bargellini  I , Saab  S , Singal  AG .  A practical guideline for hepatocellular carcinoma screening in patients at risk.   Mayo Clin Proc Innov Qual Outcomes. 2019;3(3):302-310. doi:10.1016/j.mayocpiqo.2019.04.005PubMedGoogle ScholarCrossref
Chang  TS , Wu  YC , Tung  SY ,  et al.  Alpha-fetoprotein measurement benefits hepatocellular carcinoma surveillance in patients with cirrhosis.   Am J Gastroenterol. 2015;110(6):836-844. doi:10.1038/ajg.2015.100PubMedGoogle ScholarCrossref
Yang  JD , Addissie  BD , Mara  KC ,  et al.  GALAD score for hepatocellular carcinoma detection in comparison with liver ultrasound and proposal of GALADUS score.   Cancer Epidemiol Biomarkers Prev. 2019;28(3):531-538. doi:10.1158/1055-9965.EPI-18-0281PubMedGoogle ScholarCrossref
Beal  EW , Owen  M , McNamara  M , McAlearney  AS , Tsung  A .  Patient-, provider-, and system-level barriers to surveillance for hepatocellular carcinoma in high-risk patients in the US: a scoping review.   J Gastrointest Cancer. 2022. doi:10.1007/s12029-022-00851-xPubMedGoogle ScholarCrossref
Yang  JD , Hainaut  P , Gores  GJ , Amadou  A , Plymoth  A , Roberts  LR .  A global view of hepatocellular carcinoma: trends, risk, prevention, and management.   Nat Rev Gastroenterol Hepatol. 2019;16(10):589-604. doi:10.1038/s41575-019-0186-yPubMedGoogle ScholarCrossref
Chang  MH , You  SL , Chen  CJ ,  et al; Taiwan Hepatoma Study Group.  Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study.   J Natl Cancer Inst. 2009;101(19):1348-1355. doi:10.1093/jnci/djp288PubMedGoogle ScholarCrossref
Hassany  M , Elsharkawy  A , Maged  A ,  et al.  Hepatitis C virus treatment by direct-acting antivirals in successfully treated hepatocellular carcinoma and possible mutual impact.   Eur J Gastroenterol Hepatol. 2018;30(8):876-881. doi:10.1097/MEG.0000000000001152PubMedGoogle ScholarCrossref
Rustgi  VK , Li  Y , Gupta  K ,  et al.  Bariatric surgery reduces cancer risk in adults with nonalcoholic fatty liver disease and severe obesity.   Gastroenterology. 2021;161(1):171-184.e10. doi:10.1053/j.gastro.2021.03.021PubMedGoogle ScholarCrossref
Aminian  A , Al-Kurd  A , Wilson  R ,  et al.  Association of bariatric surgery with major adverse liver and cardiovascular outcomes in patients with biopsy-proven nonalcoholic steatohepatitis.   JAMA. 2021;326(20):2031-2042. doi:10.1001/jama.2021.19569PubMedGoogle ScholarCrossref
Jiang  HY , Chen  J , Xia  CC , Cao  LK , Duan  T , Song  B .  Noninvasive imaging of hepatocellular carcinoma: from diagnosis to prognosis.   World J Gastroenterol. 2018;24(22):2348-2362. doi:10.3748/wjg.v24.i22.2348PubMedGoogle ScholarCrossref
Li  L , Hu  Y , Han  J , Li  Q , Peng  C , Zhou  J .  Clinical application of liver imaging reporting and data system for characterizing liver neoplasms: a meta-analysis.   Diagnostics (Basel). 2021;11(2):11. doi:10.3390/diagnostics11020323PubMedGoogle ScholarCrossref
Pugh  RN , Murray-Lyon  IM , Dawson  JL , Pietroni  MC , Williams  R .  Transection of the oesophagus for bleeding oesophageal varices.   Br J Surg. 1973;60(8):646-649. doi:10.1002/bjs.1800600817PubMedGoogle ScholarCrossref
Child  CG , Turcotte  JG .  Surgery and portal hypertension.   Major Probl Clin Surg. 1964;1:1-85.PubMedGoogle Scholar
Malinchoc  M , Kamath  PS , Gordon  FD , Peine  CJ , Rank  J , ter Borg  PC .  A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts.   Hepatology. 2000;31(4):864-871. doi:10.1053/he.2000.5852PubMedGoogle ScholarCrossref
Cucchetti  A , Ercolani  G , Vivarelli  M ,  et al.  Impact of Model for End-Stage Liver Disease (MELD) score on prognosis after hepatectomy for hepatocellular carcinoma on cirrhosis.   Liver Transpl. 2006;12(6):966-971. doi:10.1002/lt.20761PubMedGoogle ScholarCrossref
Vitale  A , Huo  TL , Cucchetti  A ,  et al.  Survival benefit of liver transplantation vs resection for hepatocellular carcinoma: impact of MELD score.   Ann Surg Oncol. 2015;22(6):1901-1907. doi:10.1245/s10434-014-4099-2PubMedGoogle ScholarCrossref
Teh  SH , Sheppard  BC , Schwartz  J , Orloff  SL .  Model for End-stage Liver Disease score fails to predict perioperative outcome after hepatic resection for hepatocellular carcinoma in patients without cirrhosis.   Am J Surg. 2008;195(5):697-701. doi:10.1016/j.amjsurg.2007.05.054PubMedGoogle ScholarCrossref
Johnson  PJ , Berhane  S , Kagebayashi  C ,  et al.  Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach—the ALBI grade.   J Clin Oncol. 2015;33(6):550-558. doi:10.1200/JCO.2014.57.9151PubMedGoogle Scholar
Hiraoka  A , Kumada  T , Michitaka  K ,  et al.  Usefulness of albumin-bilirubin grade for evaluation of prognosis of 2584 Japanese patients with hepatocellular carcinoma.   J Gastroenterol Hepatol. 2016;31(5):1031-1036. doi:10.1111/jgh.13250PubMedGoogle Scholar
Rajakannu  M , Coilly  A , Cherqui  D ,  et al.  Liver stiffness-based model predicts hepatic venous pressure gradient in patients with liver disease.   HPB (Oxford). 2022;24(10):1796-1803. doi:10.1016/j.hpb.2020.11.113PubMedGoogle Scholar
Mai  RY , Bai  T , Luo  XL , Wu  GB .  Indocyanine green retention test as a predictor of postoperative complications in patients with hepatitis B virus–related hepatocellular carcinoma.   Ther Clin Risk Manag. 2022;18:761-772. doi:10.2147/TCRM.S363849PubMedGoogle Scholar
Okuda  K , Ohtsuki  T , Obata  H ,  et al.  Natural history of hepatocellular carcinoma and prognosis in relation to treatment—study of 850 patients.   Cancer. 1985;56(4):918-928. doi:10.1002/1097-0142(19850815)56:4<918::AID-CNCR2820560437>3.0.CO;2-EPubMedGoogle Scholar
Kudo  M , Chung  H , Osaki  Y .  Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score).   J Gastroenterol. 2003;38(3):207-215. doi:10.1007/s005350300038PubMedGoogle Scholar
 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(3):751-755. doi:10.1002/hep.510280322PubMedGoogle Scholar
Reig  M , Forner  A , Rimola  J ,  et al.  BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update.   J Hepatol. 2022;76(3):681-693. doi:10.1016/j.jhep.2021.11.018PubMedGoogle Scholar
Tsilimigras  DI , Aziz  H , Pawlik  TM .  Critical analysis of the updated Barcelona Clinic Liver Cancer (BCLC) group guidelines.   Ann Surg Oncol. 2022;29(12):7231-7234.PubMedGoogle Scholar
Pinna  AD , Yang  T , Mazzaferro  V ,  et al.  Liver transplantation and hepatic resection can achieve cure for hepatocellular carcinoma.   Ann Surg. 2018;268(5):868-875. doi:10.1097/SLA.0000000000002889PubMedGoogle Scholar
Tsilimigras  DI , Bagante  F , Moris  D ,  et al.  Defining the chance of cure after resection for hepatocellular carcinoma within and beyond the Barcelona Clinic Liver Cancer guidelines: a multi-institutional analysis of 1010 patients.   Surgery. 2019;166(6):967-974. doi:10.1016/j.surg.2019.08.010PubMedGoogle Scholar
Chapman  WC , Klintmalm  G , Hemming  A ,  et al.  Surgical treatment of hepatocellular carcinoma in North America: can hepatic resection still be justified?   J Am Coll Surg. 2015;220(4):628-637. doi:10.1016/j.jamcollsurg.2014.12.030PubMedGoogle Scholar
Citterio  D , Facciorusso  A , Sposito  C , Rota  R , Bhoori  S , Mazzaferro  V .  Hierarchic interaction of factors associated with liver decompensation after resection for hepatocellular carcinoma.   JAMA Surg. 2016;151(9):846-853. doi:10.1001/jamasurg.2016.1121PubMedGoogle Scholar
Rajakannu  M , Cherqui  D , Ciacio  O ,  et al.  Liver stiffness measurement by transient elastography predicts late posthepatectomy outcomes in patients undergoing resection for hepatocellular carcinoma.   Surgery. 2017;162(4):766-774. doi:10.1016/j.surg.2017.06.006PubMedGoogle Scholar
European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver.  EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.   J Hepatol. 2018;69(2):406-460. doi:10.1016/j.jhep.2018.03.024PubMedGoogle Scholar
Tsilimigras  DI , Mehta  R , Paredes  AZ ,  et al.  Overall tumor burden dictates outcomes for patients undergoing resection of multinodular hepatocellular carcinoma beyond the Milan criteria.   Ann Surg. 2020;272(4):574-581. doi:10.1097/SLA.0000000000004346PubMedGoogle Scholar
Moris  D , Tsilimigras  DI , Kostakis  ID ,  et al.  Anatomic versus nonanatomic resection for hepatocellular carcinoma: a systematic review and meta-analysis.   Eur J Surg Oncol. 2018;44(7):927-938. doi:10.1016/j.ejso.2018.04.018PubMedGoogle Scholar
Xourafas  D , Pawlik  TM , Cloyd  JM .  Early morbidity and mortality after minimally invasive liver resection for hepatocellular carcinoma: a propensity score–matched comparison with open resection.   J Gastrointest Surg. 2019;23(7):1435-1442. doi:10.1007/s11605-018-4016-2PubMedGoogle Scholar
Mazzaferro  V , Regalia  E , Doci  R ,  et al.  Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.   N Engl J Med. 1996;334(11):693-699. doi:10.1056/NEJM199603143341104PubMedGoogle Scholar
Mazzaferro  V , Bhoori  S , Sposito  C ,  et al.  Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience.   Liver Transpl. 2011;17(suppl 2):S44-S57. doi:10.1002/lt.22365PubMedGoogle Scholar
Vibert  E , Schwartz  M , Olthoff  KM .  Advances in resection and transplantation for hepatocellular carcinoma.   J Hepatol. 2020;72(2):262-276. doi:10.1016/j.jhep.2019.11.017PubMedGoogle Scholar
Mazzaferro  V , Llovet  JM , Miceli  R ,  et al; Metroticket Investigator Study Group.  Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.   Lancet Oncol. 2009;10(1):35-43. doi:10.1016/S1470-2045(08)70284-5PubMedGoogle Scholar
Yao  FY , Mehta  N , Flemming  J ,  et al.  Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria.   Hepatology. 2015;61(6):1968-1977. doi:10.1002/hep.27752PubMedGoogle Scholar
Breen  DJ , Lencioni  R .  Image-guided ablation of primary liver and renal tumours.   Nat Rev Clin Oncol. 2015;12(3):175-186. doi:10.1038/nrclinonc.2014.237PubMedGoogle Scholar
Yu  J , Yu  XL , Han  ZY ,  et al.  Percutaneous cooled-probe microwave versus radiofrequency ablation in early-stage hepatocellular carcinoma: a phase III randomised controlled trial.   Gut. 2017;66(6):1172-1173. doi:10.1136/gutjnl-2016-312629PubMedGoogle Scholar
Feng  K , Yan  J , Li  X ,  et al.  A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma.   J Hepatol. 2012;57(4):794-802. doi:10.1016/j.jhep.2012.05.007PubMedGoogle Scholar
Cucchetti  A , Piscaglia  F , Cescon  M ,  et al.  Cost-effectiveness of hepatic resection vs percutaneous radiofrequency ablation for early hepatocellular carcinoma.   J Hepatol. 2013;59(2):300-307. doi:10.1016/j.jhep.2013.04.009PubMedGoogle Scholar
Huang  J , Yan  L , Cheng  Z ,  et al.  A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria.   Ann Surg. 2010;252(6):903-912. doi:10.1097/SLA.0b013e3181efc656PubMedGoogle Scholar
Couillard  AB , Knott  EA , Zlevor  AM ,  et al.  Microwave ablation as bridging to liver transplant for patients with hepatocellular carcinoma: a single-center retrospective analysis.   J Vasc Interv Radiol. 2022;33(9):1045-1053. doi:10.1016/j.jvir.2022.05.019PubMedGoogle Scholar
Chu  DZ , Hutchins  L , Lang  NP .  Regional chemotherapy of liver metastases from colorectal carcinoma: hepatic artery or portal vein infusion?   Cancer Treat Rev. 1988;15(4):243-256. doi:10.1016/0305-7372(88)90024-2PubMedGoogle Scholar
Ramsey  DE , Kernagis  LY , Soulen  MC , Geschwind  JF .  Chemoembolization of hepatocellular carcinoma.   J Vasc Interv Radiol. 2002;13(9 Pt 2):S211-S221. doi:10.1016/S1051-0443(07)61789-8PubMedGoogle Scholar
Llovet  JM , De Baere  T , Kulik  L ,  et al.  Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma.   Nat Rev Gastroenterol Hepatol. 2021;18(5):293-313. doi:10.1038/s41575-020-00395-0PubMedGoogle Scholar
Lammer  J , Malagari  K , Vogl  T ,  et al; PRECISION V Investigators.  Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study.   Cardiovasc Intervent Radiol. 2010;33(1):41-52. doi:10.1007/s00270-009-9711-7PubMedGoogle Scholar
Garin  E , Tselikas  L , Guiu  B ,  et al; DOSISPHERE-01 Study Group.  Personalised vs standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial.   Lancet Gastroenterol Hepatol. 2021;6(1):17-29. doi:10.1016/S2468-1253(20)30290-9PubMedGoogle Scholar
Lyu  N , Wang  X , Li  JB ,  et al.  Arterial chemotherapy of oxaliplatin plus fluorouracil vs sorafenib in advanced hepatocellular carcinoma: a biomolecular exploratory, randomized, phase III trial (FOHAIC-1).   J Clin Oncol. 2022;40(5):468-480. doi:10.1200/JCO.21.01963PubMedGoogle Scholar
He  M , Li  Q , Zou  R ,  et al.  Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial.   JAMA Oncol. 2019;5(7):953-960. doi:10.1001/jamaoncol.2019.0250PubMedGoogle Scholar
Li  QJ , He  MK , Chen  HW ,  et al.  Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs transarterial chemoembolization for large hepatocellular carcinoma: a randomized phase III trial.   J Clin Oncol. 2022;40(2):150-160. doi:10.1200/JCO.21.00608PubMedGoogle Scholar
Beran  A , Abuhelwa  Z , Abdulsattar  W , Alloghbi  A , Alqahtani  A , Hamouda  DM .  Hepatic arterial infusion chemotherapy vs transarterial chemoembolization in unresectable hepatocellular carcinoma: a systematic review and meta-analysis.   J Clin Oncol. 2022;40(16):e16141. doi:10.1200/JCO.2022.40.16_suppl.e16141Google Scholar
Apisarnthanarax  S , Barry  A , Cao  M ,  et al.  External beam radiation therapy for primary liver cancers: an ASTRO clinical practice guideline.   Pract Radiat Oncol. 2022;12(1):28-51. doi:10.1016/j.prro.2021.09.004PubMedGoogle Scholar
Lee  J , Shin  IS , Yoon  WS , Koom  WS , Rim  CH .  Comparisons between radiofrequency ablation and stereotactic body radiotherapy for liver malignancies: meta-analyses and a systematic review.   Radiother Oncol. 2020;145:63-70. doi:10.1016/j.radonc.2019.12.004PubMedGoogle Scholar
Hara  K , Takeda  A , Tsurugai  Y ,  et al.  Radiotherapy for hepatocellular carcinoma results in comparable survival to radiofrequency ablation: a propensity score analysis.   Hepatology. 2019;69(6):2533-2545. doi:10.1002/hep.30591PubMedGoogle Scholar
Kim  TH , Koh  YH , Kim  BH ,  et al.  Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial.   J Hepatol. 2021;74(3):603-612. doi:10.1016/j.jhep.2020.09.026PubMedGoogle Scholar
Facciuto  ME , Singh  MK , Rochon  C ,  et al.  Stereotactic body radiation therapy in hepatocellular carcinoma and cirrhosis: evaluation of radiological and pathological response.   J Surg Oncol. 2012;105(7):692-698. doi:10.1002/jso.22104PubMedGoogle Scholar
Hasan  S , Thai  N , Uemura  T ,  et al.  Hepatocellular carcinoma with child Pugh-A cirrhosis treated with stereotactic body radiotherapy.   World J Gastrointest Surg. 2017;9(12):256-263. doi:10.4240/wjgs.v9.i12.256PubMedGoogle Scholar
Wei  X , Jiang  Y , Zhang  X ,  et al.  Neoadjuvant 3-dimensional conformal radiotherapy for resectable hepatocellular carcinoma with portal vein tumor thrombus: a randomized, open-label, multicenter controlled study.   J Clin Oncol. 2019;37(24):2141-2151. doi:10.1200/JCO.18.02184PubMedGoogle Scholar
Llovet  JM , Ricci  S , Mazzaferro  V ,  et al; SHARP Investigators Study Group.  Sorafenib in advanced hepatocellular carcinoma.   N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857PubMedGoogle Scholar
Kudo  M , Finn  RS , Qin  S ,  et al.  Lenvatinib vs sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 noninferiority trial.   Lancet. 2018;391(10126):1163-1173.PubMedGoogle Scholar
Abou-Alfa  GK , Lau  G , Kudo  M ,  et al; HIMALAYA Investigators.  Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.   NEJM Evid. 2022;1(8):EVIDoa2100070. doi:10.1056/EVIDoa2100070Google Scholar
Verset  G , Borbath  I , Karwal  M ,  et al.  Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: data from the open-label, phase 2 KEYNOTE-224 trial.   Clin Cancer Res. 2022;28(12):2547-2554.PubMedGoogle Scholar
Yau  T , Park  JW , Finn  RS ,  et al.  Nivolumab vs Sorafenib in Advanced Hepatocellular Carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial.   Lancet Oncol. 2022;23(1):77-90.PubMedGoogle Scholar
Bruix  J , Qin  S , Merle  P ,  et al; RESORCE Investigators.  Regorafenib for Patients With Hepatocellular Carcinoma Who Progressed on Sorafenib Treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.   Lancet. 2017;389(10064):56-66.PubMedGoogle Scholar
Abou-Alfa  GK , Meyer  T , Cheng  AL ,  et al.  Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.   N Engl J Med. 2018;379(1):54-63.PubMedGoogle Scholar
Zhu  AX , Kang  YK , Yen  CJ ,  et al; REACH-2 Study Investigators.  Ramucirumab After Sorafenib in Patients With Advanced Hepatocellular Carcinoma and Increased α-Fetoprotein Concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.   Lancet Oncol. 2019;20(2):282-296.PubMedGoogle Scholar
Yau  T , Kang  YK , Kim  TY ,  et al.  Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: the CheckMate 040 randomized clinical trial.   JAMA Oncol. 2020;6(11):e204564.PubMedGoogle Scholar
Finn  RS , Ryoo  BY , Merle  P ,  et al; KEYNOTE-240 Investigators.  Pembrolizumab as Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: a randomized, double-blind, phase 3 trial.   J Clin Oncol. 2020;38(3):193-202.PubMedGoogle Scholar
El-Khoueiry  AB , Sangro  B , Yau  T ,  et al.  Nivolumab in Patients With Advanced Hepatocellular Carcinoma (CheckMate 040): an open-label, noncomparative, phase 1/2 dose escalation and expansion trial.   Lancet. 2017;389(10088):2492-2502.PubMedGoogle Scholar
Andre  T , Berton  D , Curigliano  G ,  et al.  Safety and efficacy of anti–PD-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient (dMMR) solid cancers: results from GARNET study.   J Clin Oncol. 2021;39(3)(suppl):9. doi:10.1200/JCO.2021.39.3_suppl.9Google Scholar
Finn  RS , Qin  S , Ikeda  M ,  et al; IMbrave150 Investigators.  Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma.   N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745PubMedGoogle Scholar
Lee  MS , Ryoo  BY , Hsu  CH ,  et al; GO30140 Investigators.  Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study.   Lancet Oncol. 2020;21(6):808-820. doi:10.1016/S1470-2045(20)30156-XPubMedGoogle Scholar
Ma  C , Kesarwala  AH , Eggert  T ,  et al.  NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis.   Nature. 2016;531(7593):253-257. doi:10.1038/nature16969PubMedGoogle Scholar
Heinrich  B , Brown  ZJ , Diggs  LP ,  et al.  Steatohepatitis impairs T-cell–directed immunotherapies against liver tumors in mice.   Gastroenterology. 2021;160(1):331-345.e6.PubMedGoogle Scholar
Toh  HC , Galle  PR , Zhu  AX ,  et al.  IMbrave150: exploratory efficacy and safety in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab beyond radiological progression until loss of clinical benefit in a global phase III study.   J Clin Oncol. 2022;40:470. doi:10.1200/JCO.2022.40.4_suppl.470Google Scholar
Brown  ZJ , Yu  SJ , Heinrich  B ,  et al.  Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma.   Cancer Immunol Immunother. 2018;67(8):1305-1315. doi:10.1007/s00262-018-2190-4PubMedGoogle Scholar
Chen  J , Ji  J , Cho  MT , Monjazeb  A , Gholami  S , Kim  EJH .  Phase I/II trial of BMS-986205 and nivolumab as first-line therapy in hepatocellular carcinoma.   J Clin Oncol. 2019;37(8):TPS57. doi:10.1200/JCO.2019.37.8_suppl.TPS57Google Scholar
Zhang  Y , Huang  G , Wang  Y ,  et al.  Is salvage liver resection necessary for initially unresectable hepatocellular carcinoma patients downstaged by transarterial chemoembolization—10 years of experience.   Oncologist. 2016;21(12):1442-1449. doi:10.1634/theoncologist.2016-0094PubMedGoogle Scholar
Kaseb  AO , Hasanov  E , Cao  HST ,  et al.  Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial.   Lancet Gastroenterol Hepatol. 2022;7(3):208-218. doi:10.1016/S2468-1253(21)00427-1PubMedGoogle Scholar
Ho  WJ , Zhu  Q , Durham  J ,  et al.  Neoadjuvant cabozantinib and nivolumab converts locally advanced HCC into resectable disease with enhanced antitumor immunity.   Nat Cancer. 2021;2(9):891-903. doi:10.1038/s43018-021-00234-4PubMedGoogle Scholar
Bruix  J , Takayama  T , Mazzaferro  V ,  et al; STORM investigators.  Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.   Lancet Oncol. 2015;16(13):1344-1354. doi:10.1016/S1470-2045(15)00198-9PubMedGoogle Scholar
A study of atezolizumab plus bevacizumab vs active surveillance as adjuvant therapy in patients with hepatocellular carcinoma at high risk of recurrence after surgical resection or ablation (IMbrave050). ClinicalTrials.gov identifier: NCT04102098. Updated November 21, 2022. Accessed November 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04102098
Huppert  LA , Gordan  JD , Kelley  RK .  Checkpoint inhibitors for the treatment of advanced hepatocellular carcinoma.   Clin Liver Dis (Hoboken). 2020;15(2):53-58. doi:10.1002/cld.879PubMedGoogle Scholar
AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity


My Saved Searches

You currently have no searches saved.


My Saved Courses

You currently have no courses saved.