The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.
Individual Disclosures for the NCCN Hepatobiliary Cancers Panel
Ryerson AB, Eheman CR, Altekruse SF, et al. Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer. Cancer 2016;122:1312–1337.
Akinyemiju T, Abera S, Ahmed M, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the Global Burden of Disease Study 2015. JAMA Oncol 2017;3:1683–1691.
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;68:723–750.
Islami F, Miller KD, Siegel RL, et al. Disparities in liver cancer occurrence in the United States by race/ethnicity and state. CA Cancer J Clin 2017;67:273–289.
Melkonian SC, Jim MA, Reilley B, et al. Incidence of primary liver cancer in American Indians and Alaska Natives, US, 1999-2009. Cancer Causes Control 2018;29:833–844.
Herbst DA, Reddy KR. Risk factors for hepatocellular carcinoma. Clin Liver Dis (Hoboken) 2013;1:180–182.
Janevska D, Chaloska-Ivanova V, Janevski V. Hepatocellular carcinoma: risk factors, diagnosis and treatment. Open Access Maced J Med Sci 2015;3:732–736.
Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004; 127(5, Suppl 1)S35–S50.
de Martel C, Maucort-Boulch D, Plummer M, et al. World-wide relative contribution of hepatitis B and C viruses in hepatocellular carcinoma. Hepatology 2015;62:1190–1200.
Sun J, Althoff KN, Jing Y, et al. Trends in hepatocellular carcinoma incidence and risk among persons with HIV in the US and Canada, 1996-2015. JAMA Netw Open 2021;4:e2037512.
Ganne-Carrié N, Nahon P. Hepatocellular carcinoma in the setting of alcohol-related liver disease. J Hepatol 2019;70:284–293.
Kanwal F, Kramer JR, Mapakshi S, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 2018;155:1828–1837 e1822.
Ascha MS, Hanouneh IA, Lopez R, et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51:1972–1978.
Elmberg M, Hultcrantz R, Ekbom A, et al. Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology 2003;125:1733–1741.
Takamatsu S, Noguchi N, Kudoh A, et al. Influence of risk factors for metabolic syndrome and non-alcoholic fatty liver disease on the progression and prognosis of hepatocellular carcinoma. Hepatogastroenterology 2008;55:609–614.
Katyal S, Oliver JH III, Peterson MS, et al. Extrahepatic metastases of hepatocellular carcinoma. Radiology 2000;216:698–703.
Natsuizaka M, Omura T, Akaike T, et al. Clinical features of hepatocellular carcinoma with extrahepatic metastases. J Gastroenterol Hepatol 2005;20:1781–1787.
Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018;67:358–380.
European Association For The Study Of The LiverEuropean Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908–943.
Zhang B-H, Yang B-H, Tang Z-Y. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417–422.
El-Serag HB, Marrero JA, Rudolph L, et al. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008;134:1752–1763.
Waidely E, Al-Yuobi AR, Bashammakh AS, et al. Serum protein biomarkers relevant to hepatocellular carcinoma and their detection. Analyst (Lond) 2016;141:36–44.
Zhang B, Yang B. Combined alpha fetoprotein testing and ultrasonography as a screening test for primary liver cancer. J Med Screen 1999;6:108–110.
Tong MJ, Rosinski AA, Huynh CT, et al. Long-term survival after surveillance and treatment in patients with chronic viral hepatitis and hepatocellular carcinoma. Hepatol Commun 2017;1:595–608.
International Consensus Group for Hepatocellular NeoplasiaThe International Consensus Group for Hepatocellular Neoplasia. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 2009;49:658–664.
Lok AS, Sterling RK, Everhart JE, et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology 2010;138:493–502.
Tangkijvanich P, Anukulkarnkusol N, Suwangool P, et al. Clinical characteristics and prognosis of hepatocellular carcinoma: analysis based on serum alpha-fetoprotein levels. J Clin Gastroenterol 2000;31:302–308.
Tzartzeva K, Obi J, Rich NE, et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology 2018;154:1706–1718.e1.
Arrieta O, Cacho B, Morales-Espinosa D, et al. The progressive elevation of alpha fetoprotein for the diagnosis of hepatocellular carcinoma in patients with liver cirrhosis. BMC Cancer 2007;7:28.
Liver imaging reporting and data system version 2017. Accessed April 2, 2019. Available at: http://www.acr.org/quality-safety/resources/LIRADS
Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol 1954;30:969–977.
Marrero JA, Hussain HK, Nghiem HV, et al. Improving the prediction of hepatocellular carcinoma in cirrhotic patients with an arterially-enhancing liver mass. Liver Transpl 2005;11:281–289.
Miller G, Schwartz LH, D’Angelica M. The use of imaging in the diagnosis and staging of hepatobiliary malignancies. Surg Oncol Clin N Am 2007;16:343–368.
Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 2008;47:97–104.
Choi JY, Lee JM, Sirlin CB. CT and MR imaging diagnosis and staging of hepatocellular carcinoma: part II. Extracellular agents, hepatobiliary agents, and ancillary imaging features. Radiology 2014;273:30–50.
Tang A, Bashir MR, Corwin MT, et al. Evidence supporting LI-RADS major features for CT- and MR imaging-based diagnosis of hepatocellular carcinoma: a systematic review. Radiology 2018;286:29–48.
Kierans AS, Kang SK, Rosenkrantz AB. The diagnostic performance of dynamic contrast-enhanced MR imaging for detection of small hepatocellular carcinoma measuring up to 2 cm: a meta-analysis. Radiology 2016;278:82–94.
Sangiovanni A, Manini MA, Iavarone M, et al. The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 2010;59:638–644.
Schellhaas B, Wildner D, Pfeifer L, et al. LI-RADS-CEUS - proposal for a contrast-enhanced ultrasound algorithm for the diagnosis of hepatocellular carcinoma in high-risk populations. Ultraschall Med 2016;37(S 01):627–634.
Chang TT, Sawhney R, Monto A, et al. Implementation of a multidisciplinary treatment team for hepatocellular cancer at a Veterans Affairs Medical Center improves survival. HPB (Oxford) 2008;10:405–411.
Yopp AC, Mansour JC, Beg MS, et al. Establishment of a multidisciplinary hepatocellular carcinoma clinic is associated with improved clinical outcome. Ann Surg Oncol 2014;21:1287–1295.
Agarwal PD, Phillips P, Hillman L, et al. Multidisciplinary management of hepatocellular carcinoma improves access to therapy and patient survival. J Clin Gastroenterol 2017;51:845–849.
Serper M, Taddei TH, Mehta R, et al. Association of provider specialty and multidisciplinary care with hepatocellular carcinoma treatment and mortality. Gastroenterology 2017;152:1954–1964.
Farinati F, Marino D, De Giorgio M, et al. Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither? Am J Gastroenterol 2006;101:524–532.
Trevisani F, D’Intino PE, Morselli-Labate AM, et al. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol 2001;34:570–575.
Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. AASLD Practice Guidelines. Accessed April 7, 2021. Available at: https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.24199
Gregory JJ, Jr., Finlay JL. Alpha-fetoprotein and beta-human chorionic gonadotropin: their clinical significance as tumour markers. Drugs 1999;57:463–467.
Torzilli G, Minagawa M, Takayama T, et al. Accurate preoperative evaluation of liver mass lesions without fine-needle biopsy. Hepatology 1999;30:889–893.
Levy I, Greig PD, Gallinger S, et al. Resection of hepatocellular carcinoma without preoperative tumor biopsy. Ann Surg 2001;234:206–209.
Lok AS, Lai CL. alpha-fetoprotein monitoring in Chinese patients with chronic hepatitis B virus infection: role in the early detection of hepatocellular carcinoma. Hepatology 1989;9:110–115.
Bialecki ES, Di Bisceglie AM. Diagnosis of hepatocellular carcinoma. HPB (Oxford) 2005;7:26–34.
Johnson PJ, Pirrie SJ, Cox TF, et al. The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers. Cancer Epidemiol Biomarkers Prev 2014;23:144–153.
Berhane S, Toyoda H, Tada T, et al. Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients. Clin Gastroenterol Hepatol 2016;14:875–886.e6.
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;28:531–538.
Best J, Bechmann LP, Sowa JP, et al. GALAD score detects early hepatocellular carcinoma in an international cohort of patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2020;18:728–735.e4.
Pomfret EA, Washburn K, Wald C, et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl 2010;16:262–278.
DeLeve LD, Valla DC, Garcia-Tsao G. Vascular disorders of the liver. Hepatology 2009;49:1729–1764.
Malaguarnera G, Paladina I, Giordano M, et al. Serum markers of intrahepatic cholangiocarcinoma. Dis Markers 2013;34:219–228.
Khan SA, Thomas HC, Davidson BR, et al. Cholangiocarcinoma. Lancet 2005;366:1303–1314.
Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. AASLD Practice Guidelines (ed 2009/08/29). Accessed April 7, 2021. Available at: https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.23190
Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335–1374.
Harding JJ, Abu-Zeinah G, Chou JF, et al. Frequency, morbidity, and mortality of bone metastases in advanced hepatocellular carcinoma. J Natl Compr Canc Netw 2018;16:50–58.
Dodd GD III, Baron RL, Oliver JH III, et al. Enlarged abdominal lymph nodes in end-stage cirrhosis: CT-histopathologic correlation in 507 patients. Radiology 1997;203:127–130.
Cooper GS, Bellamy P, Dawson NV, et al. A prognostic model for patients with end-stage liver disease. Gastroenterology 1997;113:1278–1288.
Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:1018–1022.
Groszmann RJ, Wongcharatrawee S. The hepatic venous pressure gradient: anything worth doing should be done right. Hepatology 2004;39:280–282.
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;33:550–558.
Pinato DJ, Sharma R, Allara E, et al. The ALBI grade provides objective hepatic reserve estimation across each BCLC stage of hepatocellular carcinoma. J Hepatol 2017;66:338–346.
Oikonomou T, Goulis L, Doumtsis P, et al. ALBI and PALBI grades are associated with the outcome of patients with stable decompensated cirrhosis. Ann Hepatol 2019;18:126–136.
Wan SZ, Nie Y, Zhang Y, et al. Assessing the prognostic performance of the Child-Pugh, Model for End-Stage Liver Disease, and albumin-bilirubin scores in patients with decompensated cirrhosis: a large Asian cohort from gastroenterology department. Dis Markers 2020;2020:5193028.
Boyer TD. Changing clinical practice with measurements of portal pressure. Hepatology 2004;39:283–285.
Thalheimer U, Mela M, Patch D, et al. Targeting portal pressure measurements: a critical reappraisal. Hepatology 2004;39:286–290.
Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33:464–470.
Malinchoc M, Kamath PS, Gordon FD, et al. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864–871.
Martin AP, Bartels M, Hauss J, et al. Overview of the MELD score and the UNOS adult liver allocation system. Transplant Proc 2007;39:3169–3174.
Cholongitas E, Papatheodoridis GV, Vangeli M, et al. Systematic review: the model for end-stage liver disease--should it replace Child-Pugh’s classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther 2005;22:1079–1089.
Saxena V, Lai JC. Kidney failure and liver allocation: current practices and potential improvements. Adv Chronic Kidney Dis 2015;22:391–398.
Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. J Hepatol 2001;35:421–430.
Dohmen K. Many staging systems for hepatocellular carcinoma: evolution from Child-Pugh, Okuda to SLiDe. J Gastroenterol Hepatol 2004;19:1227–1232.
Marrero JA, Fontana RJ, Barrat A, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 2005;41:707–716.
Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646–649.
Truty MJ, Vauthey J-N. Surgical resection of high-risk hepatocellular carcinoma: patient selection, preoperative considerations, and operative technique. Ann Surg Oncol 2010;17:1219–1225.
Pawlik TM, Poon RT, Abdalla EK, et al. Critical appraisal of the clinical and pathologic predictors of survival after resection of large hepatocellular carcinoma. Arch Surg 2005;140:450–457., discussion 457–458.
Chok KS, Ng KK, Poon RT, et al. Impact of postoperative complications on long-term outcome of curative resection for hepatocellular carcinoma. Br J Surg 2009;96:81–87.
Kianmanesh R, Regimbeau JM, Belghiti J. Selective approach to major hepatic resection for hepatocellular carcinoma in chronic liver disease. Surg Oncol Clin N Am 2003;12:51–63.
Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30:1434–1440.
Poon RT-P, Fan ST, Lo CM, et al. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg 2002;235:373–382.
Seo DD, Lee HC, Jang MK, et al. Preoperative portal vein embolization and surgical resection in patients with hepatocellular carcinoma and small future liver remnant volume: comparison with transarterial chemoembolization. Ann Surg Oncol 2007;14:3501–3509.
Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236.
Wei AC, Tung-Ping Poon R, Fan ST, et al. Risk factors for perioperative morbidity and mortality after extended hepatectomy for hepatocellular carcinoma. Br J Surg 2003;90:33–41.
Faber W, Stockmann M, Schirmer C, et al. Significant impact of patient age on outcome after liver resection for HCC in cirrhosis. Eur J Surg Oncol 2014;40:208–213.
Ribero D, Curley SA, Imamura H, et al. Selection for resection of hepatocellular carcinoma and surgical strategy: indications for resection, evaluation of liver function, portal vein embolization, and resection. Ann Surg Oncol 2008;15:986–992.
Berzigotti A, Reig M, Abraldes JG, et al. Portal hypertension and the outcome of surgery for hepatocellular carcinoma in compensated cirrhosis: a systematic review and meta-analysis. Hepatology 2015;61:526–536.
Santambrogio R, Kluger MD, Costa M, et al. Hepatic resection for hepatocellular carcinoma in patients with Child-Pugh’s A cirrhosis: is clinical evidence of portal hypertension a contraindication? HPB (Oxford) 2013;15:78–84.
Tsai TJ, Chau GY, Lui WY, et al. Clinical significance of microscopic tumor venous invasion in patients with resectable hepatocellular carcinoma. Surgery 2000;127:603–608.
Abdalla EK, Denys A, Hasegawa K, et al. Treatment of large and advanced hepatocellular carcinoma. Ann Surg Oncol 2008;15:979–985.
Jonas S, Bechstein WO, Steinmüller T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33:1080–1086.
Vauthey J-N, Lauwers GY, Esnaola NF, et al. Simplified staging for hepatocellular carcinoma. J Clin Oncol 2002;20:1527–1536.
Kubota K, Makuuchi M, Kusaka K, et al. Measurement of liver volume and hepatic functional reserve as a guide to decision-making in resectional surgery for hepatic tumors. Hepatology 1997;26:1176–1181.
Kishi Y, Abdalla EK, Chun YS, et al. Three hundred and one consecutive extended right hepatectomies: evaluation of outcome based on systematic liver volumetry. Ann Surg 2009;250:540–548.
Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg 2007;94:274–286.
Glantzounis GK, Tokidis E, Basourakos SP, et al. The role of portal vein embolization in the surgical management of primary hepatobiliary cancers. A systematic review. Eur J Surg Oncol 2017;43:32–41.
Schlag PM, Senn H-J, eds. Methods to improve resectability of hepatocellular carcinoma. In: Recent Results in Cancer Research, Vol. 190. Springer 2013:pp. 57-.
Chapelle T, Op de Beeck B, Roeyen G, et al. Measuring future liver remnant function prior to hepatectomy may guide the indication for portal vein occlusion and avoid posthepatectomy liver failure: a prospective interventional study. HPB (Oxford) 2017;19:108–117.
Martel G, Cieslak KP, Huang R, et al. Comparison of techniques for volumetric analysis of the future liver remnant: implications for major hepatic resections. HPB (Oxford) 2015;17:1051–1057.
Watt KD, Pedersen RA, Kremers WK, et al. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am J Transplant 2010;10:1420–1427.
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;334:693–699.
Mazzaferro V, Chun YS, Poon RTP, et al. Liver transplantation for hepatocellular carcinoma. Ann Surg Oncol 2008;15:1001–1007.
OPTN/UNOS policy notice modification to hepatocellular carcinoma (HCC) extension criteria. Accessed April 7, 2021. Available at https://optn.transplant.hrsa.gov/media/2411/modification-to-hcc-auto-approval-criteria_policy-notice.pdf
Volk ML, Vijan S, Marrero JA. A novel model measuring the harm of transplanting hepatocellular carcinoma exceeding Milan criteria. Am J Transplant 2008;8:839–846.
Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. Ann Surg 2007;246:502–509., discussion 509–511.
Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394–1403.
Yao FY, Bass NM, Nikolai B, et al. Liver transplantation for hepatocellular carcinoma: analysis of survival according to the intention-to-treat principle and dropout from the waiting list. Liver Transpl 2002;8:873–883.
Kim J, Ko ME, Nelson RA, et al. Increasing age and survival after orthotopic liver transplantation for patients with hepatocellular cancer. J Am Coll Surg 2014;218:431–438.
Kozyreva ON, Chi D, Clark JW, et al. A multicenter retrospective study on clinical characteristics, treatment patterns, and outcome in elderly patients with hepatocellular carcinoma. Oncologist 2011;16:310–318.
Kwon JH, Yoon YI, Song GW, et al. Living donor liver transplantation for patients older than age 70 years: A single-center experience. Am J Transplant 2017;17:2890–2900.
Dolnikov S, Adam R, Cherqui D, et al. Liver transplantation in elderly patients: what do we know at the beginning of 2020? Surg Today 2020;50:533–539.
Fujiki M, Aucejo F, Kim R. General overview of neo-adjuvant therapy for hepatocellular carcinoma before liver transplantation: necessity or option? Liver Int 2011;31:1081–1089.
Xing M, Sakaria S, Dhanasekaran R, et al. Bridging locoregional therapy prolongs survival in patients listed for liver transplant with hepatocellular carcinoma. Cardiovasc Intervent Radiol 2017;40:410–420.
Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698–711.
Majno P, Giostra E, Mentha G. Management of hepatocellular carcinoma on the waiting list before liver transplantation: time for controlled trials? Liver Transpl 2007; 13(11, Suppl 2)S27–S35.
Pompili M, Mirante VG, Rondinara G, et al. Percutaneous ablation procedures in cirrhotic patients with hepatocellular carcinoma submitted to liver transplantation: assessment of efficacy at explant analysis and of safety for tumor recurrence. Liver Transpl 2005;11:1117–1126.
Mazzaferro V, Battiston C, Perrone S, et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann Surg 2004;240:900–909.
Yao FY, Bass NM, Nikolai B, et al. A follow-up analysis of the pattern and predictors of dropout from the waiting list for liver transplantation in patients with hepatocellular carcinoma: implications for the current organ allocation policy. Liver Transpl 2003;9:684–692.
DuBay DA, Sandroussi C, Kachura JR, et al. Radiofrequency ablation of hepatocellular carcinoma as a bridge to liver transplantation. HPB (Oxford) 2011;13:24–32.
Tsochatzis E, Garcovich M, Marelli L, et al. Transarterial embolization as neo-adjuvant therapy pretransplantation in patients with hepatocellular carcinoma. Liver Int 2013;33:944–949.
Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003;37:429–442.
Richard HM III, Silberzweig JE, Mitty HA, et al. Hepatic arterial complications in liver transplant recipients treated with pretransplantation chemoembolization for hepatocellular carcinoma. Radiology 2000;214:775–779.
Graziadei IW, Sandmueller H, Waldenberger P, et al. Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome. Liver Transpl 2003;9:557–563.
Hayashi PH, Ludkowski M, Forman LM, et al. Hepatic artery chemoembolization for hepatocellular carcinoma in patients listed for liver transplantation. Am J Transplant 2004;4:782–787.
Nicolini D, Svegliati-Baroni G, Candelari R, et al. Doxorubicin-eluting bead vs conventional transcatheter arterial chemoembolization for hepatocellular carcinoma before liver transplantation. World J Gastroenterol 2013;19:5622–5632.
Kulik LM, Atassi B, van Holsbeeck L, et al. Yttrium-90 microspheres (TheraSphere) treatment of unresectable hepatocellular carcinoma: downstaging to resection, RFA and bridge to transplantation. J Surg Oncol 2006;94:572–586.
Sandroussi C, Dawson LA, Lee M, et al. Radiotherapy as a bridge to liver transplantation for hepatocellular carcinoma. Transpl Int 2010;23:299–306.
Lu L, Zeng J, Wen Z, et al. Transcatheter arterial chemoembolisation followed by three-dimensional conformal radiotherapy versus transcatheter arterial chemoembolisation alone for primary hepatocellular carcinoma in adults. Cochrane Database Syst Rev 2019;2:CD012244.
Toso C, Mentha G, Kneteman NM, et al. The place of downstaging for hepatocellular carcinoma. J Hepatol 2010;52:930–936.
Yao FY, Fidelman N. Reassessing the boundaries of liver transplantation for hepatocellular carcinoma: Where do we stand with tumor down-staging? Hepatology 2016;63:1014–1025.
Kulik L, Heimbach JK, Zaiem F, et al. Therapies for patients with hepatocellular carcinoma awaiting liver transplantation: A systematic review and meta-analysis. Hepatology 2018;67:381–400.
Parikh ND, Waljee AK, Singal AG. Downstaging hepatocellular carcinoma: a systematic review and pooled analysis. Liver Transpl 2015;21:1142–1152.
OPTN Policies Effective as of June 8 2020 [Modify HOPE Act Variance Correction]. Accessed April 7, 2021. https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf
Livraghi T, Goldberg SN, Lazzaroni S, et al. Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 1999;210:655–661.
Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 2003;228:235–240.
Lin S-M, Lin C-J, Lin C-C, et al. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or =4 cm. Gastroenterology 2004;127:1714–1723.
Lin SM, Lin CJ, Lin CC, et al. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut 2005;54:1151–1156.
Shiina S, Teratani T, Obi S, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 2005;129:122–130.
Brunello F, Veltri A, Carucci P, et al. Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: A randomized controlled trial. Scand J Gastroenterol 2008;43:727–735.
Giorgio A, Di Sarno A, De Stefano G, et al. Percutaneous radiofrequency ablation of hepatocellular carcinoma compared to percutaneous ethanol injection in treatment of cirrhotic patients: an Italian randomized controlled trial. Anticancer Res 2011;31:2291–2295.
Weis S, Franke A, Mössner J, et al. Radiofrequency (thermal) ablation versus no intervention or other interventions for hepatocellular carcinoma. Cochrane Database Syst Rev 2013;12:CD003046.
Huang G-T, Lee P-H, Tsang Y-M, et al. Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study. Ann Surg 2005;242:36–42.
Chen M-S, Li J-Q, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;243:321–328.
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;252:903–912.
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;57:794–802.
Fang Y, Chen W, Liang X, et al. Comparison of long-term effectiveness and complications of radiofrequency ablation with hepatectomy for small hepatocellular carcinoma. J Gastroenterol Hepatol 2014;29:193–200.
Ng KKC, Chok KSH, Chan ACY, et al. Randomized clinical trial of hepatic resection versus radiofrequency ablation for early-stage hepatocellular carcinoma. Br J Surg 2017;104:1775–1784.
Feng Q, Chi Y, Liu Y, et al. Efficacy and safety of percutaneous radiofrequency ablation versus surgical resection for small hepatocellular carcinoma: a meta-analysis of 23 studies. J Cancer Res Clin Oncol 2015;141:1–9.
Jia JB, Zhang D, Ludwig JM, et al. Radiofrequency ablation versus resection for hepatocellular carcinoma in patients with Child-Pugh A liver cirrhosis: a meta-analysis. Clin Radiol 2017;72:1066–1075.
Xu G, Qi F-Z, Zhang J-H, et al. Meta-analysis of surgical resection and radiofrequency ablation for early hepatocellular carcinoma. World J Surg Oncol 2012;10:163–163.
Cai H, Kong W, Zhou T, et al. Radiofrequency ablation versus reresection in treating recurrent hepatocellular carcinoma: a meta-analysis. Medicine (Baltimore) 2014;93:e122.
Shibata T, Iimuro Y, Yamamoto Y, et al. Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave coagulation therapy. Radiology 2002;223:331–337.
Ding J, Jing X, Liu J, et al. Comparison of two different thermal techniques for the treatment of hepatocellular carcinoma. Eur J Radiol 2013;82:1379–1384.
Groeschl RT, Pilgrim CHC, Hanna EM, et al. Microwave ablation for hepatic malignancies: a multiinstitutional analysis. Ann Surg 2013;259:1195–1200.
Zhang L, Wang N, Shen Q, et al. Therapeutic efficacy of percutaneous radiofrequency ablation versus microwave ablation for hepatocellular carcinoma. PLoS One 2013;8:e76119.
Shi J, Sun Q, Wang Y, et al. Comparison of microwave ablation and surgical resection for treatment of hepatocellular carcinomas conforming to Milan criteria. J Gastroenterol Hepatol 2014;29:1500–1507.
Hsiao CY, Huang KW. Irreversible electroporation: a novel ultrasound-guided modality for non-thermal tumor ablation. J Med Ultrasound 2017;25:195–200.
Narayanan G, Froud T, Suthar R, et al. Irreversible electroporation of hepatic malignancy. Semin Intervent Radiol 2013;30:67–73.
Lencioni R, Crocetti L, Narayanan G. Irreversible electroporation in the treatment of hepatocellular carcinoma. Tech Vasc Interv Radiol 2015;18:135–139.
Scheffer HJ, Nielsen K, de Jong MC, et al. Irreversible electroporation for nonthermal tumor ablation in the clinical setting: a systematic review of safety and efficacy. J Vasc Interv Radiol 2014;25:997–1011., quiz 1011.
Cheung W, Kavnoudias H, Roberts S, et al. Irreversible electroporation for unresectable hepatocellular carcinoma: initial experience and review of safety and outcomes. Technol Cancer Res Treat 2013;12:233–241.
Cannon R, Ellis S, Hayes D, et al. Safety and early efficacy of irreversible electroporation for hepatic tumors in proximity to vital structures. J Surg Oncol 2013;107:544–549.
Frühling P, Nilsson A, Duraj F, et al. Single-center nonrandomized clinical trial to assess the safety and efficacy of irreversible electroporation (IRE) ablation of liver tumors in humans: Short to mid-term results. Eur J Surg Oncol 2017;43:751–757.
Rand T, Loewe C, Schoder M, et al. Arterial embolization of unresectable hepatocellular carcinoma with use of microspheres, lipiodol, and cyanoacrylate. Cardiovasc Intervent Radiol 2005;28:313–318.
Huang YH, Chen CH, Chang TT, et al. The role of transcatheter arterial embolization for patients with unresectable hepatocellular carcinoma: a nationwide, multicentre study evaluated by cancer stage. Aliment Pharmacol Ther 2005;21:687–694.
Maluccio MA, Covey AM, Porat LB, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol 2008;19:862–869.
Bonomo G, Pedicini V, Monfardini L, et al. Bland embolization in patients with unresectable hepatocellular carcinoma using precise, tightly size-calibrated, anti-inflammatory microparticles: first clinical experience and one-year follow-up. Cardiovasc Intervent Radiol 2010;33:552–559.
Ramsey DE, Kernagis LY, Soulen MC, et al. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol 2002;13:S211–S221.
Lo C-M, Ngan H, Tso W-K, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35:1164–1171.
Llovet JM, Real MI, Montaña X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002;359:1734–1739.
Kong JY, Li SM, Fan HY, et al. Transarterial chemoembolization extends long-term survival in patients with unresectable hepatocellular carcinoma. Medicine (Baltimore) 2018;97:e11872.
Brown KT, Do RK, Gonen M, et al. Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone. J Clin Oncol 2016;34:2046–2053.
Poon RT, Tso WK, Pang RW, et al. A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead. Clin Gastroenterol Hepatol 2007;5:1100–1108.
Reyes DK, Vossen JA, Kamel IR, et al. Single-center phase II trial of transarterial chemoembolization with drug-eluting beads for patients with unresectable hepatocellular carcinoma: initial experience in the United States. Cancer J 2009;15:526–532.
Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 2010;33:41–52.
Malagari K, Pomoni M, Kelekis A, et al. Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma. Cardiovasc Intervent Radiol 2010;33:541–551.
Dhanasekaran R, Kooby DA, Staley CA, et al. Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC). J Surg Oncol 2010;101:476–480.
Malagari K, Pomoni M, Moschouris H, et al. Chemoembolization with doxorubicin-eluting beads for unresectable hepatocellular carcinoma: five-year survival analysis. Cardiovasc Intervent Radiol 2012;35:1119–1128.
Song MJ, Chun HJ, Song DS, et al. Comparative study between doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. J Hepatol 2012;57:1244–1250.
Golfieri R, Giampalma E, Renzulli M, et al. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer 2014;111:255–264.
Yang B, Liang J, Qu Z, et al. Transarterial strategies for the treatment of unresectable hepatocellular carcinoma: A systematic review. PLoS One 2020;15:e0227475.
Liapi E, Geschwind J-FH. Intra-arterial therapies for hepatocellular carcinoma: where do we stand? Ann Surg Oncol 2010;17:1234–1246.
Ibrahim SM, Lewandowski RJ, Sato KT, et al. Radioembolization for the treatment of unresectable hepatocellular carcinoma: a clinical review. World J Gastroenterol 2008;14:1664–1669.
Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology 2008;47:71–81.
Woodall CE, Scoggins CR, Ellis SF, et al. Is selective internal radioembolization safe and effective for patients with inoperable hepatocellular carcinoma and venous thrombosis? J Am Coll Surg 2009;208:375–382.
Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 2010;138:52–64.
Sangro B, Carpanese L, Cianni R, et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 2011;54:868–878.
Mazzaferro V, Sposito C, Bhoori S, et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study. Hepatology 2013;57:1826–1837.
Vouche M, Habib A, Ward TJ, et al. Unresectable solitary hepatocellular carcinoma not amenable to radiofrequency ablation: multicenter radiology-pathology correlation and survival of radiation segmentectomy. Hepatology 2014;60:192–201.
Abdel-Rahman OM, Elsayed Z. Yttrium-90 microsphere radioembolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev 2016;2:CD011313.
Garin E, Tselikas L, Guiu B, et al. Personalised versus 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;6:17–29.
Vilgrain V, Pereira H, Assenat E, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol 2017;18:1624–1636.
Chow PKH, Gandhi M, Tan SB, et al. SIRveNIB: Selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol 2018;36:1913–1921.
Hawkins MA, Dawson LA. Radiation therapy for hepatocellular carcinoma: from palliation to cure. Cancer 2006;106:1653–1663.
Hoffe SE, Finkelstein SE, Russell MS, et al. Nonsurgical options for hepatocellular carcinoma: evolving role of external beam radiotherapy. Cancer Contr 2010;17:100–110.
Kwon JH, Bae SH, Kim JY, et al. Long-term effect of stereotactic body radiation therapy for primary hepatocellular carcinoma ineligible for local ablation therapy or surgical resection. Stereotactic radiotherapy for liver cancer. BMC Cancer 2010;10:475–475.
Andolino DL, Johnson CS, Maluccio M, et al. Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2011;81:e447–e453.
Huang W-Y, Jen Y-M, Lee M-S, et al. Stereotactic body radiation therapy in recurrent hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2012;84:355–361.
Kang J-K, Kim M-S, Cho CK, et al. Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage treatment after incomplete transarterial chemoembolization. Cancer 2012;118:5424–5431.
Bujold A, Massey CA, Kim JJ, et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol 2013;31:1631–1639.
Cárdenes HR, Price TR, Perkins SM, et al. Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma. Clin Transl Oncol 2010;12:218–225.
Wahl DR, Stenmark MH, Tao Y, et al. Outcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J Clin Oncol 2016;34:452–459.
Velec M, Haddad CR, Craig T, et al. Predictors of liver toxicity following stereotactic body radiation therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2017;97:939–946.
Tse RV, Hawkins M, Lockwood G, et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol 2008;26:657–664.
Tanguturi SK, Wo JY, Zhu AX, et al. Radiation therapy for liver tumors: ready for inclusion in guidelines? Oncologist 2014;19:868–879.
Llovet JM, Vilana R, Brú C, et al. Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma. Hepatology 2001;33:1124–1129.
Livraghi T, Solbiati L, Meloni MF, et al. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology 2003;226:441–451.
Lencioni R, Cioni D, Crocetti L, et al. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology 2005;234:961–967.
Zhang Y-J, Liang H-H, Chen M-S, et al. Hepatocellular carcinoma treated with radiofrequency ablation with or without ethanol injection: a prospective randomized trial. Radiology 2007;244:599–607.
Kim JH, Won HJ, Shin YM, et al. Medium-sized (3.1-5.0 cm) hepatocellular carcinoma: transarterial chemoembolization plus radiofrequency ablation versus radiofrequency ablation alone. Ann Surg Oncol 2011;18:1624–1629.