Hepatocellular Carcinoma Treatment Protocols 

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Treatment protocols for hepatocellular carcinoma (HCC) are provided below. Historically, HCC treatment protocols have been divided into two broad categories: for resectable and unresectable disease. In addition, special considerations include bridge therapy for patients awaiting transplant and combination therapies. ^[1]

See the list below:

For patients with early-stage HCC, a partial hepatectomy can offer a potential cure, provided the patient is a surgical candidate, based on performance status and comorbidities. ^[2]

Hepatic resection is recommended in patients who have preserved liver function (generally Child-Pugh class A without portal hypertension) and a solitary mass without macrovascular invasion, and who will have an adequate liver remnant.

For patients with limited disease, but deemed unresectable due to tumor characteristics and location, liver transplantation may offer an alternative option for curative treatment.

Treatment regimens for patients with limited disease confined to the liver, limited to no macrovascular invasion, and no metastatic disease, are as follows:

For patients with unresectable disease who are not surgical candidates because of their performance status, comorbidities, and failure to meet UNOS criteria, National Comprehensive Cancer Network (NCCN) guidelines recommend offering locoregional therapies before initiating systemic treatment.

Locoreginal therapies comprise ablation, arterially directed therapies, and radiation therapy, ^[2]

Ablative procedures include radiofrequency, cryoablation, percutaneous alcohol injection, and microwave/thermal ablation. Tumor size and location is the limiting factor in offering this approach.

Arterially directed therapies include bland transarterial embolization (TAE), transarterial chemoembolization (TACE), TACE with drug-eluting beads (DEB-TACE), and radioembolization (RE) with yttrium-90 microspheres. Elevated bilirubin level > 3 mg/dL is a relative contraindication to this approach.

Radiation therapies include intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and external-body radiation therapy (EBRT). This therapy can be offered both for treatment and palliation. 

The following treatment regimens are used for patients with advanced disease no longer confined to the liver, major vascular involvement, and/or metastatic disease; this may include patients who are not candidates for locoregional therapies and/or those in whom local treatment has failed.

First-line systemic treatment for unresectable HCC

Sorafenib is administered as follows:

400 mg PO BID (common practice is to start at 200 mg daily, increase to 200 mg BID, then escalate to 400 mg BID) ^{[4, 5]}

For moderate liver dysfunction, use 200 mg PO BID

Use with extreme caution in patients with elevated bilirubin levels ^[6]

Lenvatinib is administered until disease progression or unacceptable toxicity occurs. The dose is based on actual body weight, as follows ^[7] :

Options for patients previously treated with sorafenib:

The NCCN notes that only limited data support the use of chemotherapy, and use in the context of a clinical trial is preferred. ^[2] However, the following regimens have shown marginal activity in small clinical trials:

Gemcitabine 1000 mg/m² IV on day 1 plus oxaliplatin 100 mg/m² on day 2; then every 14d ^{[12, 13]} or

Capecitabine 1000 mg/m² PO BID on days 1-14 plus  oxaliplatin 130 mg/m² IV on day 1; then every 21d ^[14] or

Capecitabine 1000 mg/m² PO BID on days 1-14; then every 21d ^[15] or

Doxorubicin 60-75 mg/m² IV on day 1; then every 21d ^{[16, 17]} or

Gemcitabine 1250 mg/m² IV on days 1 and 8 plus cisplatin 35 mg/m² IV on days 1 and 8; then every 21d ^{[18, 19]}

Saraswat VA, Pandey G, Shetty S. Treatment algorithms for managing hepatocellular carcinoma. J Clin Exp Hepatol. 2014 Aug. 4 (Suppl 3):S80-9. [Medline].

[Guideline] NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancers. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Version 1.2018 — February 14, 2018; Accessed: March 23, 2018.

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. 334:693-9.

Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008. 359:378-90.

Lu L, Lu M, Pei Y, Chen J, Qin L, Zhu W, et al. Down-regulation of SDF1-α expression in tumor microenvironment is associated with aspirin-mediated suppression of the pro-metastasis effect of sorafenib in hepatocellular carcinoma. Acta Biochim Biophys Sin (Shanghai). 2015 Dec. 47 (12):988-96. [Medline].

Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 2009. 27:1800-5.

Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24. 391 (10126):1163-1173. [Medline].

Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 7. 389 (10064):56-66. [Medline].

El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24. 389 (10088):2492-2502. [Medline].

Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018 Jul. 19 (7):940-952. [Medline].

Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 2018 Jul 5. 379 (1):54-63. [Medline]. [Full Text].

Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer 2007. 109:1384-90.

Edeline J, Coulouarn C, Crouzet L, Pracht M, Lepareur N, Clément B, et al. Gemcitabine and Oxaliplatin, but Not Sorafenib or Paclitaxel, Have a Synergistic Effect with Yttrium-90 in Reducing Hepatocellular Carcinoma and Cholangiocarcinoma Cell Line Viability. J Vasc Interv Radiol. 2015 Dec. 26 (12):1874-1878.e2. [Medline].

Boige V, Raoul JL, Pignon JP, et al. Multicentre phase II trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma: FFCD 03-03 trial. Br J Cancer. 2007. 97:862-7.

Patt YZ, Hassan MM, Aguayo A, et al. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer 2004;101:578-86. Cancer. 2004. 101:578-86.

Gish RG, Porta C, Lazar L, et al. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol. 2007. 25:3069-75.

Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer. 1988. 62:479-83.

Parikh PM, Fuloria J, Babu G, Doval DC, Awasthy BS, Pai VR, et al. A phase II study of gemcitabine and cisplatin in patients with advanced hepatocellular carcinoma. Trop Gastroenterol. 2005 Jul-Sep. 26(3):115-8.

Yang TS, Lin YC, Chen JS, Wang HM, Wang CH. Phase II study of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer. 2000 Aug 15. 89(4):750-6.

Mohammad Muhsin Chisti, MD, FACP Assistant Professor of Hematology and Oncology, Medical Director of Research, Karmanos Cancer Institute, Wayne State University School of Medicine

Mohammad Muhsin Chisti, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Medical Society of the State of New York

Disclosure: Nothing to disclose.

Syeda Hina Batool, MD, MBBS Assistant Professor, Oakland University William Beaumont School of Medicine; Hospitalist, Beaumont Health System

Syeda Hina Batool, MD, MBBS is a member of the following medical societies: American College of Physicians, American Medical Association, Pakistan Medical and Dental Council

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee

Christopher D Braden, DO is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

N Joseph Espat, MD, MS, FACS Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center

N Joseph Espat, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Parenteral and Enteral Nutrition, American Society of Clinical Oncology, Americas Hepato-Pancreato-Biliary Association, Association for Academic Surgery, Central Surgical Association, Chicago Medical Society, International Hepato-Pancreato-Biliary Association, Pancreas Club, Sigma Xi, Society for Leukocyte Biology, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Society of Surgical Oncology, Society of University Surgeons, Southeastern Surgical Congress, Southern Medical Association, Surgical Infection Society

Disclosure: Nothing to disclose.

Terence D Rhodes, MD, PhD Medical Oncologist, Intermountain Medical Group

Terence D Rhodes, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Hepatocellular Carcinoma Treatment Protocols 

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