Hepatocellular Carcinoma Treatment Protocols 

Updated: Feb 03, 2022
  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Treatment Protocols

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]

Treatment recommendations for patients with early-stage resectable disease

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, comorbidities,and certain disease characteristics. [2]

  • Hepatic resection is recommended in patients with early-stage HCC (non-metastasized disease) who have preserved liver function (generally Child-Pugh class A without portal hypertension) and a solitary mass without macrovascular invasion.

  • Certain patients with Child-Pugh class B without evidence of portal hypertension may also be considered for limited surgical resection.

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

  • Adjuvant transarterial thromboembolization (TACE) has shown to increase overall survival in patient with microvascular invasion–HCC with tumor size ≥ 5 cm or multinodular tumors. [3]

  • Adjuvant immunotherapy may potentially decrease disease recurrence, but this is still under investigation. [4]

Treatment recommendations for patients with unresectable disease (including those with disease limited to liver and those with advanced disease)

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

  • Liver transplantation is generally considered as a first choice for patients with early-stage HCC and moderate-severe cirrhosis (Child-Pugh class B and C), and to patients with unresectable disease.
  • Liver transplantation should be offered to those who are surgical candidates and meet United Network for Organ Sharing (UNOS) criteria (ie, a single tumor 2–5 cm in diameter, or 2-3 tumors, each ≥ 1 cm and ≤ 3 cm in diameter; and no evidence of major vascular involvement or extrahepatic disease). [5]
  • For patients with unresectable disease who are not surgical candidates because of their performance status, comorbidities, or failure to meet UNOS criteria, National Comprehensive Cancer Network (NCCN) guidelines recommend offering locoregional therapies before initiating systemic treatment. [2]  

  • Locoregional 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 are the limiting factors 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 beam radiation therapy (EBRT). Radiation 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

Bevacizumab in combination with atezolizumab resulted in better overall and progression-free survival outcomes than sorafenib, and is currently considered the first-line treatment [6, 7] :

  • Atezolizumab 1200 mg/kg IV on Day 1  then
  • Bevacizumab 15 mg/kg IV on Day 1 
  • Repeat every 3 weeks
  • Continue until disease progression or unacceptable toxicity
  • All patients must undergo upper endoscopy evaluation for esophageal varices due to risk of bleeding with bevacizumab

Other options

Sorafenib, an oral multikinase inhibitor, has shown the most benefit in patients with Child-Pugh class A, with very limited data on patients with Child-Pugh class B. Dosing is as follows:

  • Sorafenib 400 mg PO BID; common practice is to start at 200 mg daily, increase to 200 mg BID, then escalate to 400 mg BID) [8, 9]
  • For moderate liver dysfunction, use 200 mg PO BID
  • Use with extreme caution in patients with elevated bilirubin levels [10]
  • Assess tumor response to sorafeni using the RECIST or EASL criteria [11]

Lenvatinib, a receptor tyrosine kinase inhibitor, is dosed on the basis of actual body weight, as follows [12] :

  • < 60 kg: 8 mg PO once daily
  • ≥ 60 kg: 12 mg PO once daily
  • Continue until disease progression or unacceptable toxicity

The combination of lenvatinib and pembrolizumab is currently being studied for treatment of unresectable or advanced HCC. [13]

Options for patients previously treated with sorafenib:

  • Regorafenib 160 mg PO once daily for the first 21 days of each 28-day cycle; continue treatment until disease progression or unacceptable toxicity [14]
  • Cabozantinib tablets (Cabometyx) 60 mg PO once daily until disease progression or unacceptable toxicity [15]
  • Ramucirumab 8 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity; assess response with alpha fetoprotein (AFP) levels [16, 17]
  • Nivolumab 240 mg IV plus ipilimumab 3 mg/kg IV every 3 weeks (4 doses), followed by  nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks, until disease progression or unacceptable toxicity [18]
  • Pembrolizumab 200 mg IV every 3 weeks or 400 mg IV every 6 weeks until disease progression or unacceptable toxicity, or for up to 24 months in patients without disease progression [19, 20]

In 2021, the FDA withdrew the indication of nivolumab alone as a subsequent-line treatment after sorafenib for patients with Child-Pugh class A. It remains indicated only for patients with Child-Pugh class B HCC, due to the limited treatment options for these patients. [21]


The NCCN notes that only limited data support the use of chemotherapy, and use in the context of a clinical trial is preferred. [2]  FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) is a potential regimen for patients with advanced HCC that has demonstrated longer overall and progression-free survival compared with doxorubicin. [22]