Hepatocellular Carcinoma 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 for unresectable disease. In addition, special considerations include bridge therapy for patients awaiting liver transplantation, and combination therapies. ^[1]

Treatment recommendations for patients with early-stage resectable disease

For patients with early-stage (non-metastasized) 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 of early-stage HCC is recommended in patients with the following:

• Adequate liver function - Child-Pugh A without portal hypertension; certain patients with Child-Pugh B without evidence of portal hypertension may also be considered for limited surgical resection.
• Solitary mass without any major vascular invasion
• Adequate liver reserve
• Suitable liver remnant

In patients with chronic liver disease that would require major resection, consider preoperative portal vein embolization.

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

For patients with limited disease that is deemed unresectable due to tumor characteristics and location, options are as follows:

• Liver transplantation may offer an alternative 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 regimens for patients with limited disease confined to the liver, with no macrovascular invasion and no metastasis, are as follows:

• Liver transplantation is generally considered 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 the following ^[2] :

• Ablative procedures - Radiofrequency, cryoablation, percutaneous alcohol injection, and microwave/thermal ablation. Tumor size and location are the limiting factors in offering this approach.

• Arterially directed therapies - 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 - 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. 

Pharmacologic therapy

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, a VEGF inhbitor, in combination with atezolizumab, an anti–programmed death ligand 1 (PD-L1) antibody, resulted in better overall and progression-free survival outcomes than sorafenib, and is currently considered the first-line treatment ^{[6, 7]} :

• Atezolizumab 1,200 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

Tremelimumab, a CTLA-4 monoclonal antibody, plus durvalumab, a PD-L1 monoclonal antibody, demonstrated improved overall survival compared with sorafenib for unresectable HCC. ^[8] Dosing of both drugs is based on actual body weight.

For patients who weigh ≥ 30 kg, dosing is as follows:

• Cycle 1: Tremelimumab 300 mg IV × 1 dose,  then durvalumab 1,500 mg IV
• Cycle 2 and thereafter: Durvalumab 1,500 mg IV q4Weeks as a single agent
• Continue until disease progression or unacceptable toxicity

For patients who weigh < 30 kg, dosing is as follows:

• Cycle 1: Tremelimumab 4 mg/kg IV × 1 dose,  then durvalumab 20 mg/kg IV
• Cycle 2 and thereafter: Durvalumab 20 mg/kg IV q4Weeks as a single agent
• Continue until disease progression or unacceptable toxicity

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) ^{[9, 10]}
• For moderate liver dysfunction, use 200 mg PO BID
• Use with extreme caution in patients with elevated bilirubin levels ^[11]
• Assess tumor response to sorafenib using the Response Evaluation in Solid Tumors ( RECIST) or EASL criteria ^[12]

Lenvatinib, a receptor tyrosine kinase inhibitor, is dosed on the basis of actual body weight, as follows ^[13] :

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

Options for patients previously treated with sorafenib:

• Pembrolizumab, a PD-L1 inhibitor, (category 2B) 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 ^[2]
• 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), then  nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks, until disease progression or unacceptable toxicity ^[18]
• Lenvatinib (Child-Pugh A only) ^[2]
• Sorafenib (Child-Pugh A or B7) ^[2]
• Pembrolizumab (Child-Pugh A only [category 2B]) ^{[19, 20]}
• Dostarlimab, another PD-1 inhibitor, is approved for recurrent or advanced solid tumors with deficient mismatch repair (dMMR) that have progressed on or after prior treatment and who have no satisfactory alternative treatment options. ^[21] Doses 1-4: 500 mg IV q3Weeks; Dose 5 (start 3 weeks after Dose 4) and thereafter: 1,000 mg IV q6Weeks until disease progression or unacceptable toxicity
• Selpercatinib, RET kinase inhibitor, for locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. ^[22] Dosage is weight based: < 50 kg, 120 mg PO BID; ≥50 kg: 160 mg PO BID. Continue until disease progression or unacceptable toxicity

Chemotherapy

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. ^[23]