Systemic Therapy for Advanced Hepatocellular Carcinoma

Publication Date: December 20, 2020
Last Updated: March 14, 2022


First-Line Therapy

Atezolizumab-bevacizumab (atezo + bev) may be offered as first-line treatment for most patients with advanced HCC, Child-Pugh class A, ECOG PS 0-1, and following management of esophageal varices, when present, according to institutional guidelines. ( EB , B , H , S )

Qualifying statements:

  • Recommendation 1.1 is based on results from the IMbrave150 phase III RCT comparison of atezo + bev to sorafenib (HR for OS, 0.58; 95% CI, 0.42 to 0.79; P = .0006) in Child-Pugh class A patients. Caution should be exercised when applying these results to patients with more advanced liver disease who have a greater likelihood of portal hypertension because of the risk of bleeding complications associated with bevacizumab.
  • Due to risk of bleeding, patients in this trial were required to have undergone esophagogastroduodenoscopy (EGD) within 6 months of trial initiation and to have received treatment of esophageal varices when necessary. The Expert Panel recognizes that some patients may have been evaluated for varices outside the 6-month window, are receiving treatment (eg, adequately dosed nonselective β-blockers), and/or are deemed to be low risk for variceal bleed by a hepatology specialist. In these patients, the decision to forgo an EGD prior to initiation of therapy with atezo + bev may be carefully considered.

  • Patients who had a myocardial infarction or stroke within the previous 3 months, had a history of autoimmune disease, were on therapeutic anticoagulation, or had coinfection with HBV and HCV were also excluded from the IMbrave150 RCT.

Where there are contraindications to atezolizumab and/or bevacizumab, tyrosine kinase inhibitors (TKIs) sorafenib or lenvatinib may be offered as first-line treatment of patients with advanced HCC, Child-Pugh class A, and ECOG PS 0-1 (Type of recommendation: evidence based, benefits outweigh harms; Evidence quality: moderate; Strength of recommendation: strong). (EB, B, I, S)

Qualifying statements:

  • Treatment with recommended TKIs may be less effective for patients with more advanced liver cirrhosis. Careful patient selection is recommended.

  • The choice of treatment with lenvatinib or sorafenib should be made through a discussion involving the physician and patient (and caregiver, where applicable) and should include factors such as medical history, viral etiology of liver disease, toxicities associated with treatment, cost, goals of treatment, patient preference, and expected treatment benefit. Factors affecting this choice, including response rates, are discussed further in the Clinical Interpretation.

  • Several meta-analyses of RCTs have shown sorafenib to be more beneficial in patients with HCV, especially as compared with patients with HBV. In the REFLECT trial, there was a trend toward improvements across endpoints for lenvatinib over sorafenib in the HBV subgroup, though it was not significant.

  • Patients with a high tumor burden, > 50% liver involvement, or those with main portal vein invasion were excluded from the REFLECT trial of sorafenib versus lenvatinib.


Second-Line Therapy

Following first-line treatment with atezo + bev, second-line therapy with a TKI (ie, sorafenib, lenvatinib, cabozantinib, or regorafenib) may be recommended. (IC, B/H, L, W)

Qualifying statement:

  • No data have been published on therapy options after first-line treatment with atezo + bev. It is the opinion of the Expert Panel that a TKI, preferably sorafenib or lenvatinib, may be offered. Cabozantinib or regorafenib are also reasonable options for second-line therapy following atezo + bev.

Following first-line therapy with sorafenib or lenvatinib, second-line therapy with another TKI (cabozantinib or regorafenib), ramucirumab (AFP ≥ 400 ng/mL), or atezo + bev may be recommended for appropriate candidates. Considerations regarding choice of therapy are included in the Clinical Interpretation (Type: informal consensus, benefits may outweigh harms; Evidence quality: low to moderate; Strength of recommendation: weak). (IC, B/H, I/L, W)

Qualifying statement:

  • It is likely that most patients being considered for atezo + bev in the second-line setting did not have access to this combination when they started first-line treatment.

Following first-line therapy with sorafenib or lenvatinib, pembrolizumab or nivolumab are reasonable options that may be considered for appropriate candidates (Type: informal consensus, benefits may outweigh harms; Evidence quality: low; Strength of recommendation: weak). (IC, B/H, L, W)

Qualifying statement:

  • Immune checkpoint inhibitors pembrolizumab or nivolumab may be especially beneficial for patients who have contraindications to or cannot tolerate TKIs.


Recommendation Grading




Systemic Therapy for Advanced Hepatocellular Carcinoma

Authoring Organization

Publication Month/Year

December 20, 2020

Last Updated Month/Year

July 11, 2023

Document Type


External Publication Status


Country of Publication


Inclusion Criteria

Female, Male, Adult, Older adult

Health Care Settings

Ambulatory, Emergency care, Home health, Hospice, Hospital, Long term care

Intended Users

Social worker, physician, nurse, nurse practitioner, physician assistant


Management, Treatment

Diseases/Conditions (MeSH)

D006528 - Carcinoma, Hepatocellular


hepatocellular carcinoma, child-pugh class A liver disease, liver diseases

Supplemental Methodology Resources

Data Supplement, Evidence Tables


Number of Source Documents
Literature Search Start Date
January 1, 2007
Literature Search End Date
May 15, 2020