Immunotherapy for the Treatment of Hepatocellular Carcinoma

Publication Date: September 7, 2023
Last Updated: September 29, 2023

Assessment and Diagnosis

  • A multidisciplinary tumor board review of liver lesions is recommended for HCC diagnosis and the development of a management plan.
  • Notwithstanding that LI-RADS-5 is nearly 100% specific for HCC (LE: 1), histologic confirmation is recommended for patients with unresectable disease particularly prior to the initiation of systemic therapy. Histologic diagnosis is mandatory for non-cirrhotic patients.
  • Despite the controversy regarding the scoring and staging systems that could be used, before initiation of systemic therapy, an evaluation of liver function, including aspartate transaminase (AST)/alanine aminotransferase (ALT), bilirubin, prothrombin time (PT)/international normalized ratio (INR), albumin, plus platelets, is critical (LE: 2).
  • For patients being considered for immunotherapy, an HCC-specific staging system incorporating liver function assessment is suggested (LE: 2).
  • To evaluate patients prior to receiving immunotherapy, Child-Pugh classification would be the most appropriate to date (LE: 1) to measure liver function.


  • In 2022, the ICI combination of durvalumab (anti-PD-L1) with tremelimumab (anti-CTLA-4) was also approved for the treatment of unresectable HCC. Additional trials are ongoing and the therapeutic landscape continues to evolve and expand.
  • For first-line treatment of patients with advanced Child-Pugh A HCC, atezolizumab plus bevacizumab (LE:2) or tremelimumab plus durvalumab (LE:2) are recommended, unless any medications are contraindicated.
  • General contraindications to bevacizumab include high risk of cardiac disease, stroke, hemorrhage, hemoptysis, gastrointestinal perforation, or non-healing wounds (LE: 1). (For contraindications to immunotherapy, see the Patient selection and management section). Consideration should be given to timing of prior events. Additional contraindications specifically relevant to HCC include untreated or incompletely treated gastroesophageal varices at risk for bleeding (LE: 2).
  • For patients with contraindications to an ICI-containing combination therapy (ie, atezolizumab plus bevacizumab or tremelimumab plus durvalumab), lenvatinib or sorafenib should be considered as standard first-line therapy (LE:2).
  • Nivolumab monotherapy has demonstrated activity in Child-Pugh B7-B8 HCC for both first-line treatment of sorafenib-naïve patients and for second-line treatment of patients who were intolerant to or progressed on sorafenib (LE: 3).
  • For patients with good performance status who have progressed on first-line therapy and have not received prior immunotherapy, other non FDA-approved or conditionally approved anti-PD-1 checkpoint inhibitors may be considered as immunotherapeutic options (LE: 3).
  • Clinicians should encourage patients' participation in clinical trials.
  • Future biomarker development might help to select a subgroup of patients benefitting from single-agent nivolumab treatment. Designing a biomarker strategy based on pretreatment and on-treatment tissue and blood samples to assess immune cell changes and other correlatives is critical to elucidate mechanisms of response or resistance to immunotherapy in combination with local therapy in early-stage HCC.
  • Studies evaluating combinations of other immunotherapies with ICIs should be based on solid scientific rationale.
  • Future randomized studies to compare local therapy alone to local therapy combined with immunotherapy are essential to assess the expected synergy and favorable treatment outcome of the combination strategy.

Patient Selection and Management

  • For patients with advanced-stage HCC and for patients with earlier-stage disease where liver-directed therapies are not considered appropriate or who have progressed after liver-directed therapy, the data at present supports first-line and subsequent-line ICI therapy use (LE: 2). Further studies are needed to confirm the efficacy of immunotherapy in the curative setting (neoadjuvant/adjuvant/perioperative) or in conjunction with intra-arterial therapies.
  • In patients with HCC with cirrhosis, the data supports the use of immunotherapy in patients with underlying synthetic liver function consistent with well-compensated cirrhosis, specifically Child-Pugh A (LE: 2). The panel recognizes, however, that some carefully selected patients with Child-Pugh B may derive benefit (LE: 3).
  • Patients who have contraindications for the use of TKIs or anti-VEGF therapies (eg, cardiovascular comorbidities) may be suitable for anti-PD-1 monotherapy (LE: 1).
  • The panel recommends against the use of immunotherapy in the post-transplant setting (LE: 4) due to the high risk of graft failure, given known mechanisms of ICIs.
  • Additional studies are needed to assess the potential risks and benefits of immunotherapy in the pretransplant setting.
  • The panel agrees that patients can be considered for immunotherapy treatment irrespective of hepatitis viral etiology (LE: 3), though it is strongly recommended that patients with HBV be on concomitant antiviral medication and adherent.
  • While patients living with HIV have not been included in clinical trials to date, the panel believes that this is not an absolute contraindication to treatment with immunotherapy as long as the appropriate HIV therapy is instituted as per expert guidance (LE: 2), while further dedicated studies to assess such therapies in patients living with HIV remain critical.
  • Historical disparities in access to clinical trial participation for underrepresented groups should be considered, with efforts made to support diversity, equity, and inclusion.
  • The panel recommends against the use of routine testing of biomarkers for predicting immunotherapy efficacy, which, at this point, remains exploratory.
  • The panel recommends against the use of routine testing of biomarkers for predicting irAEs, which, at this point, remains exploratory.
  • Response assessment can be performed according to mRECIST criteria in patients receiving locoregional interventional therapies (LE: 3).
  • Limited data are available concerning the value of mRECIST and immune-related RECIST (irRECIST) criteria in the setting of HCC response assessment, especially in the context of ICI therapy. Further studies are needed to compare outcomes between patients with response to treatment by mRECIST versus irRECIST.
  • Pseudoprogression, while a real phenomenon, occurs rarely (LE: 4). A comprehensive assessment is encouraged. In published trials, treatment beyond progression has been allowed.
  • Hyperprogression may occur (LE: 4). It is uncommon, cannot be anticipated, and remains poorly understood.
  • Caution should be exercised in translating response assessment models developed for clinical trials into clinical practice.
  • For management of irAEs in patients with HCC, refer to general principles in published guidelines.

Patient Support and Quality of Life for Patients with HCC

  • Patient and caregiver education for HCC should include an overview of the liver’s function in the body, an explanation of underlying liver diseases such as HBV, HCV, and NASH, and a discussion of how immunotherapy works to treat their cancer.
  • Patients must know which provider is coordinating their treatment, and they need to have clear instructions to promptly report any signs or symptoms of potential immune-related toxicities.
  • Patients need counseling on the goals of treatment in advanced HCC, which is not curative in most patients, despite significant advances. Management of HCC should include focus on supportive care for uncontrolled symptoms and inclusion of palliative care specialists.
  • Patients should receive education on the expected toxicities associated with immunotherapies, including hepatitis, colitis, pneumonitis, and immune-related endocrinopathies. Detailed call parameters should be provided to promptly report signs and symptoms of irAEs.
  • Assessment of patients’ physical function and symptoms should be performed before, during, and after therapy.
  • Patients should be referred to a treatment team including a social worker and a financial manager to assist in navigating healthcare costs and identifying support systems.
  • Conversations should be initiated with patients about how the costs of immunotherapy treatment will be covered, including contributions from private insurance, Medicare and Medicaid, clinical trials, patient assistance programs, or compassionate use as needed.
  • Patients should be provided information about local advocacy and support groups specific to primary liver cancer.

Patient and caregiver education for call parameters for irAEs

You should contact your healthcare providers for any of the following symptoms (or call 911 or seek emergency services as indicated)*:
  • Abdominal pain
  • Change in stool (blood or mucus in stool, change in color, light or clay colored)
  • Increase in bowel movements, >3 movements above a patient’s baseline
  • Diarrhea, >3 watery stools
  • Nausea or vomiting
  • Jaundice (yellowish skin color)
  • Difficulty breathing, shortness of breath, or chest tightness
  • New non-productive dry cough
  • Mental status changes
  • New visual disturbances
  • Headache
  • New or worsening fatigue
  • Fever with temperature >100.4oF (38°C)
  • New weakness, muscle or joint pains
  • Unintentional weight loss >3 lbs (1.5 kg)
  • Significant weight gain with obvious abdominal swelling
  • Rash which may or may not be accompanied by tenderness or itching
*Note to providers: Call parameters for patients highlight the following conditions: colitis, pneumonitis, endocrinopathies, dermatologic toxicities. It should be noted that many conditions have overlapping symptoms.

Radiographic T-staging by LI-RADS and OPTN/UNOS

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Stage Definition
0 No HCC
1 One HCC <20 mm
2 One HCC ≥20 mm and ≤50 mm, or two or three HCCs, all ≤30 mm
3 One HCC >50 mm, or two or three HCCs, at least one >30 mm
4 4A. Four or more HCCs, regardless of size
  • HCC, hepatocellular carcinoma; LI-RADS, Liver Imaging Reporting And Data System; OPTN/UNOS, Organ Procurement and Transplantation Network/United Network for Organ Sharing; TIV, tumor in vein.

Barcelona-Clínic Liver Cancer (BCLC) classification with stage definitions and typical survival outcomes

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Stage definition (BCLC 2018 update) Estimated survival
Stage 0—Very early-stage Single nodule ≤2 cm;
Preserved liver function
>5 years
Stage A—Early-stage Single or up to three nodules ≤3 cm;
Preserved liver function
>5 years
Stage B—Intermediate-stage Multinodular;
Preserved liver function
>2 to 5 years
Stage C—Advanced-stage Portal invasion;
Extrahepatic spread;
ECOG PS 1–2;
Preserved liver function
>1 year
Stage D—Terminal-stage ECOG PS 3–4;
End-stage liver function
3 months
  • *The American Association for the Study of Liver Disease (AASLD) recommends including ECOG PS 0 to 1 in stage 0, A and B, because of the significant overlap between PS 0 and PS 1

  • BCLC, Barcelona-Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; PS, performance status.

Cirrhosis-related disorders that should be considered in the diagnostic workup of irAEs in patients with HCC

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Organ irAE Chronic liver disease
  • Pruritus

  • Rash

  • Erythema multiforme, psoriasis, urticaria and rosácea

  • Severe cutaneous adverse reactions

  • Pruritus

  • Skin disorders, including lichen planus, polyarteritis nodosa, cryoglobulinemic vasculitis, and porphyria cutanea tarda (HCV- and HBV-related)

GI tract
  • Diarrhea

  • Colitis

  • Small intestine bacterial overgrowth

  • Chronic pancreatitis

  • Hepatitis

  • Flares or viral infection

  • Pneumonitis

  • Hepatopulmonary syndrome

  • Porto-pulmonary hypertension

  • Hypothyroidism

  • Hyperthyroidism

  • Graves’ disease

  • Reduced peripheral conversion of T4 to T3

  • Thyroid dysfunction

Adrenal glands and pituitary glands
  • Adrenal insufficiency

  • Hypophysitis

  • Hypogonadism

  • Hypothalamic-pituitary dysfunction

  • Relative adrenal insufficiency

  • Nephritis

  • Hepatorenal syndrome

  • Mixed cryoglobulinemia (HCV-related)

  • HBV-related nephropathy

  • IgA nephropathy

Nervous system
  • Encephalitis

  • Aseptic meningitis

  • Peripheral neuropathy

  • Myasthenia gravis

  • Guillain-Barre syndrome

  • Autonomic neuropathy

  • Transverse myelitis

  • Porto-systemic encephalopathy (typical and atypical)

  • Viral-related peripheral neuropathy

  • Wernicke’s encephalopathy

  • Autonomic neuropathy (HCV-related)

Blood and bone marrow
  • Cytopenias

  • Hemolytic anemia

  • Red cell aplasia

  • Bone marrow failure

  • Hemophilia A

  • Hemophagocytic lymphohistiocytosis

  • Macrophage activation syndrome

  • Hypersplenism and bone marrow depression

  • Anemia due to folate or iron deficiency

  • Hemolytic anemia

  • Viral-related thrombotic thrombocytopenic purpura and aplastic anemia

  • Immune thrombocytopenia (HCV-related)

  • Lymphopenia related to HCC therapies

  • GI, gastrointestinal; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; irAE, immune-related adverse event.

Summary of ‘The Oxford Levels of Evidence

Summary of ‘The Oxford Levels of Evidence 2’ (Adapted from the OCEBM Levels of Evidence Working Group)

Level 1 Level 2 Level 3 Level 4 Level 5
Systematic review or meta-analysis Randomized trial or observational study with dramatic effect Non-randomized, controlled cohort, or follow-up study Case series, case-control, or historically controlled study Mechanism-based reasoning

Recommendation Grading



Immunotherapy for the Treatment of Hepatocellular Carcinoma

Authoring Organization

Publication Month/Year

September 7, 2023

Last Updated Month/Year

February 8, 2024

Document Type


Country of Publication


Inclusion Criteria

Male, Female, Adult, Older adult

Health Care Settings

Ambulatory, Hospital, Outpatient, Radiology services

Intended Users

Nurse, nurse practitioner, physician, physician assistant


Diagnosis, Assessment and screening, Treatment, Management

Diseases/Conditions (MeSH)

D006528 - Carcinoma, Hepatocellular


immunotherapy, Cancer immunotherapy, hepatocellular carcinoma, liver cancer

Source Citation

Addendum 1: Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma Journal for ImmunoTherapy of Cancer 2023;11:e002794add1. doi: 10.1136/jitc-2021-002794add1

Greten TF, Abou-Alfa GK, Cheng AL, Duffy AG, El-Khoueiry AB, Finn RS, Galle PR, Goyal L, He AR, Kaseb AO, Kelley RK, Lencioni R, Lujambio A, Mabry Hrones D, Pinato DJ, Sangro B, Troisi RI, Wilson Woods A, Yau T, Zhu AX, Melero I. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma. J Immunother Cancer. 2021 Sep;9(9):e002794. doi: 10.1136/jitc-2021-002794. PMID: 34518290; PMCID: PMC8438858.