Prevention, Diagnosis, and Treatment of Hepatocellular Carcinoma

Publication Date: May 22, 2023
Last Updated: June 1, 2023

EPIDEMIOLOGY AND PREVENTION

  • Public health policies and interventions should be implemented to address the significant mortality of HCC in the United States (Level 5, Strong Recommendation).
  • Vaccination for HBV infection should be given in all newborns as well as high-risk adults who failed to receive vaccination at birth to reduce the risk of HCC (Level 2, Strong Recommendation).
  • Antivirals should be given in all patients who meet criteria for treatment according to AASLD Guidance documents for HBV and HCV infection. In patients with chronic viral hepatitis, suppression of HBV and eradication of HCV infection decreases the risk of HCC development (Level 2, Strong Recommendation).
  • Patients with chronic liver disease should be counseled to maintain a healthy weight, have a balanced diet, avoid tobacco and alcohol, and achieve adequate control of comorbid conditions including components of the metabolic syndrome. A healthy lifestyle has multiple benefits and may decrease HCC risk (Level 3, Strong Recommendation).
  • Coffee consumption may be recommended for patients with chronic liver disease, as it has associated with decreased risk of HCC development (Level 5, Weak Recommendation, 12 of 15 agree).
    • There are insufficient data to recommend a specific dose, although studies suggest a dose–response curve.
  • AASLD does not advise use of other chemoprevention therapies such as statins, aspirin, and metformin solely to reduce HCC risk, despite some evidence of risk reduction (Level 5, Weak Recommendation).
    • In patients with other indications, these agents may be used in the setting of chronic liver disease (Level 3, Weak Recommendation).

SURVEILLANCE

  • Patients at high risk of developing HCC (see Table 1) should be entered into HCC surveillance programs, provided they would be candidates for HCC treatment (Level 2, Strong Recommendation).
    • Patients with Child-Turcotte-Pugh class C cirrhosis should not be enrolled in surveillance programs unless they are eligible for liver transplantation (Level 3, Strong Recommendation).
    • All patients listed for liver transplantation should undergo semiannual HCC surveillance because identification of early-stage HCC changes priority for transplantation (Level 3, Strong Recommendation).
    • AASLD recommends against HCC surveillance in patients with life-limiting comorbid conditions that cannot be remedied by liver transplantation or other directed therapies (Level 5, Strong Recommendation).
  • AASLD recommends against routine use of HCC surveillance in patients with HCV infection post-SVR with advanced fibrosis but without cirrhosis (Level 3, Weak Recommendation).
  • AASLD recommends against routine use of HCC surveillance in patients with NAFLD who have advanced fibrosis but without cirrhosis (Level 3, Weak Recommendation).
  • HCC surveillance should be performed using ultrasound and AFP at semiannual (approximately every 6 months) intervals (Level 2, Strong Recommendation).
    • AASLD recommends use of interventions such as best practice alerts or outreach programs to increase HCC surveillance adherence given the underuse of surveillance in clinical practice (Level 2, Strong Recommendation).
  • AASLD does not recommend routine use of CT- or MRI-based imaging and tumor biomarkers, outside of AFP, for HCC surveillance in at-risk patients with cirrhosis or chronic HBV (Level 5, Weak Recommendation).
    • Alternative imaging modalities, such as contrast-enhanced MRI, may be considered for HCC surveillance in select patients in whom US-based surveillance is suboptimal (Level 3, Weak Recommendation).

RECALL AND MANAGEMENT OF SURVEILLANCE RESULTS

  • US visualization should be assessed and reported for surveillance exams given its impact on recommended recall procedures (Level 5, Strong Recommendation).
    • Patients with limited ultrasound visualization may undergo surveillance contrastenhanced MRI or multiphase CT (Level 5, Weak Recommendation).
  • AASLD advises repeat short-interval ultrasound and AFP in approximately 3-6 months for patients with a <1 cm lesion on abdominal ultrasound (Level 3, Strong Recommendation).
    • Patients with stability for two or more follow-up ultrasound exams may be returned to semiannual surveillance using ultrasound and AFP (Level 5, Weak Recommendation).
  • Patients with any suspicious lesion ≥1 cm on ultrasound should undergo diagnostic evaluation with multiphasic contrast-enhanced CT or MRI (Level 1, Strong Recommendation).
  • AASLD advises diagnostic evaluation with multiphasic contrast-enhanced CT or MRI in patients with AFP ≥20 ng/ml or rising AFP (Level 3, Strong Recommendation).

DIAGNOSIS

  • In at-risk patients with cirrhosis or chronic HBV infection, the diagnosis of HCC should be based on noninvasive imaging criteria and/or pathology (Level 1, Strong Recommendation).
    • Noninvasive imaging criteria as defined by LI-RADS (see Figure 6) should be applied for HCC diagnosis in at-risk patients with cirrhosis or chronic HBV infection (Level 5, Weak Recommendation).
    • Pathological diagnosis of HCC should be based on the International Consensus recommendations using the required histological and immunohistochemical analyses (Level 5, Strong Recommendation).
    • AASLD advises against use of biomarkers, including AFP alone or liquid biopsy, to make a diagnosis of HCC given insufficient accuracy (Level 3, Weak Recommendation).
  • In the absence of cirrhosis or at-risk chronic HBV infection, the diagnosis of HCC should be confirmed by pathology. Noninvasive imaging criteria have insufficient accuracy in these patient populations (Level 1, Strong Recommendation).
  • The noninvasive diagnosis of HCC should be based on either dynamic contrast-enhanced MRI or multiphasic CT (Level 1, Strong Recommendation).
  • In patients with an LR-3 observation, AASLD advises repeat cross-sectional imaging in 3–6 months (Level 2, Weak Recommendation).
  • In patients with an LR-4 observation, AASLD advises multidisciplinary discussion to determine optimal follow-up, including repeat imaging with contrast-enhanced MRI or multiphasic CT within 3 months or immediate biopsy (Level 2, Strong Recommendation).
    • For patients in whom an immediate diagnosis would make an impact on management decisions, the AASLD advises biopsy over repeat imaging (Level 5, Strong Recommendation).
  • AASLD advises multidisciplinary consideration of biopsies for LR-4 and LR-5 observations to confirm the diagnosis or enable molecular analysis (Level 3, Weak Recommendation).
  • Biopsy should be performed in patients with an LR-M observation given the risk of mixed tumors and malignant non-HCC tumors (Level 1, Strong Recommendation).

STAGING

  • All patients with HCC should undergo staging with multiphase CT or contrast-enhanced MRI of the abdomen (Level 2, Strong Recommendation).
    • Patients with HCC beyond BCLC Stage 0 should undergo noncontrast CT of the chest to evaluate for metastatic disease (Level 5, Strong Recommendation).
    • AASLD advises against routine use of PET scan and bone scan for staging given low sensitivity for HCC (Level 3, Weak Recommendation).
  • Tumor staging including tumor burden, degree of liver dysfunction, and ECOG PS should be performed and documented at time of initial treatment evaluation in all patients with HCC (Level 5, Strong Recommendation).
  • Although there are several available staging systems, AASLD advises use of the BCLC system (Level 5, Strong Recommendation).
  • Patients should be discussed in a multidisciplinary tumor board to capture tumor stage because this practice has been shown to alter radiologic interpretation (Level 3, Strong Recommendation).

MULTIDISCIPLINARY CARE

  • Patients with HCC should be discussed and managed in a multidisciplinary care setting (Level 3, Strong Recommendation).

SURGICAL RESECTION

  • Surgical resection should be the treatment of choice for localized HCC in the absence of underlying cirrhosis (Level 2, Strong Recommendation).
  • In patients with cirrhosis, surgical resection should be considered the treatment of choice for patients with limited tumor burden, well-compensated cirrhosis without clinically significant portal hypertension, and an adequate FLR (Level 2, Strong Recommendation).
  • Minimally invasive liver resection (laparoscopic and robotic) may be performed to enhance recovery and lower risk of perioperative morbidity in selected patients (Level 3, Weak Recommendation).
  • Routine postoperative surveillance should be performed to detect recurrence using contrast-enhanced multiphasic CT or MRI every 3–6 months for all patients with HCC following liver resection (Level 3, Strong Recommendation).
    • The optimal timing and duration of surveillance after surgical resection is unknown, although AASLD recommends indefinite surveillance (Level 5, Weak Recommendation).
  • AASLD recommends use of adjuvant immune checkpoint inhibitor-based systemic therapy in patients at high risk of recurrence after liver resection or local ablation (Level 2, Strong Recommendation).
    • AASLD advises post-progression treatment after adjuvant therapy based on pattern of recurrence (Figure 11) (Level 4, Weak Recommendation).
    • AASLD advises against the use of neoadjuvant systemic therapies in patients undergoing liver resection outside of a clinical trial setting, based on currently available data (Level 2, Weak Recommendation).

LIVER TRANSPLANTATION

  • Liver transplantation should be the treatment of choice for transplant-eligible patients with early-stage HCC occurring in the setting of clinically significant portal hypertension and/or decompensated cirrhosis (Level 2, Strong Recommendation).
    • Liver transplantation should be the treatment of choice for transplant-eligible patients with HCC that recur within Milan criteria after surgical resection (Level 3, Strong Recommendation).
  • AASLD advises the use of pre-transplant locoregional bridging therapy for patients being evaluated or listed for liver transplantation, if they have adequate hepatic reserve, to reduce the risk of waitlist dropout in the context of anticipated prolonged wait times for transplant (Level 3, Strong Recommendation).
    • AASLD does not advise one LRT over another for bridging therapy. The choice of locoregional modality should be based on tumor size, location, and center expertise (Level 3, Weak Recommendation).
    • AASLD does not recommend the routine use of systemic therapy as bridging therapy for transplantation; however, its use does not preclude LT eligibility (Level 5, Weak Recommendation).
  • AASLD advises patients with decompensated cirrhosis who develop T1 HCC and are eligible for LT be monitored with cross-sectional imaging at least every 3 months until criteria are met for MELD exception before pursuing LRT (Level 3, Weak Recommendation).
    • Immediate LRT may be considered if AFP is significantly elevated or if the patient is not otherwise eligible for liver transplantation (Level 3, Weak Recommendation).
  • Patients who are otherwise transplant-eligible except with initial tumor burden exceeding the Milan criteria, especially those meeting UNOS downstaging criteria, should be considered for LT following successful downstaging to within Milan criteria after a 3-to-6-month period of
  • observation (Level 2, Strong Recommendation).
    • Patients with AFP > 1000 ng/ml must be downstaged to AFP < 500 ng/ml to be considered downstaged (Level 2, Strong Recommendation).
  • AASLD advises surveillance for detection of post-transplant HCC recurrence using multiphasic contrast-enhanced abdominal CT or MRI and chest CT scan (Level 2, Strong Recommendation).

LOCAL ABLATIVE THERAPY

  • Patients with solitary tumors ≤5 cm should be treated with curative intent using local ablative therapies if ineligible for or they decline surgical therapy (Level 1, Strong Recommendation).
  • Thermal ablation (radiofrequency or microwave ablation) should be considered the treatment of choice for patients with early-stage HCC ≤3 cm who are ineligible for or decline surgery (Level 1, Strong Recommendation).
    • AASLD does not advise one thermal ablative modality over another.
  • Targeted radioembolization (radiation segmentectomy) or EBRT may be used as alternative therapies to thermal ablation for patients with BCLC stage A HCC who are not candidates for surgical resection, including those with tumors >3 cm in size (Level 3, Strong Recommendation).

TRANSARTERIAL THERAPIES

  • Patients with BCLC Stage B HCC should be treated with transarterial chemoembolization (Level 1, Strong Recommendation).
  • AASLD advises radioembolization as an alternative therapy to chemoembolization in patients with BCLC Stage B HCC (Level 3, Strong Recommendation).
  • Transarterial therapies should be performed in a selective/segmental fashion (over lobar treatment) whenever possible given a lower risk of hepatic dysfunction (Level 5, Strong Recommendation).
  • AASLD advises against the combination of systemic therapy with transarterial therapies for BCLC Stage B HCC outside of a clinical trial setting (Level 2, Strong Recommendation).
  • AASLD advises systemic therapy in patients with intermediate HCC who are unsuitable for or refractory to locoregional therapies due to contraindications, worsening hepatic dysfunction, progression of HCC, or lack of objective response (Level 3, Strong Recommendation).

SYSTEMIC THERAPY

First Line

  • Systemic therapy should be offered to patients with preserved liver function (Child-Turcotte-Pugh A or well-selected Child-Turcotte-Pugh B cirrhosis), ECOG PS 0-1, who have BCLC Stage C HCC, or BCLC Stage B HCC not amenable to or progressing after locoregional therapy (Level 1, Strong Recommendation).
    • Patients with advanced HCC who have Child-Turcotte-Pugh A cirrhosis should be offered atezolizumab plus bevacizumab or durvalumab plus tremelimumab as preferred first-line therapy options (Level 2, Strong Recommendation).
      • Patients considered for atezolizumab plus bevacizumab should undergo an EGD to assess for high-risk stigmata of variceal or other GI bleeding (Level 5, Strong Recommendation).
      • The optimal treatment of large varices prior to atezolizumab plus bevacizumab initiation is unknown, although AASLD recommends at least one session of banding. Carvedilol may be considered as an alternative management of varices prior to atezolizumab plus bevacizumab (Level 5, Weak Recommendation).
      • Patients with recent GI bleeding within 6 months and those with high-risk stigmata for bleeding on EGD should have varices adequately treated prior to atezolizumab plus bevacizumab initiation, or these patients may be considered for durvalumab plus tremelimumab (Level 5, Strong Recommendation).
    • Patients with Child-Turcotte-Pugh A cirrhosis in whom atezolizumab plus bevacizumab and durvalumab plus tremelimumab are contraindicated should be offered first-line sorafenib or lenvatinib (Level 1, Strong Recommendation).
  • Well-selected patients with Child-Turcotte-Pugh B cirrhosis may be offered sorafenib, lenvatinib, or single-agent anti-PD1 or anti-PDL1 ICI therapy (Level 3, Weak Recommendation).

Second Line and Beyond

  • AASLD advises second-line therapy in patients with preserved liver function (Child-Turcotte-Pugh A or well-selected Child-Turcotte-Pugh B cirrhosis), ECOG PS 0-1, who develop HCC progression or intolerance with first-line systemic therapy (Level 1, Strong Recommendation).
    • AASLD advises sorafenib or lenvatinib as preferred agents after first-line atezolizumab plus bevacizumab if patients are not eligible for clinical trials (Level 5, Weak Recommendation).
      • Cabozantinib, regorafenib, or ipilimumab plus nivolumab may be used in these patients (Level 5, Weak Recommendation).
    • AASLD advises sorafenib or lenvatinib as preferred agents after first-line durvalumab plus tremelimumab if patients are not eligible for clinical trials (Level 5, Weak Recommendation).
    • AASLD advises cabozantinib or regorafenib (or ramucirumab in patients with AFP ≥400 ng/ml) as preferred agents after sorafenib or lenvatinib if patients are not eligible for clinical trials (Level 1, Strong Recommendation).
      • Pembrolizumab (in patients without prior immunotherapy exposure) or ipilimumab plus nivolumab may be used in these patients.

All Lines of Therapy

  • AASLD advises against the use of ICIs in patients with recurrent HCC after liver transplantation given increased risk of graft loss and death (Level 4, Strong Recommendation).
    • AASLD advises sorafenib or lenvatinib as first-line therapy for these patients

ADVANCE CARE PLANNING

  • Advance care planning should be offered to all patients receiving palliative-intent therapy or best supportive care for HCC, regardless of transplant eligibility (Level 5, Weak Recommendation).

Recommendation Grading

Overview

Title

Prevention, Diagnosis, and Treatment of Hepatocellular Carcinoma

Authoring Organization

Publication Month/Year

May 22, 2023

Last Updated Month/Year

September 6, 2023

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Document Objectives

This guidance document provides an updated approach to the prevention, diagnosis, and treatment of hepatocellular carcinoma (HCC). The prior American Association for the Study of Liver Diseases (AASLD) HCC guidance document was updated at this time to reflect clinically significant changes to approaches in several of these areas. Notable examples of these updates
include recommendations for use of ultrasound and alpha fetoprotein (AFP) for HCC surveillance, expanded indications for surgical therapies, incorporation of immune checkpoint inhibitor (ICI) therapy for first-line systemic therapy, and explicit recommendations for multidisciplinary care and advance care planning (ACP). This guidance on HCC was developed with the support and oversight of the AASLD Practice Guidelines Committee. AASLD guidelines are supported by systematic reviews of the literature, formal ratings of evidence quality and strength of recommendations, and, if appropriate, metaanalysis of results using the Grading of Recommendations Assessment Development and Evaluation system. In contrast, this document was developed by consensus of a multidisciplinary expert panel and provides guidance statements based on formal review and analysis of the literature on the topics and questions related to the prevention, diagnosis, and treatment of HCC. Although the literature review for this document is comprehensive and unbiased, the lack of mandatory systematic reviews facilitated more rapid publication. The expert panel rated the level of evidence for each recommendation based on the Oxford Center for Evidence-Based Medicine.(1) Additionally, the panel categorized the strength of recommendations based on the level of evidence, risk–benefit ratio, and patient preferences.

Target Patient Population

Patients with hepatocellular carcinoma

Inclusion Criteria

Male, Female, Adolescent, Adult, Child, Older adult

Health Care Settings

Ambulatory, Hospital, Long term care, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Diagnosis, Assessment and screening, Management

Diseases/Conditions (MeSH)

D008107 - Liver Diseases, D006528 - Carcinoma, Hepatocellular

Keywords

cancer, liver disease, hepatocellular carcinoma, liver cancer, hcc

Source Citation

Singal, Amit G.1; Llovet, Josep M.2,3,4; Yarchoan, Mark5; Mehta, Neil6; Heimbach, Julie K.7; Dawson, Laura A.8; Jou, Janice H.9; Kulik, Laura M.10; Agopian, Vatche G.11; Marrero, Jorge A.12; Mendiratta-Lala, Mishal13; Brown, Daniel B.14; Rilling, William S.15; Goyal, Lipika16; Wei, Alice C.17; Taddei, Tamar H.18,19. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology ():10.1097/HEP.0000000000000466, May 22, 2023. | DOI: 10.1097/HEP.0000000000000466