Updates in Hepatocellular Carcinoma

Educational Objectives

The goal of this program is to improve diagnosis and management of hepatocellular carcinoma. After hearing and assimilating this program, the clinician will be better able to:

1. Identify current guidelines and evidence-based practices for surveillance of hepatocellular carcinoma.
2. Apply the Barcelona Clinic Liver Cancer staging system to classify hepatocellular carcinoma and guide treatment decisions.

Summary

Hepatocellular carcinoma (HCC): is the sixth most common cancer worldwide; in most Asian countries, excluding Japan, hepatitis B virus infection is the dominant etiologic factor; in Eastern and Central Europe, alcoholic liver disease is the leading cause; in Western countries and the United States, hepatitis C virus (HCV) infection has emerged as the most significant risk factor for HCC; a strong association with cirrhosis is established

Barcelona Clinic Liver Cancer (BCLC) staging system: very early stage disease — includes single lesion ≤2 cm; early stage — single lesion or <3 nodules each ≤3 cm; intermediate stage — includes multifocal disease with good performance status (PS) and well preserved liver function; advanced stage disease — includes extrahepatic disease, portal vein invasion, and metastasis; PS is categorized as 1 or 2; there is also a terminal stage disease

Considerations for treatment: is based on liver function and PS; patients with very early or early stage disease have reasonable rates of survival ≥5 yr and may be treated with ablation or transplantation; catheter-based therapies may be considered for patients transitioning towards intermediate stage or those in relatively early stages

Treatment options: first-line therapies include atezolizumab plus bevacizumab and durvalumab plus tremelimumab; early diagnosis through surveillance is important, particularly in high-risk populations (cirrhosis); surveillance for patients with HCV infection alone is under investigation; it is a standard practice for patients with hepatitis B virus infection; high-risk individuals receive intensive monitoring; the focus is on improving outcomes for intermediate- and advanced-stage disease; current approved treatments offer improved tolerability compared with older options, eg, sorafenib, lenvatinib

Surveillance: includes ultrasonography and α-fetoprotein (AFP); liquid biopsy, combination of biomarkers, and cell-free DNA fragmentation are being explored; ultrasonography has sensitivity of 45%; when combined with AFP, the sensitivity increases to 63%; abbreviated magnetic resonance imaging (MRI), a shorter and more tolerable alternative to traditional MRI, is promising, with sensitivity >80% independent of disease etiology; ongoing trials are comparing its efficacy to the current standard

Immune checkpoint inhibitors: atezolizumab and durvalumab have become a cornerstone of first line therapy, restoring the immune system’s ability to recognize and attack cancer cells; simultaneously, vascular endothelial growth factor (VEGF) inhibitors target the tumor’s blood supply; VEGF inhibition may impair wound healing, increasing the risk for bleeding; 25% of patients with compensated cirrhosis on atezolizumab plus bevacizumab in the IMbrave 150 trial (Cheng et al [2022]) reported bleeding complications; esophagogastroduodenoscopy (EGD) is recommended before initiating therapy; some oncologists may begin with a single-agent immune checkpoint inhibitor; combination therapy targeting both immune checkpoint inhibitor and kinases is generally more effective; immune checkpoint therapy carries the risk for immune mediated reactions, necessitating careful monitoring

Evidence: the Himalaya trial by Abou-Alfa et al (2022) focused on the STRIDE regimen; it investigated a single priming dose of tremelimumab (a cytotoxic T-lymphocyte associated protein 4 inhibitor) followed by regular durvalumab (an immune checkpoint inhibitor) every 4 wk, comparing it to sorafenib in patients with unresectable HCC and Child-Pugh A cirrhosis; results show a significant improvement in 5-yr overall survival (OS; 20% with the STRIDE regimen vs 10% with sorafenib); increase in median OS was observed; adverse effect profiles were similar between the 4-yr and 5-yr assessments; the STRIDE regimen was evaluated in a real world cohort of patients with portal vein invasion, prior therapies (eg, transarterial chemoembolization), and metastatic disease; results showed median OS of ≈6 mo; liver function, as assessed by the albumin and bilirubin scores, was stable with the regimen

Catheter based therapies: are the initial approach for intermediate stage HCCs; recent evidence explores the efficacy of radiotherapy vs chemoembolization; systemic therapies, traditionally reserved for advanced HCC, are increasingly being combined with catheter based treatments in the intermediate stage; this combination aims to capitalize on HCC’s hypervascularity, which facilitates both catheter based interventions and the delivery of VEGF inhibitors; the progression-free survival (PFS) after catheter based therapies is 7 to 8 mo; OS may extend to ≈2.5 yr

Evidence: LEAP 012 trial by Kudo et al (2025) evaluated the combination of systemic therapy (lenvatinib plus pembrolizumab) with TACE vs TACE alone in patients with intermediate HCC; the trial enrolled patients with good PS and liver function, predominantly men with viral etiology; common adverse effects reflected the combined treatment approach, including hypertension and proteinuria (lenvatinib), postembolization syndrome (TACE), and immune mediated events (pembrolizumab); myositis and hepatitis were observed; the study found a 4.6-mo improvement in PFS with the combination; OS was not significantly improved; the EMERALD 1 trial by Sangro et al (2025) evaluated TACE, TACE plus durvalumab, and TACE, durvalumab, and bevacizumab; patients underwent 1 to 4 TACE sessions followed by systemic therapy; adverse effects included increased risk for bleeding in the TACE-durvalumab-bevacizumab group (≤20%) compared with placebo (10%), with one fatal event; a significant improvement in PFS was observed in the combination group vs placebo

American Association for the Study of Liver Diseases guidelines for HCV antiviral therapy: early evidence suggested an increased HCC risk with direct acting antiviral therapy, subsequent studies have shown no increased risk; achieving a sustained virologic response (SVR) after HCV treatment is associated with a lower incidence of HCC and improved liver function; SVR rates are higher in patients without HCC than those with HCC; treatment decisions must balance the benefits of HCV eradication with the patient’s HCC stage and treatment plan; according to the AASLD guidelines, HCC is not a contraindication for hepatitis C treatment; a delay of 4 to 6 mo after initial HCC therapy for early stage HCC may be considered to maximize virologic response; for advanced HCC, treatment should be considered, but timing should be tailored to the patient’s goals of care; candidates for liver transplantation with HCV should be treated

Readings

Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evidence. 2022;1(8). doi:10.1056/evidoa2100070; Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. New England Journal of Medicine. 2020;382(20):1894-1905. doi:10.1056/nejmoa1915745; Fitzmorris P, Singal AK. Surveillance and diagnosis of hepatocellular carcinoma. Gastroenterol Hepatol (N Y). 2015;11(1):38-46; Han K, Kim JH. Transarterial chemoembolization in hepatocellular carcinoma treatment: Barcelona clinic liver cancer staging system. World J Gastroenterol. 2015;21(36):10327-10335. doi:10.3748/wjg.v21.i36.10327; Kudo M, Ren Z, Guo Y, et al. Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study [published correction appears in Lancet. 2025 Feb 8;405(10477):468. doi: 10.1016/S0140-6736(25)00205-3.]. Lancet. 2025;405(10474):203-215. doi:10.1016/S0140-6736(24)02575-3; Ntellas P, Chau I. Updates on systemic therapy for hepatocellular carcinoma. American Society of Clinical Oncology Educational Book. 2024;44(1). doi:10.1200/edbk_430028; Sangro B, Kudo M, Erinjeri JP, et al. Durvalumab with or without bevacizumab with transarterial chemoembolisation in hepatocellular carcinoma (EMERALD-1): a multiregional, randomised, double-blind, placebo-controlled, phase 3 study. Lancet. 2025;405(10474):216-232. doi:10.1016/S0140-6736(24)02551-0; Taddei TH, Brown DB, Yarchoan M, et al. Critical Update: AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. Published online February 24, 2025. doi:10.1097/hep.0000000000001269.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Razumilava has received research support from NGM Bio and Pliant Therapeutics. Members of the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Razumilava was recorded at 27th Annual Liver Disease Wrap-Up, held December 7, 2024, in Livonia, MI, and presented by University of Michigan Medical School. For information on upcoming CME activities from this presenter, please visit medschool.umich.edu/offices/cme. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

ON160902

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.