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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