Recent Advances in Hepatocellular Carcinoma (HCC) Management

1. Staging & Risk Classification

• BCLC-B (intermediate stage) now more precisely defines "multifocal" as: >3 nodules, or ≤3 nodules with at least one >3 cm.
• Embeds the CUSE framework (Complexity, Uncertainty, Systemic factors, Ethics) for tumour boards to navigate clinical complexity beyond published trial data.
• Prognosis is driven by dominant drivers - tumour burden and/or liver function - and management adapts accordingly.

2. Surgical Management

Resection

• Anatomic resection (segmentectomy, sectionectomy) remains preferred because HCC spreads along portal venous tributaries; this approach improves recurrence-free and overall survival. - Current Surgical Therapy 14e, p. 418
• Reserved for Child-Pugh A patients without significant portal hypertension; perioperative mortality <5% in well-selected patients.
• Laparoscopic and robotic approaches are expanding rapidly. A 2025 multicentre analysis showed that laparoscopic microwave ablation (MWA) has lower morbidity than laparoscopic hepatectomy (14.7% vs. 34.7%; p = 0.006) with similar OS at 1, 3, and 5 years - offering a minimally invasive alternative even for surgical candidates.
• Anatomic hepatic resection based on Laennec's capsule is an emerging technical refinement improving surgical planes.

Liver Transplantation

• Remains the treatment of choice for patients with advanced cirrhosis and limited HCC burden (addressing both the tumour and the "field defect"). - Current Surgical Therapy 14e
• Downstaging protocols using locoregional + systemic combinations (ICI + TKI) are achieving pathological responses that enable previously ineligible patients to meet Milan criteria for transplantation.
• Data from IMbrave050 (updated January 2026) support adjuvant atezolizumab + bevacizumab post-resection or ablation in high-risk patients as the first positive adjuvant immunotherapy trial in HCC.

Ablation

• Thermal ablation (RFA, MWA) for small HCC (<2-3 cm) achieves long-term outcomes comparable to resection with lower morbidity. - Current Surgical Therapy 14e
• Irreversible electroporation (IRE) and stereotactic body radiotherapy (SBRT) are expanding the pool of ablation-eligible patients, especially for perihilar lesions.

3. Locoregional Therapies

TACE (Transarterial Chemoembolization)

• Drug-eluting bead TACE (DEB-TACE) is increasingly combined with systemic agents (TKIs and ICIs) for intermediate-stage HCC.
• EMERALD-1 (Lancet, 2025): Durvalumab ± bevacizumab added to TACE significantly improved progression-free survival vs. TACE alone in unresectable HCC, establishing a new ICI-TACE combination paradigm. [PMID: 39602117]

TARE (Transarterial Radioembolization, Y-90)

• Increasingly used in intermediate and advanced stage disease; TARE is now incorporated in BCLC 2026 alongside TACE for the intermediate-stage recommendation.

SBRT (Stereotactic Body Radiation Therapy)

• A systematic review + ISRS Practice Guidelines (2024) established SBRT as a viable alternative for patients who are not candidates for ablation, bridging the gap between ablation and systemic therapy. [PMID: 37597757]

Hepatic Arterial Infusion Chemotherapy (HAIC)

• HAIC (typically FOLFOX-based) combined with sintilimab + bevacizumab has demonstrated high response rates (~60%) in initially unresectable HCC, with successful conversion to resectability in a meaningful proportion of patients.

4. Systemic Therapy - The Central Paradigm Shift

First-Line Treatment (Unresectable / Advanced HCC)

What Failed: Setting Limits on ICI Optimization

• SKYSCRAPER-14/IMbrave152 (anti-TIGIT tiragolumab + atezo-bev) failed to improve PFS, illustrating the difficulty of building on ICI backbones without novel mechanisms.

Perioperative Systemic Therapy

• Combinations of ICI + TKI ± locoregional therapy are being tested to downstage borderline-resectable tumours, eliminate micrometastases, and improve pathological response rates.

• Adjuvant sintilimab (anti-PD-1) in resected high-risk HCC: Phase 2 RCT (Nat Med, 2024) showed improved RFS vs. active surveillance in high-risk patients. [PMID: 38242982]
• Adjuvant lenvatinib monotherapy in CNLC Stage IIb/IIIa: Median RFS 16.1 months, >60% recurrence-free at 1 year in a prospective exploratory study.
• IMbrave050 (adjuvant atezo-bev post-resection/ablation): Updated data (Jan 2026) continue to support this as a practice-changing adjuvant strategy.

Intermediate Stage: Systemic vs. TACE

• The ABC-HCC trial (phase IIIb) directly compared atezolizumab + bevacizumab vs. TACE in intermediate-stage HCC, showing improved time to failure of treatment strategy (TTFS: 14.6 vs. 9.5 months; HR = 0.55) favoring the systemic arm in specific patient subsets - challenging the historical dominance of TACE in BCLC-B.

Second-Line and Beyond

• Regorafenib (after sorafenib)
• Cabozantinib (after sorafenib ± one prior)
• Ramucirumab (AFP ≥400 ng/mL)
• Pembrolizumab (after sorafenib in anti-PD-L1 naive patients)
• Regorafenib + Nivolumab (RENOBATE trial, Nat Med 2024): Phase 2 showing encouraging activity in TKI-refractory patients. [PMID: 38374347]

5. Novel & Emerging Therapies

Personalized Neoantigen Vaccines

• A phase 1/2 trial (Nat Med, 2024) combining a personalized neoantigen vaccine with pembrolizumab in advanced HCC showed safety and early signals of immunological activity - the first steps toward tumour-specific vaccination in HCC. [PMID: 38584166]

Oncolytic Virotherapy

• VG161 (oncolytic virus) in refractory HCC: Phase I data (Nature, 2025) demonstrated safety and early anti-tumour responses in heavily pre-treated patients, opening a new mechanistic pathway. [PMID: 40108464]

Adoptive T-Cell Therapy

• ADP-A2AFP (AFP-specific T-cell receptor engineered T-cells) - first-in-human trial published: Leverages AFP as a tumour-specific antigen to deliver AFP-directed cytotoxic T-cells. Represents a pivotal advance in adoptive cell therapy for HCC, which expresses AFP as a relatively unique antigen.

Fibrosis-to-HCC Axis Targeting

• A 2025 systematic review (Hepatology Int) decodes the hepatic fibrosis-HCC axis, identifying novel druggable targets including stellate cell-derived paracrine signalling and metabolic reprogramming nodes. [PMID: 40588713]

AI and Liquid Biopsy

• AI-integrated multiparametric MRI (including radiomics models for microvascular invasion prediction) is improving pre-surgical and pre-transplant risk stratification.
• Liquid biopsy (circulating tumour DNA / cfDNA) is being refined as a minimally invasive tool for early detection, treatment response monitoring, and recurrence surveillance - potentially supplementing or replacing AFP in some contexts.

6. Biomarker-Driven Patient Selection

• Tumour microenvironment (TME) spatial ecosystems - immune "hot" vs. "cold" tumours
• AFP levels (CheckMate-9DW showed particular benefit of nivo/ipi in high-AFP patients)
• HBV/HCV etiology (camrelizumab + rivoceranib data suggest etiology-specific responses)
• ALBI score and liver function reserve for tolerability
• ctDNA/cfDNA for minimal residual disease monitoring post-resection

7. Key Ongoing Challenges

1. Treatment sequencing: No head-to-head trials compare atezo-bev vs. STRIDE vs. CheckMate-9DW - clinicians must choose without comparative evidence.
2. Post-ICI/TACE progression: Patients exposed to both modalities upfront create novel refractory scenarios without established algorithms.
3. MASH-related HCC rising: Metabolic dysfunction-associated HCC (without cirrhosis, sometimes without HBV/HCV) is a growing proportion, often with later-stage presentation and distinct biology.
4. Adjuvant therapy standardisation: Multiple positive trials (sintilimab, atezo-bev, lenvatinib) need head-to-head comparison to establish a single adjuvant standard.

Summary Table

• CARES-310 (Lancet 2023) - camrelizumab + rivoceranib vs sorafenib
• Adjuvant sintilimab RCT (Nat Med 2024) - resected high-risk HCC
• Neoantigen vaccine + pembrolizumab (Nat Med 2024)
• Regorafenib + nivolumab RENOBATE (Nat Med 2024)
• VG161 oncolytic virus (Nature 2025)
• Nivolumab + ipilimumab resectable HCC (J Hepatol 2026)
• Locoregional therapies meta-analysis (JAMA Netw Open 2024)
• SBRT guidelines (Int J Radiat Oncol 2024)
• Current Surgical Therapy 14e; Goldman-Cecil Medicine