Hepatocellular carcinoma - Emerging treatments

External beam radiotherapy (EBRT)

One Cochrane systematic review found low-quality evidence to suggest that EBRT, in combination with transarterial chemoembolisation (TACE), may be associated with lower mortality and increased complete and overall response rates in patients with unresectable hepatocellular carcinoma (HCC).[143] However, increased liver toxicity was reported.[143] [ ] One further randomised controlled trial of patients with HCC showing macroscopic vascular invasion compared a combination of EBRT and TACE with sorafenib.[144] The study found that the combination of EBRT and TACE was well tolerated and improved progression-free and overall survival compared with sorafenib. The American Society for Radiation Oncology and American College of Radiology recommend EBRT as an option in patients with liver-confined HCC who are not candidates for curative treatment, as consolidative therapy in patients with liver-confined HCC after incomplete response to other treatments, and as a salvage option for local recurrences. EBRT is conditionally recommended as a bridge to transplant or before surgery in selected patients, and palliative EBRT is conditionally recommended for symptomatic primary HCC and/or macrovascular tumour thrombi.[97][145]

Other forms of radiotherapy

Radiotherapy, including stereotactic body radiotherapy (SBRT), intensity-modulated radiotherapy (IMRT), high-dose-rate (HDR) brachytherapy, and proton beam therapy, is increasingly recognised as a treatment option for patients with HCC who are unsuitable for resection, ablation, or embolisation. Major guidelines support its use in select patients with localised tumours. While further prospective studies are warranted, SBR, in particular offers promising local control and is now widely considered part of the multidisciplinary armamentarium.[2][7][59]

Apatinib

Apatinib (also known as rivoceranib) is an investigational tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2 (VEGFR-2). In one phase 3 randomised placebo-controlled trial, apatinib monotherapy significantly improved overall survival in adult patients with advanced HCC previously refractory or intolerant to at least one line of systemic or chemotherapy or targeted therapy.[146]

Donafenib

Donafenib, an investigational novel multikinase inhibitor and a deuterated sorafenib derivative, has been shown to improve overall survival in patients with unresectable or metastatic HCC who received no prior systemic therapy compared with sorafenib in one open-label, parallel-controlled phase 2-3 trial.[147]

Pembrolizumab plus lenvatinib

Pembrolizumab and lenvatinib combination treatment has been granted breakthrough therapy designation for the treatment of newly diagnosed, advanced HCC by the US Food and Drug Administration (FDA). Both drugs are currently used as monotherapy for the management of HCC. Pembrolizumab plus lenvatinib demonstrated promising anti-tumour activity with acceptable tolerability in a phase 1b study of patients with unresectable Barcelona Clinic Liver Cancer (BCLC) stage B (not eligible for TACE) or C HCC.[148] However, in a subsequent double-blind randomised controlled phase 3 study of first-line treatment for unresectable HCC, pembrolizumab plus lenvatinib did not significantly improve overall or progression-free survival compared with lenvatinib plus placebo.[149]

Camrelizumab plus apatinib

Camrelizumab, an investigational programmed cell death protein-1-blocking monoclonal antibody, combined with apatinib represents an emerging dual immunotherapy-antiangiogenic strategy for unresectable HCC. The combination aims to enhance anti-tumour immune responses while disrupting tumour angiogenesis. Early-phase trials, such as those conducted in China, have shown promising efficacy and manageable safety profiles, with improved objective response rates and disease control in treatment-naive HCC patients.[150] One open-label phase 3 trial found that camrelizumab plus apatinib improved progression-free survival and overall survival compared with sorafenib among patients with unresectable HCC who had not received any prior systemic treatment.[151] Ongoing studies are further evaluating its role compared with standard therapies like atezolizumab plus bevacizumab.

Radioactive iodine (131-I)-labelled metuximab

Metuximab is an investigational monoclonal antibody against the CD147 antigen that is expressed in HCC. A phase 2 trial investigated 131-I-labelled metuximab's role as an adjuvant therapy after curative-intent resection of HCC expressing CD147. Patients who received one dose of transarterial 131-I-labelled metuximab 4-6 weeks after hepatectomy were compared with patients who received no adjuvant treatment. Five-year recurrence-free survival was significantly higher in the adjuvant 131-I-labelled metuximab group (43.4% vs. 21.7%).[152]

Chimeric antigen receptor (CAR) T-cell therapy

CAR T-cell therapy involves the modification of the patient's T cells to target and destroy cancer cells. One phase 1/2 study is investigating T cells engineered to detect cells expressing the HCC antigen glypican 3.[153]

Rencofilstat

Rencofilstat, an investigational oral cyclophilin inhibitor, has been granted orphan drug designation by the FDA for treating HCC. Trials of rencofilstat have been limited to patients with metabolic dysfunction-associated steatohepatitis.[154]

Neoadjuvant immunotherapy

Neoadjuvant use of immunotherapy prior to resection aims to improve the resectability of the tumours and reduce postoperative recurrence. One patient-level analysis of phase 1 and 2 trials demonstrated robust evidence that neoadjuvant immunotherapy induces high rates of major pathological response in HCC and is associated with improved relapse-free survival following resection.[155] However, the specific immunotherapy drugs, duration of treatment, and assessment of pathological response varied across the included studies.[155] Guidelines recommend against use of neoadjuvant systemic therapy outside of a clinical trial setting.[7][62][139]

Combined transarterial and systemic therapy

Several studies have investigated the combination of TACE with systemic therapy for patients with HCC. Combined TACE plus levantinib improved overall survival compared with levantinib alone in one randomised controlled trial of first-line treatment of advanced HCC.[156] Phase 3 trials of patients with early or intermediate HCC reported improved progression-free survival with TACE combined with durvalumab plus bevacizumab, and TACE combined with pembrolizumab plus lenvatinib.[157][158] Combined transarterial and systemic therapy is not yet approved, and evidence is limited by heterogeneity in study design and timing/sequencing of interventions. The American Association for the Study of Liver Diseases recommends against routine addition of TACE to systemic therapy for patients with advanced HCC, and they advise against combined transarterial and systemic therapy for patients with intermediate HCC outside of a clinical trial setting.[7] The European Society for Medical Oncology suggests that TACE combined with durvalumab plus bevacizumab, or TACE combined with pembrolizumab plus lenvatinib may be considered in patients with intermediate-stage HCC, but they acknowledge that long-term benefit of these combinations has not been established.[59]

Laser ablation

Percutaneous image-guided laser ablation is a form of thermal ablation that uses optical fibres to deliver laser energy to heat and destroy the tumour. Studies report complete tumour ablation rates ranging from 67% to 99% following laser ablation.[159] However, large-scale randomised controlled trial (RCTs) comparing laser ablation directly to radiofrequency or microwave ablation are lacking. In one RCT comparing radiofrequency ablation and laser ablation for treatment of small HCC, the survival probability at 1 and 3 years was 94% and 89% in the radiofrequency ablation group, and 94% and 80% in the laser ablation group.[160] In the UK, the National Institute for Health and Care Excellence (NICE) recommends that percutaneous image-guided laser ablation may be used for primary or secondary liver tumours (including HCC) while more evidence is generated, provided that special arrangements are in place for clinical governance, informed consent, and audit of clinical outcomes.[159]