Nonthermal locoregional therapies for liver cancer: identifying evidence gaps and a proposed research trajectory

Liver cancer remains one of the most lethal malignancies worldwide, with a five-year relative survival rate of approximately 22 percent in the United States and fewer than 4 percent for patients with distant metastatic disease. Nonthermal locoregional therapies have emerged as important options for unresectable hepatocellular carcinoma (HCC) and liver metastases. This review examines four modalities—irreversible electroporation (IRE), pulsed electric field (PEF) ablation, transarterial chemoembolization (TACE), and yttrium-90 (Y-90) transarterial radioembolization (TARE)—and identifies four underappreciated gaps and assumptions in the current evidence base. First, TARE studies are frequently pooled as though they evaluate a single intervention, despite major differences in dosimetry and patient selection between negative trials (SARAH, SIRveNIB) and positive studies (LEGACY, DOSISPHERE-01); a stratified framework treating these factors as effect modifiers is proposed. Second, no randomized trial compares the EMERALD-1 regimen (TACE plus durvalumab plus bevacizumab) with personalized-dosimetry radiation segmentectomy for solitary unresectable HCC up to 8 cm, leaving a key first-line treatment question unresolved; a three-arm phase 3 design is proposed. Third, overall survival remains the dominant endpoint despite the growing use of locoregional–immunotherapy combinations; time to next systemic therapy and treatment-free interval may better reflect clinical benefit. Fourth, IRE is generally viewed as a purely ablative technique despite evidence of immunogenic cell death and emerging ablation-immunotherapy signals, yet no phase 2 or phase 3 trial has prospectively evaluated IRE plus checkpoint inhibition in HCC; such a study is proposed for perivascular lesions. Recent phase 3 data (EMERALD-1, LEAP-012) and the 2022 BCLC update are synthesized to support these arguments. Collectively, the field has advanced beyond asking which modality performs best in isolation and now faces questions of trial design, endpoint selection, and evidence synthesis that better reflect modern combination-based and selection-dependent practice.