Hepatocellular carcinoma with macrovascular invasion: review and survival meta-analysis of initial local therapy using minimal prognostic criteria

Introduction: The presence of macrovascular invasion (MaVI) in patients with hepatocellular carcinoma (HCC) defines an advanced stage of disease and, according to the Barcelona Clinic Liver Cancer (BCLC) prognostic and staging system, these patients should be candidates for systemic therapy. While this approach is endorsed by most Western Clinical Practice Guidelines (CPGs), several Eastern CPGs advocate for surgical or locoregional treatments. To explore the current evidence regarding the role of local therapies as first-line options, we conducted a systematic review and meta-analysis of studies involving HCC patients with MaVI. Our objective was to evaluate overall survival (OS) in patients treated with modalities other than systemic therapy, applying stringent inclusion criteria to exclude studies lacking minimal prognostic data and to improve cohort comparability, to provide a comprehensive synthesis of available data to better inform clinical decision-making. Material and methods: PRISMA-guided methods were used (CRD420251051847). PubMed was searched from January 2008 to November 2024. Eligible studies reported overall survival (OS) for HCC patients with MaVI and provided baseline data on performance status and liver function; studies lacking adequate prognostic information were excluded. Treatment arms from the included studies were subsequently classified according to the evaluated treatment approach (monotherapy, combination, or sequential). OS data at 1, 2, 3, and 5 years for every treatment arm were extracted and analyzed, with heterogeneity assessed in a pooled meta-analysis. The quality of the included studies was also evaluated. Results: Seventy-three studies met criteria [104 treatment arms;10,329 patients]. Despite rigorous identification process, substantial heterogeneity persisted for most modalities (I²>80%), precluding robust pooling. Transarterial radioembolization (TARE) monotherapy was the only treatment with low heterogeneity (I²=0%) and showed a pooled 1-year OS of 34% (95%CI 2–48%). Apparent advantages of sequential strategies likely reflected confounding by indication and immortal-time bias, as only patients who lived long enough and were sufficiently fit proceeded through the full sequence. Data completeness declined beyond 12 months (missing OS: 0% at 1-year; 17.3% at 2-year; 32.7% at 3-year; 70.2% at 5-year). Conclusion: The current evidence prevents issuing a clear recommendation for non-systemic treatments in this patient population. TARE was the only treatment modality to show low heterogeneity; however, with a 1-year pooled survival rate of 34%, combined with survival outcomes reported for contemporary immunotherapy-based regimens and two randomized trials that failed to demonstrate the superiority of TARE over sorafenib, the available data remain inconclusive to recommend the use of TARE in HCC patients with MaVI. Head-to-head randomized controlled trials are therefore needed to directly compare these strategies and to identify the subgroups of HCC patients with MaVI who may benefit most from each approach.