Ladak, FarahFarahLadakMagyar, Christian Tibor JosefChristian Tibor JosefMagyarGaviria, Felipe DFelipe DGaviriaChoi, Woo JinWoo JinChoiZorigtbaatar, AnudariAnudariZorigtbaatarBucur, RoxanaRoxanaBucurRukavina, NadiaNadiaRukavinaVogel, ArndtArndtVogelO'Kane, Grainne MaryGrainne MaryO'KaneLi, ZhihaoZhihaoLiEnglesakis, MarinaMarinaEnglesakisSapisochin, GonzaloGonzaloSapisochin2026-02-052026-02-052026-01https://boris-portal.unibe.ch/handle/20.500.12422/231123Background & Aims Traditional guidelines discourage liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) with macrovascular invasion (MVI). However, emerging evidence suggests that long-term survival is possible when LT is preceded by downstaging therapies. Thus, a pooled analysis of time-dependent risk factor effect size on overall survival (OS) is warranted to determine the effect size of MVI, estimate risk mitigation through downstaging, and design future trials.Methods MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and the Cochrane Register were systematically searched from their inception to 24 January 2023. Studies with comparative oncological outcome data between patients with HCC and MVI (MVI group) and HCC patients without MVI (non-MVI group) were included. Frequentist pairwise meta-analysis (random-effects model) was performed for primary outcomes of OS and recurrence-free survival (RFS) at 5 years. Only studies with adjusted effect estimates were considered for analysis.Results In total, 10 studies were included in this systematic review and meta-analysis, contributing 15,899 patients. Seven studies included deceased donor LT, and four studies included living donor LT. In the quantitative analysis of studies reporting adjusted effect estimates, presence of MVI was associated with lower 5-year OS (hazard ratio (HR) 2.03; 95% CI 1.60-2.57; p <0.001; I2 = 55%; p = 0.05) and 5-year RFS (HR 2.55; 95% CI 1.69-3.85; p <0.001; I2 = 87%; p <0.01). When downstaging was uniformly applied, no statistically significant difference for 5-year OS was observed between the MVI group and non-MVI group (HR 1.55; 95% CI 0.88-2.73; p =0.129; I2 = 46%; p = 0.17).Conclusions Effective downstaging in carefully selected patients with HCC with MVI could achieve survival outcomes approaching those of patients without MVI. Further studies are essential to validate these findings and to clarify which downstaging approaches and tumor characteristics are most likely to confer a transplant benefit.Impact And Implications This meta-analysis provides the first pooled HRs for the effect of MVI on LT outcomes, emphasizing the potential for downstaging therapies to mitigate poor prognosis in HCC. The findings advocate for redefining LT eligibility criteria to incorporate successful downstaging protocols, potentially expanding treatment options for advanced HCC. These insights underline the need for standardized downstaging protocols and prospective trials to optimize patient selection and outcomes globally for LT.enDownstagingExpanded criteriaHepatocellular carcinomaLiver transplantPortal vein tumor thrombus600 - Technology::610 - Medicine & healtharticle10.48620/944454163590910.1016/j.jhepr.2025.101566