Systemic Lenvatinib Therapy Combined with Locoregional Chemoembolisation and Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma with Main Portal Vein Invasion: A Multicentre Retrospective Case—Control Study

Background/Objectives: Management of hepatocellular carcinoma (HCC) with main portal vein (MPV) invasion is challenging. We aimed to explore the efficacy and safety of systemic lenvatinib therapy combined with potent locoregional transarterial therapy (e.g., chemoembolisation plus infusion chemotherapy) for the treatment of HCC with MPV invasion. Methods: A direct comparison of different therapeutic regimens through a retrospective matched case—control study was conducted to evaluate the survival benefits of lenvatinib monotherapy versus lenvatinib combined with transarterial chemoembolisation (Len-TACE) versus Len-TACE plus hepatic arterial infusion chemotherapy (Len-TACE-HAIC) with oxaliplatin, fluorouracil, and leucovorin. Between January 2022 and December 2024, consecutive patients with HCC and MPV invasion who received lenvatinib, Len-TACE, or Len-TACE-HAIC from multiple centres in South China were enrolled for this analysis. Overall survival (OS), progression-free survival (PFS), and the objective response rate (ORR) were compared across the treatment groups. Adverse events (AEs) related to treatment were also recorded. Results: A total of 169 patients were included in the study: 48 patients received lenvatinib as systemic treatment, 56 received Len-TACE for locoregional and systemic therapy, and 65 received Len-TACE-HAIC for intensified locoregional and systemic treatment. Patients in the Len-TACE-HAIC group achieved a significantly greater ORR (53.8% vs. 28.6% vs. 6.3%, p < 0.001) than those in the Len-TACE group and the Len group did. Consistently, Len-TACE-HAIC resulted in markedly improved PFS (median, 7.0 vs. 5.0 vs. 2.0 months; p < 0.001) and OS (median, 15.0 vs. 10.0 vs. 7.0 months; p < 0.001). The incidence of grade 3-4 AEs was comparable across the three treatment groups. Conclusions: The results demonstrated that lenvatinib combined with potent locoregional therapy, i.e., the Len-TACE-HAIC regimen, provided superior survival benefits with an acceptable safety profile in patients with HCC and MPV invasion.