The emergence of systemic therapies has ushered in an era of chemo-diversity for hepatocellular carcinoma, in which drug sequencing is pivotal for maximizing outcomes. Among available agents, lenvatinib is notable for its potent anti-angiogenic and immunomodulatory properties. This review proposes a structured building-block strategy for optimizing sequential drug therapy, conceptualizing each treatment line as a block that contributes cumulatively to survival, and grounding the discussion in clinical insights from lenvatinib administration. We comprehensively evaluated clinical trials, preclinical investigations, and real-world data to identify actionable approaches that enhance tolerability and prolong progression-free survival, with a particular focus on mitigating adverse events, optimizing dosing schedules, and integrating with transarterial therapies. Five refinements emerge as central to maximizing therapeutic benefit: early detection and classification of adverse events, use of supportive agents such as L-carnitine and branched-chain amino acids, structured telephone follow-up, optimization of dosing schedules, including weekend-off regimens, and strategic combination with transarterial therapy. In addition, rationale-based sequencing and clinically relevant switching criteria that extend beyond RECIST are summarized. Collectively, these measures increase the height of each therapeutic block, thereby contributing to cumulative survival within the building-block strategy. In the current era of chemo-diversity, lenvatinib remains a cornerstone agent when accompanied by these clinical refinements. The review provides a practical and conceptual framework for enhancing efficacy through structured sequencing, proactive adverse-event mitigation, and synergistic locoregional strategies, with broad applicability to real-world clinical practice.

Striking advances in systemic therapy for unresectable advanced hepatocellular carcinoma (HCC) have improved the average prognosis of patients with HCC. As a result, the guidelines for the treatment of HCC have changed significantly. However, various issues have emerged in clinical practice. First, there is no established biomarker that can predict response to systemic therapy. Second, there is no established treatment regimen after primary systemic therapy, including combined immunotherapy. Third, there is no established treatment regimen for intermediate-stage HCC. These points make the current guidelines ambiguous. In this review, we present the Japanese guidelines for the diagnosis and treatment of HCC based on the latest evidence; introduce various efforts mainly in Japanese real-life practice to update these guidelines; and present our perspectives on future guidelines.

Recently, treatments for unresectable hepatocellular carcinoma (HCC) have undergone remarkable development. Various systemic chemotherapy drugs have been approved and are recommended by clinical guidelines worldwide. Although systemic treatments are effective and contribute to prolonged patient survival, their effects are unsatisfactory for some specific tumor conditions, such as macrovascular invasion. Hepatic arterial infusion chemotherapy (HAIC) is a traditional treatment for advanced HCC. As yet, there is no worldwide consensus recommending HAIC because no high-quality clinical trials have demonstrated its survival benefit. However, clinical evidence is gradually accumulating that shows its survival benefit, and it is recognized as an effective locoregional treatment for advanced HCC. Several HAIC regimens have been reported, including cisplatin monotherapy, cisplatin plus 5-fluorouracil (low-dose FP), lipiodol-suspended FP, and an oxaliplatin-based regimen. We have entered an era of chemo-diversity in the treatment of advanced HCC. This review aimed to clarify the relevance of HAIC in the era of chemo-diversity. We propose a multidisciplinary therapeutic strategy combining locoregional HAIC treatment with sequential drug therapy, with the aim of becoming cancer-free through conversion therapy.

Hepatocellular carcinoma (HCC) is usually accompanied by chronic liver damage, which sometimes influences the selection of HCC treatment. The Barcelona Clinic Liver Cancer (BCLC) staging system, which was first introduced in 1999, is the most commonly used worldwide. Although the intermediate-stage (BCLC stage B) includes the largest number and heterogeneous HCC patients, the recommended treatment option is transarterial chemoembolization (TACE) only. However, recent progress in radical treatments such as hepatic resection, liver transplantation, radiation therapy, and percutaneous therapy has made it possible to treat selected patients with BCLC stage B HCC. Radical treatments are expected to prolong survival time. To-date, TACE has also progressed. In addition to conventional TACE, balloon-occluded TACE and drug-eluting beads TACE are available. These new modalities of TACE will improve therapeutic efficacy and reduce adverse events. One of the most serious concerns of TACE is that repeated TACE reduces the treatment effect and induces liver function impairment. The decision on when TACE should be interrupted is complex. Many molecular targeted agents are now available, and immune checkpoint inhibitors will soon be available for HCC patients with Child-Pugh class A worldwide. Under these circumstances, in patients with TACE unsuitability, switching to molecular targeted agents before deterioration of liver function might improve the prognosis compared to repeated TACE. We should pay attention to stop TACE in TACE-unsuitable HCC patients as it can induce the deterioration of liver function.

Hepatocellular carcinoma (HCC) is usually accompanied by chronic liver damage, which sometimes influences the selection of HCC treatment. The Barcelona Clinic Liver Cancer (BCLC) staging system, which was first introduced in 1999, is the most commonly used worldwide. Although the intermediate-stage (BCLC stage B) includes the largest number and heterogeneous HCC patients, the recommended treatment option is transarterial chemoembolization (TACE) only. However, recent progress in radical treatments such as hepatic resection, liver transplantation, radiation therapy, and percutaneous therapy has made it possible to treat selected patients with BCLC stage B HCC. Radical treatments are expected to prolong survival time. To-date, TACE has also progressed. In addition to conventional TACE, balloon-occluded TACE and drug-eluting beads TACE are available. These new modalities of TACE will improve therapeutic efficacy and reduce adverse events. One of the most serious concerns of TACE is that repeated TACE reduces the treatment effect and induces liver function impairment. The decision on when TACE should be interrupted is complex. Many molecular targeted agents are now available, and immune checkpoint inhibitors will soon be available for HCC patients with Child-Pugh class A worldwide. Under these circumstances, in patients with TACE unsuitability, switching to molecular targeted agents before deterioration of liver function might improve the prognosis compared to repeated TACE. We should pay attention to stop TACE in TACE-unsuitable HCC patients as it can induce the deterioration of liver function.