Hideki Iwamoto

Background: Durvalumab plus tremelimumab (Dur/Tre) has shown promising efficacy in advanced hepatocellular carcinoma (HCC), but predictive biomarkers remain unclear. This study aimed to determine whether early changes in peripheral blood lymphocyte counts during Dur/Tre therapy can predict clinical outcomes. Methods: In this multicenter retrospective study, we evaluated 299 patients with advanced HCC to assess whether early changes in peripheral blood lymphocyte counts predict clinical outcomes during Dur/Tre therapy. Changes in lymphocyte counts at 2 weeks after treatment initiation (2w‐Δlymphocyte) were analyzed in relation to objective response rate (ORR), progression‐free survival (PFS), and overall survival. Results: Patients with a high‐2w‐Δlymphocyte (> +107/μL) demonstrated a significantly higher ORR (29.6% vs. 14.0%, p < 0.001) and longer PFS (4.3 vs. 2.8 months, p = 0.035) compared with those with a low‐2w‐Δlymphocyte (≤ +107/μL). Subgroup analyses showed that higher 2w‐Δlymphocyte values were associated with better PFS across modified albumin–bilirubin grades ( p = 0.011), Barcelona Clinic Liver Cancer stages ( p = 0.007), and baseline lymphocyte‐to‐monocyte ratio ( p < 0.001). Conclusions: Early increases in peripheral blood lymphocyte counts, particularly 2w‐Δlymphocyte, may be associated with treatment response to Dur/Tre and provide complementary dynamic information to established prognostic factors. Although a favorable association with PFS was observed, this association was attenuated after propensity score matching. Further prospective studies are warranted to validate the clinical utility of 2w‐Δlymphocyte.

Hepatocellular carcinoma (HCC) treatment has entered the immunotherapy era, characterized by multiple systemic and locoregional therapeutic options. Understanding how each modality modulates the tumor immune microenvironment (TIME) is essential to optimize treatment strategies. The cancer-immunity cycle provides a conceptual basis for antitumor immunity, consisting of a priming phase involving antigen release and T cell activation, and an effector phase characterized by cytotoxic T cell-mediated tumor elimination. Immune checkpoint inhibitor-based combinations play a central role in HCC treatment. Anti-programmed death ligand-1 plus anti-vascular endothelial growth factor (VEGF) therapy primarily activates the effector phase by reducing regulatory T cells and macrophages and enhancing cytotoxic T cell infiltration. In contrast, cytotoxic T lymphocyte-associated antigen 4 blockade-based regimens primarily promote the priming phase by activating CD4+ T cells and dendritic cells. Molecular-targeted agents also modulate the TIME. VEGF inhibition commonly reduces immunosuppressive cell populations, lenvatinib enhances cytotoxic T cell activation through fibroblast growth factor inhibition, and cabozantinib promotes dendritic cell-mediated immune activation via AXL inhibition. Locoregional therapies, including transarterial therapies, stereotactic body radiotherapy, and transarterial radioembolization with yttrium 90, induce tumor injury, release tumor-associated antigens, and activate inflammatory signaling. In this review, we propose the concept of “strategic driving of the cancer-immunity cycle,” in which treatment selection and sequencing are guided by their ability to activate distinct phases of the cycle. This concept may provide a rational strategy to maximize antitumor efficacy in HCC.

PURPOSE: External beam radiation therapy (EBRT) has gained delayed acceptance as a recommended first-line treatment modality for patients with hepatocellular carcinoma (HCC), given limited evidence that it improves overall survival (OS). We analyzed individual patient data (IPD) from an international cohort to assess OS among patients with HCC treated with EBRT. METHODS: We performed a systematic review of publications that assessed EBRT, met prespecified technical standards for HCC, and reported OS (search date December 15, 2022). Corresponding authors were invited to submit IPD for the study. We performed Kaplan-Meier survival analyses to determine OS and restricted mean survival time (RMST) stratified by Barcelona Clinic Liver Cancer (BCLC) stage and treatment status (ie, treatment-naïve and experienced). We performed random effects Cox proportional hazards modeling to assess clinical characteristics associated with OS. RESULTS: Data were provided on 4,913 patients treated with EBRT with a median follow-up time of 5.0 years. The median OS was 6.8 years (95% CI, 5.7 to 8.7) for BCLC-0 and 4.6 years (95% CI, 4.1 to 5.1) for BCLC-A. Among treatment-naïve patients, the median OS was not reached (95% CI, 8.6 to not reached) for BCLC-0 and was 5.4 years (95% CI, 4.5 to 6.7) for BCLC-A. In multivariable models, more advanced BCLC stage, higher tumor burden, worse performance status, and Child-Pugh class B or C were associated with a higher risk of mortality. Ablative radiation dose and more recent year of treatment were associated with a reduced risk of death. CONCLUSION: To our knowledge, this study represents the largest multinational cohort of patients with HCC treated with EBRT. OS outcomes with EBRT for very early- and early-stage HCC appear to be comparable with resection, thermal ablation, and other ablative locoregional therapies. These data support the inclusion of EBRT in the BCLC HCC clinical decision-making process.

Clinical and Molecular Hepatology

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.

Background: Malignant hepatocellular neoplasm, not otherwise specified (HCN, NOS), is a rare primary liver tumor showing overlapping features of hepatoblastoma and hepatocellular carcinoma. Because of its rarity and histopathologic heterogeneity, the optimal treatment strategy for HCN, NOS remains undefined. Aim and Methods: We report a case of a 20‐year‐old woman with initially unresectable HCN, NOS, who was treated with hepatic arterial infusion chemotherapy using a fine‐powder formulation of cisplatin suspended in Lipiodol combined with continuous 5‐fluorouracil administration (New FP). The therapeutic response was assessed radiologically and serologically after each treatment cycle, and the patient subsequently underwent surgical resection after adequate tumor regression. Results: After eight cycles of New FP, marked tumor shrinkage and a significant decline in tumor markers were achieved, enabling subsequent systemic chemotherapy according to the SIOPEL‐4 regimen. Thereafter, conversion hepatectomy was performed, and histological examination of the resected specimen demonstrated approximately 90% tumor necrosis. The patient has remained disease‐free for 20 months after surgery. Conclusion: This case demonstrates the potential of New FP as an effective hepatic arterial infusion regimen capable of achieving conversion therapy in rare liver malignancies such as HCN, NOS.

Distinct TIME Modulation by Anti-PD-1/PD-L1, VEGF, and CTLA-4 Blockade Provides a Rationale for Triplet Therapy in HCC

Background & Aims: Despite the advances in systemic therapy for unresectable hepatocellular carcinoma (HCC), patients with Child–Pugh class B (CP‐B) liver function face a significant unmet need. This study evaluated the efficacy and safety of atezolizumab plus bevacizumab (Atez/Bev) in patients with unresectable HCC and CP‐B. Methods: This retrospective study included 796 patients who received Atez/Bev between October 2020 and July 2024 from 10 institutions in Japan. The median observation period was 14.6 months. The liver function was assessed using the CP classification and modified ALBI (mALBI) grade. The progression‐free survival (PFS), overall survival (OS) and median survival time (MST) were evaluated. Results: Patients with CP‐B had significantly shorter PFS and OS than those with CP‐A (median PFS, 4.6 months vs. 7.0 months; MST, 10.3 months vs. 23.2 months) (PFS, p = 0.009; OS, p < 0.001). Although CP‐B was associated with a higher incidence of bleeding‐related events, the discontinuation rate due to adverse events did not differ from that of CP‐A. As a factor for stratifying CP‐B outcomes, significant differences in the PFS, OS and response rate were observed between mALBI grades ≤ 2b and 3 (PFS, p = 0.004; OS, p = 0.024; response rate, p = 0.001). In multivariate analysis, the mALBI grade (hazard ratio [95% CI]: 2.388 [1.186–4.810]; p = 0.014) was extracted as a factor contributing to OS in patients with CP‐B. Conclusion: Atez/Bev therapy demonstrated efficacy and safety in patients with CP‐B, especially when hepatic reserve is maintained within mALBI grade 2b.

Background and Aim: Data on sequential immune checkpoint inhibitor (ICI) retreatment following initial atezolizumab plus bevacizumab (Atez + Bev) are limited. This study aimed to evaluate the efficacy and safety of sequential ICI retreatment in patients with unresectable hepatocellular carcinoma (uHCC). Methods: Of 835 patients with uHCC treated with Atez + Bev, 75 who underwent ICI retreatment after initial Atez + Bev therapy were included in this multicenter retrospective study that assessed the efficacy and safety of ICIs. Results: The participants received one of three sequential retreatments with ICI regimens: durvalumab plus tremelimumab ( n = 58), retreatment with Atez + Bev ( n = 15), and durvalumab monotherapy ( n = 2). The objective response rates (ORRs)/disease control rates (DCRs) for the initial Atez + Bev and sequential ICI retreatment were 34.7%/89.3% and 18.7%/54.7%, respectively. No significant differences in antitumor response were observed among the three ICI retreatment regimens. Patients who achieved a good antitumor response (≥ stable disease) following retreatment showed a significantly longer overall survival. Multivariate analysis identified prior objective response to Atez + Bev as an independent predictor of disease control after retreatment (odds ratio: 3.79, p = 0.016). Immune‐related adverse events (irAEs) requiring corticosteroids occurred in 26.7% of the patients during ICI retreatment, with enterocolitis and rash being the most common. The recurrence rate of irAEs was 15.4% in patients with previous steroid‐requiring irAEs. Conclusions: Sequential ICI retreatment may be a viable therapeutic option for selected patients with uHCC, particularly those with a favorable response to prior Atez + Bev. Although less effective than first‐line therapy, careful patient selection and monitoring ensure efficacy with acceptable safety.

Aim: This study aimed to evaluate the association between the efficacy of durvalumab plus tremelimumab (Dur/Tre) and metabolic dysfunction‐associated steatotic liver disease (MASLD) in patients with hepatocellular carcinoma (HCC). Methods: A total of 239 patients with HCC who received Dur/Tre between March 2023 and October 2024 at multiple institutions in Japan were retrospectively analyzed. Patients were categorized into three groups based on underlying liver disease: viral‐related HCC ( n = 126), MASLD‐related HCC ( n = 30), and nonviral, non‐MASLD HCC ( n = 83). Results: The overall response rates (ORR) were 17.5%, 16.7%, and 19.3% in viral‐related HCC, MASLD‐related HCC, and nonviral, non‐MASLD HCC, respectively. The disease control rates (DCR) were 44.4%, 46.7%, and 51.8%, respectively. No significant differences in ORR ( p = 0.6) or DCR ( p = 0.9) were observed among the three groups. The median PFS was 3.7 months (95% CI, 2.8–4.9) in patients with viral‐related HCC, 3.6 months (95% CI, 2.3–4.8) in patients with MASLD‐related HCC, and 4.4 months (95% CI, 2.6–5.8) in patients with nonviral, non‐MASLD HCC. The median OS was 14.4 months (95% CI, 9.8–NA) in patients with viral‐related HCC and 11.0 months (95% CI, 6.4–NA) in patients with MASLD‐related HCC, whereas it was not reached in patients with nonviral, non‐MASLD HCC. No statistically significant differences in PFS ( p = 1.0) and OS ( p = 0.3) were found among the groups. Conclusions: Dur/Tre showed comparable efficacy in MASLD‐related HCC and other etiologies, warranting confirmation in larger cohorts.