Background & AimsAdvanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) carries an extremely poor prognosis, necessitating novel therapeutic strategies. This phase Ib trial evaluated the safety and preliminary efficacy of combining carbon-ion radiotherapy (C-ion RT) with immune checkpoint inhibitors (ICIs) in patients with advanced HCC with MVI.MethodsFifteen patients with MVI-positive advanced HCC were enrolled (Cohort A: durvalumab monotherapy, n = 3; Cohort B: durvalumab plus tremelimumab, n = 12). C-ion RT (60 Gy, four fractions) was delivered to the MVI-containing primary tumor, while systemic therapy with durvalumab (+tremelimumab) was administered concurrently. The primary endpoints included dose-limiting toxicities and adverse events. Secondary endpoints included progression-free survival and overall survival.ResultsNo dose-limiting toxicities were observed, and the combination exhibited a manageable safety profile. The most common adverse events were pyrexia, rash, and elevated lipase levels. Grade 3–4 adverse events occurred in 53.3%, including cytokine release syndrome and meningitis. Median progression-free survival and overall survival were 4.7 and 10.4 months, respectively. Although C-ion RT achieved effective local control of irradiated lesions, non-irradiated lesions showed limited systemic immune responses.ConclusionsThe combination of MVI-targeted C-ion RT and immune checkpoint inhibitors demonstrated safe and effective local tumor control in advanced HCC. This novel approach of selective irradiation to MVI-containing tumors, combined with systemic immunotherapy, warrants further investigation to optimize the synergistic effects and enhance systemic efficacy in this poor-prognosis group.Impact and implicationsAdvanced hepatocellular carcinoma with macrovascular invasion (MVI) has a poor prognosis, highlighting the need for new therapeutic strategies. Our phase Ib study suggests that carbon-ion radiotherapy targeting MVI combined with immune checkpoint inhibitors is feasible and achieves sustained local tumor control. RNA-sequencing revealed that immune activation pathways were enriched in responders, while resistance was associated with mesenchymal and angiogenesis signatures. These results reinforce the potential of MVI-targeted irradiation combined with immune checkpoint inhibitors as a promising treatment strategy for these high-risk patients, warranting further investigation to improve systemic tumor control.Clinical Trials RegistrationjRCT2031210046.

International audience

<h2>Abstract</h2> Steatotic liver disease (SLD) is a spectrum of highly prevalent liver disease that is encountered at many different healthcare levels. Awareness about metabolic dysfunction-associated SLD (MASLD), MetALD (MASLD and increased alcohol intake) and ALD (alcohol-related liver disease) is increasing beyond hepatology, as highlighted by the various SLD guidelines that have been issued by scientific societies from different disciplines, such as endocrinology. The guidance presented here aims to improve cross-disciplinary knowledge and know-how by providing guidance to healthcare professionals from a global, holistic, multi-society and -stakeholder perspective. The patient trajectory was used as an overarching anchor point to ensure uniform guidance at all points along the SLD spectrum, with the ultimate goal of improving patient identification and optimising their care. This consensus guidance covers patient identification and risk stratification, relevant cross-disciplinary primary and secondary care approaches, referral to and from tertiary care and strategies for disease management and monitoring. Strategies at each point of the patient trajectory are recommended and stratified as optimal (i.e., "nice-to-have") or minimal (i.e., "must-have"), per expert-opinion, making them adaptable to differences in healthcare settings, levels of resource availability and policies.