Refining Prognosis and Treatment Strategies Beyond the Barcelona Clinic Liver Cancer Stage in Hepatocellular Carcinoma with Lung Metastases: A Multicenter Cohort Study

Abstract

Lung metastasis is the most common site of extrahepatic spread in hepatocellular carcinoma (HCC) and is associated with significantly poorer outcomes. Current guidelines classify these patients as Barcelona Clinic Liver Cancer (BCLC) stage C, recommending systemic therapy alone. However, this one-size-fits-all approach may overlook potential benefits in selected patients. In this multicenter cohort study of 1203 HCC patients—including 119 with lung metastases—we evaluated prognostic factors and treatment outcomes. Lung metastasis significantly reduced overall survival, both before and after propensity score matching. However, among patients with early-stage intrahepatic tumors, curative locoregional treatments such as hepatectomy or radiofrequency ablation improved survival and led to outcomes comparable to those without metastasis. Systemic therapies including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) prolonged survival, and combination regimens yielding the greatest benefit. Interestingly, lung metastases impaired intrahepatic response to systemic monotherapy, but this effect was mitigated by combining TKIs with ICIs. These findings suggest that a subset of HCC patients with lung metastases may benefit from individualized, multimodal treatment strategies, challenging the current staging framework and supporting a more refined, personalized therapeutic approach in this population.