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.

Keywords

hepatocellular carcinoma / hepatectomy / immune checkpoint inhibitors / lung metastasis / prognostic factors / radiofrequency ablation

References

[1] Z. J. Brown, D. I. Tsilimigras, S. M. Ruff, et al., “Management of Hepatocellular Carcinoma: A Review,” JAMA Surgery 158, no. 4 (2023): 410-420.

[2] A. Vogel, T. Meyer, G. Sapisochin, R. Salem, and A. Saborowski. Hepatocellular carcinoma. Lancet (London, England) 400, no. 10360 (2022): 1345-1362.

[3] F. Xia, Q. Zhang, G. Xia, et al., “A Pathologic Scoring System for Predicting Postoperative Prognosis in Patients With Ruptured Hepatocellular Carcinoma,” Asian Journal of Surgery 47, no. 7 (2024): 3015-3025.

[4] C. Bosi, M. Rimini, A. Casadei-Gardini, and E. Giorgio, “Understanding the Causes of Recurrent HCC After Liver Resection and Radiofrequency Ablation,” Expert Review of Anticancer Therapy 23, no. 5 (2023): 503-515.

[5] H. Wang, J. Huang, W. Zhang, et al., “Prognostic factors in patients with first diagnosis of hepatocellular carcinoma presenting with pulmonary metastasis and construction of a clinical prediction model,” Updates in Surgery 76, no. 1 (2024): 71-85.

[6] J. Feng, Y. He, J. Wan, and Z. Chen, “Pulmonary Metastases in Newly Diagnosed Hepatocellular Carcinoma: A Population-based Retrospective Study,” HPB: the Official Journal of the International Hepato Pancreato Biliary Association 22, no. 9 (2020): 1295-1304.

[7] M. Reig, A. Forner, J. Rimola, et al., “BCLC Strategy for Prognosis Prediction and Treatment Recommendation: The 2022 Update,” Journal of Hepatology 76, no. 3 (2022): 681-693.

[8] G. Shao, Y. Zhi, Z. Fan, W. Qiu, and G. Lv, “Development and Validation of a Diagnostic and Prognostic Model for Lung Metastasis of Hepatocellular Carcinoma: A Study Based on the SEER Database,” Frontiers in Medicine 10 (2023): 1171023.

[9] C. Wu, X. Ren, and Q. Zhang, “Incidence, Risk Factors, and Prognosis in Patients With Primary Hepatocellular Carcinoma and Lung Metastasis: A Population-based Study,” Cancer Management and Research 11 (2019): 2759-2768.

[10] Y. Takahashi, N. Ikeda, J. Nakajima, et al., “Prognostic Analysis of Surgical Resection for Pulmonary Metastasis From Hepatocellular Carcinoma,” World Journal of Surgery 40, no. 9 (2016): 2178-2185.

[11] C. M. Lam, C. M. Lo, W. K. Yuen, C. L. Liu, and .F. ST, “Prolonged Survival in Selected Patients Following Surgical Resection for Pulmonary Metastasis From Hepatocellular Carcinoma,” The British Journal of Surgery 85, no. 9 (1998): 1198-1200.

[12] S. Arora, C. Harmath, R. Catania, A. Mandler, K. J. Fowler, and A. A. Borhani. “Hepatocellular Carcinoma: Metastatic Pathways and Extra-hepatic Findings,” Abdominal Radiology (New York) 46, no. 8 (2021): 3698-3707.

[13] Y. Zhao, Y. Jia, J. Wang, et al., “circNOX4 activates an Inflammatory Fibroblast Niche to Promote Tumor Growth and Metastasis in NSCLC via FAP/IL-6 Axis,” Molecular Cancer 23, no. 1 (2024): 47.

[14] K. Schütte, R. Schinner, M. P. Fabritius, et al., “Impact of Extrahepatic Metastases on Overall Survival in Patients With Advanced Liver Dominant Hepatocellular Carcinoma: A Subanalysis of the SORAMIC Trial,” Liver Cancer 9, no. 6 (2020): 771-786.

[15] A. Abbas, S. Medvedev, N. Shores, et al., “Epidemiology of Metastatic Hepatocellular Carcinoma, a Nationwide Perspective,” Digestive Diseases and Sciences 59, no. 11 (2014): 2813-2820.

[16] S. Chen, X. Li, Y. Liang, et al., “Short-term Prognosis for Hepatocellular Carcinoma Patients With Lung Metastasis: A Retrospective Cohort Study Based on the SEER Database,” Medicine 101, no. 45 (2022): e31399.

[17] S. Shan and J. Jia, “The Clinical Management of Hepatocellular Carcinoma in China: Progress and Challenges,” Clinical and Molecular Hepatology 29, no. 2 (2023): 339-341.

[18] C. H. Zhang, Y. Cheng, S. Zhang, J. Fan, and Q. Gao, “Changing Epidemiology of Hepatocellular Carcinoma in Asia,” Liver International: Official Journal of the International Association for the Study of the Liver 42, no. 9 (2022): 2029-2041.

[19] K. N. Han, Y. T. Kim, J. H. Yoon, et al., “Role of Surgical Resection for Pulmonary Metastasis of Hepatocellular Carcinoma,” Lung Cancer (Amsterdam, Netherlands) 70, no. 3 (2010): 295-300.

[20] K. Kitano, T. Murayama, M. Sakamoto, et al., “Outcome and Survival Analysis of Pulmonary Metastasectomy for Hepatocellular Carcinoma,” European Journal of Cardio-Thoracic Surgery : Official Journal of the European Association for Cardio-Thoracic Surgery 41, no. 2 (2012): 376-382.

[21] Y. S. Yoon, H. K. Kim, J. Kim, et al., “Long-term Survival and Prognostic Factors After Pulmonary Metastasectomy in Hepatocellular Carcinoma,” Annals of Surgical Oncology 17, no. 10 (2010): 2795-2801.

[22] S. M. Jung, J. W. Jang, C. R. You, et al., “Role of Intrahepatic Tumor Control in the Prognosis of Patients With Hepatocellular Carcinoma and Extrahepatic Metastases,” Journal of Gastroenterology and Hepatology 27, no. 4 (2012): 684-689.

[23] J. I. Lee, J. K. Kim, D. Y. Kim, et al., “Prognosis of Hepatocellular Carcinoma Patients With Extrahepatic Metastasis and the Controllability of Intrahepatic Lesions,” Clinical & Experimental Metastasis 31, no. 4 (2014): 475-482.

[24] J. Wu, P. Zhu, Z. Zhang, et al., “A New Tumor-associated Antigen Prognostic Scoring System for Spontaneous Ruptured Hepatocellular Carcinoma After Partial Hepatectomy,” Cancer Biology & Medicine 15, no. 4 (2018): 415-424.

[25] Z. Hu, P. Huang, Z. Zhou, et al., “Aggressive Intrahepatic Therapies for Synchronous Hepatocellular Carcinoma With Pulmonary Metastasis,” Clinical & Translational Oncology: Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 20, no. 6 (2018): 729-739.

[26] C. Hu, J. Yang, Z. Huang, et al., “Diagnostic and Prognostic Nomograms for Bone Metastasis in Hepatocellular Carcinoma,” BMC Cancer 20, no. 1 (2020): 494.

[27] X. Guo, Y. Xu, X. Wang, et al., “Advanced Hepatocellular Carcinoma With Bone Metastases: Prevalence, Associated Factors, and Survival Estimation,” Medical Science Monitor: International Medical Journal of Experimental and Clinical Research 25 (2019): 1105-1112.

[28] F. Xia, Z. Huang, Q. Zhang, et al., “Clinically Significant Portal Hypertension (CSPH) on Early-stage HCC Following Hepatectomy: What's the Impact?,” European Journal of Surgical Oncology: The Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 49, no. 4 (2023): 771-779.

[29] K.-J. Chu, Y. Kawaguchi, and K. Hasegawa, “Current use of intraoperative ultrasound in modern liver surgery,” Oncology and Translational Medicine 9, no. 4 (2023): 168-175.

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