Integrating Quality of Life and Survival in Systemic Therapy for Advanced Hepatocellular Carcinoma

Importance: Multiple immunotherapy-based combinations and tyrosine kinase inhibitors are approved for first-line treatment of unresectable or advanced hepatocellular carcinoma (HCC). While overall survival remains the primary efficacy end point, health-related quality of life (HR-QoL) represents a crucial complementary outcome that has not been comprehensively compared across available treatments. Objective: To compare the HR-QoL effects associated with different first-line treatments for unresectable or advanced HCC and to integrate treatment-induced survival benefit with impact on patients' HR-QoL. Data Sources: The MEDLINE, CENTRAL, and Scopus databases were systematically searched for studies published from inception through November 2024. The search was supplemented with manual reviews of reference lists and abstracts from main oncology conferences from the past 5 years (2020-2024). Study Selection: Phase 3 randomized clinical trials comparing tyrosine kinase inhibitor monotherapy to immune checkpoint inhibitor-based therapies in first-line advanced HCC and reporting HR-QoL deterioration were included. Data Extraction and Synthesis: Study selection and data extraction were performed by 2 independent reviewers, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Cochrane Collaboration tool was used to assess risk of bias. A bayesian network meta-analysis was performed using sorafenib as the comparator. Main Outcomes and Measures: Time to deterioration of HR-QoL domains were assessed using the European Organization for Research and Treatment of Cancer's Quality-of-Life Questionnaire Core 30 and HCC18. Treatment ranking was calculated using surface under the cumulative ranking (SUCRA) for HR-QoL items. Results: Seven HR-QoL items from 9 randomized clinical trials enrolling 6425 patients met inclusion criteria. SUCRA calculations showed that atezolizumab plus bevacizumab had the highest probability of reducing deterioration of global health status and QoL (85%), abdominal swelling (95%), jaundice (89%), and pain (86%). When integrating HR-QoL with overall survival, atezolizumab plus bevacizumab outperformed all other treatments across all items. Conclusions and Relevance: This network meta-analysis found that atezolizumab plus bevacizumab provides the best balance between QoL preservation and overall survival benefit compared to other systemic therapy options in unresectable or advanced HCC. This integrated assessment of survival and quality of life outcomes offers a more patient-centered approach for treatment selection in clinical practice.