Integrating overall survival and health-related quality of life to prioritize first-line systemic therapies for unresectable advanced gastric cancer: a network meta-analysis.

Purpose: This study aimed to compare the effects of various first-line systemic therapies on health-related quality of life (HR-QoL) in patients with unresectable advanced gastric cancer (GC), and to comprehensively integrate survival benefits and HR-QoL outcomes associated with different treatments. Methods: A systematic literature search was conducted in the MEDLINE, CENTRAL and Scopus databases for studies published from database inception to December 2025. Manual retrieval of reference lists and abstracts from major oncology conferences held between 2016 and 2025 was performed as supplementary screening. Eligible studies were phase III randomized controlled trials (RCTs) that compared immune checkpoint inhibitors or targeted agents with platinum-based chemotherapy as first-line regimens for advanced GC and reported data on HR-QoL deterioration. Time to deterioration (TTD) of HR-QoL domains was assessed using the EORTC QLQ-C30, EORTC QLQ-STO22 and EQ-5D questionnaires. The surface under the cumulative ranking curve (SUCRA) was applied to rank all included treatments based on HR-QoL indicators. We further performed an exploratory composite analysis integrating overall-survival and HR-QoL outcomes via the minimum distance criterion. Results: In total, 10 RCTs enrolling over 8000 patients and covering six HR-QoL domains met the inclusion criteria. SUCRA analyses indicated that trastuzumab and tislelizumab had the lowest probability of the deterioration of global health status, physical function, nausea/vomiting, appetite loss and pain. When HR-QoL was combined with overall survival (OS) via an exploratory minimum distance criterion composite analysis, trastuzumab and tislelizumab showed favorable comprehensive performance across most evaluated domains. This composite metric remains exploratory without established uncertainty estimates and should not serve as primary evidence for clinical decision-making. Conclusions: This network meta-analysis suggests that trastuzumab (for HER2-positive disease) and tislelizumab (for largely biomarker-unselected populations) deliver the balance between HR-QoL preservation and OS benefit within their respective biomarker-eligible patient subgroups among systemic treatment options for unresectable advanced GC. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420261422326.