Radiotherapy and immunotherapy for advanced cancers: A meta-analysis of dose, sequencing, and survival patterns

BACKGROUND: Combining radiotherapy (RT) with immune checkpoint inhibitors (ICIs) offers potential synergy through RT-induced immunogenic cell death and enhanced systemic immunity. However, optimal RT dose, fractionation, and sequencing with ICIs remain unresolved. This meta-analysis evaluates the impact of biologically effective dose (BED), treatment timing, and ICI agents on progression-free survival (PFS) and safety in advanced cancers. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane Library (2010-2024) identified 18 studies (727 patients). Pooled PFS and treatment-related adverse events (TRAEs) were analyzed using random-effects models. Subgroup analyses stratified outcomes by cancer type, RT regimen, BED (low: ≤50; moderate: 50-100; high: >100), treatment sequence (concurrent/sequential), and ICI agents. This study was registered on PROSPERO (CRD420251044176). RESULTS: The synthesis of PFS revealed extreme between study heterogeneity, with a wide 95% prediction interval ranging from 0.90 to 41.21 months. Despite this variance, reconstructed individual patient data suggested that moderate BED regimens between 50 and 100 showed a more favorable median PFS compared to low or high dose regimens. Concurrent administration of radiotherapy and immunotherapy demonstrated a longer reconstructed median PFS than sequential strategies. Furthermore, PD-1 and PD-L1 based regimens appeared to perform better than CTLA-4-only approaches. The pooled incidence of grade 3 or higher TRAEs was 0.22, indicating a manageable overall safety profile. CONCLUSION: This descriptive meta-analysis and reconstructed individual patient data synthesis provide hypothesis-generating insights into combined radioimmunotherapy. Concurrent administration of moderate BED radiotherapy with PD-1 and PD-L1 inhibitors suggests a plausible balance of efficacy and safety. However, extreme heterogeneity limits direct clinical application, underscoring the critical need for standardized dose protocols and rigorous sequencing in future randomized trials.