Psychological and quality of life outcomes associated with multikinase inhibitors versus immune checkpoint inhibitors in advanced hepatocellular carcinoma.

To compare the effects of multikinase inhibitors (sorafenib/lenvatinib) and immune checkpoint inhibitors (PD-1/PD-L1) on anxiety, depression, and quality of life (QoL) in patients with advanced hepatocellular carcinoma (HCC) and to analyse their correlations with clinical indicators. This retrospective cohort study included 304 patients with advanced HCC (BCLC stage B/C) who received first-line monotherapy between 2018 and 2023. Propensity score matching (1:1) was used to categorize patients into two groups: those treated with multikinase inhibitors (n = 152) and those treated with PD-1/PD-L1 inhibitors (n = 152). Anxiety and depression (Hospital Anxiety and Depression Scale (HADS)), and QoL (EORTC QLQ-C30) were assessed at baseline and during follow-up (every 3 months). Correlations between the treatment duration, survival outcomes, and adverse events (AEs) were analysed. The PD-1/PD-L1 group presented significant reductions in anxiety (HADS-A: mean difference [MD] = - 2.4) and depression (HADS-D: MD = - 2.3) at 6 months (both *p < 0.001), with lower rates of clinically significant anxiety (28.3% vs. 42.1%) and depression (24.3% vs. 38.8%; p < 0.05). QoL improved markedly (6-month MD = + 10.3, p < 0.001), particularly when the treatment was administered as the first-line therapy (MD = + 14.2 vs. second-line MD = + 3.8; interaction p < 0.001). PD-1/PD-L1 inhibitors were associated with longer treatment durations (median 9.5 vs. 5.8 months, p < 0.001) and superior overall survival (median 18.2 vs. 12.5 months; HR = 0.62, p = 0.002). Fatigue (grade ≥ 2) independently predicted depression (OR = 1.82, p = 0.002), whereas immune-related AEs were correlated with a reduced QoL (ρ=-0.22, p = 0.004). Compared with multikinase inhibitors, PD-1/PD-L1 inhibitors significantly improve the psychological outcomes, QoL, and survival of patients with advanced HCC, especially when administered as first-line therapies. Fatigue is a critical modifiable risk factor for depression. These findings support prioritizing immunotherapy when treating atients with advanced hepatocellular carcinoma.