Clinical Efficacy of immunotherapy in combination of locoregional therapies for advanced hepatocellular carcinoma: A Systematic Review and Meta-Analysis

Xinyue Chen¹Mohan Huang¹Ranran Liu²Lawrence Wing Chi Chan^1*

• ¹Health Technology and Informatics, Hong Kong Polytechnic University, Kowloon, Hong Kong, SAR China
• ²School of Nursing, Hong Kong Polytechnic University, Kowloon, Hong Kong, SAR China

Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is the leading cause of cancer-related deaths worldwide. The majority of HCC patients are diagnosed at an advanced stage, resulting in limited treatment options. In recent years, numerous clinical trials have confirmed that immunotherapy, particularly anti-programmed cell death 1 (anti-PD-1)/programmed cell death ligand 1 (PD-L1), has emerged as a promising treatment for advanced HCC. However, in real-world practice, the clinical efficacy of adding immunotherapy to locoregional therapies remains unknown, representing a knowledge gap. Aims: This meta-analysis aims to evaluate the clinical efficacy of immunotherapy combined with locoregional therapies, including TACE, HAIC, and HAIC/TACE combined with targeted agents, versus locoregional therapies alone in advanced HCC patients. Methods: Eligible studies were identified by searching Embase, PubMed, Cochrane Library, and Web of Science. The clinical outcomes were overall survival(OS), progression-free survival(PFS), disease control rate(DCR), objective response rate(ORR), and adverse events(AEs). Pooled hazard ratios (HRs), odds ratios, meta-regression were used to estimate clinical outcomes. Quality assessments were performed using the Newcastle-Ottawa Quality Assessment Form. The funnel plot was used for detecting publication bias. Results: Nineteen cohort studies with 3720 advanced HCC patients were included. Immunotherapy-added group was superior in prolonging OS (HR=0.36, 95% CI [0.29,0.46] and p<0.001), PFS (HR=0.41, 95% CI[0.31,0.54] and p<0.001), DCR (OR=2.17, 95% CI [1.80, 2.62], p<0.001), and ORR (OR=1.85, 95% CI[1.62, 2.12], p<0.001). The immunotherapy-added group had a higher risk of developing grade>=3 AEs as compared to locoregional-only therapy group (OR 1.26, 95% CI [1.06,1.49], p=0.009). Pooled results also indicated an increased risk of fatigue (OR=1.17, P=0.04), pneumonitis (OR=2.97, P<0.01), and myocarditis (OR=9.08, P=0.01) in the immunotherapy‑added group. Conclusions: This meta-analysis compared the clinical outcomes of locoregional therapies versus immunotherapy plus locoregional therapies. This study found that adding immunotherapy was associated with improved overall survival, progression-free survival, disease control rate, and objective response rate in patients with advanced HCC compared with those treated with locoregional regimens alone. Meanwhile, the addition of immunotherapy may be associated with an increased risk of grade ≥3 adverse events and specific immune-related adverse events in patients with advanced hepatocellular carcinoma.