# Clinical efficacy of immunotherapy in combination of locoregional therapies for advanced hepatocellular carcinoma: a systematic review and meta-analysis

## TL;DR

Adding immunotherapy to local treatments for advanced liver cancer improves survival and response rates but increases serious side effects.

## Contribution

This study provides the first comprehensive meta-analysis on combining immunotherapy with locoregional therapies for advanced hepatocellular carcinoma.

## Key findings

- Immunotherapy added to locoregional therapies significantly improved overall and progression-free survival in advanced HCC patients.
- The combination therapy increased disease control and objective response rates compared to locoregional therapies alone.
- The addition of immunotherapy was linked to a higher risk of severe adverse events and immune-related side effects.

## Abstract

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 patients with HCC 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.

This meta-analysis aims to evaluate the clinical efficacy of immunotherapy combined with locoregional therapies, including transarterial chemoembolization (TACE), hepatic artery infusion chemotherapy (HAIC), and HAIC/TACE combined with targeted agents, versus locoregional therapies alone in patients with advanced HCC.

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 (ORs), and 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.

Nineteen cohort studies with 3,720 patients with advanced HCC were included. The immunotherapy-added group was superior in prolonging OS [HR = 0.36, 95% confidence interval (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 the 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.

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 OS, PFS, DCR, and ORR 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 AEs and specific immune-related AEs in patients with advanced HCC.

https://www.crd.york.ac.uk/PROSPERO/recorddashboard, identifier CRD420251039316.