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Efficacy and safety of immune checkpoint inhibitors for hepatocellular carcinoma patients with macrovascular invasion or extrahepatic spread: a systematic review and meta-analysis of 54 studies with 6187 hepatocellular carcinoma patients

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Abstract

Background and aims

The impacts of macrovascular invasion (MVI) or extrahepatic spread (EHS) on the efficacy and safety of immune checkpoint inhibitors (ICIs) among hepatocellular carcinoma (HCC) patients remain unclear. Thus, we conducted a systematic review and meta-analysis to clarify whether ICI therapy is a feasible treatment option for HCC with MVI or EHS.

Methods

Eligible studies published before September 14, 2022, were retrieved. In this meta-analysis, the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and occurrence of adverse events (AEs) were outcomes of interest.

Results

Fifty-four studies involving 6187 individuals were included. The findings indicated that the presence of EHS in ICI-treated HCC patients may indicate an inferior ORR (OR 0.77, 95% CI 0.63–0.96), but may not significantly affect the PFS (multivariate analyses: HR 1.27, 95% CI 0.70–2.31) and OS (multivariate analyses: HR 1.23, 95% CI 0.70–2.16). Additionally, the presence of MVI in ICI-treated HCC patients may not have significant prognostic impact on ORR (OR 0.84, 95% CI 0.64–1.10), but may indicate inferior PFS (multivariate analyses: HR 1.75, 95% CI 1.07–2.84) and OS (multivariate analyses: HR 2.03, 95% CI 1.31–3.14). The presence of EHS or MVI in ICI-treated HCC patients may not significantly impact the occurrence of any serious immune-related adverse events (irAEs) (grades ≥ 3) (EHS: OR 0.44, 95% CI 0.12–1.56; MVI: OR 0.68, 95% CI 0.24–1.88).

Conclusion

The presence of MVI or EHS in ICI-treated HCC patients may not significantly impact the occurrence of serious irAEs. However, the presence of MVI (but not EHS) in ICI-treated HCC patients may be a significant negative prognostic factor. Therefore, ICI-treated HCC patients with MVI warrant more attention.

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Abbreviations

AEs:

Adverse events

CI:

Confidence intervals

CTLA-4:

Cytotoxic T lymphocyte-associated protein 4

EHS:

Extrahepatic spread

HCC:

Hepatocellular carcinoma

HR:

Hazard ratios

ICIs:

Immune checkpoint inhibitors

irAEs:

Immune-related adverse events

MVI:

Macrovascular invasion

NOS:

Newcastle–Ottawa Scale

OR:

Odds ratio

ORR:

Objective response rate

OS:

Overall survival

PD-1:

Programmed cell death 1

PD-L1:

Programmed cell death ligand-1

PFS:

Progression-free survival

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analysis

PVTT:

Portal vein tumor thrombus

RoB2:

Risk of bias tool 2.0

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Funding

This work was supported by the grants from the Taishan Scholars Program of Shandong Province (Grant No. tstp20221158), National Natural Science Foundation of China (Grant Nos. 82073200 and 81874178), Major basic research of Shandong Provincial Natural Science Foundation (Grant No. ZR2021ZD26) and funds for Independent Cultivation of Innovative Team from Universities in Jinan (Grant No. 2020GXRC023).

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Author notes

  1. Tao Li

    Present address: Department of General Surgery, Qilu Hospital, The Second Hospital of Shandong University, 107 West Wen Hua Road, Jinan, 250012, People’s Republic of China

  2. Cheng Long Han and Bao Wen Tian have contributed equally as first author.

Authors and Affiliations

  1. Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250012, People’s Republic of China

    Cheng-Long Han, Bao-Wen Tian, Lun-Jie Yan, Zi-Niu Ding, Hui Liu, Xin-Cheng Mao, Jin-Cheng Tian, Jun-Shuai Xue, Si-Yu Tan, Zhao-Ru Dong, Yu-Chuan Yan, Jian-Guo Hong, Zhi-Qiang Chen & Dong-Xu Wang

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Contributions

CL–H, BW-T, and T-L designed the meta-analysis. CL–H, BW-T, and T-L conducted the systematic search of relevant articles. CL–H, BW-T, LJ-Y, ZN-D, and T-L determined eligible studies and evaluated the study quality. CL–H, BW-T, H–L, XC-M, and JC-T extracted eligible data from the manuscript and supplementary materials of all original articles. CL–H, BW-T, JS-X, SY-T, ZR-D, and YC-Y analyzed, interpreted the data. CL–H, BW-T, and JG-H drafted this manuscript. CL–H, BW-T, ZQ-C, DX-W, and LT revised this manuscript. All authors have assessed and approved the final version of this manuscript.

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Correspondence to Tao Li.

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Han, CL., Tian, BW., Yan, LJ. et al. Efficacy and safety of immune checkpoint inhibitors for hepatocellular carcinoma patients with macrovascular invasion or extrahepatic spread: a systematic review and meta-analysis of 54 studies with 6187 hepatocellular carcinoma patients. Cancer Immunol Immunother 72, 1957–1969 (2023). https://doi.org/10.1007/s00262-023-03390-x

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