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Adverse events of immune checkpoint inhibitors in hepatocellular carcinoma: a systemic review and meta-analysis

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Abstract

The introduction of immune checkpoint inhibitors (ICIs) has reshaped the therapy of hepatocellular carcinoma (HCC). ICIs are a novel therapy with frequent adverse events (AEs), including treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). However, no comprehensive overview of the toxicity spectrum of ICIs in HCC patients has been provided. Electronic databases were searched to identify eligible studies. A meta-analysis of the incidence rate of AEs in HCC patients treated with ICIs was performed. Lastly, the prognostic value of irAEs in HCC patients treated with ICIs was verified. Forty-seven studies with 6472 participations met the inclusion criteria. The pooled all-grade trAEs incidence rate was 83.4% (95% confidence interval [95% CI] 77.0–89.1%), ≥ grade 3 trAEs incidence rate was 33.0% (95% CI 26.9–39.5%), all-grade irAEs incidence rate was 34% (95% CI 22–47%), and ≥ grade 3 irAEs incidence rate was 9% (95% CI 5–14%). Aspartate aminotransferase (AST) increase (38%, 95% CI 35–40%) is the most common trAEs. Fatigue (14%, 95% CI 7–23%) is the most common irAEs. The pooled results also showed that 18.8% (95% CI 13.2–25.2%) of patients required systemic steroid therapy due to AEs, while 6.6% (95% CI 4.6–9.0%) of patients withdrew from treatment due to AEs. Additionally, patients experiencing irAEs may have a better progression-free survival (PFS) (multivariate analysis: hazard ratio [HR] = 0.41, 95% CI 0.27–0.61, I2 = 36.3%) but not overall survival (OS) (multivariate analysis: HR = 0.54, 95% CI 0.22–1.36, I2 = 83.2%) than those with no irAEs. Our study presents a systemic assessment of the AEs profile in HCC patients receiving ICIs, providing important reference for clinicians on toxicity profile. Besides, patients with irAEs may have a better PFS. More large-scale and prospective studies are needed to confirm our conclusions.

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Abbreviations

ICIs:

Immune checkpoint inhibitors

HCC:

Hepatocellular carcinoma

AEs:

Adverse events

trAEs:

Treatment-related adverse events

irAEs:

Immune-related adverse events

95% CI:

95% Confidence interval

HR:

Hazard ratio

AST:

Aspartate aminotransferase

PFS:

Progression-free survival

OS:

Overall survival

aHCC:

Advanced hepatocellular carcinoma

PD-1:

Programmed cell death-1

PD-L1:

Programmed cell death ligand-1

CTLA-4:

Cytotoxic T lymphocyte-associated protein-4

VEGF:

Vascular endothelial growth factor

NSCLC:

Non-small cell lung carcinoma

RCT:

Randomized control trial

ORR:

Objective response rate

DCR:

Disease control rate

RECIST:

Response evaluation criteria in solid tumors

mRECIST:

Modified response evaluation criteria in solid tumors

CTCAE:

Common terminology criteria for adverse events

ALT:

Alanine aminotransferase

ECOG:

Eastern Cooperative Oncology Group

Tregs:

Regulatory T cells

Th1:

CD4 + helper T cells 1

IL-6/17:

Interleukin-6/17

Th-17:

T helper cell 17

HPD:

Hyperprogressive disease

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Funding

This work was supported by the grants from the Taishan Scholars Program of Shandong Province, National Natural Science Foundation of China (Grant Nos. 82073200, 81874178), major basic research of Shandong Provincial Natural Science Foundation (Grant No. ZR202105070027), and funds for Independent Cultivation of Innovative Team from Universities in Jinan (Grant No. 2020GXRC023).

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Authors and Affiliations

  1. Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China

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

  2. Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, No. 247 Beiyuan Street, Jinan, 250033, China

    Tao Li

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  1. Jin-Cheng Tian
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Contributions

JCT, HL, and TL designed the study; JCT, LJY, and ZND contributed to data search from databases; HL, LJY, and ZND formulated inclusion criteria; JCT, HL, JSX, XCM, and YCY selected eligible studies; JCT, CLH, BWT, SYT, ZRD, DXW, XCM, and YCY acquired, analyzed, or interpreted data; JCT and HL assessed study quality and wrote the manuscript; TL resolved differences and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Tao Li.

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Jin-Cheng Tian and Hui Liu have contributed equally to this paper.

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Tian, JC., Liu, H., Yan, LJ. et al. Adverse events of immune checkpoint inhibitors in hepatocellular carcinoma: a systemic review and meta-analysis. Clin Exp Med 23, 2115–2129 (2023). https://doi.org/10.1007/s10238-022-00938-6

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