Risk factors for immune-mediated hepatotoxicity in patients with cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis

ABSTRACT

Introduction

Immune checkpoint inhibitors (ICIs) are effective for the treatment of various cancers, but can lead to immune-mediated hepatotoxicity (IMH). The aim of this study was to analyze the risk factors for IMH in cancer patients treated with ICIs.

Areas covered

The PubMed, EMBASE, and Cochrane Library databases were searched. Eligible studies should compare the difference between patients who developed and did not develop IMH. Odds ratio (OR) and weighted mean difference (WMD) with 95% confidence interval (CI) were calculated.

Expert opinion

Among the 5030 papers initially identified, 13 studies were included. Meta-analyses indicated that age (WMD: −5.200, 95%CI: −7.481 to −2.919), history of ICIs treatment (OR: 4.491, 95%CI: 2.205 to 9.145), ICIs combination therapy (OR: 5.353, 95%CI: 1.663 to 17.232), and aspartate aminotransferase (AST) level (WMD: 5.039, 95%CI: 1.220 to 8.857) were significantly associated with the risk of any grade IMH; and age (WMD: −5.193; 95%CI: −9.669 to −0.718) was significantly associated with the risk of grade ≥3 IMH. These findings provide the evidence for identifying patients at a high risk of IMH. Appropriate intervention may be given to prevent from IMH in high-risk patients, thereby enabling ICIs to achieve an expected tumor response.

PLAIN LANGUAGE SUMMARY

At present, immune checkpoint inhibitors (ICIs) are one of the most important treatment choices for cancer. ICIs can enhance the antitumor response by inhibiting the immune checkpoint pathway. The immune checkpoint pathways include CTLA-4 pathway and PD-1 pathway, which inhibit the activation of the immune system. Among them, CTLA-4 pathway stops potentially autoreactive T-cell at the initial stage of T-cell activation, and the PD-1 pathway regulates activated T-cell at the later stage of an immune response. However, excessively enhanced immune activity may cause immune cells to attack health organs like the liver, developing immune-mediated hepatotoxicity (IMH), which may affect the tumor response of ICIs. Therefore, it is crucial to explore the risk factors for IMH in cancer patients treated with ICIs. We searched 3 medical databases: PubMed, EMBASE, and Cochrane Library, and then the studies that evaluated the difference between patients who developed and did not develop IMH were included in our systematic review and meta-analysis. The meta-analyses showed younger patients, patients with history of ICIs treatment, patients who had ICIs combination therapy, and patients with higher liver enzyme AST levels were more likely to develop IMH. Therefore, doctors should pay more attention to the patients at high-risk for IMH with the goal of improving the chances that they achieve a good response from their ICIs therapy.

KEYWORDS:

• Cancer
• Clinical features
• Immune checkpoint inhibitors
• Immune-mediated hepatotoxicity
• Risk factors

Article highlights

• The incidence of any grade immune-mediated hepatotoxicity (IMH) and grade ≥3 IMH is about 18% and 6% in cancer patients treated with immune checkpoint inhibitors (ICIs), respectively.

• IMH often develops about 50 days after the first ICIs treatment, and can lead to the treatment discontinuation of ICIs in about 13% of patients.

• Young age, history of ICIs treatment, ICIs combination therapy, and high AST level are risk factors for IMH in cancer patients treated with ICIs.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

All authors have made an intellectual contribution to the manuscript and approved the submission.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2022.2134854

Additional information

Funding

This paper was not funded.