Thyroid-related Adverse Events Caused by Immune Checkpoint Inhibitors Associated with Therapeutic Outcomes in Cancer Patients: a systematic review and meta-analysis

Abstract

Introduction: The development of immune checkpoint inhibitors (ICIs) marked a revolutionary milestone in the immunotherapy of cancers. Although ICIs have shown survival benefits and potential clinical prospects, these drugs also triggered a myriad of autoimmune side effects, termed immune-related adverse events (irAEs). Notably, thyroid-related adverse events (AEs) are one of the most common immune-related adverse events (irAEs) in immunotherapy, also frequently with the clinical consequences for the patients. It need a consequent analysis to tell the difference between the general thyrotoxicosis and the thyroid irAEs. As the association between side effects caused by ICIs and survival outcomes of cancer patients remains unknown, we performed a meta-analysis to evaluate the thyroid-related AEs and ICI effects on the prognosis of cancer patients. Material and method: The aim of this meta-analysis was to assess the effect of thyroid irAEs on the prognosis of cancer patients treated with ICIs. A literature search of published articles related to thyroid-related AEs in patients with ICI therapy was conducted in PubMed, Embase, and Medline on May 2, 2022. Revman software were used to assess the quality or risk of bias of included studies, and Stata software for the effect size measures to be pooled. The hazard ratios (HR) were used to assess the correlation between thyroid-related AEs and the overall survival (OS) and progression-free survival (PFS) with ICI therapy. Subgroup analyses were performed for the impact of thyroid-related AEs by a type of cancer and a PD-(L)1 monotherapy. Heterogeneity and publication bias were also assessed by Begg’s funnel plot. Result: A total of 28 studies and 29 cohorts comprising 17058 patients were included in this meta-analysis. All the studies are low level in the risk of bias and have over 50 cases in the sample sizes. Compared to the non-irAEs in the thyroid, the occurrence of thyroid-related AEs was significantly related to improved OS (HR: 0.51; 95% CI: 0.44-0.60; P < 0.01) and PFS (HR: 0.56; 95% CI: 0.47-0.66; P < 0.01). In addition, our subgroup analysis suggested that patients with NSCLC had a better survival benefit in terms of OS (HR: 0.41; 95% CI: 0.35–0.48; P <0.01) and PFS (HR: 0.57; 95% CI: 0.49–0.66; P <0.01) when treated with ICI therapy when developing thyroid-related AEs. Under the PD-(L)1 monotherapy, it also showed a better OS and PFS of patients with different cancers or a single NSCLC. Conclusion: The results indicated a significant correlation between thyroid-related AEs and improved survival outcomes for cancer patients with ICI therapy, especially for NSCLC. However melanoma have not shown a positive relation with the occurrence of thyroid irAEs. For other malignances, thyroid-related AEs might be a predictive factor for ICI efficacy.