Endocrine-Related Adverse Events Related to Immune Checkpoint Inhibitors: Proposed Algorithms for Management

Abstract

Immune checkpoint inhibitors have proven to be effective for various advanced neoplasia. Immune-related adverse events (irAEs) as a result of increased T cell activation are unique and potentially life-threating toxicities associated with the use of immune checkpoint inhibitors. Multiple endocrine irAEs, including primary hyperthyroidism and hypothyroidism, thyroiditis, primary adrenal insufficiency, type 1 diabetes mellitus, and hypophysitis, have been reported with the use of various immune checkpoint inhibitors. In some cases, these irAEs can lead to discontinuation of treatment. Here we propose for the general oncologist algorithms for managing endocrine irAEs to aid in the clinical care of patients receiving immunotherapy. KEY POINTS: There is a relative high risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors, particularly when combination therapy is implemented. Patients treated with anti-CTLA-4 antibodies have an increased risk of hypophysitis, whereas patients treated with anti-PD-1/PD-L1 antibodies have a higher risk of primary thyroid dysfunction. Rarely, patients develop T1DM and central diabetes insipidus, and hypoparathyroidism is a rare occurrence. A growing clinical understanding of endocrine irAEs has led to effective treatment strategies with hormone replacement.

Figure 1

Proposed algorithm for the management of endocrine immune‐related adverse events: Hypohysitis. The National Cancer Institute has recommended that adverse events on patients with cancer chemotherapy be graded as per the Common Terminology Criteria for Adverse Events Version 5.0. Abbreviations: ACTH, adrenocorticotropic hormone; ADL, activities of daily living; free T4, free thyroxine; FSH, follicle stimulating hormone; GH, growth hormone; LH, luteinizing hormone; MRI, magnetic resonance imaging; TSH, thyroid‐stimulating hormone; WNL, within normal limits.

Figure 2

Proposed algorithm for the management of endocrine immune‐related adverse events: Adrenal insufficiency. The National Cancer Institute has recommended that adverse events on patients with cancer chemotherapy be graded as per the Common Terminology Criteria for Adverse Events Version 5.0. Abbreviations: ACTH, adrenocorticotropic hormone; i.v., intravenous.

Figure 3

Proposed algorithm for the management of endocrine immune‐related adverse events: Hypothyrodism. The National Cancer Institute has recommended that adverse events on patients with cancer chemotherapy be graded as per the Common Terminology Criteria for Adverse Events Version 5.0. Abbreviations: ADL, activities of daily living; free T4, free thyroxine; i.v., intravenous; LT4, levothyroxine; TSH, thyroid‐stimulating hormone.

Figure 4

Proposed algorithm for the management of endocrine immune‐related adverse events: Hyperthyroidism. The National Cancer Institute has recommended that adverse events on patients with cancer chemotherapy be graded as per the Common Terminology Criteria for Adverse Events Version 5.0. Abbreviations: ADL, activities of daily living; BB, beta blockers; EKG, electrocardiogram; free T4, free thyroxine; i.v., intravenous; MMI, methimazole; NSAID, nonsteroidal anti‐inflammatory drug; PTU, propylthiouracil; TSH, thyroid‐stimulating hormone.

Figure 5

Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitors with data from Barroso Sousa et al. [51, 95]. Combination indicates nivolumab (PD‐1) plus ipilimumab (CTLA‐4). Abbreviations: CTLA‐4, cytotoxic T‐lymphocyte associated protein 4; PD‐1, programmed cell death‐1; PD‐L1, programmed cell death ligand‐1.