Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review

Abstract

Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.

Characteristics of Immune-Related Thyroid Adverse Events in Patients Treated with PD-1/PD-L1 Inhibitors

“…Additional important aspect is to decide whether thyroid hormone replacement is to be maintained after stopping PD-1/PD-L1 inhibitor therapy. Current guidelines recommend to maintain thyroid hormone replacement during PD-1/PD-L1 inhibitor therapy and consider cessation of thyroid hormone replacement by re-measurement of thyroid function status after complete interruption of the therapy [ 3 , 29 ]. In the present study, most patients (11/13, 84.6%) who stopped PD-1/PD-L1 inhibitor therapy required same doses of levothyroxine, while two patients required reduced doses of levothyroxine during the follow-up period.…”

Immune Checkpoint Inhibitors-Related Thyroid Dysfunction: Epidemiology, Clinical Presentation, Possible Pathogenesis, and Management

“…Transient thyroiditis was diagnosed as noticeable hyperthyroidism or subclinical hyperthyroidism at the time of diagnosis and subsequently progressing to hypothyroidism ( 22 ). The latest review and meta-analyze have reported high thyroid IRAEs frequencies, especially relatively high risk for hypothyroidism ( 42 ). Notably, ICIs-related thyroid dysfunction incidences lie on the type of malignant tumor and ICIs employed ( Table 1 ).…”

“…Stelmachowska-Banas et al. ( 42 ) summarized that combination therapy has been associated with the highest estimated incidence of high thyroid dysfunction frequencies, ranging from 8.0 to 16.4%, remarkably higher than monotherapy with anti-PD-1 drugs (2.8-8.5%) or anti-PD-L1 drugs (0.6-6.0%) or anti-CTLA-4 (0.2-5.2%). The combination of multiple immunotherapies can increase the risk of thyroid dysfunction ( 23 , 43 – 46 ).…”

“…The dynamic changes of free triiodothyronine (FT3), FT4, and TSH can be detected but there are few reports of positive TPO-Ab and TG-Ab. Additionally, based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, recommended by the National Cancer Institute ( 58 ), thyroid IRAEs are mostly graded from level 1 to 3 ( Tables 1 and 2 ) ( 9 , 42 , 45 , 59 ).…”

“…Nevertheless, with the increasing use of immunosuppressive therapy, clinicians should identify and regulate thyroid IRAEs to prevent further rising incidence. At present, there is no prospective trial to determine the best treatment for thyroid IRAEs and the currently recommended treatment is based on the consensus of endocrinologists and guidelines ( Figure 4 ) ( 18 , 42 , 91 , 92 ).…”