Immune Checkpoint Inhibitors: Review and Management of Endocrine Adverse Events

Abstract

In recent years, immune checkpoint inhibitors have emerged as effective therapies for advanced neoplasias. As new checkpoint target blockers become available and additional tumor locations tested, their use is expected to increase within a short time. Immune-related adverse events (irAEs) affecting the endocrine system are among the most frequent and complex toxicities. Some may be life-threatening if not recognized; hence, appropriate guidance for oncologists is needed. Despite their high incidence, endocrine irAEs have not been fully described for all immunotherapy agents available. This article is a narrative review of endocrinopathies associated with cytotoxic T lymphocyte-associated antigen-4, blockade of programmed death receptor 1 and its ligand inhibitors, and their combination. Thyroid dysfunction is the most frequent irAE reported, and hypophysitis is characteristic of ipilimumab. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for clinical management are suggested. Heterogeneous terminology and lack of appropriate resolution criteria in clinical trials make adequate evaluation of endocrine AEs difficult. It is necessary to standardize definitions to contrast incidences and characterize toxicity patterns. To provide optimal care, a multidisciplinary team that includes endocrinology specialists is recommended. The Oncologist 2016;21:804-816 Implications for Practice: Immune checkpoint inhibitors are already part of oncologists' therapeutic arsenal as effective therapies for otherwise untreatable neoplasias, such as metastatic melanoma or lung cancer.Their use is expected to increase exponentially in the near future as additional agents become available and their approval is extended to different tumor types. Adverse events affecting the endocrine system are among the most frequent and complex toxicities oncologists may face, and some may be lifethreatening if not recognized. This study reviews endocrinopathies associated to immune checkpoint inhibitors available to date. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for management are proposed.

Endocrine side effects of cancer immunotherapy

“…Hypophysitis and hypothyroidism are the most common endocrinopathies, seen in up to 10% of patients treated with anti-CTLA-4 and anti-PD-1/ PD-L1 antibodies (Corsello et al 2013, Topalian et al 2014, O'Donnell et al 2015, Eggermont et al 2016, González-Rodríguez et al 2016, Byun et al 2017. The growing recognition that immunotherapy is potentially associated with endocrine-related adverse events has resulted in higher reported rates of hypophysitis, as clinical suspicion and routine laboratory testing have become a more routine practice (Albarel et al 2015, Min et al 2015, Faje 2016.…”

Immune-Checkpoint Inhibitors in the Era of Precision Medicine: What Radiologists Should Know

“…4N) (58). Clinical picture and imaging findings resemble those seen with primary lymphocytic hypophysitis, with avid enhancement of the hypophysis on contrast enhanced CT, T1 precontrast and T2 hypointensity and homogeneous enhancement on MRI (57). Additional rare immune-related endocrinopathies have been described and include Ipilimumab Graves’ ophthalmopathy and anti PD-1 Type I diabetes mellitus, which has been reported in only 4 patients to date, but imaging features have yet to be described (Fig.…”

“…They have to be promptly recognized by the radiologist, as symptoms can resolve with adequate hormone replacement, allowing the patients to continue a therapy they are benefiting from. Thyroid disorders are the most common clinically reported endocrine irAEs, particularly in women on anti-PD-1 inhibitors and can clinically manifests with hypothyroidism, most commonly, followed by hyperthyroidisim, whereas thyroiditis has not yet been reported (5057). Imaging features have been described as new enlargement of the thyroid gland, enhancement and diffuse fludeoxyglucose (FDG) uptake on PET/CT, as reported by a study on Ipilimumab related adverse event (50).…”

The role of novel immunotherapies in non-Hodgkin lymphoma

“…With low-grade endocrine toxicity, the drugs can be continued with supportive care and close monitoring. If adrenal crisis is suspected, stress dose steroids should be administered (65). …”