Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports

Abstract

BackgroundSince 2011 six immune checkpoint inhibitors (ICI) have been approved to treat patients with many advanced solid tumor and hematological malignancies to improve their prognosis. Case reports of their endocrine immune-related adverse events [irAEs]) are increasingly published as more real-world patients with these malignancies are treated with these drugs. They alert physicians of a drug’s AEs (which may change during a drug’s life cycle) and contribute to post-marketing safety surveillance. Using a modified framework of Arksey and O’Malley, we conducted a scoping review of the spectrum and characteristics of ICI-induced endocrinopathies case reports before and after ICIs are marketed.MethodsIn July 2017, we searched, without date and language restrictions, 4 citation databases for ICI-induced endocrinopathies. We also hand-searched articles’ references, contents of relevant journals, and ran supplemental searches to capture recent reports through January 2018. For this study, a case should have information on type of cancer, type of ICI, clinical presentation, biochemical tests, treatment plus temporal association of ICI initiation with endocrinopathies. Two endocrinologists independently extracted the data which were then summarized and categorized.ResultsOne hundred seventy nine articles reported 451 cases of ICI-induced endocrinopathies - 222 hypopituitarism, 152 thyroid disorders, 66 diabetes mellitus, 6 primary adrenal insufficiencies, 1 ACTH-dependent Cushing’s syndrome, 1 hypoparathyroidism and 3 diabetes insipidus cases. Their clinical presentations reflect hormone excess or deficiency. Some were asymptomatic and others life-threatening. One or more endocrine glands could be affected. Polyglandular endocrinopathies could present simultaneously or in sequence. Many occur within 5 months of therapy initiation; a few occurred after ICI was stopped. Mostly irreversible, they required long-term hormone replacement. High dose steroids were used when non-endocrine AEs coexisted or as therapy in adrenal insufficiency. There was variability of information in the case reports but all met the study criteria to make a diagnosis.ConclusionsThe spectrum of ICI-induced endocrinopathies is wide (5 glands affected) and their presentation varied (12 endocrinopathies). Clinical reasoning integrating clinical, biochemical and treatment information is needed to properly diagnose and manage them. Physicians should be vigilant for their occurrence and be able to diagnose, investigate and manage them appropriately at onset and follow-up.Electronic supplementary materialThe online version of this article (10.1186/s40842-018-0073-4) contains supplementary material, which is available to authorized users.

Immune checkpoint inhibitor‐associated pituitary‐adrenal dysfunction: A systematic review and meta‐analysis

“…Notably, few case reports for this event have been published in clinical trials, but hypopituitarism seemed higher in the spectrum of ICI-induced endocrinopathies in cancer patients based on the scoping review of case reports. 8 Our study has some limitations. First, because of the heterogeneity of the included studies, an assessment of additional potential risk factors, including the role of sex, age, and baseline pituitary-adrenal function, is needed.…”

“…However, the risk of hypopituitarism was significantly higher in patients treated with ICI regimens than in those in the control group. Notably, few case reports for this event have been published in clinical trials, but hypopituitarism seemed higher in the spectrum of ICI‐induced endocrinopathies in cancer patients based on the scoping review of case reports …”

Endocrine‐related adverse events associated with immune‐checkpoint inhibitors in patients with melanoma

“…Endocrinopathies affecting the pituitary and thyroid glands are emerging as some of the most common adverse events associated with immunotherapy and often the most symptomatic among these ICI‐related endocrinopathies (irEs) . Meanwhile, apart from hypophysitis and thyroid dysfunction, insulin‐deficient diabetes mellitus and primary adrenal insufficiency have recently been reported as less frequent irEs due to ICI therapy and even more rarely hypoparathyroidism, however, all of them can be life‐threatening if not promptly recognized and treated . Several observational studies and case series have reported that hypophysitis is mainly associated with anti‐CTLA4 therapy and thyroid dysfunction with anti‐PD1 therapy …”

“…4 Meanwhile, apart from hypophysitis and thyroid dysfunction, insulin-deficient diabetes mellitus and primary adrenal insufficiency have recently been reported as less frequent irEs due to ICI therapy and even more rarely hypoparathyroidism, however, all of them can be life-threatening if not promptly recognized and treated. 5,6 Several observational studies and case series have reported that hypophysitis is mainly associated with anti-CTLA4 therapy and thyroid dysfunction with anti-PD1 therapy. 3 The precise mechanisms of action underlying these endocrine irEs remain to be elucidated.…”

Development of a Functional Assessment of Chronic Illness Therapy item library and primary symptom list for the assessment of patient-reported adverse events associated with immune checkpoint modulators

“…Our literature review yielded 25 articles documenting irAE incidence, management guidelines, toxicity profiles, and associated symptomatology [4,9,[11][12][13][14][15][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] . From these, we identified 75 possible inflammatory reactions/immune conditions across 11 organ systems, ranging from very common to rare.…”