TY - JOUR
TI - Endocrine-related adverse events associated with immune-checkpoint inhibitors in patients with melanoma
AU - Kassi, E.
AU - Angelousi, A.
AU - Asonitis, N.
AU - Diamantopoulos, P.
AU - Anastasopoulou, A.
AU - Papaxoinis, G.
AU - Kokkinos, M.
AU - Giovanopoulos, I.
AU - Kyriakakis, G.
AU - Petychaki, F.
AU - Savelli, A.
AU - Benopoulou, O.
AU - Gogas, H.
JO - Cancer Medicine
PY - 2019
VL - 8
TODO - 15
SP - 6585-6594
PB - Wiley-Blackwell Publishing Ltd
SN - 2045-7634
TODO - 10.1002/cam4.2533
TODO - atezolizumab;  cytotoxic T lymphocyte antigen 4;  ipilimumab;  nivolumab;  pembrolizumab;  programmed death 1 ligand 1;  CD274 protein, human;  CTLA4 protein, human;  cytotoxic T lymphocyte antigen 4;  PDCD1 protein, human;  programmed death 1 ligand 1;  programmed death 1 receptor, adrenal insufficiency;  adult;  adverse event;  aged;  Article;  cancer immunotherapy;  cohort analysis;  controlled study;  disease course;  endocrine disease;  endocrine function test;  ethnic difference;  female;  follow up;  genetic difference;  human;  hypogonadotropic hypogonadism;  hypophysitis;  hypothyroidism;  incidence;  major clinical study;  male;  melanoma;  middle aged;  monotherapy;  observational study;  priority journal;  prospective study;  risk assessment;  screening;  spectroscopy;  thyroid disease;  treatment duration;  hypophysitis;  immunology;  immunotherapy;  melanoma;  thyroid disease, Aged;  B7-H1 Antigen;  CTLA-4 Antigen;  Female;  Humans;  Hypophysitis;  Immunotherapy;  Incidence;  Male;  Melanoma;  Middle Aged;  Programmed Cell Death 1 Receptor;  Prospective Studies;  Thyroid Diseases
TODO - Background: Immune-checkpoint inhibitors have been shown to improve survival in melanoma patients, but can also trigger immune-related endocrinopathies, especially hypophysitis and thyroid dysfunction. Methods: To assess the incidence and the spectrum of endocrinopathies in melanoma patients treated with immunotherapy a prospective observational study was conducted. Forty out of 339 patients, treated with immune-checkpoint inhibitors, developed endocrinopathies. All patients had hormonal functional tests at screening (before the initiation of immunotherapy) and during follow-up. Results: The total incidence of endocrinopathies was 11.8%, 13.4% due to anti-PD1/PDL1, 5% due to anti-CTLA4, and 18.5% due to sequential and/or combination treatment. Twenty-one patients (6.2%) presented with isolated anterior hypophysitis, eleven (3.2%) with primary thyroid dysfunction and eight (2.4%) with both abnormalities. The most frequent anterior pituitary hormone deficiency was central adrenal insufficiency, followed by central hypothyroidism and hypogonadotrophic hypogonadism. None of the patients with corticotroph axis failure recovered during follow-up. Endocrinopathies occurred after a median of 22 weeks (range: 4-156) from treatment initiation. Of note, sequential and/or combination therapy with anti-CTLA4 and anti-PD1/anti-PDL1 led to an almost threefold incidence of hypophysitis compared to either monotherapy. Only one of 120 patients receiving anti-CTLA4 monotherapy developed primary hypothyroidism. Conclusions: Our cohort demonstrated an increased incidence of hypophysitis with anti-PD1/anti-PDL1 in contrast to the rarity of primary thyroid dysfunction with anti-CTLA4 treatment. These results could be attributed to genetic/ethnic differences. Sequential treatment is, for the first time to our knowledge, reported to increase the risk of developing hypophysitis to a level as high as that of combination therapy. © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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