Thyroid disorders induced by checkpoint inhibitors
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Immune checkpoint inhibitors are drugs that inhibit the “checkpoint molecules”. Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). The increased immune response induced by these agents leads to immune-related adverse events (irAEs), that can vary from mild to fatal, according to the organ system and severity. Immune-related endocrine toxicities are thyroid dysfunctions, hypophysitis, adrenal insufficiency, and type 1 diabetes mellitus, and are usually irreversible in 50%. In particular, hypophysitis is the most frequent anti-CTLA-4-antibodies-related irAE, while thyroid abnormalities (as hypothyroidism, thyrotoxicosis, painless thyroiditis, or even “thyroid storm”) are more frequently associated with anti-PD-1-antibodies. The combination of anti-CTLA-4-antibodies, with anti-PD-1-antibodies, is associated with about 30% of irAEs. Clinical signs and symptoms vary according to the influenced target organ. Endocrinopathies can often be managed by the treating oncologist. However in more severe cases (i.e. in the presence of insulin-dependent diabetes, adrenal insufficiency, or disorders of gonadal hormones, or severe hyperthyroidism, or hypothyroidism, or long-lasting management of hypophysitis) an endocrinological evaluation, and a prompt therapy, are needed.
KeywordsImmune checkpoint inhibitors CTLA-4 PD-1 PD-L1 Thyroid disorders Hypophysitis
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Research involving human participants
This article does not contain any studies with human participants or animals performed by any of the authors.
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The authors declare that they have no conflict of interest.
- 9.https://www.drugs.com/history/yervoy.html [Accessed June 2018].
- 10.https://www.drugs.com/history/keytruda.html [Accessed June 2018].
- 11.Hansen ED, Wang X, Case AA, Puzanov I, Smith T. Immune checkpoint inhibitor toxicity review for the palliative care clinician. J Pain Symptom Manage. 2018 May 21. https://doi.org/10.1016/j.jpainsymman.2018.05.015. [Epub ahead of print], Immune Checkpoint Inhibitor Toxicity Review for the Palliative Care Clinician.
- 14.Luke JJ, Callahan MK, Postow MA, Romano E, Ramaiya N, Bluth M, et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer. 2013;119:3687–95.CrossRefGoogle Scholar
- 20.Lebbé C, McDermott DF, Robert C, Lorigan P, Ottensmeier CH, Wolchok J, et al. Ipilimumab improves survival in previously treated, advanced melanoma patients with poor prognostic factors: subgroup analysis from a phase III trial [abstract]. Ann Oncol. 2010;21(suppl 8):13240.Google Scholar
- 21.Chandra S, Madden KM, Kannan R, Pavlick AC. Evaluating the safety of anti-CTLA-4 therapy in elderly patients with unresectable melanoma [abstract]. J Clin Oncol. 2013;31(suppl):9063.Google Scholar
- 22.Queirolo P, Spagnolo F, Ascierto PA, Simeone E, Marchetti P, Scoppola A, et al. Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J Neuro-Oncol. 2014;118:109–16.Google Scholar
- 24.Hodi FS, Topalian SL, Brahmer JR, McDermott DF, Smith DC, Gettinger S, et al. Survival and long-term safety in patients (pts) with advanced solid tumors receiving nivolumab (anti-PD-1; BMS-936558; ONO-4538) [abstract]. Eur J Cancer. 2013;49(suppl 2):880.Google Scholar
- 27.Prete A, Salvatori R. Hypophysitis. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, et al. editors. Source Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–2018 Aug 15.
- 28.Sarne D. Effects of the Environment, Chemicals and Drugs on Thyroid Function. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–2016 Sep 27.
- 65.Verma I, Modi A, Tripathi H, Agrawal A. Nivolumab causing painless thyroiditis in a patient with adenocarcinoma of the lung. BMJ Case Rep. 2016;2016.Google Scholar
- 68.Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17:1558–68.CrossRefGoogle Scholar
- 69.Osorio JC, Ni A, Chaft JE, Pollina R, Kasler MK, Stephens D, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol. 2017;28:583–9.Google Scholar
- 72.Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) toxicity management working group. J Immunother Cancer 2017;5:95.Google Scholar
- 73.Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of Immune-Related Adverse Events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36:1714–68.CrossRefGoogle Scholar
- 74.National Comprehensive Cancer Network. Management of Immunotherapy-Related Toxicities. (Version 1.2018). https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. [Accessed 30 March 2018].
- 76.Merck. Pembrolizumab US full prescribing information. 2014. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. [Accessed April 2017].
- 77.Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26:2375–91.Google Scholar
- 78.Genentech. Atezolizumab US full prescribing information. 2016. http://www.gene.com/download/pdf/tecentriq_prescribing.pdf. [Accessed June 2018].