Table 2.

Management of endocrinopathies after ICIs according to grading

Endocrinopathies	Grade 1 Asymptomatic or mild symptoms	Grade 2 Moderate symptoms	Grade 3 Severe but not life-threatening symptoms	Grade 4 Life-threatening consequences	Grade 5 Death
Hypophysitis Inflammation of the pituitary gland	•Low cortisol (<5 μg/dl or <18 μg/dl after ACTH stimulation test), low ACTH and asymptomatic or mild symptoms •Consider holding ICIs •Hydrocortisone (15-25 mg/day) in 2-3 doses or equivalent •If central hypothyroidism also present, start levothyroxine always several days after hydrocortisone and monitor with FT4 levels •If hypogonadism also present, testosterone in men or estrogen/progestogen therapy in women, only in those without contra-indications •GH replacement is contraindicated in patients with active malignancy •Endocrine consultation	•Low cortisol and moderate symptoms •Hold ICIs until symptoms resolve •Management as in G1, but ×2-3 initial dose hydrocortisone	•Severe symptoms •Hold ICIs until symptoms resolve •Hospitalize for i.v. fluids and hydrocortisone (100 mg at presentation) •High-dose systemic corticosteroids (prednisolone 1 mg/kg/day) should be reserved for few severe cases	•Life-threatening symptoms •Management as in G3	–
Hypothyroidism Decrease in production of thyroid hormones	•TSH 4-10 mIU/l, normal FT4 and asymptomatic •Continue ICIs •TSH every 4-6 weeks	•TSH >10 mIU/l or TSH 4-10 mIU/l with low FT4 and/or with moderate symptoms •Hold ICIs until symptoms resolve •Levothyroxine (starting dose ~1.1 μg/kg/day or 25-50 μg for elderly and patients with CVD) •TSH every 6 weeks while titrating to optimal dose •FT4 can be used in the short term (2 weeks) to ensure adequacy	•Severe symptoms •Management as in G2 •Endocrine consultation	•Life-threatening symptoms •Management as in G3 •Hospitalize patient for i.v. therapy if signs of myxedema	–
Hyperthyroidism Increase in production of thyroid hormones	•TSH <0.4 mIU/l and asymptomatic or mild symptoms •Continue ICIs •TSH, FT4, T3 every 2-3 weeks to diagnose persistent hyperthyroidism or hypothyroidism (due to destructive thyroiditis)	•Low TSH and moderate symptoms •Hold ICIs until symptoms resolve •Beta blockers •TRAb (TSI) measurement •Methimazole if persistent hyperthyroidism •TSH, FT4, T3 every 4-6 weeks •Endocrine consultation	•Severe symptoms •Management as in G2 •Consider corticosteroids	•Life-threatening symptoms •Management as in G3 •Hospitalize patient with concern of thyroid storm	–
Diabetes mellitus Increase of blood glucose levels	•Fasting glucose >126 mg/dl and asymptomatic or mild symptoms •Continue ICIs •Close follow-up of blood glucose	•Fasting glucose >160 mg/dl and moderate symptoms •Hold ICIs until symptoms resolve •pH and urine ketones •Insulin if persistent hyperglycemia and insulin deficiency (0.3-0.4 units/kg/day, half units for long-acting and half for divided prandial doses) •Close follow-up of blood glucose •Endocrine consultation	•Severe symptoms •Management as in G2	•Life-threatening symptoms •Management as in G3 •Hospitalize patient for i.v. insulin therapy in case of DKA	–
Primary adrenal insufficiency Disorder of the adrenal cortex	•Low cortisol (<5 μg/dl or <18 μg/dl after ACTH stimulation test), high ACTH (×2 upper limit) and asymptomatic or mild symptoms •Consider holding ICIs •Hydrocortisone (15-25 mg/day) in 2-3 doses or equivalent •Fludrocortisone (starting dose 50-100 μg) •Endocrine consultation	•Low cortisol and moderate symptoms •Hold ICIs until symptoms resolve •Management as in G1, but ×2-3 initial dose hydrocortisone	•Severe symptoms •Hold ICIs until symptoms resolve •Hospitalize for i.v. fluids and hydrocortisone (100 mg at presentation)	•Life-threatening symptoms •Management as in G3	–

ACTH, adrenocorticotropic hormone; CVD, cardiovascular disease; DKA, diabetic ketoacidosis; FT4, free thyroxine; G, grade; GH, growth hormone; ICIs, immune checkpoint inhibitors; i.v., intravenous; T3, triiodothyronine; TRAb, TSH receptor antibodies; TSH, thyroid stimulating hormone; TSI, thyroid stimulating immunoglobulin.