*6.1. Hypopituitarism*

Table 2 presents management strategies for hypopituitarism according to the Common Terminology Criteria for Adverse Events (CTCAE) grade. Treatment generally involves hormone replacement therapy. ACTH deficiency is treated with hydrocortisone (10 to 20 mg/day). High doses of glucocorticoids have been reported to improve pituitary enlargement [24,45]. On the other hand, it has been reported that high doses of glucocorticoids do not contribute to restoration of the secretory capacity of ACTH and are associated with relatively high mortality [24,45]. High-dose glucocorticoids are recommended only if the condition is associated with headache and pituitary enlargement with visual field damage. When both TSH and ACTH secretion disorders are present, hydrocortisone replacement therapy must be preceded by hormone replacement therapy. The use of ICIs in patients with treatment-induced hypopituitarism should be discontinued until treatment stabilizes their general condition.



CTCAE, Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitor; BID, bis in die

#### *6.2. Adrenal Insu*ffi*ciency*

Table 3 presents management strategies for adrenal insufficiency according to the CTCAE grade. The condition should be managed according to its severity. Hydrocortisone (10–20 mg/day) replacement therapy should be initiated for patients with only laboratory abnormalities or mild symptoms that permit activities of daily living [46]. In case of adrenal crisis, systemic management and early administration of hydrocortisone are necessary. In all cases, consultation with an endocrinologist is recommended for medical care. If primary adrenal insufficiency due to ICI treatment occurs, the drugs should be discontinued and administered after stabilization of the patient's general condition by treatment.


CTCAE, Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitor.

#### *6.3. Thyroid Dysfunction*

Tables 4 and 5 show the management strategies for hyperthyroidism and hypothyroidism, respectively, according to the CTCAE grade. For thyrotoxicosis caused by destructive thyroiditis, antithyroid drugs are not necessary because the duration of symptoms is usually short. When symptoms

such as tremors and motivation are recognized, symptomatic treatment with a β-blocker is required. Antithyroid drugs are reserved for patients with Basedow's disease.


**Table 4.** Management of hyperthyroidism induced by immune checkpoint inhibitors.

CTCAE, Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitor; TSH, thyroid-stimulating hormone; FT4, free T4.


**Table 5.** Management of hypothyroidism induced by immune checkpoint inhibitors.

CTCAE, Common Terminology Criteria for Adverse Events; ICI, immune checkpoint inhibitor; TSH, thyroid-stimulating hormone; FT4, free T4; FT3, free T3.

In case of hypothyroidism, if the TSH level is <10 mIU/L and no symptoms are observed, ICI administration is continued and serum TSH, FT4, and FT3 levels are monitored. If the TSH level is ≥10 mIU/L and moderate symptoms are present, thyroid hormone replacement therapy is planned [37]. In case of concomitant adrenal insufficiency, careful monitoring is required, and thyroid hormone replacement should be preceded by the administration of hydrocortisone if the adrenal insufficiency worsens.

ICI treatment can be resumed when treatment with or without thyroid hormone replacement therapy results in amelioration of symptoms.
