**7. Adrenal Insu**ffi**ciency in Tumor-Bearing Patients**

As noted above, primary/secondary adrenal insufficiency is a less common but potentially fatal irAE, and it often includes adrenal crisis, in patients receiving ICIs. On the other hand, symptoms are often nonspecific, such as anorexia and malaise, which are also common symptoms in cancer patients. Adrenal insufficiency is also a common condition in cancer patients, and efforts must be made to detect it at an early stage.

Causes of adrenal insufficiency other than ICI treatment in cancer patients include steroid withdrawal syndrome, adrenal metastases from primary disease, and autoimmune adrenalitis.

Long-term corticosteroid treatment may be used for various purposes in cancer patients, including palliation of symptoms such as fatigue, resolution of cerebral edema, and treatment of drug-induced or radioactive organ damage. In addition, they are often administered during anticancer drug therapy. Long-term corticosteroid use causes hypothalamic–pituitary–adrenal suppression and adrenal atrophy. Steroid withdrawal syndrome may occur when steroids are suddenly reduced or discontinued, and many patients present with clinical features of acute adrenal insufficiency. It is necessary to pay attention to sudden dose reduction and discontinuation in patients who have been receiving long-term steroid treatment, and steroid withdrawal syndrome should be suspected when symptoms indicating adrenal insufficiency are observed. In case of steroid withdrawal syndrome, the symptoms rapidly disappear when the steroid dose is increased in most cases.

Moreover, when physical stresses such as diarrhea, trauma, and dehydration occur in patients receiving long-term corticosteroid treatment, relative steroid deficiency may develop and result in adrenal insufficiency symptoms. The causative disease should be treated, and the dose of the steroid drug should be increased. Failure to take appropriate measures may result in adrenal crisis and potentially fatal conditions. On the other hand, in cancer patients, metastatic adrenal tumors may cause adrenal insufficiency. A previous study involving autopsy of malignant tumors found adrenal metastasis in approximately 3% cases [47]. Further, chronic primary adrenocortical insufficiency due to metastatic adrenal tumors is rare and has been reported to occur in approximately 1% patients [47]. Even in cases of metastatic adrenal tumors, cortisol secretion is preserved until approximately 90% of the bilateral adrenal glands are destroyed, and the typical symptoms may not appear in many cases, which complicates diagnosis [48].
