Immunotherapy has transformed cancer care by harnessing the body’s immune system to target and eliminate cancer cells. While offering significant benefits, this treatment can also lead to immune-related adverse events (irAEs). Adrenal insufficiency, a condition where the adrenal glands do not produce enough cortisol, is a recognized but less common complication.
Adrenal Insufficiency as an Immunotherapy Side Effect
Immunotherapy agents, such as immune checkpoint inhibitors (ICIs), activate the immune system to fight cancer. This heightened immune activity can sometimes lead to an autoimmune attack on healthy tissues, including endocrine glands. When this occurs in the adrenal glands, it causes inflammation (adrenalitis), impairing their ability to produce cortisol. The pituitary gland, which regulates adrenal function, can also become inflamed (hypophysitis), leading to secondary adrenal insufficiency.
Cortisol, often called the “stress hormone,” regulates metabolism, blood pressure, inflammation, and the body’s stress response. A deficiency in cortisol disrupts these vital bodily functions.
Immunotherapy-induced adrenal insufficiency can be primary or secondary. Primary adrenal insufficiency results from direct damage to the adrenal glands, while secondary adrenal insufficiency typically arises from hypophysitis, affecting the pituitary gland’s control over cortisol production. Secondary adrenal insufficiency is more prevalent than primary in patients receiving PD-1/PD-L1 inhibitors. While generally uncommon (incidence 0.7% to 4.2% depending on the specific immunotherapy and whether it’s used alone or in combination), its occurrence is increasing with the wider use of these cancer treatments.
Diagnosing and Managing Adrenal Insufficiency
Symptoms of low cortisol can be subtle and overlap with those of cancer or other treatment side effects. Common indicators include profound fatigue, weakness, nausea, vomiting, abdominal pain, dizziness, and unintended weight loss. Low blood pressure, particularly when standing, is a frequent symptom, and electrolyte imbalances like low sodium (hyponatremia) may occur.
Diagnosis involves specific blood tests to measure morning cortisol and adrenocorticotropic hormone (ACTH) levels. Low morning cortisol with high ACTH levels indicates primary adrenal insufficiency. Low cortisol with low or normal ACTH suggests secondary adrenal insufficiency. An ACTH stimulation test, where synthetic ACTH is administered and cortisol levels are measured before and after, can confirm the diagnosis.
Management involves cortisol replacement therapy, typically with hydrocortisone or prednisone. Patients are educated on “stress dosing,” increasing their medication during physical stress (illness, injury, surgery) to mimic the body’s natural response. For primary adrenal insufficiency, mineralocorticoid replacement with fludrocortisone may also be necessary to regulate salt and water balance.
Decision-Making Regarding Immunotherapy Continuation
Deciding whether to discontinue immunotherapy for low cortisol is a complex, individualized process. This decision requires careful consideration by a team of specialists, including oncologists and endocrinologists. The severity of the adrenal insufficiency is a primary factor.
If adrenal insufficiency is mild and effectively managed with hormone replacement therapy, immunotherapy may often continue with close monitoring. Discontinuation is typically considered for severe, life-threatening cases, such as an adrenal crisis, especially if difficult to control with medication. The effectiveness of immunotherapy in treating the cancer is another consideration; if the cancer is responding well, continuing immunotherapy might be weighed against the manageable side effect.
The availability and effectiveness of alternative cancer treatments also play a role. If other viable options exist, stopping immunotherapy may be a more favorable path. Patient preference and quality of life are also important aspects. In some instances, after adrenal insufficiency symptoms are stabilized with appropriate hormone replacement, immunotherapy may be carefully reintroduced.
Long-Term Considerations and Follow-Up
Long-term management is typically required for patients who develop immunotherapy-induced adrenal insufficiency. Cortisol replacement therapy is often a lifelong commitment, as the endocrine dysfunction is frequently permanent. Ongoing care involves regular follow-up appointments with both an endocrinologist and an oncologist to monitor hormone levels, adjust medication dosages, and assess overall health.
Patient education is a significant part of long-term management. Individuals are advised to carry medical alert information, such as a wallet card or bracelet, indicating their adrenal insufficiency and cortisol dependency. They are also instructed on emergency protocols, including how to administer an injectable hydrocortisone dose in situations like severe illness or injury, which could precipitate an adrenal crisis.
While adrenal insufficiency is often lifelong, some rare cases, particularly secondary adrenal insufficiency resulting from hypophysitis, might experience partial recovery of pituitary-adrenal function. This is uncommon, especially in primary adrenal insufficiency. Proper management of adrenal insufficiency generally allows patients to maintain a good quality of life. Adrenal insufficiency can sometimes develop even months after immunotherapy has been discontinued.