Immunotherapy may place patients at risk for distinctive toxicities that differ from traditional chemotherapy. One example is endocrine dysfunction, including hypophysitis, hypo- or hyperthyroidism, type 1 diabetes, and primary adrenal insufficiency.
The Process of Hypophysitis
Hypophysitis, or inflammation of the pituitary gland, is quite rare. Primary hypophysitis refers to inflammatory conditions isolated to the pituitary gland. Secondary hypophysitis is inflammation of the pituitary associated with systemic conditions such as hemochromatosis, amyloidosis, or sarcoidosis. Secondary hypophysitis may also occur from infections or medications such as immunotherapy. Hypophysitis is more often associated with anti-CTLA-4 therapy such as ipilimumab, although other immunotherapy agents are linked to it as well. It is one of the more common endocrine-related toxicities associated with immune checkpoint inhibitors and may occur weeks to months after initiation of therapy.
The condition results in permanent deficiency in one or more of the pituitary hormones, most commonly thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), and follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Less commonly seen are deficiencies in growth hormone and decreased prolactin levels. Although central hypothyroidism and hypogonadotropic hypogonadism are usually transient, central adrenal insufficiency will likely be permanent. Oncology professionals must be alert to signs of hormonal deficiencies, especially central adrenal insufficiency that could cause a life-threatening adrenal crisis because of cortisol deficiency.
The incidence of any-grade hypophysitis is higher in patients treated with combination therapy. For example, with ipilimumab and nivolumab, the incidence of hypophysitis was 4.6% in patients with renal cell carcinoma and 3.4% in patients with colorectal cancer. The medium time to onset was 2.8 months. A meta-analysis of 34 studies of patients receiving immunotherapy noted all-grade hypophysitis to be 6.4% with the combination therapy, 3.2% with anti-CTLA-4 therapy, 0.4% with anti-PD1 therapy, and less than 0.1% with anti-PD-L1 therapy. Other retrospective studies have reported a higher incidence of hypophysitis.
Diagnosis and Management
Symptoms of hypophysitis are often nonspecific and commonly include headache and fatigue. However, mental status changes, abdominal pain, unusual bowel habits, loss of libido, cold intolerance, hot flashes, weight loss, anorexia, and hypotension may also occur. Onset is usually within a few weeks to months after initiation of immunotherapy, however, it can occur at any time throughout therapy.
Imaging may show moderate to diffuse pituitary enlargement. NCCN guidelines recommended using brain magnetic resonance imaging with pituitary/sellar cuts if a patient is symptomatic. A sensitive and specific sign of hypophysitis is pituitary stalk thickening, which will usually resolve in several weeks. Enlargement of the pituitary may precede the diagnosis of hypophysitis, but do not rule out hypophysitis if the pituitary gland does not show any abnormalities.
Lab testing could include thyroid studies (TSH, T3, and T4), ACTH, cortisol, FSH or LH, estradiol (in women), testosterone (in men), and prolactin. TSH and free T4 should be checked at baseline and with every treatment for at least the first five cycles of immunotherapy. The ipilimumab prescribing information advises monitoring a chemistry panel, ACTH, and thyroid function tests prior to administering each dose. Chang et al. recommended that ACTH be checked simultaneously with cortisol in the morning when both levels are at their peak. NCCN recommended evaluating morning cortisol, FSH, LH, TSH, free T4, and testosterone in men and estradiol in women.
Management involves hormone replacement and supportive care. Levothyroxine, corticosteroids, and estrogen or testosterone may be prescribed depending on the presenting deficiency. For symptomatic patients with signs of pituitary swelling (headache, vision disturbance, or neurologic dysfunction), hold immunotherapy until acute symptoms resolve and consider giving prednisone or methylprednisolone at 1–2 mg/kg per day. Without pituitary swelling, immunotherapy may continue while hormone replacement therapy is added. An endocrine consultation should be considered if the patient is symptomatic.
Advanced practice RNs need to understand that immunotherapy may cause unusual toxicities of the endocrine system, including hypophysitis, and be able to recognize them early and manage them expertly.