By Wendy H. Vogel, MSN, FNP, AOCNP®

Immunotherapy has a unique set of toxicities in comparison to traditional chemotherapy. Endocrine dysfunction, including hypo- or hyperthyroidism, hypophysitis, type-1 diabetes, and primary adrenal insufficiency, may occur. Advanced practice RNs (APRNs) have a role in monitoring and treating patients for endocrine-related toxicities.

Risk Factors for Hypothyroidism

Hypothyroidism secondary to immunotherapy is more common with PD-1 and PD-L1 inhibitors and when combining CTLA4 and PD1 blockade therapy. A recent meta-analysis by Barroso-Sousa et al. estimated that the incidence of all-grade hypothyroidism in patients on immune checkpoint inhibitors was 6.6%, although the literature notes a range of 3%–22%. See sidebar for specific incidence rates.

Assessment

The most common signs of hypothyroidism are fatigue and weight gain. Other signs may include constipation, cold intolerance, and dry skin. However, these symptoms are generally mild and nonspecific, particularly in the oncology population, even when blood counts have dramatic changes. Immune-related thyroid dysfunction may occur within weeks to months after beginning immunotherapy. Hypothyroidism may present as transient thyrotoxicosis followed by hypothyroidism. Symptoms are most often mild with transient thyrotoxicosis, last a few weeks, then resolve and progress to euthyroidism or hypothyroidism. Hypothyroidism may be transient or permanent, requiring lifelong thyroid replacement.  

A thorough history and physical examination must be conducted and baseline levels of physical status reviewed. Note bradycardia, dry skin, fullness of the face, periorbital edema, tongue swelling, and delayed relaxation of deep-tendon reflexes

Use the Common Terminology Criteria for Adverse Events to grade the frequency and severity (see sidebar) and define management strategies. Most immunotherapy-related toxicities secondary to hypothyroidism are grade 1–2 (mild to moderate). 

Primary thyroid dysfunction is different from treatment-related (secondary) dysfunction. Primary hypothyroidism usually has elevated TSH with low to mid-normal levels of free T4, and secondary hypothyroidism usually has low to mid-normal levels of TSH with a low free T4. Acute illness can cause levels of T3 to be inaccurate. Secondary hypothyroidism may indicate that a diagnosis of hypophysitis should be considered. Overt hypothyroidism is defined by an elevated TSH and a low free T4. Subclinical hypothyroidism has an elevated TSH and a normal free T4. 

Ongoing Monitoring

Baseline TSH and free T4 should be measured prior to beginning immunotherapy and then monitored periodically. Chang et al. recommended measuring TSH and free T4 prior to each infusion for at least five cycles. If a patient presents with symptoms of hypothyroidism, even if symptoms are nonspecific and common to cancer, a TSH and free T4 should be checked. When abnormalities are noted, TSH and free T4 should be monitored every four to six weeks. Testing intervals can be extended out to every 12–18 weeks as clinically indicated. Patients with pre-
existing hypothyroidism must be monitored closely because their thyroid replacement may need to be increased, and they should also be monitored for transient thyrotoxicosis. 

If secondary hypothyroidism is suspected, hypophysitis should be considered and worked up. If adrenal insufficiency is present with hypothyroidism, corticosteroid replacement must be given prior to thyroid hormone replacement. If thyrotoxicosis is noted (low TSH with high free T4/total T3), further workup with thyroid peroxidase antibody and thyroid-stimulating hormone receptor antibody is indicated.

Treatment

Management of hypothyroidism is mainly hormone replacement and symptom control. Guidelines for management of immune-related hypothyroidism are published by the American Society of Clinical Oncology, NCCN, and European Society for Medical Oncology. 

For a TSH level of 4 to < 10 mIU/l and a normal free T4, therapy may be continued and no interventions are needed. For a TSH > 10 mIU/l and a normal T4, therapy may be continued and levothyroxine may be considered. Chang et al. recommended treatment of overt hypothyroidism by initiating levothyroxine at 0.8 mcg/kg daily in younger patients without history of cardiovascular disease. In patients with subclinical hypothyroidism (TSH > 10 mIU/l), levothyroxine could be considered. In patients with known cardiovascular disease, recommendations are to start levothyroxine at a lower dose (e.g., 12.5–25 mcg daily). In patients older than 65, levothyroxine may also be started a lower dose with a higher TSH goal of 4–6 mIU/l. 

If clinical, primary hypothyroidism is present (TSH > 10 with low free T4), immunotherapy may be continued and consideration given to thyroid hormone supplementation. Endocrinology consultation may be indicated, and concomitant adrenal insufficiency should be ruled out. In general, TSH and free T4 should be reassessed in four to six weeks and titrated according to results and symptoms. Labs may need to be monitored more frequently in older patients. 

In most cases, immunotherapy may be continued despite hypothyroidism because it is usually transient with mild symptoms. Endocrinology consults may be needed. Little data suggest routine use of high-dose corticosteroids in the management of immunotherapy-related hypothyroidism, but in some cases, corticosteroids may be helpful in relieving acute inflammation in thyrotoxicosis. 

ONS’s Qualified Clinical Data Registry has a quality measure for immune-related adverse events. Learn more and how you can use it by emailing research@ons.org.