Endocrinopathies: The New Price of Cancer Treatment

Anupam Kotwal, MBBS

Disclosures

March 29, 2019

Editorial Collaboration

Medscape &

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block checkpoints—namely cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death protein-ligand 1 (PD-L1)—thus leading to de-repression of cytotoxic T-cell function[1,2] and enhanced antitumor immune response (Figure 1).

Figure 1. Mechanisms of immune checkpoint inhibitors.

In 2011, the US Food and Drug Administration approved the first ICI, ipilimumab, for use in melanoma. Since then, five ICIs have been approved for clinical practice, including PD-1 inhibitors (pembrolizumab and nivolumab) and PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab).

ICIs have emerged as a novel cause of endocrine immune-related adverse events (IRAEs) affecting the pituitary, thyroid, endocrine pancreas, and (rarely) adrenal and parathyroid glands. The underlying mechanism for these endocrinopathies appears to be immune mediated, mostly by T cells; however, the specific mechanisms have yet to be elucidated and are the subject of recent and ongoing studies.[3,4,5,6]

The increased use of ICIs, which are very effective against various malignancies, is likely to increase the population burden of these endocrinopathies. Hence, it is essential for clinicians to be able to identify them and initiate their management.

Monitoring for Endocrinopathies

Before initiation of ICIs, patients should undergo laboratory testing that includes serum TSH, serum free thyroxine, serum 8 AM cortisol, serum ACTH, and fasting plasma glucose. If any of these tests are abnormal, further testing and monitoring can be performed. Specific laboratory tests should also be performed when there are symptoms or signs of any endocrinopathy, as will be discussed below.

The clinician should have a low threshold to test for endocrinopathy if the patient has a personal or family history of autoimmunity or has developed other IRAEs. On the basis of our clinical experience and the National Comprehensive Cancer Network guidelines,[7] the inciting ICI may need to be temporarily discontinued if a patient presents with hypophysitis with mass effects, adrenal crisis, severe thyrotoxicosis, or diabetic ketoacidosis.

Hypophysitis

Hypophysitis is the most common endocrinopathy associated with the CTLA-4 inhibitor ipilimumab, occurring in 8%-11% of patients.[8,9,10,11] It is seen less frequently with PD-1 and PD-L1 inhibitors (0%-5%).[4,11,12] Although hypophysitis usually occurs 6-12 weeks after initiation of ICIs, some cases have been reported after a prolonged duration of therapy.[9,10,11]

Presentation and management

Hypophysitis can present with mass effects due to pituitary gland enlargement, with headache, double vision, and visual field defects. Whether there are mass effects or not, all cases have pituitary hormone deficiencies—most commonly secondary adrenal insufficiency,[9] which may present as an emergency of "adrenal crisis." It may also cause central hypothyroidism and sometimes secondary hypogonadism.[9,13]

Symptoms like fatigue, weakness, nausea, confusion, memory loss, loss of libido, anorexia, hallucinations, temperature intolerance, and subjective sensation of fever and chills may occur. These symptoms are often nonspecific and may overlap with cancer-related constitutional symptoms.

Therefore, the clinician should have a high suspicion when evaluating for hypophysitis, especially because the accompanying secondary adrenal insufficiency may be life-threatening if not recognized and managed promptly. The posterior pituitary is rarely involved, hence central diabetes insipidus is uncommon in the setting of ICI use.

Diagnostic testing should include brain MRI (Figure 2) and testing the hormones produced by the pituitary and target glands.

Figure 2a. MRI of the head, demonstrating enlargement and enhancement of the pituitary gland, with thickening of the stalk.

Figure 2b. MRI of the head, demonstrating destruction of the pituitary gland, appearing like an empty sella.

In addition to hormone abnormalities, electrolyte abnormalities like hyponatremia and hypoglycemia may occur because of a deficiency of cortisol and thyroxine.

When a patient presents with mass effects like headache or vision abnormalities, hospitalization should be considered. High-dose glucocorticoids (eg, prednisone/methylprednisolone 1 mg/kg/day or dexamethasone 4 mg every 6 hours) should be administered as soon as there is concern for mass effects from hypophysitis.

Patients presenting with hypotension, confusion, and hypoglycemia may be in adrenal crisis, which needs to be managed with a stress dose of glucocorticoids and fluid resuscitation. Once the adrenal crisis and mass effects resolve, or if the patient presents with only mild to moderate symptoms of hormone deficiencies, hormone replacement is the mainstay of management. Most patients who develop hypopituitarism require life-long hormone replacement.[9,11]

Thyroiditis

Thyroid dysfunction is the most common endocrinopathy associated with PD-1 and PD-L1 inhibitors (6%-21%).[3,4,12] It occurs less commonly with the CTLA-4 inhibitor ipilimumab.[11] Combination therapy with ipilimumab and a PD-1 inhibitor has demonstrated the highest rates of thyroid dysfunction,[14] which usually occurs 8-10 weeks after initiation of an ICI but can be delayed for up to 2 years.[4,12,15]

Presentation and management

Thyroiditis may present with primary hypothyroidism, sometimes preceded by a thyrotoxic phase during which thyroid hormones are released. Patients with preexisting Hashimoto thyroiditis may have worsening of hypothyroidism, suggested by an increase in thyroid hormone replacement dosage.[4,12]

There appears to be a higher risk for progression to permanent hypothyroidism in ICI-induced thyroiditis compared with painless thyroiditis, and this is especially true when thyroid peroxidase antibodies (TPOs) are elevated.[3,16] Persistent hyperthyroidism, such as Graves disease, has rarely been reported with the use of CTLA-4 inhibitors.[17,18]

Many patients are asymptomatic because of the acute or mild nature of thyroid hormone dysfunction, highlighting the importance of monitoring thyroid hormone levels before each ICI infusion. Most patients who present with or progress to overt hypothyroidism require long-term thyroid hormone replacement.[16]

Diagnosis can be easily established using thyroid function tests. TSH-receptor antibodies only need to be tested when hyperthyroidism is persistent for more than 8 weeks, in which case a positive TSH-receptor antibody test would suggest Graves disease.

Imaging is usually not required to make a diagnosis of ICI-induced thyroiditis. In some cases, thyroid ultrasound can help confirm the diagnosis of thyroiditis, with the thyroid appearing heterogeneous and hypovascular (Figure 3).

Figure 3. Ultrasound image demonstrating a heterogeneous and hypoechoic thyroid gland parenchyma, which is also hypovascular.

FDG-PET scans performed as part of a malignancy workup or monitoring usually demonstrate diffusely increased FDG uptake in the thyroid, consistent with thyroiditis (Figure 4).[4,12]

Figure 4. FDG-PET scan demonstrating diffusely increased FDG uptake in the thyroid.

Management depends on the phase of thyroiditis during which the diagnosis is made. Transient thyrotoxicosis can usually be managed symptomatically with beta-blockers. If there is significant neck discomfort, which is rare, glucocorticoids may be considered, but they are usually not required.

For overt hypothyroidism or symptomatic subclinical hypothyroidism, T4 replacement therapy with levothyroxine should be initiated and its dose titrated on the basis of TSH.

Insulin-Dependent Diabetes Mellitus

New onset of diabetes mellitus has not been reported in clinical trials of CTLA-4 inhibitors and has been reported in < 1% of patients in studies of PD-1 inhibitors.[14] However, rates of up to 1.5% were recently reported with combined use of CTLA-4 and PD-1 inhibitors.[19]

PD-L1 inhibitors have been shown to not only lead to new-onset insulin-dependent diabetes but also worsen preexisting diabetes.[20] The frequently encountered high titers of type 1 diabetes–associated antibodies[20] are in line with the immune process.

New-onset insulin-dependent diabetes usually occurs 20 weeks after starting PD-1 inhibitor therapy but has been reported as early as 2 weeks and as late as 3-4 years after treatment initiation.[20,21]

Presentation and management

Depending on the severity of insulin deficiency, emergency from diabetic ketoacidosis may occur and has been reported quite frequently.[20,22]

It is recommended that patients on ICIs presenting with hyperglycemia be tested for hemoglobin A1c (usually not extremely elevated because of the acute nature of hyperglycemia), C-peptide (usually low) with concomitant plasma glucose, and type 1 diabetes antibodies. When there is any concern for diabetic ketoacidosis, serum bicarbonate, anion gap, beta-hydroxybutyrate, and urine ketones should be tested. Clinicians should have a low threshold to manage these patients as those having insulin-deficient diabetes on initial presentation.

Once the initial episode of hyperglycemia has resolved—and if antibodies are negative and C-peptide levels suggest appropriate insulin production, especially in the absence of preprandial hyperglycemia—cautious de-escalation of therapy may be considered, but patients should be monitored very closely because they may be in the "honeymoon phase" of insulin deficiency.

Most patients with ICI-induced diabetes require intensive insulin therapy with a basal-bolus regimen or insulin pump on follow-up,[20,22] suggesting that remission is unlikely. This adds significantly to the morbidity of patients who are already dealing with cancer.

Rare Endocrinopathies: Adrenalitis and Hypoparathyroidism

A clinical presentation suggestive of primary adrenal insufficiency has been described in some case reports,[23] but it is usually difficult to differentiate from secondary adrenal insufficiency due to hypophysitis or chronic glucocorticoid use (for cancer or the management of other IRAEs).

Recently, two cases of hypocalcemia and low parathyroid hormone suggestive of immune-mediated hypoparathyroidism have been reported with the use of PD-1 inhibitors,[24,25] one of them showing antibodies against calcium-sensing receptor.[24]

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