Endocrine Dysfunction From Immune Checkpoint Inhibitors

Pearls and Pitfalls in Evaluation and Management

Anupam Kotwal, MD; Jordan E. Perlman, MD; Whitney S. Goldner, MD; Alissa Marr, MD; Jennifer S. Mammen, MD, PhD, MPhil

J Oncol Pract. 2023;19(7):395-402.

Abstract and Introduction

Abstract

Immune checkpoint inhibitors (ICPis) have proven extremely efficacious in cancer therapy but also lead to a plethora of immune-related adverse events (irAEs). The endocrine irAEs are not only quite common but also may pose a challenge to the clinician while managing a patient with cancer treated with ICPis. The clinical features of endocrine dysfunction are usually nonspecific and may overlap with concurrent illnesses, underlying the importance of accurate hormone testing and efforts toward case-finding. The management of endocrine irAEs is unique in the focus being on hormone replacement rather than curtailing the autoimmune process. Although the management of thyroid irAEs appears straightforward, adrenal insufficiency and insulin-dependent diabetes can be life-threatening if not promptly recognized and treated. This clinical review synthesizes the studies to provide pearls and pitfalls in the evaluation and management of endocrine irAEs with specific reference to guidelines from oncologic societies.

Introduction

The use of immune checkpoint inhibitors (ICPis) has grown at an exponential rate since the first approval in 2011, with new combinations of inhibitors, inclusion in cytotoxic chemotherapy regimens, and novel agents continuing to be developed. The percentage of patients with cancer treated with ICPis increased from 0.14% in 2011 to 12.46% in 2018.^[1] The indications for ICPis are broad, ranging from adjuvant to neoadjuvant to metastatic treatment and in many tumor types. With increasing use, the prompt recognition and management of immune-related adverse events (irAEs) is vital to avoid a significant source of morbidity. These can affect almost any organ system in the body and frequently target endocrine glands causing an acute loss of hormonal function. Different agents, including cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), PD-1, and PD-L1 ICPis, have overlapping but specific toxicity profiles that are often enhanced by combination therapy. Large cohort studies in different geographic regions are concordant in their reporting of the frequencies of endocrine irAEs by ICPi class, such that combination therapy with CTLA-4 and PD-1/PD-L1 ICPis has the highest frequency of all endocrine irAEs, otherwise hypophysitis is more frequent after CTLA-4 ICPi, whereas thyroid dysfunction and diabetes are more frequent after PD-1/PD-L1 ICPi. No specific cancer type associations have been firmly established. This clinical review focuses on pearls and pitfalls in the evaluation and management of endocrine irAEs with particular attention to the rapid identification and treatment of the highest-risk hormonal losses, and with reference to the latest 2021 ASCO ^[2] and 2022 National Comprehensive Cancer Network (NCCN) guidelines.^[3]

Although there are no absolute contraindications to the use of ICPis, careful assessment must be undertaken before their initiation, particularly in patients with pre-existing autoimmune conditions and prior transplantation. Knowing when to suspect endocrine dysfunction can be clinically challenging because symptoms are often nonspecific and vague, such as fatigue and brain fog. In many cases, the onset of clinically apparent hormonal deficiency is precipitated by an underlying stressor, such as a concurrent infection to which symptoms may be attributed. Although investigated as potential markers of disease, baseline antibodies have relatively low sensitivity for both thyroid dysfunction and diabetes. Therefore, baseline testing for tissue-specific antibodies is not currently recommended, and negative testing at the time of presentation cannot rule out an irAE.^[2] However, since thyroid dysfunction is common, and since adrenal insufficiency (AI) and insulin-dependent diabetes can be life-threatening, informed monitoring of hormonal levels and aggressive case-finding are recommended to facilitate the detection of endocrine irAEs in all patients.

The treatment of endocrine irAEs is also unique, with the target outcome being hormone replacement rather than interruption of the autoimmune process. Currently, there are no proven therapies to prevent endocrine irAEs. High-dose glucocorticoids initiated at irAE onset have not been found to prevent the loss of hormone function and are not routinely indicated,^[2,3] although such treatment can be used to control symptoms in adrenal crisis, high-grade symptomatic hyperthyroidism, or with mass effects from pituitary enlargement. Once treated with hormone replacement at physiologic levels, ICPi therapy can be resumed. When appropriately managed, endocrine irAEs are unlikely to adversely affect survival in this population. Although thyroid hormone replacement is relatively straightforward, and many oncologists are comfortable with management, patients with hypophysitis, diabetes, or atypical presentations benefit from the involvement of endocrinology in a multidisciplinary care model.

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Table 1. Summary of Pearls and Pitfalls in the Evaluation and Management of Endocrine irAEs
MRI sella^a should be done for symptoms ofmass effect (headache, diplopia, and visual field deficit) or DI
ICPis can cause primary and secondary hormone dysfunction; measuring both the pituitary and the primary hormone allows for localization
ACTH stimulation test is not preferred for diagnosing pituitary dysfunction
Central hypothyroidism should not be treated before testing for and treating any adrenal insufficiency
In the setting of new hyperglycemia, have a low threshold to evaluate for insulin deficiency and DKA

Abbreviations: ACTH, adrenocorticotropic hormone; DI, diabetes insipidus; DKA, diabetic ketoacidosis; ICPi, immune checkpoint inhibitor; irAEs, immune-related adverse events; MRI, magnetic resonance imaging.
^aIn addition, MRI can be done for multiple pituitary hormone deficiencies if the diagnosis is in question.

Table 2. Endocrine Referral Indications and Interim Care for Patients With Endocrine irAEs
Reasons for Endocrine Referrala	Interim Management While Awaiting Endocrinology Consultation
Persistent hyperthyroidism (>6–8 weeks)	Beta-blocker (propranolol/atenolol) for sympathetic symptoms
Persistent hyperthyroidism (>6–8 weeks)	NSAIDs for painful thyroid gland
Uncontrolled hypothyroidism (TSH not normalizing within 8 weeks of weight-based dosing)	Confirm primary hypothyroidism with a free T4 level
	Review adherence to thyroid hormone
	Increase the levothyroxine dose
Biochemically confirmed pituitary dysfunction	It is never wrong to start glucocorticoid replacement when suspecting adrenal insufficiency
Biochemically confirmed pituitary dysfunction	Adrenal crisis: admit and manage with stress-dose glucocorticoids and hydration
New insulin-dependent diabetes mellitus	Nonemergent hyperglycemia: basal insulin and blood glucose monitoring can be initiated
New insulin-dependent diabetes mellitus	Diabetic ketoacidosis or severe hyperglycemia with hyperosmolarity: admit and manage with intravenous insulin and hydration

Abbreviations: irAEs, immune related adverse events; NSAIDs, nonsteroidal anti-inflammatory drugs; TSH, thyroid-stimulating hormone; T4, thyroxine.
^aWe recommend endocrine referral under any circumstances where the treating oncologist is uncomfortable with management.

Table 3. Summary of the Presentation Along With Clinical, Biochemical, and Radiographic Features of Endocrine irAEs
Presentation of Various Endocrine irAEs	Clinical Features	Biochemical Features	Radiographic Features
Thyroid dysfunction	Usually asymptomatic Thyroid tenderness is rare	Usually diagnosed by screening thyroid function tests	Usually not required for diagnosis Ultrasound: heterogeneous thyroid echotexture Scintigraphy: reduced thyroidal uptake PET: diffuse thyroidal FDG uptake
Thyrotoxicosis	Tachycardia, tremors, diaphoresis, and heat intolerance	TSH below reference range and T4/T3 normal (subclinical) or elevated (overt)
Primary hypothyroidism	Fatigue, cold intolerance, and constipation	TSH above reference range and T4/T3 normal (subclinical) or below reference range (overt)
Pituitary dysfunction			MRI: enlarged pituitary gland and/or stalk with gadolinium enhancement (initially) or normal or small-appearing pituitary such as empty sella or partial empty sella (during course 2–3 months later) Isolated ACTH deficiency usually with PD-1/PD-L1 ICPi does not have the typical pituitary gland enlargement
Mass effects from pituitary enlargement	Headache, diplopia, and visual field deficit	Not applicable
Secondary AI	Symptoms can be nonspecific such as fatigue, nausea, malaise, muscle aches, abdominal discomfort, and diarrhea	Serum 8 am cortisol <3 mcg/dL and ACTH low or normal For serum 8 am cortisol 3–15mcg/dL with typical AI symptoms or another pituitary hormone deficiency, start glucocorticoid, and repeat test in 3 months
Adrenal crisis	Hypotension, vomiting, confusion/delirium, hypoglycemia, and hypovolemic shock	As above, but treatment with stress-dose glucocorticoids and fluid hydration takes priority over ascertaining etiology
Central hypothyroidism	Like primary hypothyroidism	TSH low or inappropriately normal and T4 below reference range
Hypogonadotropic hypogonadism	Different in males v females; wait for 3 months after presentation to evaluate	Low testosterone or estradiol with low or inappropriately normal FSH and LH
Diabetes mellitus			Maybe performed for other reasons but not required for diagnosis CT: inflamed pancreas (initially) or atrophied pancreas (during course) PET: diffuse pancreatic FDG uptake
New-onset insulindeficient diabetes	Thirst, polyuria, polydipsia, and blurred vision	Hyperglycemia HbA1c increase relatively small due to acuity C-peptide levels low initially or during follow-up
Worsening of baseline prediabetes or type 2 diabetes	Same as above and/or worsening hyperglycemia without other causes
DKA	Same as above along with ketosis features (fatigue, dehydration, and confusion)	In addition to above: low serum bicarbonate elevated ketones in blood and urine
Primary AI	In addition to secondary AI, more severe hypotension and hyperkalemia	Serum 8 am cortisol <3 mcg/dL and ACTH high, failed 250 mcg ACTH stimulation test, high renin, and low aldosterone (usually not needed)	Maybe performed for other reasons but not required for diagnosis CT: enlarged adrenals PET: diffuse adrenal FDG uptake
Hypoparathyroidism	Mild: constipation and paresthesia Severe: altered consciousness	Hypocalcemia Hyperphosphatemia Decreased serum intact PTH	Not applicable

Abbreviations: ACTH, adrenocorticotropic hormone; AI, adrenal insufficiency; CT, computed tomography; DKA, diabetic ketoacidosis; FDG, fluorodeoxyglucose; FSH, follicle-stimulating hormone; HbA1c, glycated hemoglobin; ICPi, immune checkpoint inhibitor; irAEs, immune-related adverse events; LH, luteinizing hormone; MRI, magnetic resonance imaging; PET, positron emission tomography; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, thyroxine.

Authors and Disclosures

Anupam Kotwal, MD¹, Jordan E. Perlman, MD², Whitney S. Goldner, MD¹, Alissa Marr, MD³ and Jennifer S. Mammen, MD, PhD, MPhil²

¹Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE ²Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University Medical Center, Baltimore, MD ³Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE

Corresponding Author
Jennifer S. Mammen, MD, PhD, MPhil, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University Medical Center, Baltimore, MD 21224; e-mail: jmammen1@jhmi.edu.

Authors' Disclosures of Potential Conflicts of Interest
Endocrine Dysfunction From Immune Checkpoint Inhibitors: Pearls and Pitfalls in Evaluation and Management
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Whitney S. Goldner
Employment: DaVita
Leadership: Endocrine Society, ABIM Subspecialty Board
Research Funding: Roche (Inst), Siemens Healthcare Diagnostics

Jennifer S. Mammen
Stock and Other Ownership Interests: Johnson & Johnson, Bristol Myers Squibb
Research Funding: Interpace Diagnostics

No other potential conflicts of interest were reported.

Author Contributions
Conception and design: Anupam Kotwal, Whitney S. Goldner, Alissa Marr, Jennifer S. Mammen
Administrative support: Anupam Kotwal
Collection and assembly of data: Anupam Kotwal, Jennifer S. Mammen
Data analysis and interpretation: Anupam Kotwal, Jordan E. Perlman, Jennifer S. Mammen
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors