Endocrine - bmshkmedinfo

Management guidelines for endocrine irAEs

Common endocrine irAE symptoms

Endocrinopathy

Adrenal insufficiency

Hypothyroidism/hyperthyroidism

Diabetes mellitus & diabetic ketoacidosis

International guideline (ASCO, ESMO and NCCN) recommendations for endocrine irAEs^{1-3^}

^{^} For detailed guidelines, please refer to original publication

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Hypothyroidism	Assessment	Management
Subclinical hypothyroidism	TSH between 4 to <10 Normal FT4 Patient asymptomatic	Continue immunotherapy Continue to monitor TFTs
Subclinical hypothyroidism	Elevated TSH (>10) Normal FT4	Continue immunotherapy Consider levothyroxine Treat as overt hypothyroidism upon symptom presentation
Overt hypothyroidism	Elevated TSH (>10) Low FT4	Hold immunotherapy until adrenal insufficiency is ruled out and replacement endocrine therapy has started Consider endocrine consultation Check serum cortisol Administer levothyroxine Repeat TSH in 4–6 weeks to guide dosing changes
Central hypothyroidism	Normal or low TSH Low FT4	Hypophysitis/Central hypothyroidism; exclude recovery from thyrotoxicosis and non-thyroidal illness
Thyrotoxicosis	Assessment	Management
Lab-based diagnosis	Low or suppressed TSH with high FT4/total T3	Continue immunotherapy if asymptomatic Consider propranolol, atenolol or metoprolol as needed for symptoms until resolved Repeat TFTs in 4–6 weeks Consider endocrine consultation if symptomatic If persistent, consider evaluation for Graves’ disease

FT4, free thyroxine; NCCN, National Comprehensive Cancer Network; T3, triiodothyronine; TFT, thyroid function test; TSH, thyroid-stimulating hormone.

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	Assessment	Management
Hypothyroidism	Low FT4 with elevated TSH or TSH >10 with normal FT4	Continue ICI therapy Thyroxine 0.5–1.5 μg/kg
Thyrotoxicosis	DDx thyroiditis, Graves diseases	If unwell, withhold ICI therapy and consider restarting when symptoms are controlled Propranolol or atenolol for symptoms Carbimazole indicated for Graves’ disease Consider prednisolone 0.5 mg/kg and taper

DDx, differential diagnosis; FT4, free thyroxine; ICI, immune checkpoint inhibitor; TSH, thyroid-stimulating hormone.

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Hypothyroidism	Assessment	Management
Grade 1	TSH>4.5 and <10 mIU/L and asymptomatic	Continue immunotherapy Monitor TSH (and optionally FT4) every 4–6 weeks
Grade 2	Moderate symptoms, able to perform ADL. TSH persistently >10 mIU/L	Consider holding immunotherapy until symptoms resolve Consider endocrine consultation Consider thyroid hormone supplementation Monitor TSH every 4–8 weeks, consider FT4 monitoring
Grade 3–4	Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL	Hold immunotherapy Endocrine consultation Hospital admission for developing myxoedema Thyroid supplementation and reassessment
Thyrotoxicosis	Assessment	Management
Grade 1	Asymptomatic or mild symptoms	Continue immunotherapy Administer beta-blockers for symptomatic relief such as atenolol or propranolol Close monitoring every 2–3 weeks Treat transition to elevated TSH and low FT4 as primary hypothyroidism Consider endocrine consultation
Grade 2	Moderate symptoms, able to perform ADL	Consider holding immunotherapy Consider endocrine consultation Administer beta-blockers for symptomatic relief such as atenolol or propranolol Hydration and supportive care
Grade 3–4	Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL	Hold immunotherapy Endocrine consultation Administer beta-blockers such as atenolol or propranolol Hydration and supportive care Consider hospitalisation

ADL, activities of daily living; ASCO, American Society of Clinical Oncology; FT4, free thyroxine; TSH, thyroid-stimulating hormone.

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Assessment	Diagnosis	Management
New-onset fasting glucose >200 mg/dL Random blood glucose >250 mg/dL History of T2DM with fasting/random glucose >250 mg/dL	Consider new-onset ICI-T1DM Measure C-peptide with repeat serum glucose Evaluate for DKA via blood pH, metabolic panel, and urine/serum ketones Consider measurement of autoantibodies	C-peptide low + DKA present Hold immunotherapy until DKA resolves Inpatient care Urgent endocrine consultation Manage DKA as per institutional guidelines Initiate insulin Close glucose monitoring
		C-peptide low + DKA not present Continue immunotherapy Urgent endocrine consultation Consider inpatient care Initiate insulin and close glucose monitoring
		C-peptide appropriate for serum glucose Continue immunotherapy Continue monitoring of serum glucose and consider HgbA1c Consider insulin resistance (T2DM) or steroid-related hyperglycaemia Consider medical therapy, diet and lifestyle interventions

DKA, diabetic ketoacidosis; DM, diabetes mellitus; HgbA1c, hemoglobin A1c; ICI, immune checkpoint inhibitor; NCCN, National Comprehensive Cancer Network; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

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	Assessment	Management
Grade 1	Asymptomatic or mild symptoms T2DM with fasting glucose value >ULN to 160mg/dL No evidence of CIADM such as ketoacidosis or laboratory evidence of pancreatic autoimmunity	Continue immunotherapy Consider initiating oral therapy for those with new-onset T2DM Intensify medical therapy for those with worsening T2DM
Grade 2	Moderate symptoms, able to perform ADL; T2DM with fasting glucose value >160–250 mg/dL No ketoacidosis or metabolic derangements but other evidence of CIADM at any glucose level	Consider holding immunotherapy Urgent endocrine consultation for patients with new-onset CIADM Initiate insulin for CIADM Referral to ED or hospital admission if unable to initiate therapy, outpatient specialist evaluation is not available, developing ketoacidosis, or other concerns for CIADM
Grade 3–4	Severe symptoms Medically significant or life-threatening consequences Unable to perform ADL Grade 3: >250–500 mg/dL Grade 4: >500 mg/dL	Hold immunotherapy Admit for inpatient management of DKA, volume and electrolyte resuscitation, and insulin initiation Endocrine consultation Insulin therapy

ADL, activities of daily living; ASCO, American Society of Clinical Oncology; CIADM, checkpoint inhibitor-associated diabetes mellitus; DKA, diabetic ketoacidosis; ED, emergency department; T2DM, type 2 diabetes mellitus; ULN, upper limit of normal.

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Assessment	Management
Evaluate for symptoms Measure cortisol and ACTH, TSH, FT4, and sex hormones as appropriate Cosyntropin stimulation testing is not recommended in acute settings Brain MRI ± contrast with pituitary/sellar cuts	Hold immunotherapy Endocrine consultation and patient education Consider high-dose steroids (e.g. IV methylprednisolone 1mg/kg/day) Treat with physiologic hormone replacement Secondary adrenal insufficiency: Administer physiologic steroids in ambulatory patients and stress dosing for acute illness or surgery/procedures Central hypothyroidism: Thyroid hormone replacement, titrate to FT4 level

ACTH, adrenocorticotropic hormone; FT4, free thyroxine; IV, intravenous; MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; TSH, thyroid-stimulating hormone.

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Grade	Assessment	Management
Grade 1	Vague symptoms, no headache or asymptomatic	Continue immunotherapy Replace cortisol and/or thyroxine Conduct pituitary axis assessment MRI pituitary protocol Endocrine consultation
Grade 2	Moderate symptoms such as headache but no visual disturbance	Hold immunotherapy Endocrine consultation Tests as described in Grade 1 + monitor TFTs Oral prednisolone 0.5–1 mg/kg, wean corticosteroids based on symptoms over 1–2 weeks to 5 mg. Do not stop corticosteroids If no improvement in 48 hours, treat as severe
Grade 1–2	Fatigue or mood alteration but haemodynamically stable, no electrolyte distribution	Continue immunotherapy Tests as described in Grade 1 and 2 Replace cortisol and/or thyroxine
Grade 3–4	Severe mass effect symptoms such as severe headache, any visual disturbance, severe hypoadrenalism	Withhold immunotherapy Tests as described in Grade 1 and 2 Consider formal visual field assessment Initiate IV methylprednisolone 1 mg/kg Analgesia as needed for headache Aim to convert prednisolone and wean over 2–4 weeks to 5 mg. Do not stop corticosteroids

ESMO, European Society for Medical Oncology; IV, intravenous; MRI, magnetic resonance imaging; TFT, thyroid function test.

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Grade	Assessment	Management
Grade 1	Asymptomatic or mild symptoms	Consider holding immunotherapy Endocrine consultation Corticosteroid replacement (hydrocortisone, 15–20 mg in divided doses) for adrenal insufficiency Initiate other hormone replacement only after any needed adrenal replacement Consider thyroid hormone replacement Consider testosterone or oestrogen therapy if needed Recommend patient education, emergency injectable, and medical alert
Grade 2	Moderate symptoms, able to perform ADL	Consider holding immunotherapy Endocrine consultation Clinic evaluation to assess need for steroids and volume repletion Consider oral pulse dose therapy for those with MRI findings of swelling or threatened optic chiasm compression (prednisone 1 mg/kg/day or equivalent). Taper over 1–2 weeks Hormone supplementation
Grade 3–4	Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL	Hold immunotherapy Endocrine consultation Hospitalise or make referral for: Normal saline ≥2L or monitored free water replacement if DI IV stress dose steroids: hydrocortisone 50–100 mg Q6–8 hours initial dosing Oral pulse dose therapy: prednisone 1 mg/kg/day or equivalent tapered over at least 1–2 weeks Taper stress dose corticosteroids down to oral maintenance doses over 5–7 days Maintenance therapy as in Grade 1

2L, 2 litres; ADL, activities of daily living; ASCO, American Society of Clinical Oncology; DI, diabetes insipidus; IV, intravenous; MRI, magnetic resonance imaging, Q6–8 , every 6 to 8 hours.

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Grade	Assessment	Management
Grade 1	Asymptomatic or mild symptoms	Consider holding immunotherapy Endocrine consultation Initiate replacement therapy with hydrocortisone (15–20 mg in divided doses) Titrate up to 30 mg daily for residual AI symptoms Reduce maintenance dosing for symptoms of iatrogenic Cushing’s syndrome Consider fludrocortisone (0.05–0.1 mg/day)
Grade 2	Moderate symptoms, able to perform ADL	Consider holding immunotherapy Endocrine consultation Assess need for hydration, supportive care, and hospitalisation Initiate outpatient corticosteroid treatment at 2–3x maintenance to manage acute symptoms Initiate fludrocortisone (0.05–0.1 mg/day) Decrease stress dose corticosteroids down to maintenance after 2 days Maintenance therapy as in Grade 1
Grade 3–4	Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL	Hold immunotherapy Endocrine consultation Consider inpatient management if necessary, including normal saline (≥2L) and hydrocortisone (50–100 mg Q6–8 hours initial dosing) Taper stress dose corticosteroids over 5–7 days

*NCCN and ESMO do not provide specific guidelines for primary adrenal insufficiency.
2L, 2 litres; ADL, activities of daily living; AI , adrenal insufficiency; ASCO, American Society of Clinical Oncology; Q6–8, every 6 to 8 hours.

References:

Schneider BJ, et al. J Clin Oncol 2021;39:4073–4126. Available at: https://ascopubs.org/doi/full/10.1200/JCO.21.01440. Accessed April 2025.
Haanen J, et al. Ann Oncol 2022;33:1217–1238. Available at: https://www.annalsofoncology.org/article/S0923-7534(22)04187-4/fulltext. Accessed April 2025.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Management of immunotherapy-Related Toxicities. Version 1.2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed April 2025.
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A. Thyroid dysfunction

NCCN grading and management 3

ESMO grading and management 2

ASCO grading and management 1

B. Hyperglycaemia & diabetes

NCCN grading and management 3

ASCO grading and management 1

C. Hypophysitis

NCCN grading and management 3

ESMO grading and management4 2

ASCO Grading and Management 1

D. Primary adrenal insufficiency

ASCO grading and management 1