Management guidelines for endocrine irAEs1,2,6
Common endocrine irAE symptoms
BMS-recommended management guidelines for endocrine irAE2
Unless an alternative aetiology has been identified, signs or symptoms of endocrinopathies should be considered irAEs
| Grade 1 | Grade 2–4 | |
|---|---|---|
| Definition | Asymptomatic (e.g. hypothyroidism, hyperthyroidism, hypophysitis) | Symptomatic (e.g. hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism) |
| Dual NIVO + IPI or NIVO alone | Continue treatment | Hypo- or hyperthyroidism
Grade 2–3: Withhold treatment Grade 4: Permanently discontinue treatment Hypophysitis Grade 2 : Withhold treatment Grade 3 : Withhold6 or Permanently discontinue treatment2 Grade 4 : Permanently discontinue treatment Adrenal insufficiency Grade 2: Withhold treatment Grade 3 or 4: Permanently discontinue treatment |
| Monitoring | If TSH <0.5× LLN, or TSH >2× ULN, or consistently out of range in two subsequent measurements, include free T4 at subsequent cycles as clinically indicated | Evaluate endocrine function
Consider pituitary scan Repeat labs in 1–3 weeks/MRI in 1 month if symptoms persist but normal lab/pituitary scan |
| Consultations1 | Consider endocrinology | Consider endocrinology |
| Medication | Hypothyroidism
Start thyroid hormone replacement therapy Hyperthyroidism Start anti-thyroid medication Consider methylprednisolone equivalents 1–2 mg/kg/day if acute inflammation of the thyroid is suspected Hypophysitis Start hormone replacement as needed Consider methylprednisolone equivalents 1–2 mg/kg/day if acute inflammation of the pituitary gland is suspected Adrenal insufficiency Start physiologic corticosteroid replacement as needed |
Hypothyroidism (Grade 2–4)
Start thyroid hormone replacement therapy Consider methylprednisolone equivalents 1–2 mg/kg/day Hyperthyroidism (Grade 2–4) Start anti-thyroid medication Consider methylprednisolone equivalents 1–2 mg/kg/day if acute inflammation of the thyroid is suspected Hypophysitis (Grade 2–4) Start hormone replacement Consider methylprednisolone equivalents 1–2 mg/kg/day Adrenal insufficiency (Grade 2–4) Start physiologic corticosteroid replacement |
| Endocrine tests | – | Laboratory assessments, pituitary scan |
| Follow-up | Continue standard monitoring | If improved (with or without hormone replacement):
Resume treatment, continue standard monitoring |
IPI, ipilimumab; irAE, immune-related adverse event; LLN, lower limit of normal; MRI, magnetic resonance imaging; NIVO, nivolumab; T4, thyroxine; TSH, thyroid-stimulating hormone; ULN, upper limit of normal
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
|---|---|---|---|---|
| Hypophysitis | Asymptomatic or mild symptoms;
clinical or diagnostic observations only; intervention not indicated |
Moderate;
minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL |
Severe or medically significant, but not immediately life-threatening;
hospitalisation or prolongation of existing hospitalisation indicated; disabling; limiting self-care ADL |
Life-threatening consequences;
urgent intervention indicated |
| Adrenal insufficiency | Asymptomatic; clinical or diagnostic observations only; intervention not indicated | Moderate symptoms; medical intervention indicated | Severe symptoms; hospitalisation indicated | Life-threatening consequences; urgent intervention indicated |
| Hyperglycaemia (fasting glucose level) | >ULN–160 mg/dL (8.9 mmol/L) | >160–250 mg/dL (8.9–13.9 mmol/L) | >250–500 mg/dL (13.9–27.8 mmol/L) hospitalisation indicated | >500 mg/dL (27.8 mmol/L) life-threatening consequences |
ADL, activities of daily living; ULN, upper limit of normal
International guideline (ASCO, ESMO and NCCN) recommendations for endocrine irAEs3–5^
^ For detailed guidelines, please refer to original publication
| Hypothyroidism | Thyrotoxicosis | |
|---|---|---|
| Immunotherapy | Continue immunotherapy at Grade 1; consider holding at Grade 25; hold if patient unwell4 or Grade 3–45 | |
| Consultation | (Consider)3–5 Consult endocrinology (Grade 3–4)5 | Consider5 (Grade 1) and refer to endocrinology (Grade 2) for persistent thyrotoxicosis (>6 weeks)3; endocrine consultation for all patients (Grade3–4)3 |
| Monitoring/testing | Continue 4–6 weekly TSH and FT4 testing (FT4 optional according to ASCO guidelines)3
If primary hypothyroidism, exclude concomitant adrenal insufficiency3 |
Monitor TSH + FT4 every 2–3 weeks until clear if persistent or hypothyroidism develops3or
Repeat TFTs in 4–6 weeks5
|
| Interventions | Consider (levo)thyroxine/thyroid hormone supplementation if elevated TSH (>10 mIU/L),3–5 or if symptomatic5
Adjust supplementation based on updated monitoring/testing |
Beta-blocker (e.g. atenolol3–5, propanolol3–5, metoprolol5) for symptomatic relief
Hydration and supportive care3,4 |
| Admission | If signs of myxoedema, consider admitting for IV therapy3 | Consider hospitalising patients in severe cases as inpatient endocrine consultation can guide the use of additional medical therapies including
|
| Additional considerations | Adrenal dysfunction, if present, must always be replaced before thyroid hormone therapy is initiated3 | Physical examination findings of ophthalmopathy or thyroid bruit are diagnostic of Graves’ disease and should prompt early endocrine referral3
Carbimazole indicated for Graves’ disease4 Thyrotoxicosis often evolves to hypothyroidism (50–90%) requiring thyroid hormone replacement therapy5 |
ADL, activities of daily living; FT4, free thyroxine; IV, intravenous; SSKI, saturated solution of potassium iodide; TSH, thyroid-stimulating hormone
Thyroid dysfunction is defined as elevated TSH with normal (asymptomatic/subclinical hypothyroidism)5 or low FT4 (primary hypothyroidism).3–5 Thyrotoxicosis is defined as low or suppressed TSH with high FT4 / total T3.5 Test TSH and FT4 every 4–6 weeks as part of routine clinical monitoring on therapy or for case detection in symptomatic patients.3,4 Where patients are receiving an anti-CTLA4 (with or without a PD-1 inhibitor), monitor TFTs every cycle.4
FT4, free thyroxine; PD-1, programmed cell death 1; TFT, thyroid function test; TSH, thyroid-stimulating hormone
| ASCO grading | ||
|---|---|---|
| Primary hypothyroidism3 | ||
| Grade 1 | Grade 2 | Grade 3–4 |
| TSH >4.5 and <10 mIU/L, asymptomatic | TSH persistently >10 mIU/L, moderate symptoms, able to perform ADL | Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL |
| Thyrotoxicosis3 | ||
| Grade 1 | Grade 2 | Grade 3–4 |
| Asymptomatic or mild symptoms | Moderate symptoms, able to perform ADL | Severe symptoms, medically significant or life-threatening consequences, not able to perform ADL |
ADL, activities of daily living; ASCO, American Society of Clinical Oncology; TSH, thyroid-stimulating hormone
| Grade 1 | Grade 2 | Grade 3–4 | |
|---|---|---|---|
| Immunotherapy | Continue immunotherapy with close clinical follow-up and laboratory evaluation3,5 | May hold immunotherapy until glucose control is obtained3 | Hold immunotherapy until glucose control is obtained on therapy with reduction of toxicity to Grade ≤11,3 |
| Consultation | Consider endocrine consultation if symptomatic and/or persistently uncontrolled hyperglycaemia5 | Urgent endocrine consultation for all T1DM | Endocrine consultation for all patients3,5 |
| Monitoring/testing | Screen for T1DM if appropriate | Evaluate for DKA if clinically appropriate5 | Evaluate for DKA3,5 |
| Interventions | May initiate oral therapy for new-onset T2DM; intensify medical therapy for those with worsening T2DM3
Diet and lifestyle modification5 |
Insulin as default therapy or
titrate oral therapy or add insulin for worsening control in T2DM3 |
Initiate insulin therapy for all patients,3 treatment for DKA as per local protocol5 |
| Admission | – | Consider admission for T1DM if early outpatient evaluation is not available3 or signs of ketoacidosis are present3,5 | Inpatient care for DKA management, volume and electrolyte resuscitation, and insulin initiation3,5 |
Additional considerations3: Sliding-scale insulin in T2DM, and lower insulin doses in T1DM (estimated total daily requirement: 0.3–0.4 units/kg/day)
DKA, diabetic ketoacidosis; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
T2DM: A combination of insulin resistance and insufficiency that may require oral or insulin therapy; new onset or exacerbated during therapy for nonimmunologic reasons (e.g. corticosteroid use).3
T1DM (autoimmune): Islet cell destruction often of acute onset, with ketosis and an insulin requirement.3
Blood glucose levels (fasting glucose preferred5) should be regularly monitored in patients treated with immunotherapy to detect the emergence of diabetes.3–5 In cases of new onset hyperglycaemia, a patient’s medical background, exposure history, and risk factors should be considered for each subtype of DM.3–5 Additional tests to distinguish between T1DM and T2DM include C-peptide and antibodies against glutamic acid decarboxylase and islet cells.3,4
DM, diabetes mellitus; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
| ASCO grading of diabetes3 | ||
|---|---|---|
| Grade 1 | Grade 2 | Grade 3–4 |
| Asymptomatic or mild symptoms; no evidence of CIADM or such as ketoacidosis or evidence of pancreatic autoimmunity | Moderate symptoms, able to perform ADL, no ketoacidosis or metabolic derangement but other evidence of CIADM at any glucose level | Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL, ketoacidosis or other metabolic abnormality |
| ASCO grading of hyperglycaemia3 | ||
|---|---|---|
| Fasting glucose | Glucose level | |
| Grade 1 | >ULN (160 mg/dL; 8.9 mmol/L) | – |
| Grade 2 | >160–250 mg/dL; >8.9–13.9 mmol/L | – |
| Grade 3 | – | >250–500 mg/dL; >13.9–27.8 mmol/L |
| Grade 4 | – | >500 mg/dL; >27.8 mmol/L |
ADL, activities of daily living; ASCO, American Society of Clinical Oncology; DM, diabetes mellitus; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; ULN, upper limit of normal
| Grade 1 | Grade 2 | Grade 3–4 | |
|---|---|---|---|
| Immunotherapy | (Consider)1,3 Hold immunotherapy until patient is stabilised on hormone replacement therapy1,3–5 | ||
| Consultation | Endocrine consultation3,5 | ||
| Monitoring/testing | Follow FT4 for thyroid hormone replacement titration3,5
Laboratory confirmation of adrenal insufficiency should not be attempted until treatment with corticosteroids for other disease is ready to be discontinued3 |
||
| Interventions |
|
or
|
or
|
Initiate hormone replacement therapy* as indicated:5
*Hormone replacement therapy dosing as per management guidelines for adrenal insufficiency and primary hypothyroidism |
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| Admission | – | – | Hospitalise or make an ED referral for:
In patients with significant swelling on MRI, optic chiasm compression, severe headache, or visual changes,3 oral pulse prednisolone 1–2 mg/kg daily (or equivalent) tapered over 1–2 weeks to physiologic maintenance |
| Additional considerations3 | Always start corticosteroids several days before thyroid hormone to prevent precipitating adrenal crisis | ||
DI, diabetes insipidus; FT4, free thyroxine
Immunotherapy-induced hypophysitis is defined as inflammation of the pituitary with varying effects on hormone function.3,4 Common presentation with adrenal insufficiency (low ACTH, low cortisol5), central hypothyroidism (low TSH, low FT45), diabetes insipidus (hypernatraemia and volume depletion) and hypogonadism (low testosterone/oestradiol with low LH and FSH) are also possible.3
Testing of hypophysitis includes ACTH, cortisol (AM), TSH, FT4, testosterone (in males)/oestrogen (in females)5 and electrolytes.3,5 Consider evaluating LH and FSH, and MRI (± contrast) with pituitary/sellar cuts if symptomatic.3,5
ACTH, adrenocorticotropic hormone; AM, morning; FSH, follicle-stimulating hormone; FT4, free thyroxine; LH, luteinizing hormone; MRI, magnetic resonance imaging; TSH, thyroid-stimulating hormone
| Grading for hypophysitis3,4 | ||
|---|---|---|
| Grade 1 | Grade 2 | Grade 3–4 |
| ASCO: Asymptomatic or mild symptoms
ESMO: Vague symptoms (e.g. mild fatigue, anorexia), no headache or asymptomatic, mood alteration but haemodynamically stable, no electrolyte disturbance |
ASCO: Moderate symptoms, able to perform ADL
ESMO: Moderate symptoms, i.e. headache but no visual disturbance, fatigue or mood alteration but haemodynamically stable, no electrolyte disturbance |
ASCO: Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL
ESMO: Severe mass effect symptoms i.e. severe headache, any visual disturbance or severe hypoadrenalism, hypotension, severe electrolyte disturbance |
ADL, activities of daily living; ASCO, American Society of Clinical Oncology
| Grade 1 | Grade 2 | Grade 3–4 | |
|---|---|---|---|
| Immunotherapy | Consider holding immunotherapy until patient is stabilised on replacement hormone | Hold immunotherapy until patient is stabilised on replacement hormone3–5 | |
| Consultation | Endocrine consultation | ||
| Interventions3 | Hydrocortisone 15–20 mg in divided doses, with a maximum of 30 mg daily total dose
Consider initiating fludrocortisone 0.05–0.1 mg/day if needed |
Initiate outpatient treatment at 2–3× maintenance to manage acute symptoms:
Initiate fludrocortisone 0.05–0.1 mg/day |
An emergency department referral for normal saline (at least 2 L) and initiate stress-dose hydrocortisone 50–100 mg IV Q6–8H |
| Additional consideration | Titrate dose up or down as symptoms dictate | Maintenance therapy as in Grade 1
Taper stress-dose corticosteroid down to maintenance dose over 2 days3 |
Taper stress-dose corticosteroid down to maintenance dose over 5–7 days after discharge3 |
IV, intravenous; OD, once daily
Adrenal gland failure leading to low morning cortisol, high morning ACTH, as well as hyponatraemia and hyperkalaemia with orthostasis and volume depletion due to loss of aldosterone.3
When adrenal insufficiency is suspected, conduct blood tests for ACTH and cortisol level (both AM), basic metabolic panel (Na, K, CO2, glucose). Consider ACTH stimulation test for indeterminate results.3 If primary adrenal insufficiency (high ACTH, low cortisol) is found biochemically, evaluate for precipitating cause of crisis such as infection and perform an adrenal CT for metastasis/haemorrhage.3
ACTH, adrenocorticotropic hormone; AM, morning; CO2, carbon dioxide; CT, computed tomography; K, potassium; Na, sodium
| ASCO grading for primary adrenal insufficiency3 | ||
|---|---|---|
| Grade 1 | Grade 2 | Grade 3–4 |
| Asymptomatic or mild symptoms. | Moderate symptoms, able to perform ADL. | Severe symptoms, medically significant or life-threatening consequences, unable to perform ADL. |
ADL, activities of daily living; ASCO, American Society of Clinical Oncology
ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; irAE, immune-related adverse event; NCCN, National Comprehensive Cancer Network
References:
- OPDIVO® (nivolumab) Product Information, BMS Hong Kong.
- Bristol Myers Squibb. Immune-Related Adverse Reaction (irAR) Management Guide. 1506AU2002148-01. April 2020.
- Schneider BJ, et al. J Clin Oncol 2021;39:4073–4126. Available at: https://ascopubs.org/doi/full/10.1200/JCO.21.01440. Accessed March 2023.
- Haanen J, et al. Ann Oncol 2022;33:1217–1238. Available at: https://www.annalsofoncology.org/article/S0923-7534(22)04187-4/fulltext. Accessed March 2023.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Management of immunotherapy-Related Toxicities. Version 1.2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed 13 February 2022.
- YERVOY® (ipilimumab) Product Information, BMS Hong Kong.
