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Immunotherapy often inflames the thyroid gland. It can briefly make the thyroid overactive (racing heart, sweating, shakiness) and then underactive (tiredness, feeling cold), and the underactive phase is often permanent. It is found on routine blood tests, treated with tablets rather than steroids, and immunotherapy usually carries on.
The commonest endocrine irAE. Hypothyroidism occurs in about 8% on PD-(L)1 inhibitors, 3% on CTLA-4 inhibitors and 15% on combinations (SITC 2021); ESE 2022 gives 3.9 to 8.5%, 2.5 to 3.8% and 10.2 to 16.4%, with onset at a median 8 to 12 weeks. A thyrotoxic phase, typically 4 to 6 weeks after starting and lasting about 6 weeks, often precedes it, and hypothyroidism is often permanent.
Monitoring: TSH and free T4 every 4 to 6 weeks on treatment and every 6 to 12 months after (SITC; ESE suggests before every cycle for the first 6 months). Thyrotoxicosis is treated with beta-blockers for symptoms; persistent thyrotoxicosis needs assessment for Graves' disease with TSH receptor antibodies. Morning cortisol is checked before levothyroxine, because replacing thyroid hormone in untreated adrenal insufficiency can precipitate a crisis. High-dose glucocorticoids are not used for thyroiditis (ESE, +000). Immunotherapy is usually continued.
The two guidelines differ on when and how much levothyroxine to start: SITC considers it for a persistently raised TSH with normal free T4 and starts at 1.5 to 1.6 µg/kg/day in young healthy patients; ESE suggests it when free T4 is low and TSH above 10 mIU/L (++00), advises against routine treatment for TSH 4 to 10 with normal free T4 (+000), and starts at 1.0 µg/kg/day. ESMO 2022 could not be read.
Why: Thyroid problems are often silent and can start months after the last dose.
“Thyroid function (TSH, fT4) should be tested every 4–6 weeks during ICI treatment, and should continue to be tested every 6–12 months following the conclusion of ICI treatment.”
Why: A controlled thyroid problem is not a reason to stop cancer treatment.
“Patients experiencing endocrine toxicities should be treated with hormone replacement, and immunotherapy should generally be continued as soon as patients are stable (often without interruption).”
Why: Steroids have not been shown to save the thyroid, and they bring their own side effects.
“We recommend against the use of high-dose glucocorticoids for the treatment of thyroiditis; except in severe thyrotoxicosis and severe thyroid eye disease”
European Society of Endocrinology, European Journal of Endocrinology 2022 · +000
Why: Most cases are mild, and the overactive phase usually passes on its own.
“We suggest that cases of clinically and biochemically mild thyrotoxicosis or hypothyroidism can be monitored without treatment”
European Society of Endocrinology, European Journal of Endocrinology 2022 · good clinical practice
Why: A beta-blocker calms a racing heart and shakiness while the inflammation settles.
“Patients with low TSH and normal fT4 should receive repeat TSH and fT4 testing routinely, and if symptoms of hyperthyroidism or high fT4 develop patients should be treated with beta-blockers. Patients with asthma or chronic obstructive pulmonary disease should be treated with cardioselective beta-blockers such as atenolol or metoprolol.”
Why: Graves' disease is rare after immunotherapy but needs different treatment (anti-thyroid drugs) from thyroiditis.
“TSH receptor antibody should be considered in patients with suspected ir-Graves’ disease, as the condition is managed differently from ir-thyroiditis.”
Why: Replacing thyroid hormone when adrenal insufficiency is untreated can trigger an adrenal crisis.
“Patients with symptoms of hypothyroidism and/or with elevated TSH and low fT4 should be tested for morning cortisol to identify possible concurrent adrenal insufficiency.”
Why: Treating an underactive thyroid improves tiredness and other symptoms.
“We suggest replacement with levothyroxine in primary hypothyroidism in cases with fT4 below the lower reference limit and TSH > 10 mIU/L.”
European Society of Endocrinology, European Journal of Endocrinology 2022 · ++00
Why: A mildly raised TSH often settles or stays harmless.
“We recommend against routine replacement with levothyroxine of ICI-treated patients with a TSH between 4–10 mIU/L and a normal fT4”
European Society of Endocrinology, European Journal of Endocrinology 2022 · +000
Why: Levothyroxine takes weeks to reach a steady level, so earlier changes overshoot.
“Regular monitoring of thyroid hormones (TSH and fT4) is needed in order to titrate levothyroxine dosage at intervals of at least 6 weeks.”
European Society of Endocrinology, European Journal of Endocrinology 2022
Why: Thyroid problems can develop late and the symptoms are vague.
“In case of ICI cessation, ongoing monitoring of thyroid function (TSH and fT4) is still indicated, albeit less frequently (e.g. every 6–12 months and in case of symptoms and signs of thyroid dysfunction).”
European Society of Endocrinology, European Journal of Endocrinology 2022
How care is usually carried out, read from the guidelines and standards cited. Your own team's protocol and their judgement come first; this page is for understanding it, not for doing it yourself.
SITC 2021 and ESE 2022 agree on regular TSH and free T4 testing, beta-blockers for symptomatic thyrotoxicosis, a check for adrenal insufficiency before levothyroxine, no high-dose steroids for thyroiditis, and continuing immunotherapy. They disagree on when and how much levothyroxine to start. SITC considers levothyroxine for a persistently raised TSH with a normal free T4 (subclinical hypothyroidism) and starts at 1.5 to 1.6 µg/kg/day in young healthy patients (25 or 50 µg/day if older than 65 or with heart disease), without a grade. ESE suggests replacement only when free T4 is below range and TSH above 10 mIU/L (++00), recommends against routine replacement for TSH 4 to 10 with a normal free T4 (+000), and starts at 1.0 µg/kg/day (25 µg/day in older people or those with heart disease). ESE is a GRADE-based endocrine guideline with a systematic review behind it, so its thresholds are the better supported; SITC's are expert consensus. The SITC 2025 endocrine definitions take a middle line: replacement for a TSH above 10 mIU/L whatever the free T4.
European Society of Endocrinology, European Journal of Endocrinology 2022 · SITC, Journal for ImmunoTherapy of Cancer 2021 · Journal for ImmunoTherapy of Cancer 2025
Where it differs: Tests TSH and free T4 before every treatment cycle for the first 6 months, then every 2 to 3 months for 6 months, then every 6 months, instead of a flat every 4 to 6 weeks.
Evidence: Described in the text as general advice; not a graded recommendation.
European Society of Endocrinology, European Journal of Endocrinology 2022
Where it differs: Defines overt hypothyroidism as a high TSH with low free T4, or a TSH above 10 mIU/L regardless of free T4, and starts replacement in either case.
Evidence: Modified Delphi consensus (RAND/UCLA appropriateness method) of an expert panel; not graded.
Where it differs: Starts 1.5 to 1.6 µg/kg/day for young, healthy patients and 25 or 50 µg/day above 65 or with heart disease, and considers treating a persistent raised TSH with normal free T4.
Evidence: Expert consensus; no level of evidence printed for this recommendation.
| Recommendation | Grade, as printed | Source |
|---|---|---|
| A controlled endocrinopathy is not a contraindication to starting or continuing checkpoint inhibitors “We recommend that a controlled endocrinopathy is not a contraindication for initiation and/or continuation of ICI therapy” | ++00 | European Society of Endocrinology, European Journal of Endocrinology 2022 |
| No high-dose glucocorticoids for thyroiditis, except severe thyrotoxicosis or thyroid eye disease | +000 | European Society of Endocrinology, European Journal of Endocrinology 2022 |
| Beta-blockers in symptomatic thyrotoxicosis “We recommend using beta-blockers in symptomatic thyrotoxicosis” | good clinical practice | European Society of Endocrinology, European Journal of Endocrinology 2022 |
| Levothyroxine when free T4 is below range and TSH above 10 mIU/L | ++00 | European Society of Endocrinology, European Journal of Endocrinology 2022 |
| No routine levothyroxine for TSH 4 to 10 mIU/L with normal free T4 | +000 | European Society of Endocrinology, European Journal of Endocrinology 2022 |
| Consider tapering and stopping low-dose levothyroxine periodically to see whether the thyroid has recovered “We suggest considering tapering and stopping levothyroxine periodically in patients with low-dose replacement to assess whether thyroid function has recovered” | +000 | European Society of Endocrinology, European Journal of Endocrinology 2022 |
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