What is the treatment for hypothyroidism (underactive thyroid) following cancer immunotherapy?

Treatment of Hypothyroidism Following Cancer Immunotherapy

Immediate Management Approach

Start levothyroxine replacement therapy immediately once hypothyroidism is confirmed, and immune checkpoint inhibitor (ICI) therapy can typically be continued without interruption for grades 1-2 hypothyroidism. 1

When to Hold Immunotherapy

• Hold ICI only for grade ≥3 hypothyroidism (severe symptoms limiting self-care activities or life-threatening consequences) until symptoms resolve to grade 2 or better with appropriate thyroid hormone replacement 1
• For grades 1-2 hypothyroidism, ICI can be safely continued while initiating thyroid hormone replacement 1

Critical Safety Consideration: Rule Out Adrenal Insufficiency First

Before initiating levothyroxine in any patient with suspected central hypothyroidism or hypophysitis, always start corticosteroid replacement first to prevent precipitating adrenal crisis. 1

• In ICI-induced hypophysitis, both central adrenal insufficiency and central hypothyroidism occur in >75% of patients 1
• Starting thyroid hormone before addressing adrenal insufficiency accelerates cortisol clearance and can trigger life-threatening adrenal crisis 1
• For primary hypothyroidism (elevated TSH with low free T4), this precaution is not necessary 1

Levothyroxine Dosing Strategy

Initial Dosing for ICI-Associated Hypothyroidism

The optimal starting dose for ICI-associated hypothyroidism is higher than traditional Hashimoto's thyroiditis, at approximately 1.45 mcg/kg/day based on actual body weight. 2

Age-Based Dosing Algorithm:

For patients <70 years without cardiac disease:

• Start with full replacement dose: 1.45-1.6 mcg/kg/day 1, 2
• This can be initiated as a single daily dose 1

For patients ≥70 years OR with known cardiovascular disease:

• Start conservatively at 25-50 mcg/day 1
• Titrate gradually every 6-8 weeks to avoid cardiac complications 1
• Elderly patients with coronary disease risk cardiac decompensation even with therapeutic doses 3

Key Dosing Distinction from Other Causes

ICI-associated hypothyroidism requires approximately 16% higher levothyroxine doses compared to Hashimoto's thyroiditis (1.45 vs 1.25 mcg/kg/day), likely due to residual thyroid inflammation and altered hormone metabolism 2. This difference persists even after accounting for age and interfering medications 2.

Monitoring Protocol

Initial Monitoring Phase (First 20 Weeks)

Check TSH and free T4 every 4-6 weeks during the first 20 weeks of immunotherapy, as thyroid dysfunction typically manifests within this timeframe. 1, 4

• Thyrotoxicosis from thyroiditis occurs an average of 1 month after starting ICI 1
• Progression to hypothyroidism occurs approximately 1 month after the thyrotoxic phase (2 months from ICI initiation) 1
• TFT fluctuations are most pronounced around weeks 6-8 of treatment 4

Dose Titration Monitoring

Recheck TSH and free T4 every 6-8 weeks after each dose adjustment until stable euthyroid state is achieved. 1

• Target TSH: 0.5-4.5 mIU/L with normal free T4 1
• Wait full 6-8 weeks between adjustments to reach steady state 1
• Adjust dose by 12.5-25 mcg increments based on TSH response 1

Long-Term Surveillance

After achieving stable euthyroid state, monitor TSH every 12 weeks through week 20, then space to every 6-12 months. 1, 4

• Annual monitoring is sufficient once maintenance dose is established 1
• Recheck sooner if symptoms change or new interfering medications are started 1

Special Clinical Scenarios

Thyrotoxic Phase Management

If patients present with initial hyperthyroidism from ICI-induced thyroiditis, manage conservatively with beta-blockers only—do NOT use antithyroid drugs. 1

• Thyroiditis-induced thyrotoxicosis is self-limiting and resolves to hypothyroidism 1
• Use non-selective beta-blockers (atenolol 25-50 mg daily) for symptomatic relief 1
• Monitor TSH/free T4 every 2-3 weeks to catch transition to hypothyroidism 1
• Initiate levothyroxine when free T4 falls below reference range 1, 2

Pre-Existing Hypothyroidism

For patients already on levothyroxine before starting immunotherapy, expect to increase the dose by approximately 20-30% during treatment. 4

• Monitor TFTs every 4 weeks initially, as dose requirements fluctuate 4
• The levothyroxine dose at 54 weeks trends higher than baseline (p=0.06) 4
• Continue close monitoring even with pre-existing thyroid disease 4

Central Hypothyroidism from Hypophysitis

Patients with ICI-induced hypophysitis require lower levothyroxine doses (mean 0.9 mcg/kg) compared to primary hypothyroidism. 4

• Start at 1 mcg/kg rather than 1.45 mcg/kg for primary hypothyroidism 1, 4
• The observed dose is significantly lower than weight-based calculations predict (mean difference -58.3 mcg, p<0.0001) 4
• Always replace cortisol first, then initiate thyroid hormone after corticosteroids are started 1

Common Pitfalls to Avoid

Critical Errors in Management

Never start levothyroxine before ruling out adrenal insufficiency in patients with suspected hypophysitis or central hypothyroidism. 1

Do not use standard Hashimoto's dosing (1.25 mcg/kg) for ICI-associated hypothyroidism—this will result in persistent undertreatment. 2

Avoid treating transient thyrotoxicosis with antithyroid drugs (methimazole/PTU)—this phase is self-limiting and will progress to hypothyroidism. 1

Monitoring Errors

Do not adjust levothyroxine doses more frequently than every 6-8 weeks—steady state is not reached before this interval. 1

Do not rely on TSH alone in central hypothyroidism—target free T4 in the upper half of reference range instead. 1

Overtreatment Risks

Approximately 25% of patients are inadvertently maintained on excessive doses causing TSH suppression, increasing risks for atrial fibrillation, osteoporosis, and cardiac complications. 1

• Monitor for symptoms of hyperthyroidism: tachycardia, tremor, heat intolerance, weight loss 1
• If TSH falls below 0.1 mIU/L, reduce dose by 25-50 mcg immediately 1
• Elderly patients and those with cardiac disease are at highest risk for complications from overtreatment 1, 3

Prognosis and Duration of Treatment

ICI-associated hypothyroidism is typically permanent, requiring lifelong thyroid hormone replacement in most cases. 1

• Only 2 of 103 patients (1.9%) experienced spontaneous thyroid function recovery 2
• Hypothyroidism persists a median of 54 days but usually becomes permanent 5
• Both adrenal insufficiency and hypothyroidism from hypophysitis represent long-term sequelae requiring lifelong replacement 1

Patient Education Requirements

All patients with ICI-induced hypothyroidism should receive education on medication adherence, stress dosing (if concurrent adrenal insufficiency), and when to seek medical attention. 1

• Take levothyroxine on empty stomach, 30-60 minutes before breakfast with full glass of water 3
• Separate from interfering medications by at least 4 hours 3
• For concurrent adrenal insufficiency: obtain medical alert bracelet, learn stress dosing, and carry emergency injectable steroids 1