When do we interrupt immunotherapy in a patient with elevated isolated Thyroid-Stimulating Hormone (TSH) but normal Triiodothyronine (T3) and Thyroxine (T4) levels?

Management of Isolated TSH Elevation During Immunotherapy

Direct Answer

Continue immunotherapy without interruption for isolated TSH elevation with normal T3 and T4, and initiate levothyroxine replacement therapy based on TSH level and symptom severity. 1

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When to Continue Immunotherapy (Most Cases)

Immunotherapy should NOT be interrupted for isolated thyroid dysfunction in the vast majority of cases. 1, 2 The key principle is that thyroid dysfunction during checkpoint inhibitor therapy is:

• Transient and easily managed 2
• Mild in severity 2
• Does not require treatment interruption 1, 2

Specific Management Algorithm

For TSH >10 mIU/L with normal T3/T4:

• Continue immunotherapy 1
• Start levothyroxine replacement immediately (0.5-1.5 μg/kg, starting low in elderly or those with cardiac history) 1
• Monitor TSH every cycle for first 3 months, then every second cycle 1

For TSH 4.5-10 mIU/L with normal T3/T4:

• Continue immunotherapy 1
• Consider levothyroxine if symptomatic (fatigue or other hypothyroid complaints) 1, 3
• Repeat TSH next cycle if asymptomatic 1
• Monitor TSH every cycle for first 3 months 1

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The ONLY Scenario to Withhold Immunotherapy

Withhold immunotherapy ONLY if the patient is unwell with symptomatic hyperthyroidism (during the thyrotoxic phase that may precede hypothyroidism). 1 This presents as:

• Symptomatic hyperthyroidism requiring beta-blockers 1
• Rarely requiring carbimazole or steroids 1
• Restart immunotherapy when symptoms are controlled 1

Isolated TSH elevation with normal T3/T4 does NOT meet criteria for treatment interruption. 1

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Monitoring Strategy During Immunotherapy

Anti-PD-1/Anti-PD-L1 Monotherapy:

• TSH every cycle for first 3 months 1
• Every second cycle thereafter (if on 2-weekly schedule) 1
• Check 9 am cortisol if TSH falls across two measurements (suggests hypophysitis) 1

Anti-CTLA4 or Combination Therapy:

• TSH every cycle 1
• Higher risk of thyroid dysfunction (20% with combination vs 6-9% with anti-PD-1/PD-L1 alone) 2, 4
• TSH 4-6 weeks after cycle 4 1

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Treatment Thresholds for Levothyroxine

Mandatory Treatment (Continue Immunotherapy):

• TSH >10 mIU/L regardless of symptoms 1, 3, 5
• Any TSH elevation with symptoms of hypothyroidism (fatigue, cold intolerance, weight gain) 1, 3
• Painful thyroiditis (consider prednisolone 0.5 mg/kg and taper) 1

Consider Treatment (Continue Immunotherapy):

• TSH 4.5-10 mIU/L with fatigue or hypothyroid symptoms 1, 3
• Even subclinical hypothyroidism warrants consideration if symptomatic 1, 2

Monitor Without Treatment (Continue Immunotherapy):

• TSH <10 mIU/L with normal T3/T4 and no symptoms 1
• Repeat next cycle 1

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Critical Distinction: Primary Hypothyroidism vs Hypophysitis

A falling TSH across two measurements with normal or lowered T4 suggests pituitary dysfunction (hypophysitis), not primary hypothyroidism. 1 This requires:

• Weekly cortisol measurements 1
• Rule out adrenal insufficiency BEFORE starting levothyroxine 1, 3
• Start corticosteroids first if hypophysitis confirmed 1

In suspected hypophysitis, always replace cortisol for 1 week prior to thyroxine initiation to prevent adrenal crisis. 3

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Levothyroxine Dosing in Immunotherapy Context

Start conservatively in immunotherapy-induced hypothyroidism:

• De-novo hypothyroidism from immunotherapy requires LOWER doses than typical primary hypothyroidism 6
• Initiate at 0.9-1.2 mcg/kg (not the standard 1.6 mcg/kg) 6
• Observed doses are significantly lower than weight-based calculations 6
• For elderly or cardiac disease: start 25-50 mcg daily 1, 3

Recheck TSH and free T4 in 6-8 weeks after initiation or dose adjustment. 3

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Common Pitfalls to Avoid

Do NOT interrupt immunotherapy for:

• Isolated TSH elevation with normal T3/T4 1, 2
• Asymptomatic subclinical hypothyroidism 1
• Mild symptoms manageable with levothyroxine 1

Do NOT overlook:

• Iodine from CT scans can transiently affect thyroid function 1
• Subclinical hyperthyroidism (low TSH, normal FT4) often precedes overt hypothyroidism 1
• Falling TSH may indicate hypophysitis, not improving thyroid function 1
• Adrenal insufficiency must be excluded before starting levothyroxine in suspected hypophysitis 1, 3

Do NOT use standard dosing:

• Immunotherapy-induced hypothyroidism requires 30-40% lower levothyroxine doses than typical primary hypothyroidism 6
• Hypophysitis requires even lower doses (mean 0.9 mcg/kg at week 54) 6

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Evidence Quality and Rationale

The recommendation to continue immunotherapy during thyroid dysfunction is based on:

• High-quality guideline evidence from ESMO 2017 1
• Thyroid dysfunction occurs in 6-9% with anti-PD-1/PD-L1 and 16-20% with combination therapy 2, 4
• Onset of thyroid dysfunction is mainly transient, easy to treat, and mild 2
• Treatment interruption is rarely necessary 1, 2

The lower levothyroxine dosing recommendation is supported by:

• Retrospective multicenter analysis of 822 patients showing significantly lower observed doses than calculated weight-based doses 6
• Most clinically significant for hypophysitis (mean difference -58.3 mcg, p<0.0001) 6

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Baseline Risk Stratification

Patients at higher risk for developing thyroid dysfunction during immunotherapy:

• Baseline TSH >1.72 mIU/L (100% NPV for remaining dysfunction-free if TSH <1.72) 4
• Positive anti-thyroid antibodies at baseline (independently associated with overt dysfunction, p=0.009) 4
• Combination anti-CTLA4 + anti-PD-1 therapy (20% incidence vs 6-9% monotherapy) 2

These patients require more vigilant monitoring but still continue immunotherapy. 1, 2