Thyroid Monitoring for Keytruda (Pembrolizumab)
Baseline and Routine Monitoring Protocol
Patients on Keytruda require TSH and free T4 monitoring before every infusion for the first 3 months, then every second cycle thereafter (for 2-weekly schedules). 1
Initial Assessment
- Measure TSH and free T4 (FT4) before starting pembrolizumab 1
- Baseline abnormal thyroid values do not preclude treatment, but discuss with endocrinology if uncertain 1
- Check TSH 4-6 weeks after cycle 4 (with restaging CT) 1
Ongoing Monitoring Schedule
- First 3 months: Check TSH (and optionally FT4) every cycle 1
- After 3 months: Check TSH every second cycle for 2-weekly infusion schedules 1
- Continue monitoring even if asymptomatic, as thyroid dysfunction occurs in 5-10% of patients on anti-PD-1 therapy like pembrolizumab 1
Incidence and Timing of Thyroid Dysfunction
Thyroid dysfunction with pembrolizumab occurs in approximately 21% of patients, with 80% of affected patients developing anti-thyroid antibodies. 2 The dysfunction typically manifests early, with a median onset of 42 days after starting treatment. 2
Clinical Pattern
- Hyperthyroidism phase: Often transient, occurring first in 60% of patients who develop thyroid dysfunction 2
- Hypothyroidism phase: Follows hyperthyroidism or occurs de novo, usually requiring long-term thyroid hormone replacement 1
- Most thyroid dysfunction is asymptomatic and detected only through routine blood testing 1
Interpretation of Results
Normal TSH with Normal FT4
Elevated TSH (Hypothyroidism)
For TSH >10 mIU/L or any TSH elevation with low FT4:
- Start levothyroxine 0.5-1.5 μg/kg (start low in elderly or those with cardiac history) 1
- Continue pembrolizumab—do not interrupt immunotherapy 1
- Consider propranolol or atenolol for symptomatic relief 1
For TSH elevation with normal FT4 (subclinical hypothyroidism):
- Consider thyroid hormone replacement even for subclinical hypothyroidism if fatigue or other hypothyroid complaints are present 1
- Continue pembrolizumab 1
Low TSH with Elevated FT4 (Hyperthyroidism)
This typically represents transient thyroiditis:
- Start propranolol or atenolol for symptomatic control (tachycardia, tremor, anxiety) 1
- Consider carbimazole if anti-TSH receptor antibodies are positive 1
- Continue pembrolizumab if patient is well 1
- If patient is unwell, withhold pembrolizumab temporarily and restart when symptoms are controlled 1
For painful thyroiditis:
- Consider prednisolone 0.5 mg/kg with taper 1
Falling TSH Across Two Measurements with Normal or Low T4
This pattern suggests pituitary dysfunction (hypophysitis):
- Perform weekly cortisol measurements 1
- Rule out adrenal insufficiency before starting or increasing thyroid hormone, as this can precipitate adrenal crisis 1
- If hypophysitis is confirmed, start physiologic dose steroids 1 week prior to thyroid hormone replacement 1
Critical Management Principles
When to Continue Pembrolizumab
- Continue immunotherapy in nearly all cases of thyroid dysfunction 1
- Thyroid dysfunction rarely requires treatment interruption 1
- High-dose corticosteroids are rarely required for thyroid-related adverse events 1
When to Temporarily Hold Pembrolizumab
- Only withhold if patient is significantly unwell from hyperthyroidism 1
- Restart when symptoms are controlled with beta-blockers or other symptomatic management 1
Hormone Replacement Considerations
- Thyroid hormone replacement is usually long-lasting and often permanent 1
- Even subclinical hypothyroidism warrants treatment consideration if fatigue or other complaints are present 1
- Do not reduce or discontinue pembrolizumab due to thyroid dysfunction—it does not necessitate dose modification 1
Important Caveats
Iodine Exposure
- CT contrast containing iodine can transiently impact thyroid function tests 1
- Consider timing of imaging studies when interpreting borderline results 1
Late Endocrine Dysfunction
- Thyroid dysfunction can occur late in the treatment course 1
- Maintain vigilance even after completing pembrolizumab therapy 1