Table 4.

Guidelines for the treatment of ir thyroid disorders.

Ir Thyroid Disorder	Clinical Practice Guidelines Experts’ Committees [Ref]
	ASCO [80]	SITC [89]	NCCN [90]	ESMO [91]
Hypothyroidism	G 1: Continue ICPi. with frequent TFT. G 2: May hold ICPi until resolution of symptoms. Endocrine consultation. TSH > 10 mIU/L or TSH > 4 mIU/L plus symptoms: THR. TFT Q 6–8 wk for THR titration until TSH normalization and, accordingly, annually or guided by symptoms. G 3–4: THR Hold ICPi. Endocrine consultation. IV L-thyroxine for myxedema.	G ≤ 2: L-thyroxine: 1.6 μg/kg/d (young, healthy) 25–50 μg (elderly, patients with CVD). TFT Q 6–8 wk for titration. Increments of L-thyroxine dose by 12.5–25 μg if indicated. After TSH normalization, TFT Q 1 y, or earlier if needed. G ≥ 3: Hold ICPi THR as G ≤ 2.	SH: Continue ICPi TFT TSH > 10 and/or symptoms: Start L-thyroxine Continue ICPi if no symptoms Endocrine consultation TFT Q 4–6 wk	THR (L-thyroxine: 50–100 μg/day.) SH: THR if fatigue. Τitration of L-thyroxine until TSH normalization. Inflammatory thyroiditis: prednisone orally 1 mg/kg tapered gradually. Consider holding ICPi if patient is symptomatic.
Thyrotoxicosis	G 1: Continue ICPi with frequent TFT. G 2: May hold ICPi until resolution of symptoms. Administer b- blockers. Hydration and supportive care. Thyrotoxicosis >6 wk, or clinical suspicion of GD: Diagnostic work-up for GD. Treat GD as indicated, preferably starting with thionamide. G 3–4: As in G2. For severe symptoms: Inpatient management. 1 to 2 mg/kg/d prednisone or equivalent tapered over 1 to 2 wk. Saturated solution of potassium iodide or thionamide.	b-blockers (e.g., atenolol 25–50 mg daily, titrate for HR < 90 if BP allows). TFT (mainly f T4) Q 2 wk Treat GD per standard guidelines. Hold ICPi if G ≥ 3.	No symptoms: Continue ICPi Administer b-blockers (propranolol or atenolol or metoprolol). TFT in 4–6 weeks: If normal: no further therapy. If abnormal: Diff dx of GD from destructive thyroiditis. If thyrotoxicosis evolves to hypothyroidism: Initiate L-thyroxine when TSH >10 mIU/L.	Administer b-blockers (propranolol or atenolol) and rarely carbimazole or steroids. Hold ICPi until resolution of symptoms.

Abbreviations: ASCO, American Society of Clinical Oncology; BP, blood pressure; CVD, cardiovascular disease; Diff dx, differential diagnosis; fT4, free T4; G, grade; GD, Graves’ disease; HR, heart rate; ICPi, immune checkpoint inhibitors; IV, intravenously; NCCN, National Comprehensive Cancer Network; Q, every, SH, subclinical hypothyroidism; SITC, Society for Immunotherapy of Cancer; TFT, thyroid function tests; THR, thyroid hormone replacement; TSH, thyroid stimulating hormone; wk, week; y, year. The treatment of ir hypothyroidism consists of the administration of L-thyroxine in all patients with TSH > 10 mIU/l [80] and in selected patients with 4 mIU/l < TSH < 10 mIU/l [92] and normal fT4 levels who present symptoms of hypothyroidism. The usual initiating dose of L-thyroxine is 1.6 μg/kg/day or lower (25–50 μg/day) for elderly or fragile patients with multiple comorbidities [80]. Titration is based on monitoring the TSH and fT4 levels every 6–8 weeks, according to the ASCO [80] and Society for Immunotherapy of Cancer (SITC) [89] guidelines, or every 4–6 weeks, according to the National Comprehensive Cancer Network (NCCN) guidelines [90]. Notably, any deficiency of cortisol should be corrected before the initiation of L-thyroxine [80].