**5. Conclusions**

328 Thyroid Hormone

induced hypothyroidism (i.e. sunitinib).

better clinical outcomes [159].

thyrotoxicosis may affect the metabolism of other medications [151]. Finally, it should be considered that thyroid dysfunction, although rarely, can lead to life-threatening consequences in cancer patients, as warned by case reports of patients who experienced myxedematous coma [152] or impaired cardiac function [153,154] as a complication of TKI-

Therefore, clinicians should maintain an adequate level of surveillance for thyroid abnormalities when patients receive certain anticancer treatments, such as TKI or certain immunomodulatory drugs, present with symptoms consistent with hypothyroidism (i.e. constipation, bradycardia, hypothermia, unexpected weight gain, dry skin or dry hair and brittle nails) or thyrotoxicosis (i.e. palpitations, weight loss, heat intolerance, frequent bowel movements, tremor, proximal muscle weakness, tachycardia, lid retraction or lid lag, insomnia, irritability, fever). Of note, hypophysitis has recently emerged as an unusual, peculiar side effect of ipilimumab/tremelimumab. Symptoms like headache, visual impairment, nausea, vomiting, loss of appetite, fatigue, weakness, asthenia, fever, lethargy, hypotension, hypoglycemia and hyponatremia in patients recently treated with ipilimumab should lead physicians to suspect hypophysitis. The early diagnosis of this side-effect allows to prevent primarily a life-threatening complication such as adrenal insufficiency, but also central hypothyroidism and other endocrine consequences of hypopituitarism [84]. Monitoring thyroid function even in asymptomatic patients has emerged as a prognostic tool as well. A lower cancer risk and a more indolent disease has been noted in patients with primary hypothyroidism and breast cancer [155]. The association between the appearance of treatment-induced hypothyroidism has been related to an increased likelihood of response to therapy and even of better outcomes. The development of hypothyroidism following radiotherapy for head and neck cancer was associated with better survival [156]. Propylthiouracil-induced hypothyroidism was associated with improved survival in patients with glioma [157]. Thyroid autoimmunity may predict an improved tumor response to interleukin 2 therapy for melanoma [62] and RCC [48,49,60]. When patients with RCC are treated with sorafenib or sunitinib, a higher rate of remission and better overall survival are seen in those who developed hypothyroidism compared to those who did not [126,158]. Studies of anti-CTLA4 monoclonal antibodies suggest that the presence of immune-related adverse events, including hypophysitis and thyroiditis, is associated with

In patients who are going to start drugs potentially associated with thyroid side-effects, an accurate screening for thyroid function should be carried out at baseline and monitored throughout the period of treatment and follow-up. Despite specific guidelines generated by

Successful treatment of thyroid dysfunction such as hypo- and hyperthyroidism, is likely to improve patient quality of life and may prevent erroneous withdrawal from effective anticancer therapies. Patients with TSH greater than 10 mIU/L or with low free T4 levels, should receive thyroid hormone replacement with LT4 at an average dose of 1.6 μg/kg per day. In the case of coronary artery disease, a lower initial dose (e.g. 50 μg/d) should be used

high level evidence are lacking, rational approaches have been proposed [1,160].

Thyroid dysfunctions are emerging as a variably common endocrine toxicity of several highly selective anticancer drugs. Routine testing for thyroid abnormalities in patients receiving these agents are recommended at baseline, during the treatment and follow up. Furthermore, thyroid function tests should be included in routine toxicity assessment of TKIs and possibly in other classes of targeted drugs under clinical evaluation. Hypothyroidism *per se* is not an indication for dose reduction or discontinuation of these agents. The clinical relevance of overt and subclinical hypothyroidism, the value of thyroid hormone replacement in individuals with abnormal serum TSH levels following anticancer

systemic therapy, and the correct timing of thyroid replacement therapy need to be more accurately defined. Additional prospective clinical trials are necessary to investigate these important aspects. In parallel, these trials could offer the unique opportunity to clarify the molecular mechanisms underlying thyroid toxicities induced by an increasing number of anticancer agents.

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 331

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