**4. Why is it important to assess thyroid function in cancer patients?**

Abnormalities of thyroid function induced by anticancer drugs are variably common, accordingly to the agent used. Identifying thyroid dysfunction and disease in cancer patients may have important consequences for diagnostic, therapeutic and prognostic purpose.

Diagnostic challenges are tendered by symptoms of thyroid dysfunction. For example, fatigue and constipation are present in the majority of patients with hypothyroidism, but they may be caused also by underlying malignancy, antineoplastic treatment(s) received, or medications used for control of other symptoms (i.e. nausea or pain) [1]. Similarly, many symptoms of thyrotoxicosis are similar to those attributable to other complications, such as sepsis. Inability to diagnose the presence of thyroid dysfunction or disease as treatmentrelated toxic effects may lead to misguided treatment strategies, unjustified dose reduction or even to treatment withdrawal [1]. In addition, unrecognized hypothyroidism or 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 TKIinduced hypothyroidism (i.e. sunitinib).

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 329

for the first few weeks [1]. Monitoring thyroid hormone replacement is usually carried out by serum TSH measurements, aimed at maintaining TSH within the normal range. On the contrary, in patients who develop central hypothyroidism (i.e. secondary to bexarotene and anti-CTLA4 monoclonal antibodies), TSH concentrations cannot be used, and free T4 levels

The treatment of subclinical hypothyroidism (TSH 5–10 mIU/L with a normal free T4) is questionable in cancer patients. In general, treatment of this condition is discouraged in a healthy population because there is insufficient evidence of benefit [161,162]. However, it may be offered to patients with subclinical hypothyroidism and antiTPO/anti-TG antibodies, hypercolesterolemia, thyroid nodules, or symptoms (i.e. fatigue) that may greatly worsen quality of life of patients [5]. In one study [111], at least half of patients who started LT4 for sunitinib-associated hypothyroidism had improvement of their symptoms of fatigue [111]. Conversely, Garfield et al. [163] warned that some preclinical, epidemiological and clinical evidence suggests that LT4 is permissive for tumor growth. Possible actions of thyroid hormones on cancer cells include the amplification of *EGFR*, phosphorylation of insulin-like growth factor 1 receptor, stimulation of migration, a direct trophic effect on

Practical suggestions for the treatment of individual cancer patients showing TKI-induced subclinical hypothyroidism are available [5]. However, the best approach seems to to start low-dose LT4 in individual patients as a therapeutic trial [1]. This prudent method may be extended to patients who develop this condition as a side effect of other anticancer agents. However, specific prospective studies evaluating the influence of thyroid replacement therapy in cancer patients, not only in term of quality of life, but also in term of survival, are urgently needed [165]. Thyrotoxicosis induced by anticancer drugs may result from an Hashi-toxocosis or Graves' disease. Thyrotoxicosis from thyroiditis is generally self-limiting and specific treatment is not required. Corticosteroid and β-blockers, usually propranolol, can be efficacious in symptom control. However, patients with this side effect should be monitored for subsequent hypothyroidism. Patients presenting with Graves disease, are usually treated with antithyroid drugs (i.e. methimazole), followed by 131I ablation if indicated. However, due to its complexity, anticancer drug-induced thyrotoxicosis is

should be monitored, with a goal of about 1–1.5 ng/dL [1].

tumor cells, cell specific anti apoptotic activity and angiogenesis [164].

advisable to be managed under close consultation with an endocrinologist [1].

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

**5. Conclusions** 

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 better clinical outcomes [159].

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

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 for the first few weeks [1]. Monitoring thyroid hormone replacement is usually carried out by serum TSH measurements, aimed at maintaining TSH within the normal range. On the contrary, in patients who develop central hypothyroidism (i.e. secondary to bexarotene and anti-CTLA4 monoclonal antibodies), TSH concentrations cannot be used, and free T4 levels should be monitored, with a goal of about 1–1.5 ng/dL [1].

The treatment of subclinical hypothyroidism (TSH 5–10 mIU/L with a normal free T4) is questionable in cancer patients. In general, treatment of this condition is discouraged in a healthy population because there is insufficient evidence of benefit [161,162]. However, it may be offered to patients with subclinical hypothyroidism and antiTPO/anti-TG antibodies, hypercolesterolemia, thyroid nodules, or symptoms (i.e. fatigue) that may greatly worsen quality of life of patients [5]. In one study [111], at least half of patients who started LT4 for sunitinib-associated hypothyroidism had improvement of their symptoms of fatigue [111]. Conversely, Garfield et al. [163] warned that some preclinical, epidemiological and clinical evidence suggests that LT4 is permissive for tumor growth. Possible actions of thyroid hormones on cancer cells include the amplification of *EGFR*, phosphorylation of insulin-like growth factor 1 receptor, stimulation of migration, a direct trophic effect on tumor cells, cell specific anti apoptotic activity and angiogenesis [164].

Practical suggestions for the treatment of individual cancer patients showing TKI-induced subclinical hypothyroidism are available [5]. However, the best approach seems to to start low-dose LT4 in individual patients as a therapeutic trial [1]. This prudent method may be extended to patients who develop this condition as a side effect of other anticancer agents. However, specific prospective studies evaluating the influence of thyroid replacement therapy in cancer patients, not only in term of quality of life, but also in term of survival, are urgently needed [165]. Thyrotoxicosis induced by anticancer drugs may result from an Hashi-toxocosis or Graves' disease. Thyrotoxicosis from thyroiditis is generally self-limiting and specific treatment is not required. Corticosteroid and β-blockers, usually propranolol, can be efficacious in symptom control. However, patients with this side effect should be monitored for subsequent hypothyroidism. Patients presenting with Graves disease, are usually treated with antithyroid drugs (i.e. methimazole), followed by 131I ablation if indicated. However, due to its complexity, anticancer drug-induced thyrotoxicosis is advisable to be managed under close consultation with an endocrinologist [1].
