**3.1. Cytokines**

312 Thyroid Hormone

cancer [8].

are discussed.

necessary [20].

**2. Cytotoxic agents** 

toxicities attributed to these drugs are anecdotic.

prostate cancer, have shown only marginally influence on thyroid function and thyroid

In contrast to cytotoxics and hormonal therapies, several novel antineoplastic agents, including targeted therapies and immunotherapies, are unexpectedly associated with

Even diagnostic procedures using iodinated contrast agents can be associated with acute effects on the thyroid, including hyperthyroidism (i.e. in patients with thyroid autonomous nodules or mild Graves disease), or transient hypothyroidism (i.e. in patients with Hashimoto thyroiditis) [6,7]. Radiation therapy can be responsible for hypothyroidism from direct damage on the thyroid or secondary to hypopituitarism from brain irradiation. Irradiation received during childhood has been associated with thyroid nodules and thyroid

In this chapter, available data on thyroid abnormalities induced by anticancer drugs only

Cytotoxic chemotherapy seems to alter endocrine functions in a relatively small proportion of patients and is infrequently associated with thyroid abnormalities in the absence of irradiation. Cytotoxics may sensitize the thyroid gland to the effects of concomitant radiation therapy, increasing the risk of radiation-induced primary hypothyroidism [9].

In a small published series, some agents such as 5-fluorouracil, glucocorticoids, estrogens, tamoxifen, podophyllin and L-asparaginase alter levels of thyroid hormone–binding proteins without any clinical consequence [10-15]. L-asparaginase can also be responsible for transient hypothalamic or pituitary hypothyroidism [16]. Other agents such as lomustine, vincristine, and cisplatin have *in vitro* effects on thyroid cells, but clinically relevant consequences have not been reported [17]. Mitotane is the only active agent against advanced adrenocortical cancer (ACC) and is under evaluation in patients who underwent radical resection of this rare disease. Mitotane showed a complex interference on the endocrine system that may require multiple hormone replacement therapy. In a prospective trial [18] on 17 patients who underwent radical resection for ACC, a marked reduction in free-T4 (FT4) levels was found, without any significant changes in serum thyroid stimulating hormone (TSH) and free-T3 (FT3) concentration. FT4 reduction was inversely correlated with mitotane concentrations and dropped in the hypothyroid range in most evaluable patients. These findings mimic central hypothyroidism and are consistent with data from clinical experiments which showed that mitotane directly reduces both secretory activity and cell viability on pituitary TSH-secreting mouse cells [19]. Alternatively, it has been suggested that mitotane may affect deiodase activity, thus changing the FT4 to FT3 ratio. However, despite limited information on free thyroid hormone concentrations during mitotane treatment has been reported, for some patients thyroxine replacement may be

thyroid dysfunction and thyroid disease, despite their high selectivity of action [5].

#### *3.1.1. Interferon-*

Interferon- is a human recombinant cytokine that increases the expression of major histocompatibility complex (MHC) class I and tumor-specific antigens on the tumor cell surface, stimulating immune-mediated destruction of these cells, as well as possibly exerting direct antitumor effects [25]. Interferon- demonstrated variable efficacy in patients affected by melanoma, renal cell carcinoma (RCC), AIDS-related Kaposi's sarcoma, follicular lymphoma, hairy cell leukemia, and chronic myelogenous leukemia [25]. Reduction in viral load is another relevant activity of interferons. In combination with ribavidin, interferon prolongs survival in patients with hepatitis C [26,27]. Flu-like syndrome, malaise, neuropsychiatric disorders, hematologic and liver toxicity are the most common doselimiting side-effects.

Thyroid diseases secondary to treatment with Interferon- are common and may become clinically evident as destructive thyroiditis, autoimmune hypothyroidism or Graves-like hyperthyroidism. Patients receiving the drug for hepatitis appear more prone to present thyroid dysfunction than patients with malignant disease [28]. However, the infection from the hepatitis C virus itself has been demonstrated to increase the risk of thyroid damage [28]. The pegylated form of interferon- is more effective than interferon- in triggering antiviral response, but showed a similar rate of thyroid dysfunction [29].

Destructive or autoimmune thyroiditis is the most common thyroid abnormality following treatment with interferon-. This condition may lead to hypothyroidism after a brief

thyrotoxic phase and usually occurs in the first few weeks of interferon treatment and is in close temporal relationship with the appearance of thyroid autoantibodies, especially antithyroglobulin (anti-TG) antibodies. Another form of autoimmune thyroid toxicity associated to interferon- is characterized by the development of thyroid antibodies without hypothyroidism. In the setting of interferon therapy, the risk of hypothyroidism is 2.4%– 10% [30-35], with a risk of thyroid autoimmunity onset (including development of thyroid autoantibodies) approaching 20% [36,37]. Hypothyroidism is persistent in the majority of patients [33,38], even though although transient hypothyroidism has also been described [39]. The presence of anti-thyroperoxidase (anti-TPO) antibodies before treatment considerably increases the risk of hypothyroidism [40-42]. Thyroid abnormalities can occur as early as 4 weeks and as late as 23 months after initiating treatment, with a median of 4 months [30,34].

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 315

measurement every 2 months and then every six months in the case of negative anti-thyroid

Interleukin-2 is a cytokine involved in several mechanisms of immune response, including activation of natural killer cells and antigen-specific T-cells. These properties are used to stimulate tumor cell killing, also in combination with interferon or lymphokine-activated killer cells. Interleukin-2 is approved for the treatment of metastatic melanoma and RCC, although its use has been recently reduced in concomitance with the availability of more

Several autoimmune side-effects have been associated to interleukin-2 therapy, including thyroid disease with an incidence of 10%–50% [48-54]. Hypothyroidism usually occurs 4–17 weeks after initiation of treatment [48,49]. It may be reversible following discontinuation of the drug [49,55]. Most patients who developed hypothyroidism showed positive anti-TG or anti-TPO antibodies. In addition to hypothyroidism, thyroiditis and thyrotoxicosis have also been reported at a lesser frequency [55,56]. An early phase of presumably destructive

Evidence suggests that thyroid disease associated to interleukin-2 may be induced by stimulating autoreactive lymphocytes, leading to autoimmune thyroiditis. Patients under treatment with interleukin-2 showed high levels of interferon-γ and tumor necrosis factor-, which may trigger autoimmunity by enhancing the presentation of human leukocyte antigen class II and associated autoantigens by thyrocytes. Also, interleukin-2 may have direct effects on thyrocyte functioning [58,59]. Increase in serum thyroid autoantibodies levels [48,53] and lymphocyte infiltration of the thyroid gland [57] were found in patients treated with interleukin-2, suggesting a cell-mediated autoimmune mechanism. Similarly to interferon, preexisting positivity of thyroid autoantibodies seems to predict an increased risk of developing hypothyroidism during interleukin-2

Occurrence of hypothyroidism was associated with a favorable response to treatment [48,60], but other studies did not confirm these results [61]. It has been suggested that thyroid dysfunction may develop more often in the responders because they receive longer courses of the treatment [46,62]. Patients with interleukin-2-induced hypothyroidism may be treated with LT4, while thyrotoxicosis only requires symptom control with β-blockers and corticosteroids. Measuring TSH before treatment and then every 2–3 months during

Thalidomide and lenalidomide are immunomodulatory drugs with antineoplastic activity [63,64]. These agents enhance T-cell stimulation and proliferation, induce endogenous cytokine release, and increase number and function of natural killer cells, thus enhancing

thyrotoxicosis is common, with variable degrees of hyperthyroidism [57].

peroxidase (anti-TPO) antibodies [1].

effective and better tolerated agents.

*3.1.2. Interleukin-2* 

treatment [49].

treatment with interleukin-2 is advisable [1].

**3.2. Thalidomide and lenalidomide** 

Interferon- has also been associated with classical Graves disease and sometimes Graves' ophthalmopathy also develops, however the latter is less common [30]. This condition does not generally remit on withdrawal of the drug [35].

Several evidence supports the hypothesis that thyroid toxicity may likely be related to an autoimmune response to interferon-. Overexpression of MHC class I antigens are associated with activation of cytotoxic T-cells resulting in cellular destruction [43]. It has been reported that interferon- increases MHC class I expression on thyroid tissue from Graves patients, provided that lymphocytes are present in the thyroid tissue [44]. Hence, interferon- might worsen local immune response in subjects who have preexisting subclinical thyroiditis with intrathyroidal lymphocytes [44]. In addition, interferon- can shift the immune response to a Th1-mediated immune response, with increased production of the proinflammatory cytokines interferon-γ and interleukin-2, which may in turn amplify an autoimmune response. Interferon- has been demonstrated to elicit a direct damage on thyroid cells, which may be responsible for the onset of destructive thyroiditis [28,35,42,45]. However, despite accumulating evidence, the precise mechanisms underlying thyroid toxicity associated to interferon, especially in cancer patients, remain to be elucidated.

Levothyroxine (LT4) therapy is indicated as treatment of interferon-induced hypothyroidism and withdrawal of interferon is not generally needed. When destructive thyroiditis is present, treatment with corticosteroids is needed and β-blockers are often useful to control the signs and symptoms of thyrotoxicosis. When interferon causes hyperthyroidism, antithyroid agents such as methimazole or propylthiouracil may be administered, if clinically indicated. In patients with relapsing flares of thyroiditis during prolonged courses of interferon-, ablation with 131I during remission may be offered to prevent further episodes of the condition [46].

Despite specific recommendations for patients treated with interferon- for oncological diseases are lacking, it appears rational to apply the recommendations available for patients with hepatitis C [47]. In particular, the same serological screening is suggested, including pretreatment TSH and anti-TPO antibodies evaluation, followed by TSH serum measurement every 2 months and then every six months in the case of negative anti-thyroid peroxidase (anti-TPO) antibodies [1].
