**1. Introduction**

310 Thyroid Hormone

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> Advances in systemic chemotherapy and radiotherapy have had a profound effect on the prognosis of patients affected by many cancer histotypes. Nonetheless, one of the main challenges for modern oncology is in improving the tolerability of these treatments. The frequency and pathophysiology of the most common side effects induced by cytotoxic agents are well known. They may be immediate or delayed in onset and prevalently involve bone marrow, gastrointestinal system, liver, and cutaneous annexes.

> Abnormalities in thyroid function and thyroid disease are variably associated with cancer or cancer therapy [1]. These disorders encompass a broad variety of pathophysiological mechanisms, may be subtle in presentation, sometimes difficult to be identified, and even more difficult to relate to a particular chemotherapeutic regimen due to the lack of specific wide clinical trials [2]. The alteration of thyroid hormone metabolism, more commonly known as "euthyroid sick syndrome", may occur in patients with advanced cancers. Thyroid dysfunction, such as the altered synthesis or clearance of thyroid hormone-binding proteins are observed in certain malignancies, or may be caused by treatments that modify total but not free concentration of thyroid hormones. However, the clinical influence of this abnormalities is marginal, if any.

> Endocrine disorders are among the most commonly reported long-term complications of cancer treatment by adult survivors of childhood cancers [3]. In adults, cytotoxic drugs are infrequently associated to overt endocrine toxicity. However, excluding gonadotoxic consequence [4], only few studies thoroughly evaluated the endocrine dysfunction induced by cytotoxic anticancer therapy in this population [2]. Similarly, hormonal therapies, widely used as effective treatment of patients affected by endocrine responsive breast cancer and

© 2012 Torino et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

prostate cancer, have shown only marginally influence on thyroid function and thyroid toxicities attributed to these drugs are anecdotic.

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 313

An increased incidence of primary hypothyroidism has been documented in patients treated with multiple drug regimens, with or without radiotherapy [2]. In patients with testicular cancer who received combinations of cisplatin, bleomycin, vinblastine, etoposide, and dactinomycin, 4 out of 27 individuals (15%) developed primary hypothyroidism. In particular, the cumulative doses of cisplatin and vincristine seem to exacerbate these symptoms [21]. In another trial evaluating the combination of mechlorethamine, vinblastine, procarbazine and prednisolone (MOPP regimen) as treatment of Hodgkin's disease, 44% of patients developed elevated serum TSH concentrations, even though a causative role of iodine load during lymphangiograpy cannot be excluded [22]. Children with brain tumors (not involving the hypothalamic-pituitary axis) who receive vincristine, carmustine or lomustine, and procarbazine in combination and brain irradiation have a 35% incidence of hypothyroidism, compared with a 10% incidence in the group with brain irradiation alone [23]. Young age and use of chemotherapy have been associated with a higher incidence of hypothyroidism in patients receiving radiotherapy for medulloblastoma [24]. Again, the highest incidence occurred when the thyroid gland was included in the radiation field. Finally, there is no evidence that cytotoxic agents by itself may represent a risk factor for

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 dose-

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

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

antiviral response, but showed a similar rate of thyroid dysfunction [29].

developing thyroid tumors, compared to radiotherapy [2].

**3. Immunoregulatory agents** 

**3.1. Cytokines** 

*3.1.1. Interferon-*

limiting side-effects.

In contrast to cytotoxics and hormonal therapies, several novel antineoplastic agents, including targeted therapies and immunotherapies, are unexpectedly associated with thyroid dysfunction and thyroid disease, despite their high selectivity of action [5].

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 cancer [8].

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