**6. Renal cell carcinoma**

Among the side effects of chemotherapeutic tyrosine kinase inhibitors (TKIs) used in management of renal cell carcinoma (RCC) is induction of preclinical primary hypothyroidism. The "preclinical" state is an elevation of circulating TSH with normal range serum T4 and T3 concentrations. An extensive clinical literature documents that response of metastatic RCC to TKIs sorafenib and sunitinib is importantly enhanced when drug-induced hypothyroidism complicates tumor management [28, 30, 44–48]. TKIs may cause hypothyroidism in up to 40% of treated patients. The therapeutic response to the recognition of druginduced preclinical primary hypothyroidism in RCC patients was administration of exogenous T4 to the point of returning host TSH to the normal range. In the noncancerous patient with preclinical hypothyroidism, the American Thyroid Association has endorsed a strategy of replacement thyroid hormone as needed to prevent symptoms of hypothyroidism and maintain serum TSH below 10 mIU/ mL [49]. This approach may be adequate to take advantage of the TKI support that preclinical hypothyroidism provides with reduction in circulating T4 within the normal range.

**5**

*Thyroid Hormone Replacement Therapy in Patients with Various Types of Cancer*

The relevance of the thyroid hormone receptor on integrin αvβ3 to RCC has been shown in xenograft studies in the nude mouse [20]. Tetrac and chemically modified tetrac significantly reduced xenograft volume and xenograft vascularity in 20-day studies. The clinical and preclinical information available on RCC documents the importance of thyroid hormone to RCC. When drug-induced or spontaneous early hypothyroidism complicates the course of RCC, substantial decision-making surrounds when and with what hormone the hypothyroid state should be addressed.

Pancreatic cancer is an aggressive tumor locally and metastasizes regionally and systemically with sufficient frequency to have a very unsatisfactory 5-year survival. The relevance of thyroid hormone to tumor behavior has been shown in xenograft studies [50]. Unmodified and chemically modified tetrac in 15-day studies reduced xenograft size by up to 50% and reduced graft vascularity. Tumor gene expression studies showed that chemically modified tetrac acted via αvβ3 to reduce epidermal growth factor receptor (EGFR) gene and anti-apoptotic XIAP gene transcription and to increase expression of pro-apoptotic p53 and anti-angiogenic thrombospondin 1. The implication of these results is that T4—whose binding to αvβ3 is inhibited

by tetrac—may play an important tumor support role in this form of cancer. In contrast to RCC, there is not a significant literature on chemotherapeutic drug-induced hypothyroidism in patients with pancreatic carcinoma. Induction of euthyroid hypothyroxinemia appears to slow the course of advanced pancreatic

At the cancer cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3, T4 is an active hormone, supporting a variety of critical tumor cell functions [5, 10, 26]. In contrast, T4 within normal cells and cancer cells can serve as a prohormone source for T3. T4 is the standard of care for management

A small minority of hypothyroid patients coincidentally have an experience with cancer of various types, as pointed out above. The behavior of the tumors is reported in most clinical studies of this combination of diseases to be less aggressive. But interpretation of the data is sometimes difficult because a distinction may not be made between T4-treated and untreated spontaneous hypothyroid states and the appearance or behavior of the cancer. However, substantial information is now available about the link of hypothyroid state to tumor behavior in those patients in whom hypothyroidism is a side effect of chemotherapy, e.g., TKI use in RCC patients [28, 47, 51], or the clinical use of euthyroid hypothyroxinemia in patients

A body of preclinical evidence also exists to indicate that T4 stimulates proliferation of a variety of tumors, and this effect is initiated at a plasma membrane receptor for thyroid hormone that is generously expressed in cancer cells [5]. At this receptor site, T4 is also anti-apoptotic [5] and supports tumor-relevant angiogenesis

Against this background, we raise the issue of whether prescription of T4 replacement in hypothyroid patients with concurrent cancer should be routine. T3 is not active at physiological concentrations at the integrin receptor for thyroid hormone

[5]. The integrin may also be involved in tumor cell radioresistance [32, 33].

*DOI: http://dx.doi.org/10.5772/intechopen.86289*

**7. Pancreatic carcinoma**

cancer [27].

**8. Discussion**

of hypothyroidism [49].

with advanced cancers [27].

#### *Thyroid Hormone Replacement Therapy in Patients with Various Types of Cancer DOI: http://dx.doi.org/10.5772/intechopen.86289*

The relevance of the thyroid hormone receptor on integrin αvβ3 to RCC has been shown in xenograft studies in the nude mouse [20]. Tetrac and chemically modified tetrac significantly reduced xenograft volume and xenograft vascularity in 20-day studies.

The clinical and preclinical information available on RCC documents the importance of thyroid hormone to RCC. When drug-induced or spontaneous early hypothyroidism complicates the course of RCC, substantial decision-making surrounds when and with what hormone the hypothyroid state should be addressed.
