*3.4.7. Nilotinib*

Nilotinib is a second-generation TKI with greater potency and specificity for BCR-ABL inhibition compared with imatinib [141,142]. It is approved for the treatment of Philadelphia-positive chronic myeloid leukemia (Ph-positive CML). Kim et al. [143] retrospectively assessed the effect of nilotinib on TFT in 55 patients with Ph-positive CML. In 12 patients (22%), TFTs were consistent with hypothyroidism (6 subclinical, 6 clinical) and in 18 (33%) patients with hyperthyroidism (10 subclinical, 8 clinical) at some point during their therapy. Six (11%) of these patients were on thyroid medication prior to starting the nilotinib and in most patients an increase in LT4 dose was not required. In 4 patients evidence of thyroiditis was found (3 had positive anti-thyroid antibodies) with an episode of hyperthyroidism preceding the development of hypothyroidism.

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 327

patients. Only 20 (3%) patients with a TSH elevation received LT4. Hypothyroidism was registered as a Grade 1/2 adverse event in 26 (4%) patients. Thyroid dysfunction was never

Hypothyroidism was also reported with cediranib, another blocker of VEGFR 1-3 and c-Kit kinases in 45% of patients affected by advanced non-small-cell lung cancer enrolled in a randomized, double-blind trial of carboplatin and paclitaxel taking either oral cediranib or placebo daily [147]. Similarly, in a randomized phase II study on 46 patients affected by recurrent epithelial ovarian or fallopian tube cancer and treated with cediranib as single agent, Grade 2 hypothyroidism occurred in 56% of patients [148]. Details regarding the rate of patients requiring LT4 or effects of this treatment on hypothyroidism-related symptoms

Bexarotene is a selective agonist of the retinoid X receptor (RXR), a nuclear hormone receptor. It is approved for the treatment of cutaneous T cell lymphoma and has been found to induce secondary hypothyroidism [102]. Bexarotene appears to interfere with the normal feedback of thyroid hormone on the pituitary gland [102,149]. T3 binding to its receptor in the pituitary leads to heterodimerization of the receptor with RXR, which suppresses transcription of the β-subunit of TSH, which is required for thyroid stimulation. Bexarotene also has TSH-independent effects on thyroid hormone metabolism. Thyroidectomized thyroid cancer patients receiving thyroid hormone replacement who started bexarotene had a dramatic decrease in total T3 and T4, and free T4 levels with TSH levels that failed to rise appropriately [150].This may be probably due to an effect on peripheral thyroid hormone

**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

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

reported as a severe adverse event in any patient.

metabolism via non-deiodinase mechanisms.

*3.4.10. Cediranib* 

was not reported.

**3.5. Bexarotene** 

purpose.

Recently, a case of overt hypothyroidism following initiation of treatment with nilotinib has been described in a 76-year-old euthyroid male with CML [144]. Serum TSH was 30.23 μU/mL with low free T4 and free T3, and negative anti-thyroid antibodies. The ultrasound examination showed a normal size gland, markedly decreased inhomogeneous echo signals and slightly reduced vascularity, all compatible with thyroiditis. In this case symptoms dramatically regressed following the initiation of LT4 and nilotinib was not withdrawn.
