*3.4.10. Cediranib*

326 Thyroid Hormone

*3.4.7. Nilotinib* 

*3.4.8. Dasatinib* 

*3.4.9. Pazopanib* 

modification of LT4 was not required [143].

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

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 In this case symptoms dramatically regressed following the initiation of LT4 and nilotinib was not withdrawn.

Dasatinib is another second-generation TKI with activity against BCR-ABL and Src family kinases that is approved for the treatment of imatinib-resistant Ph-positive CML and Phpositive acute lymphoblastic leukemia [145]. In a retrospective survey on patients with Phpositive CML who received dasatinib, 5 (50%) patients had TFT abnormalities consistent with hypothyroidism (4 subclinical, 1 clinical) and 2 patients (20%) had thyroid values consistent with subclinical hyperthyroidism. No patient required LT4, except one patient who developed hypothyroidism and was also taking amiodarone, a medication known to cause thyroid dysfunction. Two patients were on LT4 prior to starting dasatinib and

Pazopanib is an oral angiogenesis inhibitor targeting VEGFR-1, PDGFR, and c-Kit. Pazopanib is under clinical development for the treatment of multiple tumor types and has been recently approved for the treatment of advanced RCC. Preliminary data on the incidence and severity of thyroid dysfunction in patients who received pazopanib as treatment for RCC in 3 prospective trials have been recently reported [146]. TFTs were systematically assessed in 578 patients with serum TSH values collected at baseline and every 12 weeks and serum free T3 and T4 at baseline and if TSH was abnormal during the treatment. Elevated TSH (>5 μUI/mL) before initiating pazopanib was found in 37 (6%) patients. TSH value >5 μUI/mL during the treatment was found in 167 (29%) patients. Overt hypothyroidism was diagnosed in 34 (6%) patients. Hyperthyroidism was seen in 8 (1%)

hyperthyroidism preceding the development of hypothyroidism.

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 was not reported.
