*3.4.5. Vandetanib*

324 Thyroid Hormone

*3.4.4. Motesanib* 

Clement *et al.* [128] prospectively monitored thyroid function in 38 patients with metastatic RCC who were treated with sorafenib 400 mg twice daily. Thyroid function was assessed at baseline and on day 1 of each treatment cycle. Out of 23 patients with normal baseline thyroid function, seven patients (30%) developed at least one elevated serum TSH and 1 patient (5%) developed low TSH levels. For these abnormalities no therapy was required. In addition, out of 15 patients with either thyroid dysfunction at baseline or previous treatment potentially interfering with thyroid function, two patients with baseline subclinical hypothyroidism (defined as an increase in serum TSH above normal and ≤ 10 mU/L, with normal T3 and T4 values) developed clinical hypothyroidism (TSH ≥ 10 mU/L or T3 and T4

In another prospective observational study [129] on 69 Japanese patients affected by metastatic RCC refractory to cytokine therapy and subsequently treated with sorafenib for at least 12 weeks, thyroid function was assessed before and every 4 weeks after the initiation of sorafenib treatment. Forty-six (67.7%) patients developed hypothyroidism. Interestingly, 11 (23.9%) of these patients first showed a suppressed TSH value accompanying the increase in free T3 and/or free T4, before developing hypothyroidism. This pattern clearly suggests that sorafenib may have induced thyroiditis. LT4 was needed by 4 patients (5.8%) who presented severe clinical symptoms caused by hypothyroidism. Among several factors examined, only age was

Sorafenib-associated thyroid dysfunction was not reported in two registration trials in patients affected by advanced hepatocellular carcinoma (HCC). More recently, in a series of 38 consecutive patients with HCC treated with sorafenib, 5 (13%) of them developed subclinical hypothyroidism (TSH levels, 7,41 μIU/mL; range, 6,38-8,94 μIU/mL (unpublished data) [130]. Other case reports of patients affected by HCC showed progressive destructive thyroiditis after taking sorafenib. These data highlight the possibility that also hypothyroidism induced by sorafenib may be the result of an initial thyrotoxicosis [131].

Abdulrahman *et al.* [132] in a small prospective study on 21 patients with progressive nonmedullary thyroid carcinoma treated with sorafenib, measured serum total T4, free T4, total T3, free T3, reverse T3, and TSH concentrations at baseline and after 26 weeks of treatment with sorafenib. Results from this study suggested that sorafenib enhances T4 and

Motesanib diphosphate is a highly selective, oral inhibitor of VEGFR-1, -2, and -3; PDGFRs and c-KIT. The association between motesanib and thyroid function was recognized in a phase II study of 93 patients with progressive radioiodine-resistant differentiated thyroid cancer who daily received motesanib diphosphate [102]. All the patients had previously undergone thyroidectomies and were on thyroid hormone replacement therapy. Increased serum TSH concentrations, hypothyroidism or both were observed in 20 patients (22%). The Authors suggested that alterations in the absorption or metabolism of LT4 may explain

T3 metabolism, which may be probably caused by an increased type 3 deiodination.

values below the normal range) requiring thyroid hormone replacement therapy.

significantly associated with the risk of developing hypothyroidism.

changes in thyroid hormone levels while on motesanib.

Vandetanib is an oral inhibitor of VEGFR-2 and -3, RET kinases, and at higher concentrations, the epidermal growth factor receptor kinases. This drug has been approved in the United States for unresectable locally advanced or metastatic MTC and is under evaluation in phase III trials on patients affected by several cancer types [134].

In a phase II study of vandetanib, 19 patients with advanced hereditary MTC received vandetanib 100 mg daily [135]. All patients had undergone prior total thyroidectomy and were receiving LT4 therapy. In all 17 patients who had available baseline TFTs, an increase in serum TSH levels was observed. TSH elevation reached a maximum by day 84 after the start of vandetanib treatment with a median 7.3-fold increases over baseline. No patients were reported to have symptomatic hypothyroidism, but LT4 was increased in two patients.

Interestingly, in a study on 39 patients with progressive medullary or differentiated thyroid cancer included in two randomized placebo-controlled trials using vandetanib 300 mg/day [136] LT4 had to be increased by 50 μg/d to maintain serum TSH within the normal range, probably by increased type 3 deiodinase activity as described using sorafenib [132].
