*3.4.2. Sunitinib*

Sunitinib is an oral, multitarget inhibitor of VEGF receptor 1 (VEGFR1), VEGFR2, Fms-like tyrosine kinase 3 (Flt3), colony stimulating factor 1 receptor (CSF1R), RET, c-Kit, and PDGFR. This agent has been found to influence the thyroid function of patients with GIST or RCC.

In total, 2 out of 56 patients with RCC and a history of well controlled hypothyroidism, and 7 out of 21 patients with imatinib-resistant GIST, had a worsening hypothyroidism during sunitinib treatment [109,111,122], reported the case of a woman with GIST who was resistant to imatinib and received LT4 after thyroidectomy and 131I-ablation for follicular thyroid carcinoma. The patient's dose of LT4 needed to be increased after sunitinib treatment. In this report, the marked increase in TSH levels has been attributed to a potential interference of sunitinib with thyroid hormone action at the pituitary level [122].

Desai *et al.* [123] prospectively evaluated the thyroid function tests (TFTs) in a phase I/II study of sunitinib therapy in 42 patients with imatinib-resistant GIST. Most patients received 50 mg sunitinib daily every 4–6 weeks, each consisting of 2–4 weeks of sunitinib followed by 2 weeks of wash-out. Initially, TFT were performed only if clinically indicated. Thereafter, serum TSH was evaluated before each sunitinib cycle. In total, 42 patients with normal baseline TFT who received at least 3 sunitinib treatment cycles for a median of 37 weeks were evaluated. Abnormal serum TSH concentrations were documented in 26 patients (62%). Sunitinib caused persistent primary hypothyroidism in 15 patients (36%), after an average of 50 weeks of therapy (range 12–94 weeks). Seven additional patients (17%) experienced transient, mild serum TSH elevation (5.0–7.0 mU/L). In 4 patients TSH was suppressed, but they discontinued treatment before the TFTs could be repeated. Out of 15 patients with hypothyroidism, 6 (40%) had at least one TSH value below 0.5 mU/L before developing the condition, which suggests a thyroiditis-induced thyrotoxicosis. The risk of hypothyroidism increased with the duration of sunitinib therapy. Subclinical or overt hypothyroidism was observed in 4 out of 22 patients [18%] who received sunitinib for 9 months, and in 5 of 17 patients (29%) who received sunitinib for longer than 12 months. In patients treated for longer than 96 weeks, 90% developed increased levels of TSH. The mean time to onset of hypothyroidism was 50 weeks. Among the patients with TSH concentrations greater than 10 mU/L, none had spontaneous biochemical resolution. During the titration of LT4, serum TSH values remained elevated for a median of 17 weeks (range 4–117 weeks). The TSH concentrations returned to normal in all patients who received conventional doses of LT4. Interestingly, in 2 patients with hypothyroidism and normal baseline TFTs, ultrasonography revealed atrophic thyroid tissue, which suggests destructive thyroiditis. This clinical trial was the first to report the prevalence of sunitinib related hypothyroidism [123].

320 Thyroid Hormone

*3.4.2. Sunitinib* 

or RCC.

receptor (PDGFR) /β. It is currently approved for the treatment of chronic myeloid leukemia, gastrointestinal stromal tumors (GIST) and dermatofibrosarcoma protuberans. The influence of daily 400–800 mg imatinib on LT4 was reported in a cohort of 11 patients (10 with medullary thyroid carcinoma and 1 with GIST) [98]. Among the patients with medullary thyroid carcinoma, eight underwent thyroidectomy and received LT4 and three had thyroid carcinoma *in situ.* Thyroid function was evaluated before, during and 2 weeks after therapy with imatinib or LT4. Symptoms of hypothyroidism occurred in all patients who had undergone thyroidectomy, but not in those with intact thyroid. Patients who had undergone thyroidectomy had markedly elevated TSH levels, and required an increase of LT4 during imatinib dosing. The effect was reversible after discontinuation of treatment,

In another study on 68 patients with intact thyroid gland who received imatinib for chronic myeloid leukemia, no case of drug-induced alterations in thyroid laboratory parameters was observed. These data sustain the hypothesis that imatinib-induced thyroid dysfunction is limited to athyreotic patients and are not the consequence of a direct action of the drug on thyroid gland [121], but more probably of an interference of the drug in the nondeiodination

Sunitinib is an oral, multitarget inhibitor of VEGF receptor 1 (VEGFR1), VEGFR2, Fms-like tyrosine kinase 3 (Flt3), colony stimulating factor 1 receptor (CSF1R), RET, c-Kit, and PDGFR. This agent has been found to influence the thyroid function of patients with GIST

In total, 2 out of 56 patients with RCC and a history of well controlled hypothyroidism, and 7 out of 21 patients with imatinib-resistant GIST, had a worsening hypothyroidism during sunitinib treatment [109,111,122], reported the case of a woman with GIST who was resistant to imatinib and received LT4 after thyroidectomy and 131I-ablation for follicular thyroid carcinoma. The patient's dose of LT4 needed to be increased after sunitinib treatment. In this report, the marked increase in TSH levels has been attributed to a potential interference of

Desai *et al.* [123] prospectively evaluated the thyroid function tests (TFTs) in a phase I/II study of sunitinib therapy in 42 patients with imatinib-resistant GIST. Most patients received 50 mg sunitinib daily every 4–6 weeks, each consisting of 2–4 weeks of sunitinib followed by 2 weeks of wash-out. Initially, TFT were performed only if clinically indicated. Thereafter, serum TSH was evaluated before each sunitinib cycle. In total, 42 patients with normal baseline TFT who received at least 3 sunitinib treatment cycles for a median of 37 weeks were evaluated. Abnormal serum TSH concentrations were documented in 26 patients (62%). Sunitinib caused persistent primary hypothyroidism in 15 patients (36%), after an average of 50 weeks of therapy (range 12–94 weeks). Seven additional patients (17%) experienced transient, mild serum TSH elevation (5.0–7.0 mU/L). In 4 patients TSH was suppressed, but they discontinued treatment before the TFTs could be repeated. Out of

clearance of LT4 through the induction of hepatic microsomal enzymes [98].

sunitinib with thyroid hormone action at the pituitary level [122].

suggesting that imatinib might be the causative agent.

Rini *et al.* [111] described thyroid abnormalities in a retrospective study of 66 patients with metastatic RCC treated with sunitinib. In all, 30 patients were pretreated with cytokinebased therapy (6 of them were treated with bevacizumab), and 30 patients were treatmentnaive. All patients received the standard sunitinib dose of 50 mg daily for 4 weeks, followed by 2 weeks off therapy. TFT assessment, including free thyroxine index, was initiated in 29 patients (and subsequently in another 37 patients) as a routine laboratory assessment at baseline and on day 28 of every even numbered cycle. Out of the 66 patients, 56 (85%) had one or more TFT abnormality. These abnormalities were consistent with hypothyroidism in all patients and primarily included the elevation of TSH, decreased levels of T3 and, less commonly, decreases in T4 and/or of the free thyroxine index. TFT abnormalities were detected early (the median time of detection was at cycle 2). Among patients with abnormal TFTs, signs and symptoms related to hypothyroidism were found in 47 patients (84%). These symptoms included fatigue, cold intolerance, anorexia, periorbital edema, fluid retention, and alterations in skin or hair. LT4 therapy was given at the discretion of the physician, on the basis of the degree of biochemical abnormality and/or clinical symptoms. A resolution of biochemical abnormalities occurred in all 17 patients treated with LT4, and an improvement of symptoms was recorded in 9 patients. Anti-TG antibodies were measured in 44 patients and were abnormal in 13 (30%). No association was observed between the presence of anti-TG antibodies and the incidence or severity of TFT abnormalities [111].

Feldman *et al.* [124] reported that hypothyroidism was found in 14 (18%) out of the 80 patients enrolled in a prospective clinical trial that investigated the efficacy of sunitinib in metastatic RCC. Serum TSH levels were obtained only from symptomatic patients and ranged from 6.0 to 146.4 mU/L (normal range 0.35–5.5 mU/L). Hypothyroidism was detected after a median time of 10 months of therapy (range 1–26 months), being fatigue the predominant symptom. The Authors highlighted that the lower incidence of hypothyroidism reported might depend on the fact that TFT assessment was performed on symptomatic patients only [124].

Wong *et al.* [109] explored the potential effects of sunitinib on thyroid function in a cohort of 40 patients affected by different tumor histotypes, the majority of whom were affected by imatinib-resistant GIST. In this study a new onset or worsening condition of hypothyroidism occurred in 21 out of 40 patients (53%) patients who underwent TFTs. Patients developed elevated TSH levels after a median of 5 months of treatment (range, 1–36 months). The median TSH level was 21.4 mU/L (range, 4.6–174 mU/L). The influence of sunitinib on peroxidase activity was assessed by testing its effects on guaiacol oxidation and protein iodination caused by lactoperoxidase. The potency of sunitinib antiperoxidase activity was about 25% of that noted with propylthiouracil. The Authors proposed that the antithyroid effect of sunitinib is mediated by the inhibition of peroxidase activity, which is involved in the synthesis of the thyroid hormone [109].

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 323

process. The Authors noted that after sunitinib withdrawal, TSH levels returned to the

Interestingly, the association between TKI-induced thyroid dysfunction and clinical efficacy has been demonstrated in two larger studies. Schmidinger *et al.* [126] in a prospective analysis of 87 patients with metastatic RCC who were to receive treatment with sunitinib or sorafenib, thyroid function was monitored every 4 weeks during the first 2 months of treatment and every 2 to 4 weeks thereafter. Subclinical hypothyroidism was present in five patients at baseline and was diagnosed in 30 patients (36.1%) within the first 2 months of therapy. Patients with subclinical hypothyroidism had a statistically significant objective remission rate of 28.3% *versus* 3.3% in euthyroid patients (p<0.001) and median duration of survival (not reached *versus* 13.9 months in euthyroid patients; p=0.016). In addition, in a multivariate analysis, the development of subclinical hypothyroidism within 2 months of treatment was found to be an independent predictor of survival (p=0.014). In another study on patients with metastatic RCC who received sunitinib or sorafenib, Riesenbeck *et al.* [127] found that 21 (38.1%) out of the 66 evaluable patients developed hypothyroidism. Hypothyroidism was associated with a longer PFS (16.0 ± 0.8 months *versus* 6.0 ± 0.8 months, p=0.032). In agreement with the study by Schmidinger *et al.* [126], hypothyroidism was found to be an independent predictor of

Sorafenib is an oral multikinase inhibitor that inhibits the kinase activity of RAF/MEK/ERK, VEGFR2 and VEGFR3, Flt3, fibroblast growth factor receptor 1, RET, cMET, PDGFR β, Kit and other receptors involved in tumor progression and angiogenesis. It is approved for the treatment of advanced RCC and unresectable hepatocellular carcinoma. In addition, it is under clinical evaluation in a number of tumor types, including lung, pancreatic, prostate, melanoma and differentiated thyroid cancer. Tamaskar *et al.* [114] retrospectively investigated the incidence of TFT abnormalities in 39 patients with metastatic RCC treated with 400 mg sorafenib twice daily. Most patients had received at least one prior treatment. Out of the 39 patients, 16 (41%) had one or more serum TFT values outside the laboratory normal reference range during treatment with sorafenib. The median timing of the abnormal test was 1.8 months (range 0.6–7.3 months). Biochemical hypothyroidism occurred in 7 out of 39 patients (18%) during treatment, which was first observed 2–4 months after sorafenib initiation. Six of these patients had mild TSH level elevations (5.5–10.0 mU/L). Another patient showed a rapid onset of hypothyroidism with TSH level rising from 5.74 to 160.64 mU/L, and T3 level decreasing from 72 to 49 ng/dl over 1.5 months. One patient had normal TSH concentration (2.42 mU/L) but low T3 and T4 at 4 months after starting sorafenib treatment, these abnormalities worsened over the next 4 months with further reductions of T3 and T4 levels, and abnormal TSH (9.930 mU/L). Both these patients received LT4. In two of the seven hypothyroid patients anti-TG antibody titers increased; two patients had persistent serum TSH elevation and in one case a normalization of the TSH

normal range in a maximum of 60 days.

survival (p=0.01) in a multivariate analysis.

*3.4.3. Sorafenib* 

values was observed.

Wolter *et al.* [125] prospectively evaluated the incidence of hypothyroidism in patients with GIST or metastatic RCC treated with sunitinib at the standard dose [125]. TFTs included assessment of serum TSH, T3, free thyroxine index and thyroid antibodies (anti-TG, anti-TPO antibodies, and TSH receptor antibodies) and was measured on days 1 and 28 of each treatment cycle. The analysis revealed that 16 patients (27%) developed sub- or clinical hypothyroidism requiring thyroid hormone replacement and 20 patients (34%) showed at least one thyroid test abnormality. The median time to develop thyroid dysfunction was 4 weeks and patients who did not develop hypothyroidism within the first cycles did not develop hypothyroidism later during therapy.

In another prospective phase I-II study, Mannavola *et al.* [110] evaluated TFT (serum TSH, free T3 and T4, thyroglobulin, anti-TG and anti-TPO antibodies) in 24 patients with GIST who were treated with sunitinib (4 weeks of 50 mg daily and 2 weeks of withdrawal). Urinary iodine was measured in 18 patients and urinary fluorine was assessed in 10 patients. Thyroid ultrasonography and echocolor-Doppler were performed, both at enrollment and after a variable number of treatment cycles. To study thyroid function, 123I thyroidal uptake and scintigraphy were performed in 6 unselected patients at the end of the treatment and withdrawal periods. Hypothyroidism was documented in 46% of patients, and a transient elevation of TSH levels in 25% of cases. The overall prevalence of elevated TSH levels after sunitinib was 71%. At onset, hypothyroidism was subclinical in all but one patient with Hashimoto thyroiditis, the only one with detectable antithyroid autoantibodies. TSH levels were found to fluctuate according to whether treatment was given or withdrawn, and progressively increased during treatment. In most cases, progressive worsening of hypothyroidism was shown, but in a few cases a sudden development of severe hypothyroidism was observed. The normal echographic and echocolor-Doppler patterns, obtained both at baseline and during treatment, indicate that hypothyroidism is unlikely to be the consequence of a direct toxic effect on thyroid cells or secondary to an autoimmune process. Inhibition of iodine uptake seems to be a more likely explanation for hypothyroidism. Indeed, radioiodine uptake impairment has been demonstrated by a reduced uptake at the end of treatment periods, with a partial or total recovery during the withdrawal phase. Of particular interest was the observation of a blunted early 123I uptake curve, which suggests an alteration in the uptake phase rather than in the organification process. The Authors noted that after sunitinib withdrawal, TSH levels returned to the normal range in a maximum of 60 days.

Interestingly, the association between TKI-induced thyroid dysfunction and clinical efficacy has been demonstrated in two larger studies. Schmidinger *et al.* [126] in a prospective analysis of 87 patients with metastatic RCC who were to receive treatment with sunitinib or sorafenib, thyroid function was monitored every 4 weeks during the first 2 months of treatment and every 2 to 4 weeks thereafter. Subclinical hypothyroidism was present in five patients at baseline and was diagnosed in 30 patients (36.1%) within the first 2 months of therapy. Patients with subclinical hypothyroidism had a statistically significant objective remission rate of 28.3% *versus* 3.3% in euthyroid patients (p<0.001) and median duration of survival (not reached *versus* 13.9 months in euthyroid patients; p=0.016). In addition, in a multivariate analysis, the development of subclinical hypothyroidism within 2 months of treatment was found to be an independent predictor of survival (p=0.014). In another study on patients with metastatic RCC who received sunitinib or sorafenib, Riesenbeck *et al.* [127] found that 21 (38.1%) out of the 66 evaluable patients developed hypothyroidism. Hypothyroidism was associated with a longer PFS (16.0 ± 0.8 months *versus* 6.0 ± 0.8 months, p=0.032). In agreement with the study by Schmidinger *et al.* [126], hypothyroidism was found to be an independent predictor of survival (p=0.01) in a multivariate analysis.

#### *3.4.3. Sorafenib*

322 Thyroid Hormone

Wong *et al.* [109] explored the potential effects of sunitinib on thyroid function in a cohort of 40 patients affected by different tumor histotypes, the majority of whom were affected by imatinib-resistant GIST. In this study a new onset or worsening condition of hypothyroidism occurred in 21 out of 40 patients (53%) patients who underwent TFTs. Patients developed elevated TSH levels after a median of 5 months of treatment (range, 1–36 months). The median TSH level was 21.4 mU/L (range, 4.6–174 mU/L). The influence of sunitinib on peroxidase activity was assessed by testing its effects on guaiacol oxidation and protein iodination caused by lactoperoxidase. The potency of sunitinib antiperoxidase activity was about 25% of that noted with propylthiouracil. The Authors proposed that the antithyroid effect of sunitinib is mediated by the inhibition of peroxidase activity, which is

Wolter *et al.* [125] prospectively evaluated the incidence of hypothyroidism in patients with GIST or metastatic RCC treated with sunitinib at the standard dose [125]. TFTs included assessment of serum TSH, T3, free thyroxine index and thyroid antibodies (anti-TG, anti-TPO antibodies, and TSH receptor antibodies) and was measured on days 1 and 28 of each treatment cycle. The analysis revealed that 16 patients (27%) developed sub- or clinical hypothyroidism requiring thyroid hormone replacement and 20 patients (34%) showed at least one thyroid test abnormality. The median time to develop thyroid dysfunction was 4 weeks and patients who did not develop hypothyroidism within the first cycles did not

In another prospective phase I-II study, Mannavola *et al.* [110] evaluated TFT (serum TSH, free T3 and T4, thyroglobulin, anti-TG and anti-TPO antibodies) in 24 patients with GIST who were treated with sunitinib (4 weeks of 50 mg daily and 2 weeks of withdrawal). Urinary iodine was measured in 18 patients and urinary fluorine was assessed in 10 patients. Thyroid ultrasonography and echocolor-Doppler were performed, both at enrollment and after a variable number of treatment cycles. To study thyroid function, 123I thyroidal uptake and scintigraphy were performed in 6 unselected patients at the end of the treatment and withdrawal periods. Hypothyroidism was documented in 46% of patients, and a transient elevation of TSH levels in 25% of cases. The overall prevalence of elevated TSH levels after sunitinib was 71%. At onset, hypothyroidism was subclinical in all but one patient with Hashimoto thyroiditis, the only one with detectable antithyroid autoantibodies. TSH levels were found to fluctuate according to whether treatment was given or withdrawn, and progressively increased during treatment. In most cases, progressive worsening of hypothyroidism was shown, but in a few cases a sudden development of severe hypothyroidism was observed. The normal echographic and echocolor-Doppler patterns, obtained both at baseline and during treatment, indicate that hypothyroidism is unlikely to be the consequence of a direct toxic effect on thyroid cells or secondary to an autoimmune process. Inhibition of iodine uptake seems to be a more likely explanation for hypothyroidism. Indeed, radioiodine uptake impairment has been demonstrated by a reduced uptake at the end of treatment periods, with a partial or total recovery during the withdrawal phase. Of particular interest was the observation of a blunted early 123I uptake curve, which suggests an alteration in the uptake phase rather than in the organification

involved in the synthesis of the thyroid hormone [109].

develop hypothyroidism later during therapy.

Sorafenib is an oral multikinase inhibitor that inhibits the kinase activity of RAF/MEK/ERK, VEGFR2 and VEGFR3, Flt3, fibroblast growth factor receptor 1, RET, cMET, PDGFR β, Kit and other receptors involved in tumor progression and angiogenesis. It is approved for the treatment of advanced RCC and unresectable hepatocellular carcinoma. In addition, it is under clinical evaluation in a number of tumor types, including lung, pancreatic, prostate, melanoma and differentiated thyroid cancer. Tamaskar *et al.* [114] retrospectively investigated the incidence of TFT abnormalities in 39 patients with metastatic RCC treated with 400 mg sorafenib twice daily. Most patients had received at least one prior treatment. Out of the 39 patients, 16 (41%) had one or more serum TFT values outside the laboratory normal reference range during treatment with sorafenib. The median timing of the abnormal test was 1.8 months (range 0.6–7.3 months). Biochemical hypothyroidism occurred in 7 out of 39 patients (18%) during treatment, which was first observed 2–4 months after sorafenib initiation. Six of these patients had mild TSH level elevations (5.5–10.0 mU/L). Another patient showed a rapid onset of hypothyroidism with TSH level rising from 5.74 to 160.64 mU/L, and T3 level decreasing from 72 to 49 ng/dl over 1.5 months. One patient had normal TSH concentration (2.42 mU/L) but low T3 and T4 at 4 months after starting sorafenib treatment, these abnormalities worsened over the next 4 months with further reductions of T3 and T4 levels, and abnormal TSH (9.930 mU/L). Both these patients received LT4. In two of the seven hypothyroid patients anti-TG antibody titers increased; two patients had persistent serum TSH elevation and in one case a normalization of the TSH values was observed.

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

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 325

In a phase II study [101] on 91 patients affected by locally advanced or metastatic medullary thyroid cancer (MTC), motesanib was taken orally at the standard dose for up to 48 weeks or until unacceptable toxicity or disease progression. Thirty-seven patients (41%) had

In another phase II study assessing the tolerability and activity of motesanib in 138 patients with imatinib-resistant GIST, only 3 patients (2%) developed hypothyroidism, but only in

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

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

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,

Axitinib is an oral TKI that acts selectively inhibiting all VEGFR kinases [137]. The drug is approved by the FDA for the treatment of advanced RCC after the failure of one prior systemic therapy. In a Japanese study on 18 patients affected by various solid tumors receiving axitinib at different dosage, 16 (89%) patients experienced elevation in serum TSH

In a phase II study on 60 patients with thyroid cancers resistant or not appropriate for 131I, who received axitinib (starting dose, 5 mg orally twice daily), no thyroid tests abnormalities were registered, except for the initial decreases in thyroglobulin seen in most patients, regardless of their clinical response to therapy. In another phase II study on 62 patients with metastatic RCC refractory to prior therapies, including sorafenib, G1-2 hypothyroidism was registered in 29% of patients [139]. In preclinical studies with axitinib inhibition of VEGFR-2 and VEGFR-3 induced by axitinib lead to thyroid capillary regression [115,140]. Again, destructive thyroiditis mediated by the destruction of thyroid capillary appears a plausible

mechanism of action explaining axitinib-associated hypothyroidism.

probably by increased type 3 deiodinase activity as described using sorafenib [132].

elevated serum TSH levels compared with baseline and/or hypothyroidism.

evaluation in phase III trials on patients affected by several cancer types [134].

one case related to treatment [133].

*3.4.5. Vandetanib* 

two patients.

*3.4.6. Axitinib* 

above the upper limit of normal range [138].

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 significantly associated with the risk of developing hypothyroidism.

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

## *3.4.4. Motesanib*

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 changes in thyroid hormone levels while on motesanib.

In a phase II study [101] on 91 patients affected by locally advanced or metastatic medullary thyroid cancer (MTC), motesanib was taken orally at the standard dose for up to 48 weeks or until unacceptable toxicity or disease progression. Thirty-seven patients (41%) had elevated serum TSH levels compared with baseline and/or hypothyroidism.

In another phase II study assessing the tolerability and activity of motesanib in 138 patients with imatinib-resistant GIST, only 3 patients (2%) developed hypothyroidism, but only in one case related to treatment [133].
