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A Novel Tyrosine-Kinase Selective Inhibitor, Sunitinib, Induces Transient Hypothyroidism by Blocking Iodine Uptake

Department of Medical Sciences (D.M., G.V., P.B.-P., L.F.), University of Milan and Endocrine Unit, and Nuclear Medicine Division (M.C.), Fondazione Policlinico Istituto di Ricovero e Cura a Carattere Scientifico, 20122 Milan, Italy; and Department of Oncology (P.Co., R.B., P.Ca.), Istituto Nazionale dei Tumori, 20133 Milan, Italy

Address all correspondence and requests for reprints to: Laura Fugazzola, M.D., Endocrine Unit, Department of Medical Sciences, Fondazione Policlinico Istituto di Ricovero e Cura a Carattere Scientifico, Via F. Sforza, 35, 20122 Milan, Italy. E-mail: l.fugazzola{at}policlinico.mi.it.

	Abstract

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Context: Sunitinib (sunitinib malate; SU11248; Sutent; Pfizer Inc., New York, NY) is a multitarget inhibitor of tyrosine kinases for the treatment of some human cancers. A myxedematous coma in a patient treated with sunitinib for a gastrointestinal stromal tumor was unexpectedly observed.

Objective: Our objective was to evaluate the effect of sunitinib on thyroid function in 24 patients with gastrointestinal stromal tumors.

Design: This was a prospective, observational cohort study.

Setting: The study was performed at two tertiary care hospitals.

Patients: A total of 24 patients receiving the following cycles of therapy were included in the study: 4-wk daily treatment at the dose of 50 mg orally (ON) and 2-wk withdrawal (OFF).

Interventions: Thyroid function tests, ultrasonography, and iodine-123 (¹²³I) thyroidal uptake were performed at the end of several ON and OFF periods.

Results: After one to six cycles of treatment, 46% of patients developed hypothyroidism. Initially, TSH levels were elevated at the end of ON periods and normalized at the end of OFF periods, but a worsening in following cycles was always observed. Neither echographic alterations nor variations in thyroglobulin and antithyroid autoantibodies were found during the ON and OFF periods. On the contrary, ¹²³I uptake was significantly reduced at the end of ON periods, with partial or total normalization at the end of OFF periods.

Conclusions: A high prevalence of hypothyroidism, very severe in some cases, was observed during sunitinib. Significant variations in ¹²³I uptake strongly suggest that the underlying mechanism is an impaired iodine uptake. The absence of thyroid autoimmunity, the lack of a preceding transient hyperthyroidism, and the normal echographic pattern exclude autoimmune and/or destructive mechanisms. Patients on sunitinib should be strictly monitored for the appearance of hypothyroidism and promptly treated.

	Introduction

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SUNITINIB (sunitinib malate; SU11248; Sutent; Pfizer Inc., New York, NY) is an oral tyrosine kinase inhibitor tested in vivo in human acute myeloid leukemia and in solid tumors, including imatinib-resistant gastrointestinal stromal tumors (GIST) (1, 2, 3, 4, 5, 6, 7). It has a well-documented efficacy and few mild to moderate, reversible side effects. The most common side effect is fatigue, recorded in 50% of cases (2, 8, 9).

The starting point of the present study was the observation, after the third cycle of sunitinib treatment, of a myxedematous coma in one patient with GIST, who died despite prompt initiation of iv L-T₄ and L-T₃ treatment.

On the basis of this case, we prospectively evaluated the thyroid function in a cohort of patients treated with sunitinib for a GIST. The results indicate a selective block in iodine uptake at the basis of thyroid function impairment.

	Patients and Methods

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Patients

A total of 24 patients (11 females and 13 males, age range 40–75 yr) with GIST were enrolled for a phase I/II clinical trial with sunitinib that was administered according to the following 6-wk cycle scheme: 4-wk daily administration (ON) and 2-wk withdrawal (OFF). The follow-up range was of 1.5–25.5 months (median 9.75). The updated clinical status of the patients is reported in Table 1. No personal and/or familial history of thyroid diseases was recorded except for patient no. 1A with Hashimoto’s thyroiditis. No patients were on drugs known to interfere with thyroid function or had received neck external irradiation.

Biochemical evaluations

Blood samples were collected on the last day of both ON and OFF periods. Serum TSH [normal values (nv) 0.26–4.2 mU/liter), free T₃ (FT3) (nv 3.8–8 pmol/liter), free T₄ (FT4) (nv 9–20 pmol/liter), and antithyroid antibodies (thyroglobulin antibody and thyroid peroxidase antibody, nv < 35 U/liter) were measured using the AutoDELFIA technique, and thyroglobulin was measured by an immunoradiometric DELFIA assay (PerkinElmer-Life Sciences, Wallac, Turku, Finland). Urinary iodine was measured in 18 patients by a colorimetric method (nv 150–300 µg/d), and urinary fluorine was assessed in 10 patients by an ion selective electrode measurement (nv 0.2–1.1 mg/g urinary creatinine).

Instrumental investigations

Thyroid ultrasound and echo-color Doppler were performed both at enrollment and after a variable number of treatment cycles. To study the thyroid function in vivo, iodine-123 (¹²³I) thyroidal uptake and scintiscan were performed in six unselected patients (nos. 2A, 8A, 9A, 1B, 3B, and 5B) at the end of OFF and ON periods. For this purpose, 37 MBq ¹²³I was administered iv, and uptake measured at 2, 4, and 24 h.

Role of the funding source

The phase I/II trial of sunitinib was totally funded by Pfizer Inc., and the results of the trial have been reported elsewhere (7). There was no additional funding by Pfizer Inc., and/or other industries. Only authors of the present paper had a role in the collection and interpretation of these data. Ethic Committees of the two institutions involved gave permission to perform these investigations.

	Results

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At enrollment, TSH levels were in the normal range in all patients, except no. 1A (Table 1). According to the degree of thyroid function impairment during sunitinib, three groups of patients were identified. Group A included patient no. 1A and 10 additional patients who developed hypothyroidism after a median of three cycles of sunitinib (Table 1). Group B included six patients who occasionally showed TSH levels at the upper normal limit at the end of ON periods. In this latter group, TSH elevation was always transient, and neither progressive increases of TSH nor low FT4 levels were recorded during the follow-up. Finally, seven patients remained euthyroid during the entire follow-up and were classified as group C. Thus, in the present cohort, the prevalence of hypothyroidism during sunitinib was 46% (10 of 24 patients), increasing to 71% (16 of 24 patients) if patients of group B were also included.

At the first observation, hypothyroidism was subclinical in all patients except no. 7A (Table 1). In all patients, fluctuating TSH concentrations were observed. In particular, TSH levels were above the normal range at the end of the ON periods and normalized at the end of the OFF periods, but a progressive increase of TSH levels was observed up to the lack of normalization during the OFF periods (Fig. 1A). However, in some patients hypothyroidism showed a more rapid worsening, with a 5- to 6-fold increase of TSH levels in the course of one to two cycles of treatment. Before L-T4 treatment, FT4 concentrations remained in the low-normal range in all patients (range 6.9–11.7 pmol/liter), except patient no. 7A. On the contrary, FT3 values were almost always below the lower limit (range 1.1–3.7 pmol/liter), as expected in patients with chronic and severe diseases (low-T₃ syndrome).

View larger version (26K): [in this window] [in a new window]   FIG. 1. Serum TSH and 123I thyroidal uptake in patients treated with sunitinib. A, Serum TSH fluctuating levels during the first seven cycles of sunitinib treatment in three representative patients before they were given L-T4 replacement treatment. Gray areas indicate the ON periods (4-wk drug administration), white areas the OFF periods (2-wk withdrawal). Dotted line indicates the upper normal limit of serum TSH. B, 123I thyroidal uptake (at 24 h) at the end of the ON (striped columns) and OFF periods (white columns). Dotted line indicates the lower normal limit of radioiodine uptake (15–45%). All patients, but no. 5B, had a reduced uptake (range 3–8.8%, nv 15–45%) at the end of the ON periods, with a partial or total recovery at the end of OFF periods (range 16.2–30.5%). The lack of recovery observed in patient nos. 8A and 1B is related to the iodized contrast medium used for abdominal computed tomography (CT) scan just before thyroid uptake measurement at the end of the OFF period, as indicated by the high iodine urinary levels. The numbers at the bottom of the columns indicate TSH values and urinary iodine (UI) levels at the thyroid scan. C, 123I thyroidal uptake curves at the end of the ON (black circles: TSH, 25.9 mU/liter) and OFF periods (white circles: TSH, 16.3 mU/liter) in an exemplified case (no. 2A). The of early 123I uptake are reported for each curve. Note that at the end of the ON period, both a decreased uptake and a reduced were found, indicating a specific inhibition of iodine uptake.

Finally, hypothyroidism appeared to be transient. Indeed, in the three patients (nos. 3A, 8A, and 9A) who could be evaluated after definitive withdrawal of sunitinib, L-T₄ was also withdrawn, and TSH levels normalized after 2 months. Random measurements of gonadotropins, estrogens, testosterone, prolactin, GH and IGF-I, ACTH and cortisol, and PTH and serum calcium were performed in several patients, but no significant differences were observed, either between ON and OFF periods or between different cycles (data not shown).

Instrumental investigations

At baseline, ultrasonography showed a thyroid gland normal for volume and echographic pattern in nine of 11 patients examined, whereas an autoimmune pattern and solid nodule were documented in patient nos. 1A and 4A, respectively. In all cases, no variations in volume and/or echographic pattern were recorded during the ON and OFF periods or during the following cycles. Moreover, no alterations in thyroidal vascularization were documented at echo-color Doppler.

To study the thyroid function in vivo, six patients (nos. 2A, 8A, 9A, 1B, 3B, and 5B) were submitted to radioiodine thyroidal uptake and scintiscan at the end of both ON and OFF periods. At the end of the ON periods, ¹²³I uptake at 24 h was below the normal limit in five of the six patients (Fig. 1B). Interestingly, the 24-h uptake returned in the normal range at the end of the OFF periods in all but two cases, in which iodized contrast medium was used for abdominal computed tomography scan. Of interest was that the uptake measured at the end of the ON period showed a blunted curve of early uptake (between the second and fourth hour), whereas the same curve was normal at the end of the OFF period (Fig. 1C). This phenomenon is suggestive for a specific inhibition in radioiodine thyroidal uptake.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In the present cohort, hypothyroidism was documented in 46% of patients and a transient elevation of TSH levels in another 25% of cases. Thus, the overall prevalence of elevated TSH levels after sunitinib was 71%, in accordance with recent reports (10, 11, 12, 13). At onset, hypothyroidism was subclinical in all but one patient (no. 7A). Except patient no. 1A with Hashimoto’s, antithyroid autoantibodies were negative in all cases, both at baseline and during the cycles of treatment. The possible presence of a concomitant low-T₃ syndrome in these patients was not a confounding element. Indeed, in this condition the levels of TSH are normal in most patients or, in severely compromised patients, below the normal range (14, 15). On the contrary, in the present cohort, TSH levels were found to fluctuate according to the ON or OFF period and to increase progressively during following cycles of treatment.

The onset of hypothyroidism was not predictable because no significant differences in age, gender, and severity of neoplastic disease were recorded between the different groups. In most cases, hypothyroidism showed a progressive worsening, but in some cases, a sudden development of severe hypothyroidism was observed.

A recent study (10) suggested a destructive mechanism at the basis of sunitinib-induced hypothyroidism, but neither biochemical nor instrumental data are given to support that hypothesis. Present data, based on the normal echographic and echo-color Doppler patterns obtained both at baseline and during treatment, clearly exclude the hypothesis of a direct toxic effect on thyroid cells or of the triggering of an autoimmune process. At variance, strong evidence is given for inhibition of iodine uptake as the cause of, indeed, hypothyroidism. Certainly, radioiodine uptake impairment has been demonstrated by the observation of a reduced uptake at the end of ON periods with a partial or total recovery at the end of OFF periods. Of particular interest was the observation of a blunted early ¹²³I uptake curve, indicat-ing an alteration in the uptake phase rather than in the organification process. This phenomenon was also observed in patients of group B (nos. 1B and 3B), who only had a transient TSH elevation, likely predicting the development of an impaired thyroid function in the following cycles.

After definitive sunitinib withdrawal, TSH levels returned in the normal range in a maximum period of 60 d, suggesting the transitoriness of hypothyroidism and further indicating that the block of iodine uptake is strictly related to the drug administration, similarly to the other reported side effects of sunitinib, which are dose and time dependent (2, 8, 9).

A direct effect of sunitinib on sodium iodide symporter (NIS) or TSH receptor can be hypothesized as the underlying mechanism, particularly considering the transitoriness of hypothyroidism, strong association with the drug administration, and short latency time. Nonetheless, TSH receptor is not likely to be involved because other endocrine axes that signal through the cAMP pathway are not affected, as first demonstrated in the present paper. Therefore, the inhibition of iodine thyroidal uptake at the level of NIS seems to be the more likely mechanism. It is intriguing to hypothesize that fluorine, contained in high doses (one atom of fluorine, corresponding to 1.78 mg/50 mg capsule) in sunitinib, could act on NIS as a competitive inhibitor for iodine uptake like other monovalent anions, including perchlorate, thiocyanate, and nitrate. Nonetheless, normal fluorine levels found in treated patients seem not to confirm this hypothesis.

In conclusion, before starting and during sunitinib, screening of thyroid function is mandatory. Indeed, the prompt replacement therapy could ameliorate the fatigue that is often present in these patients, and the prevention of hypothyroidism may be beneficial for treatment efficacy. Finally, hypothyroidism must be recognized and treated because a sudden worsening can occur, possibly leading to myxedematous coma and death.

	Footnotes

 
Disclosure Statement: The authors have nothing to declare.

First Published Online June 26, 2007

Abbreviations: FT3, Free T₃; FT4, free T₄; GIST, gastrointestinal stromal tumor; ¹²³I, iodine-123; NIS, sodium iodide symporter; nv, normal values; OFF, 2-wk withdrawal; ON, 4-wk daily administration.

Received March 14, 2007.

Accepted June 20, 2007.

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