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Hypothyroidism after Sunitinib Treatment for Patients with Gastrointestinal Stromal Tumors

Jayesh Desai, MD; Leila Yassa, MD; Ellen Marqusee, MD; Suzanne George, MD; Mary C. Frates, MD; Ming Hui Chen, MD; Jeffrey A. Morgan, MD; Samuel S. Dychter, MD; P. Reed Larsen, MD; George D. Demetri, MD; and Erik K. Alexander, MD
[+] Article and Author Information

From Brigham and Women's Hospital, Dana Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts, and Pfizer, Inc., New York, New York.


Note: Drs. Desai and Yassa are equal first authors. Drs. Demetri and Alexander are equal corresponding authors. These data were presented in part at the 2005 meeting of the American Society of Clinical Oncology, Orlando, Florida, 13–17 May 2005, and the 2006 meeting of the American Thyroid Association, Phoenix, Arizona, 11–15 October 2006.

Acknowledgments: The authors thank Drs. Massimo Santoro and Robert Utiger for reviewing this manuscript.

Grant Support: Funding for this clinical study was provided in part by Pfizer, Inc., New York, New York. It was also funded by philanthropic support from the following sources: The Virginia and Daniel K. Ludwig Trust for Cancer Research, the Rubenstein Foundation, the Katz Foundation, the Quick Family Fund for Cancer Research, the Ronald O. Perelman Fund for Cancer Research at the Dana Farber Cancer Institute, the Stutman GIST Cancer Research Fund, and Leslie's Links.

Potential Financial Conflicts of Interest:Employment: S.S. Dychter (Pfizer, Inc.); Consultancies: J. Desai (Pfizer, Inc.); P.R. Larsen (Pfizer, Inc.); G.D. Demetri (Novartis, Pfizer); Honoraria: J. Desai (Pfizer, Inc.); G.D. Demetri (Novartis, Pfizer); Expert testimony: G.D. Demetri (Novartis, Pfizer); Grants received: G.D. Demetri (Novartis, Pfizer).

Requests for Single Reprints: Erik K. Alexander, MD, Division of Endocrinology, Metabolism, and Diabetes, Brigham and Women's Hospital, 75 Francis Street, PBB-B4, Boston, MA 02115; e-mail, ekalexander@partners.org.

Current Author Addresses: Dr. Desai: Ludwig Oncology Unit, Austin Medical Centre, Studley Road, Heidelberg, Victoria, Australia 3084.

Drs. Yassa, Marqusee, Larsen, and Alexander: Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

Drs. George, Morgan, and Demetri: Department of Medical Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.

Dr. Frates: Department of Radiology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

Dr. Chen: Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

Dr. Dychter: Department of Safety and Risk Management, Pfizer, Inc., 150 East 42nd Street, New York, NY 10017.

Author Contributions: Conception and design: J. Desai, S. George, M.H. Chen, J.A. Morgan, P.R. Larsen, G.D. Demetri, E.K. Alexander.

Analysis and interpretation of the data: J. Desai, J.A. Morgan, S.S. Dychter, P.R. Larsen, G.D. Demetri, E.K. Alexander.

Drafting of the article: J. Desai, S.S. Dychter, P.R. Larsen, G.D. Demetri, E.K. Alexander.

Critical revision of the article for important intellectual content: J. Desai, E. Marqusee, M.C. Frates, J.A. Morgan, P.R. Larsen, G.D. Demetri, E.K. Alexander.

Final approval of the article: J. Desai, S. George, E. Marqusee, M.C. Frates, M.H. Chen, P.R. Larsen, G.D. Demetri, E.K. Alexander.

Provision of study materials or patients: J. Desai, S. George, E. Marqusee, M.C. Frates, G.D. Demetri.

Statistical expertise: E.K. Alexander.

Obtaining of funding: G.D. Demetri.

Administrative, technical, or logistic support: G.D. Demetri, E.K. Alexander.

Collection and assembly of data: J. Desai, E. Marqusee, M.C. Frates, G.D. Demetri, E.K. Alexander.


Ann Intern Med. 2006;145(9):660-664. doi:10.7326/0003-4819-145-9-200611070-00008
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During the phase I/II trial of sunitinib, 15 of 42 (36%) patients developed hypothyroidism after an average of 50 weeks of therapy (range, 12 to 94 weeks) (Table). Of these, 9 had TSH concentrations more than 20 mU/L (mean maximal serum TSH concentration, 100 mU/L) and 6 had TSH concentrations between 7.0 and 20 mU/L. Seven additional patients (17%) had at least 1 TSH concentration between 5.0 and 7.0 mU/L while receiving sunitinib that subsequently normalized. Four patients developed TSH suppression while receiving sunitinib but discontinued the study protocol before repeated thyroid function studies could be performed. In summary, abnormal serum TSH values were documented in 26 of 42 (62%) patients receiving sunitinib. Eastern Cooperative Oncology Group functional status was similar in patients with normal thyroid function and in those who were hypothyroid, suggesting that acute illness did not selectively influence thyroid function in affected patients.

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Figures

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Figure 1.
Biochemical findings of thyroid dysfunction in a patient treated with sunitinib for recurrence of gastrointestinal stromal tumor.

The figure depicts sequential thyroid-stimulating hormone (TSH) measurements during 2 years of sunitinib therapy. l-Thyroxine therapy was initiated at week 74.

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Figure 2.
Thyroid ultrasonogram from a patient with severe hypothyroidism following 5 weeks of sunitinib therapy for recurrence of gastrointestinal stromal tumor.

No thyroid tissue is visualized. C = carotid artery; E = esophagus; TR = trachea.

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Laboratory Abnormalities Suggesting Thyroid Dysfunction in Patients Treated with Sunitinib
Posted on November 26, 2006
Pascal Wolter
Department of General Medical Oncology, University Hospital Gasthuisberg, Catholic University Leuven
Conflict of Interest: None Declared

TO THE EDITOR: In the November 7, 2006, issue of the Annals of Internal Medicine, Desai et al. have reported on hypothyroidism as a frequent complication of treatment with Sunitinib (Sutent®) in patients with gastrointestinal stromal tumours (GIST) refractory to Imatinib (Gleevec®) (1).

There is indeed growing evidence that Sunitinib can cause thyroid function test abnormalities in 30-65 % of patients with metastatic renal cell cancer (RCC) and Imatinib-resistant GIST (2, 3). Our group has experience with Sunitinib in 65 patients with RCC and GIST and we can confirm that 30-40 percent of patients treated with Sunitinib develop thyroid dysfunction (4).

Nevertheless, we would like to make some constructive remarks on the data published by Desai et al. First, the definition of hypothyroidism and the definition of reference values for TSH is an ongoing debate (5). Desai et al. considered a TSH serum concentration > 5 mU/L abnormal but the definition of hypothyroidism is not really clear in the study presented. Following most authors the definition of subclinical hypothyroidism is: serum TSH above the statistically defined upper limit of the reference range when serum free T4 (fT4) concentration is within its reference range (6). Overt hypothyroidism normally is defined as: low serum fT4 and elevated serum TSH (6). It is very difficult to define "clinically significant thyroid impairment". The chosen serum concentration of > 20 mU/L is somewhat arbitrary, it would be more informative if fT4 serum values would be provided. Criteria for starting replacement therapy are not clearly stated.

Secondly, Desai et al. attributed symptoms such as progressive fatigue, cold intolerance, hoarseness and constipation to hypothyroidism. The clinical presentation of patients with hypothyroidism is highly variable and non-specific and the well-known side-effects of Sunitinib can be very similar to symptoms of hypothyroidism, surely in patients with advanced malignancies. It is very difficult to discriminate these non- specific symptoms and it is interesting to note that in our population in patients developing objective hypothyroidism under Sunitinib and treated with replacement therapy symptoms attributed to hypothyroidism do not resolve in all individuals. Therefore, we are not sure that fatigue in patients treated with Sunitinib can exclusively be explained by primary hypothyroidism.

Third, presented determinations of serum TSH were performed at the beginning of each Sunitinib treatment cycle, that means after the period of two weeks rest. We know from our own patient population that most of our patients develop elevated thyroid dysfunction on day 28 of the treatment cycle, that means at the end of the four week treatment period with Sunitinib. In some of our patients elevated TSH was already present after one course of treatment, which is in contrast to the observations of Desai et al.

Desai et al. state that the participants did not receive medication known to cause thyroid dysfunction, but it is very likely that CT-scans with iodinated contrast were performed according to protocol, which may also have interfered with the thyroid function.

The authors conclude that the proportion of patients affected far exceeds that which would be expected based on the prevalence of this condition, which is about 4-8.5 % in the general population (6). We agree with this statement, but we have to take into consideration that the prevalence increases in women older than 60 years to up to 20% (6). It would be interesting to know more about age > 60 years and gender of the patient population in Desai's study. Interestingly, there are no reliable data about prevalence of hypothyroidism in the general cancer population, but there are some preliminary data suggesting a slightly higher prevalence in some types of cancer (7).

The authors hypothesize that drug-induced thyroiditis might be the underlying mechanism. Desai et al. found in six of the fifteen patients with hypothyroidism one or more TSH concentrations less than 0.5 mU/L, thus subclinical hyperthyroidism, before experiencing hypothyroidism, which could support this hypothesis. Unfortunately, TPO-antibodies (TPO- Ab), which are normally detectable in cases of auto-immune thyroiditis as the most common cause of hypothyroidism in the general population was performed in only two out of fifteen patients and the test was not done at baseline. Also, information about eventually elevated serum-thyroglobulin levels as a marker of thyroid destruction and thyroiditis is lacking. In our series TPO-Ab were performed on a routine base and most of the patients did not have elevated TPO antibodies neither before nor at the moment of developing hypothyroidism, suggesting that auto-immune thyroiditis as the underlying cause is indeed unlikely. As stated before, we observed already during the early course of treatment with Sunitinib thyroid dysfunction. In our patient population time to development of abnormal TSH levels was much shorter, nevertheless we can confirm that the risk of developing laboratory evidence of hypothyroidism increases with duration of Sunitinib therapy since in our retrospective analysis of 8 evaluable patients all but one showed elevated TSH (up 119 mIU/l) after median treatment time of 83 weeks (35-102), needing replacement therapy (4).

The mechanisms by which Sunitinib induces thyroid dysfunction are currently unclear. It is interesting to note that de Groot and colleagues recently reported on a GIST patient, who was treated simultaneously with Sunitinib and Levothyroxine because of a previous thyroidectomy and ¹³¹I- ablation for follicular thyroid carcinoma. They describe an elevated TSH and increased need for Levothyroxine despite absence of thyroid tissue (8). This suggests that Sunitinib might not only have a direct effect on the thyroid, but also might interfere with metabolism of T4/T3 ("metabolic hypothesis"). Also the observation that VEGF inhibition at least in the mouse model can induce capillary regression and might therefore also cause damage to thyroid endothelium resulting in thyroid dysfunction already very early in the course of treatment is intriguing, important to note that in the study of Baffert et al. TSH was increased in mice treated with VEGF inhibition (9) ("VEGF-capillary regression hypothesis").

To resume, the study by Desai and colleagues gives an important insight of an unexpected toxicity of a compound considered as "targeted therapy" and therefore initially presumed to affect not or only slightly normal tissue. Since hypothyroidism is not regarded as a classical or frequent side effect of systemic anticancer treatment, thyroid abnormalities were probably under-reported in the initial studies and this most likely related to the fact that thyroid function was not routinely evaluated (10, 11). We agree with Desai et al. that patients receiving Sunitinib or similar compounds should be closely monitored for thyroid dysfunction. We suggest that thyroid function should be systematically assessed at baseline and during the course of their treatment both within and outside of clinical trials. We propose to perform serum-TSH and -fT4 with thyroid antibodies at baseline and serum-TSH on days 1 and 28 of each cycle. We confirm that patients with elevated TSH can be effectively managed with thyroid hormone replacement and we agree that hypothyroidism itself should not prompt to discontinue or reduce treatment of a possibly life- threatening condition. There still remains a doubt concerning the relevance of biochemical diagnosis of hypothyroidism in this setting, for this reason the value of thyroid hormone replacement in individuals with abnormal TSH and the correct timing of starting replacement therapy should be evaluated prospectively in appropriately designed trials.

REFERENCES

1. Desai J, Yassa L, Marqusee E et al.: Hypothyroidism after Sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med. 2006; 145: 660-664.

2. Shaheen PE, Tamaskar IR, Salas RN et al.: Thyroid function tests abnormalities in patients treated with metastatic renal cell carcinoma treated with sunitinib. J Clin Oncol. 2006; 24 (18S): 4605.

3. Desai J, Dileo P, Morgan PR et al.: Hypothyroidism may accompany SU11248 therapy in a subset of patients (pts) with metastatic (met) gastrointestinal stromal tumors (GIST) and is manageable with replacement therapy. J Clin Oncol. 2005; 23 (16S): 3040.

4. Schöffski P, Wolter P, Himpe U et al.: Sunitinib-related thyroid dysfunction: a single center retrospective and prospective evaluation. J Clin Oncol. 2006; 24 (18S): 3092. 5. Wartofsky L, Dickey RA: The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrin Met. 2005; 90(9): 5483- 5488. 6. Surks MI, Ortiz E, Daniels GH et al.: Subclinical Thyroid Disease "“ Scientific Review and Guidelines for diagnosis and Management. JAMA 2004; 291: 228-238.

7. Shah M, Orengo IF, Rosen T: High prevalence of hypothyroidism in male patients with cutaneous melanoma. Dermatology Online Journal 2006; 12 (1): 1

8. De Groot JWB, Links TP, Van der Graaf WTA: Tyrosine kinase inhibitors causing hypothyroidism in a patient on levothyroxine. Ann Oncol. 2006; 17(11): 1719-1720.

9. Baffert F, Le T, Sennino B et al.: Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signalling. Am J Physiol Heart Circ Physiol. 2006; 290: 547-559.

10. Faivre J, Delbaldo C, Vera K et al.: Safety, Pharmacokinetic , and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients with Cancer. J Clin Oncol. 2006; 24: 1"“11.

11. Motzer RJ, Michaelson MD, Redman BG, et al.: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006; 24: 16"“24.

Authors: Pascal Wolter, Herlinde Dumez and Patrick Schöffski Department of General Medical Oncology, University Hospital Gasthuisberg, Catholic University Leuven, Leuven Cancer Institute, Belgium

Corresponding Author : Dr. P. Wolter, MD, UZ Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium, phone 32 16 34 69 00, fax 32 16 34 69 01, e-mail Pascal.Wolter@uz.kuleuven.ac.be

Conflict of Interest:

None declared

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Summary for Patients

Underactive Thyroid Function after Treatment with Sunitinib for Gastrointestinal Cancer

The summary below is from the full report titled “Hypothyroidism after Sunitinib Treatment for Patients with Gastrointestinal Stromal Tumors.” It is in the 7 November 2006 issue of Annals of Internal Medicine (volume 145, pages 660-664). The authors are J. Desai, L. Yassa, E. Marqusee, S. George, M.C. Frates, M.H. Chen, J.A. Morgan, S.S. Dychter, P.R. Larsen, G.D. Demetri, and E.K. Alexander.

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