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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

7 November 2006 | Volume 145 Issue 9 | Pages 660-664

Background: Sunitinib malate is an oral tyrosine kinase inhibitor recently approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Because the ret proto-oncogene is also inhibited by this agent, clinical evaluation of thyroid function was performed.

Objective: To describe the prevalence and clinical presentation of thyroid dysfunction related to sunitinib therapy.

Design: Prospective, observational cohort study.

Setting: Tertiary care hospital.

Patients: 42 patients treated for a median of 37 weeks (range, 10 to 167 weeks).

Measurements: Following analysis of serial thyroid-stimulating hormone (TSH) measurements collected prospectively during a clinical trial of sunitinib, the authors determined the proportion of patients with thyroid dysfunction.

Results: Abnormal serum TSH concentrations were documented in 26 of 42 patients (62%): 15 (36%) developed persistent, primary hypothyroidism; 4 (10%) developed isolated TSH suppression; and 7 (17%) experienced transient, mild TSH elevations. The risk for hypothyroidism increased with the duration of sunitinib therapy. Six of 15 (40%) hypothyroid patients had suppressed TSH concentrations before developing hypothyroidism, suggesting thyroiditis. Two hypothyroid patients evaluated with thyroid ultrasonography had no visualized thyroid tissue despite normal baseline thyroid function.

Limitations: The exploratory nature of this study precluded more frequent biochemical and sonographic analysis that may better define the mechanism of sunitinib-associated thyroid dysfunction.

Conclusion: Hypothyroidism is a frequent complication of sunitinib therapy. Regular surveillance of thyroid function is warranted in patients receiving the drug. Although the mechanism by which this complication occurs is unknown, the observations of preceding TSH suppression and subsequent absence of visualized thyroid tissue in some patients suggest that sunitinib may induce a destructive thyroiditis through follicular cell apoptosis. This provides a rationale for further investigation of sunitinib treatment in patients with advanced thyroid cancer.

Editors' Notes Context Sunitinib, a tyrosine kinase inhibitor, has recently been approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Contribution In a series of imatinib-resistant patients treated with sunitinib for gastrointestinal stromal tumors, 36% developed hypothyroidism during the course of treatment. Incidence of hypothyroidism increased progressively with duration of treatment. Implications Disruption of specific cellular signaling pathways by kinase inhibitors that are intended to interfere with malignant cell growth may have profound and unanticipated metabolic consequences. Patients receiving kinase inhibitors should be closely monitored for the occurrence of adverse effects on other organ systems. —The Editors

 

Author and Article 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{at}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.

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