Abstract
In recent years, tyrosine kinase inhibitors (TKIs) have emerged as a new class of anti-cancer therapy with proven efficacy in several types of carcinoma. Although generally considered less toxic than cytotoxic chemotherapy, TKIs do have significant side effects including fatigue and hypertension. In addition, TKI-induced thyroid dysfunction is now recognized as a common toxicity that is associated with some TKI inhibitors. Detection of TKI-induced thyroid dysfunction requires routine monitoring of thyroid function and, in some cases, may require treatment. This review provides a comprehensive assessment of literature evaluating TKI-induced thyroid dysfunction, focusing on the potential mechanisms that result in this toxicity, whether the development of thyroid dysfunction is clinically meaningful, and controversies regarding treatment with thyroid hormone therapy.
Similar content being viewed by others
References
Rini BI, Tamaskar I, Shaheen P, Salas R, Garcia J, Wood L, Reddy S, Dreicer R, Bukowski RM (2007) Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 99:81–83
Wong E, Rosen LS, Mulay M, Vanvugt A, Dinolfo M, Tomoda C, Sugawara M, Hershman JM (2007) Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid 17:351–355
Schoeffski P WP, Himpe U, Dychter SS, Baum CM, Prenen H, Wildiers H, Bex M, Dumez H, (2006). Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I Vol 24, No 18S (June 20 Supplement), 2006:3092
Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, Morgan JA, Dychter SS, Larsen PR, Demetri GD, Alexander EK (2006) Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 145:660–664
Mannavola D, Coco P, Vannucchi G, Bertuelli R, Carletto M, Casali PG, Beck-Peccoz P, Fugazzola L (2007) A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 92:3531–3534
Wolter P, Stefan C, Decallonne B, Dumez H, Bex M, Carmeliet P, Schoffski P (2008) The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation. Br J Cancer 99:448–454
Tamaskar I, Bukowski R, Elson P, Ioachimescu AG, Wood L, Dreicer R, Mekhail T, Garcia J, Rini BI (2008) Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib. Ann Oncol 19:265–268
Clement P WP, Stefan C, Decallonne B, Dumez H, Wildiers H, Schöffski P(2008) J Clin Oncol 26 (May 20 suppl; abstr 16145)
de Groot JW, Zonnenberg BA, van Ufford-Mannesse PQ, de Vries MM, Links TP, Lips CJ, Voest EE (2007) A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab 92:3466–3469
de Groot JW, Zonnenberg BA, Plukker JT, van Der Graaf WT, Links TP (2005) Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther 78:433–438
Dora JM, Leie MA, Netto B, Fogliatto LM, Silla L, Torres F, Maia AL (2008) Lack of imatinib-induced thyroid dysfunction in a cohort of non-thyroidectomized patients. Eur J Endocrinol 158:771–772
Weisberg E, Catley L, Wright RD, Moreno D, Banerji L, Ray A, Manley PW, Mestan J, Fabbro D, Jiang J, Hall-Meyers E, Callahan L, DellaGatta JL, Kung AL, Griffin JD (2007) Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias. Blood 109:2112–2120
Manley PW, Drueckes P, Fendrich G, Furet P, Liebetanz J, Martiny-Baron G, Mestan J, Trappe J, Wartmann M, Fabbro D (2010) Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta 1804:445–453
Kim TD, Schwarz M, Nogai H, Grille P, Westermann J, Plockinger U, Braun D, Schweizer U, Arnold R, Dorken B, le Coutre P (2010) Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia. Thyroid 20:1209–1214
Yoshizato T, Nannya Y, Yoshiki Y, Nakamura F, Imai Y, Ichikawa M, Kurokawa M (2011) Nilotinib-induced hypothyroidism in a patient with chronic myeloid leukemia. Int J Hematol 93:400–402
Sherman SI, Wirth LJ, Droz JP, Hofmann M, Bastholt L, Martins RG, Licitra L, Eschenberg MJ, Sun YN, Juan T, Stepan DE, Schlumberger MJ (2008) Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med 359:31–42
Wells SA, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Vasselli JR, Read J, Schlumberger M (2010) Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): a randomized, double-blind phase III trial (ZETA). J Clin Oncol 28 (Suppl; abstr 5503)
Robinson BG, Paz-Ares L, Krebs A, Vasselli J, Haddad R (2010) Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab 95:2664–2671
Kelly RJ, Rixe O (2010) Axitinib (AG-013736). Recent Results Cancer Res 184:33–44
Fujiwara Y, Kiyota N, Chayahara N, Suzuki A, Umeyama Y, Mukohara T, Minami H (2011) Management of axitinib (AG-013736)-induced fatigue and thyroid dysfunction, and predictive biomarkers of axitinib exposure: results from phase I studies in Japanese patients. Investig New Drugs. doi:10.1007/s10637-011-9637-1
Wolter P SC, Decallonne B, Dumez H, Fieuws S, Wildiers H, Clement P, Debaere D, Van Oosterom A, and Schoffski P (2008) Evaluation of thyroid dysfunction as a candidate surrogate marker for efficacy of sunitinib in patients (pts) with advanced renal cell cancer (RCC). J Clin Oncol 26 (May 20 suppl; abstr 16145)
Sato S, Muraishi K, Tani J, Sasaki Y, Tokubuchi I, Tajiri Y, Yamada K, Suekane S, Miyajima J, Matsuoka K, Hiromatsu Y (2010) Clinical characteristics of thyroid abnormalities induced by sunitinib treatment in Japanese patients with renal cell carcinoma. Endocr J 57:873–880
Grossmann M, Premaratne E, Desai J, Davis ID (2008) Thyrotoxicosis during sunitinib treatment for renal cell carcinoma. Clin Endocrinol (Oxf) 69:669–672
Sakurai K, Fukazawa H, Arihara Z, Yoshida K (2010) Sunitinib-induced thyrotoxicosis followed by persistent hypothyroidism with shrinkage of thyroid volume. Tohoku J Exp Med 222:39–44
Rogiers A, Wolter P, Op de Beeck K, Thijs M, Decallonne B, Schoffski P (2010) Shrinkage of thyroid volume in sunitinib-treated patients with renal-cell carcinoma: a potential marker of irreversible thyroid dysfunction? Thyroid 20:317–322
Viglietto G, Romano A, Manzo G, Chiappetta G, Paoletti I, Califano D, Galati MG, Mauriello V, Bruni P, Lago CT, Fusco A, Persico MG (1997) Upregulation of the angiogenic factors PlGF, VEGF and their receptors (Flt-1, Flk-1/KDR) by TSH in cultured thyrocytes and in the thyroid gland of thiouracil-fed rats suggest a TSH-dependent paracrine mechanism for goiter hypervascularization. Oncogene 15:2687–2698
Yamada E, Yamazaki K, Takano K, Obara T, Sato K (2006) Iodide inhibits vascular endothelial growth factor-A expression in cultured human thyroid follicles: a microarray search for effects of thyrotropin and iodide on angiogenesis factors. Thyroid 16:545–554
Jebreel A, England J, Bedford K, Murphy J, Karsai L, Atkin S (2007) Vascular endothelial growth factor (VEGF), VEGF receptors expression and microvascular density in benign and malignant thyroid diseases. Int J Exp Pathol 88:271–277
Hoffmann S, Hofbauer LC, Scharrenbach V, Wunderlich A, Hassan I, Lingelbach S, Zielke A (2004) Thyrotropin (TSH)-induced production of vascular endothelial growth factor in thyroid cancer cells in vitro: evaluation of TSH signal transduction and of angiogenesis-stimulating growth factors. J Clin Endocrinol Metab 89:6139–6145
Baffert F, Le T, Sennino B, Thurston G, Kuo CJ, Hu-Lowe D, McDonald DM (2006) Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol 290:H547–H559
Kamba T, Tam BY, Hashizume H, Haskell A, Sennino B, Mancuso MR, Norberg SM, O’Brien SM, Davis RB, Gowen LC, Anderson KD, Thurston G, Joho S, Springer ML, Kuo CJ, McDonald DM (2006) VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol 290:H560–H576
Salem AK, Fenton MS, Marion KM, Hershman JM (2008) Effect of sunitinib on growth and function of FRTL-5 thyroid cells. Thyroid 18:631–635
Williams KJ, Telfer BA, Shannon AM, Babur M, Stratford IJ, Wedge SR (2007) Combining radiotherapy with AZD2171, a potent inhibitor of vascular endothelial growth factor signaling: pathophysiologic effects and therapeutic benefit. Mol Cancer Ther 6:599–606
Alexandrescu DT, Popoveniuc G, Farzanmehr H, Dasanu CA, Dawson N, Wartofsky L (2008) Sunitinib-associated lymphocytic thyroiditis without circulating antithyroid antibodies. Thyroid 18:809–812
Illouz F, Laboureau-Soares S, Dubois S, Rohmer V, Rodien P (2009) Tyrosine kinase inhibitors and modifications of thyroid function tests: a review. Eur J Endocrinol 160:331–336
Rivas M, Santisteban P (2003) TSH-activated signaling pathways in thyroid tumorigenesis. Mol Cell Endocrinol 213:31–45
Calebiro D, de Filippis T, Lucchi S, Martinez F, Porazzi P, Trivellato R, Locati M, Beck-Peccoz P, Persani L (2006) Selective modulation of protein kinase A I and II reveals distinct roles in thyroid cell gene expression and growth. Mol Endocrinol 20:3196–3211
Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G (2009) Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol 6:219–228
Novartis Pharmaceuticals Corporation (2010) Gleevec (imatinib mesylate): full prescribing information. Novartis Pharmaceuticals Corporation, East Hanover
Shinohara N TM, Kamishima T, Ikushima H, Sazawa A, Kanayama H, Nonomura K (2009) Efficacy and thyroidal effects of sunitinib in Japanese patients with metastatic renal cell carcinoma: hypothyroidism and thyroid atrophy as potential biomarkers for sunitinib? J Clin Oncol 27 (suppl; abstr e16097)
Schmidinger M, Vogl UM, Bojic M, Lamm W, Heinzl H, Haitel A, Clodi M, Kramer G, Zielinski CC (2011) Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 117:534–544
Riesenbeck LM, Bierer S, Hoffmeister I, Kopke T, Papavassilis P, Hertle L, Thielen B, Herrmann E (2010) Hypothyroidism correlates with a better prognosis in metastatic renal cancer patients treated with sorafenib or sunitinib. World J Urol. doi:10.1007/s00345-010-0627-2
Garfield D, Hercbergs A, Davis P (2007) Unanswered questions regarding the management of sunitinib-induced hypothyroidism. Nat Clin Pract 4:674
Theodossiou C, Skrepnik N, Robert EG, Prasad C, Axelrad TW, Schapira DV, Hunt JD (1999) Propylthiouracil-induced hypothyroidism reduces xenograft tumor growth in athymic nude mice. Cancer 86:1596–1601
Goodman AD, Hoekstra SJ, Marsh PS (1980) Effects of hypothyroidism on the induction and growth of mammary cancer induced by 7,12-dimethylbenz(a)anthracene in the rat. Cancer Res 40:2336–2342
Cristofanilli M, Yamamura Y, Kau SW, Bevers T, Strom S, Patangan M, Hsu L, Krishnamurthy S, Theriault RL, Hortobagyi GN (2005) Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma. Cancer 103:1122–1128
Hercbergs AA, Goyal LK, Suh JH, Lee S, Reddy CA, Cohen BH, Stevens GH, Reddy SK, Peereboom DM, Elson PJ, Gupta MK, Barnett GH (2003) Propylthiouracil-induced chemical hypothyroidism with high-dose tamoxifen prolongs survival in recurrent high grade glioma: a phase I/II study. Anticancer Res 23:617–626
Nelson M, Hercbergs A, Rybicki L, Strome M (2006) Association between development of hypothyroidism and improved survival in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 132:1041–1046
Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT (2004) Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. Endocr Pract 10:497–501
Fatourechi V (2009) Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc 84:65–71
Feldman DR, Martorella AJ, Robbins RJ, Motzer RJ (2007) Re: hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Nat Cancer Inst 99:974–975, author reply 976–977
Dedecjus M, Kolomecki K, Brzezinski J, Adamczewski Z, Tazbir J, Lewinski A (2007) Influence of L-thyroxine administration on poor-platelet plasma VEGF concentrations in patients with induced short-term hypothyroidism, monitored for thyroid carcinoma. Endocr J 54:63–69
Bladou F GG, Sabatier R, Deville J, Walz J, Narbonne H, Marcy M, Salem N, Brunelle S, Eymard J (2010) Hypothyroidism and survival during sunitinib therapy in metastatic renal cell carcinoma (mRCC): a prospective observational analysis. J Clin Oncol 28 (suppl; abstr e15013)
Acknowledgements
The author thanks Drs. Renee Aronsohn, Colleen Flynn, and Shanika Samarasinghe for reviewing this manuscript.
Conflict of interest statement
No benefits in any form have been received from a commercial party related directly or indirectly to the topic of this article. No funds were received to support this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Brown, R.L. Tyrosine kinase inhibitor-induced hypothyroidism: incidence, etiology, and management. Targ Oncol 6, 217–226 (2011). https://doi.org/10.1007/s11523-011-0197-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11523-011-0197-2