Background: The objective of this study was to evaluate if hypothyroidism developing during sunitib therapy in patients with metastatic renal cell carcinoma (mRCC) is associated with a better outcome. Methods: Thirty-one consecutive patients with clear cell mRCC were retrospectively analyzed. Thyroid function was assessed prior to therapy, every 6 weeks during the first 6 months and every 2–4 months thereafter. Hypothyroidism was considered present if thyroid-stimulating hormone (TSH) exceeded the upper normal limit (UNL) with normal triiodothyronine (T3) and thyroxine (T4). Results: Hypothyroidism occurred in 16 patients (52%) within 3 months (range 0.7–22.9) of treatment initiation. Thyroid replacement corrected TSH below the UNL in 10 patients (63%). The distribution according to Motzer prognostic criteria revealed good prognosis in 16 patients (52%), intermediate in 9 (29%) and poor in 6 (19%). The hypothyroid patients tended to have longer progression-free survival (PFS; median 12.2 vs. 9.4 months; p = 0.234) and longer survival (median 22.4 vs. 13.9 months; p = 0.234) than the euthyroid patients. Clinical benefits were similar in both groups. Conclusions: Hypothyroidism that develops in mRCC patients treated with sunitinib is associated with a trend toward prolonged PFS and survival, with a similar clinical benefit rate.

Kruit WH, Bolhuis RL, Goey SH, Jansen RL, Eggermont AM, Batchelor D, Schmitz PI, Stoter G: Interleukin-2-induced thyroid dysfunction is correlated with treatment duration but not with tumor response. J Clin Oncol 1993;11:921–924.
Wong E, Rosen LS, Mulay M, Vanvugt A, Dinolfo M, Tomoda C, Sugawara M, Hershman JM: Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid 2007;17:351–355.
Rini BI, Tamaskar I, Shaheen P, Salas R, Garcia J, Wood L, Reddy S, Dreicer R, Bukowski RM: Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2007;99:81–83.
Feldman DR, Martorella AJ, Robbins RJ, Motzer RJ: Re: hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2007;99:974–975, author reply 976–977.
Wolter P, Stefan C, Decallonne B, Dumez H, Bex M, Carmeliet P, Schöffski P: The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation. Br J Cancer 2008;99:448–454.
Sabatier R, Eymard JC, Walz J, Deville JL, Narbonne H, Boher JM, Salem N, Marcy M, Brunelle S, Viens P, Bladou F, Gravis G: Could thyroid dysfunction influence outcome in sunitinib-treated metastatic renal cell carcinoma? Ann Oncol 2012;23:714–721.
Shinohara N, Takahashi M, Kamishima T, Ikushima H, Sazawa A, Kanayama H, Nonomura K: Efficacy and thyroidal effects of sunitinib in Japanese patients with metastatic renal cell carcinoma: hypothyroidism and thyroid atrophy as potential biomarkers for sunitinib? (abstract). J Clin Oncol 2009;27(suppl):e16097.
Bladou F, Gravis G, Sabatier R, Deville J, Walz J, Narbonne H, Marcy M, Salem N, Brunelle S, Eymard J: Hypothyroidism and survival during sunitinib therapy in metastatic renal cell carcinoma (mRCC): a prospective observational analysis (abstract). J Clin Oncol 2010;28(suppl):e15013).
Pinto A, Moreno V, Espinosa E, Redondo A, Barón MG: New onset hypothyroidism and macrocytosis as surrogate markers for the efficacy of sunitinib in the treatment of advanced renal cell carcinoma. 2010 Genitourinary Cancers Symposium, San Francisco, Calif., 2010, abstract 338.
Schmidinger M, Vogl UM, Bojic M, Lamm W, Heinzl H, Haitel A, Clodi M, Kramer G, Zielinski CC: Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 2011;117:534–544.
Riesenbeck LM, Bierer S, Hoffmeister I, Köpke T, Papavassilis P, Hertle L, Thielen B, Herrmann E: Hypothyroidism correlates with a better prognosis in metastatic renal cancer patients treated with sorafenib or sunitinib. World J Urol 2011;29:807–813.
Schmidinger M, Bellmunt J: Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma. Cancer Treat Rev 2010;36:416–424.
Hershman JM, Liwanpo L: How does sunitinib cause hypothyroidism? Thyroid 2010;20:243–244.
Rogiers A, Wolter P, Op de Beeck K, Thijs M, Decallonne B, Schöffski P: Shrinkage of thyroid volume in sunitinib-treated patients with renal-cell carcinoma: a potential marker of irreversible thyroid dysfunction? Thyroid 2010;20:317–322.
Kappers MH, van Esch JH, Smedts FM, de Krijger RR, Eechoute K, Mathijssen RH, Sleijfer S, Leijten F, Danser AH, van den Meiracker AH, Visser TJ: Sunitinib-induced hypothyroidism is due to induction of type 3 deiodinase activity and thyroidal capillary regression. J Clin Endocrinol Metab 2011;96:3087–3094.
Makita N, Miyakawa M, Fujita T, Iiri T: Sunitinib induces hypothyroidism with a markedly reduced vascularity. Thyroid 2010;20:323–326.
Baldazzi V, Tassi R, Lapini A, Santomaggio C, Carini M, Mazzanti R: The impact of sunitinib-induced hypothyroidism on progression-free survival of metastatic renal cancer patients: a prospective single-center study. Urol Oncol 2010, E-pub ahead of print.
Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ: Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228–238.
Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT: Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. J Clin Endocrinol Metab 2005;90:581–585.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115–124.
Atkinson BJ, Perpich J, Tannir NM, Jonasch E: Schedule modifications and treatment outcomes for sunitinib-related adverse events (abstract). J Clin Oncol 2010;28(suppl):e15115.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–216.
Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M: Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20:289–296.
Anderson JR, Cain KC, Gelber RD: Analysis of survival by tumor response and other comparisons of time-to-event by outcome variables. J Clin Oncol 2008;26:3913–3915.
Biondi B, Cooper DS: The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008;29:76–131.
Hercbergs AH, Ashur-Fabian O, Garfield D: Thyroid hormones and cancer: clinical studies of hypothyroidism in oncology. Curr Opin Endocrinol Diabetes Obes 2010;17:432–436.
Cristofanilli M, Yamamura Y, Kau SW, Bevers T, Strom S, Patangan M, Hsu L, Krishnamurthy S, Theriault RL, Hortobagvi GN: Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma. Cancer 2005;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: Propylthiouracil-induced chemical hypothyroidism with high-dose tamoxifen prolongs survival in recurrent high grade glioma: a phase I/II study. Anticancer Res 2003;23:617–626.
Nelson M, Hercbergs A, Rybicki L, Strome M: Association between development of hypothyroidism and improved survival in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 2006;132:1041–1046.
Lin HY, Sun M, Tang HY, Lin C, Luidens MK, Mousa SA, Incerpi S, Drusano GL, Davis FB, Davis PJ: L-Thyroxine vs. 3,5,3′-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Am J Physiol Cell Physiol 2009;296:980–991.
Hueston WJ: Treatment of hypothyroidism. Am Fam Physician 2001;64:1717–1724.
Escobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F, Morreale de Escobar G: Review: treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab 2005;90:4946–4954.
Grabenstein J: T3, the other thyroid hormone. Clin Cornerstone 2005;7(suppl 2): s16–s19.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.