**6. References**


<sup>\*</sup> Corresponding Author

[12] Dong BJ. How medications affect thyroid function. West J Med 2000;172(2):102–106.

330 Thyroid Hormone

anticancer agents.

**Author details** 

Francesco Torino

**6. References** 

2012;19(2):R21-33.

 \*

Corresponding Author

Oncol 2009;6(4):219-228.

*Rome, Italy* 

systemic therapy, and the correct timing of thyroid replacement therapy need to be more accurately defined. Additional prospective clinical trials are necessary to investigate these important aspects. In parallel, these trials could offer the unique opportunity to clarify the molecular mechanisms underlying thyroid toxicities induced by an increasing number of

*Department of Internal Medicine, Chair of Medical Oncology, University of Rome "Tor Vergata",* 

[1] Hamnvik OP, Larsen PR, Marqusee E. Thyroid dysfunction from antineoplastic agents.

[2] Yeung SC, Chiu AC, Vassilopoulou-Sellin R, Gagel RF. The endocrine effects of

[3] Stava CJ, Jimenez C, Vassilopoulou-Sellin R. Endocrine sequelae of cancer and cancer

[4] Torino F, Barnabei A, De Vecchis L, Appetecchia M, Strigari L, Corsello SM. Recognizing menopause in women with amenorrhea induced by cytotoxic chemotherapy for endocrine-responsive early breast cancer. Endocr Relat Cancer

[5] Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin

[6] van der Molen AJ, Thomsen HS, Morcos SK. Effect of iodinated contrast media on

[7] Markou K, Georgopoulos N, Kyriazopoulou V, Vagenakis AG. Iodine-induced

[8] Schneider AB, Sarne DH. Long-term risks for thyroid cancer and other neoplasms after

[9] Hancock SL, Cox RS, McDougall IR. Thyroid diseases after treatment of Hodgkin's

[10] Beex L, Ross A, Smals A, Kloppenborg P. 5-fluorouracil-induced increase of total serum

[11] Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995;333(25):1688–1694.

exposure to radiation. Nat Clin Pract Endocrinol Metab 2005;1(2):82–91.

thyroxine and triiodothyronine. Cancer Treat Rep 1977;61(7):1291–1295.

Agnese Barnabei, Roberto Baldelli and Marialuisa Appetecchia\*

J Natl Cancer Inst 2011;103(21):1572-87.

treatments. J Cancer Surviv 2007;1(4):261-274.

hypothyroidism. Thyroid 2001;11(5):501–510.

disease. N Engl J Med 1991;325(9):599–605.

thyroid function in adults. Eur Radiol 2004;14(5):902–907.

*Endocrinology Unit, National Institute of Cancer "Regina Elena", Rome, Italy* 

nonhormonal antineoplastic therapy. Endocr Rev 1998;19(2):144–172.


[28] Tomer Y, Blackard JT, Akeno N. Interferon alpha treatment and thyroid dysfunction. Endocrinol Metab Clin North Am 2007;36(4):1051–1066.

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 333

[42] Roti E, Minelli R, Giuberti T, Marchelli S, Schianchi C, Gardini E, Salvi M, Fiaccadori F, Ugolotti G, Neri TM, Braverman LE. Multiple changes in thyroid function in patients with chronic active HCV hepatitis treated with recombinant interferon-alpha. Am J

[43] Corssmit EP, de Metz J, Sauerwein HP, Romijn JA. Biologic responses to IFN-alpha

[44] Yue SJ, Enomoto T, Matsumoto Y, Kawai K, Volpe R. Thyrocyte class I and class II upregulation is a secondary phenomenon and does not contribute to the pathogenesis

[45] Caraccio N, Giannini R, Cuccato S, Faviana P, Berti P, Galleri D, Dardano A, Basolo F, Ferrannini E, Monzani F. Type I interferons modulate the expression of thyroid peroxidase, sodium/iodide symporter, and thyroglobulin genes in primary human

[47] Ward DL, Bing-You RG. Autoimmune thyroid dysfunction induced by interferon-alpha treatment for chronic hepatitis C: screening and monitoring recommendations. Endocr

[48] Weijl NI, Van der Harst D, Brand A, Kooy Y, Van Luxemburg S, Schroder J, Lentjes E, Van Rood JJ, Cleton FJ, Osanto S. Hypothyroidism during immunotherapy with interleukin-2 is associated with antithyroid antibodies and response to treatment. J Clin

[49] Atkins MB, Mier JW, Parkinson DR, Gould JA, Berkman EM, Kaplan MM. Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer

[50] Fraenkel PG, Rutkove SB, Matheson JK, Fowkes M, Cannon ME, Patti ME, Atkins MB, Gollob JA. Induction of myasthenia gravis, myositis, and insulin-dependent diabetes mellitus by high-dose interleukin-2 in a patient with renal cell cancer. J Immunother

[51] Krouse RS, Royal RE, Heywood G, Weintraub BD, White DE, Steinberg SM, Rosenberg SA, Schwartzentruber DJ. Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma treated with interleukin-2 alone. J Immunother Emphasis

[52] Vialettes B, Guillerand MA, Viens P, Stoppa AM, Baume D, Sauvan R, Pasquier J, San Marco M, Olive D, Maraninchi D. Incidence rate and risk factors for thyroid dysfunction during recombinant interleukin-2 therapy in advanced malignancies. Acta

[53] Schwartzentruber DJ, White DE, Zweig MH, Weintraub BD, Rosenberg SA. Thyroid dysfunction associated with immunotherapy for patients with cancer. Cancer

[54] Jacobs EL, Clare-Salzler MJ, Chopra IJ, Figlin RA. Thyroid function abnormalities associated with the chronic outpatient administration of recombinant interleukin-2 and

recombinant interferon-alpha. J Immunother 1991;10(6):448–455.

administration in humans. J Interferon Cytokine Res 2000;20(12):1039–1047.

of autoimmune thyroid disease. Thyroid 1998;8(9):755–763.

thyrocyte cultures. J Clin Endocrinol Metab. 2005;90(2):1156–1162. [46] Barbesino G. Drugs affecting thyroid function. Thyroid 2010;20(7):763-70.

Med 1996;101(5):482–487.

Pract 2001;7(1):52–58.

2002;25(4):373–378.

1991;68(11):2384–2390.

Oncol 1993;11(7):1376–1383.

cells. N Engl J Med 1988;318(24):1557–1563.

Tumor Immunol 1995;18(4):272–278.

Endocrinol [Copenh] 1993;129(1):31–38.


2009;24(7):1163–1168.

6):242–254.

Hepatol 1999;30(5):794–800.

1990;26(11–12):1152–1156.

2011;4(1):2. doi:10.1186/1756-6614-4-2

therapy. Hepatology 1997;26(1):206–210.

1996;24(1):38–47.

1996;44(6):635–642.

[28] Tomer Y, Blackard JT, Akeno N. Interferon alpha treatment and thyroid dysfunction.

[29] Tran HA, Malcolm Reeves GE, Gibson R, Attia JR. Development of thyroid diseases in the treatment of chronic hepatitis C with alpha-interferon may be a good prognosticator in achieving a sustained virological response: a metaanalysis. J Gastroenterol Hepatol

[30] Kakizaki S, Takagi H, Murakami M, Takayama H, Mori M. HLA antigens in patients with interferon-alpha-induced autoimmune thyroid disorders in chronic hepatitis C. J

[31] Dumoulin FL, Leifeld L, Sauerbruch T, Spengler U. Autoimmunity induced by interferon-alpha therapy for chronic viral hepatitis. Biomed Pharmacother 1999;53(5–

[32] Marcellin P, Pouteau M, Benhamou JP. Hepatitis C virus infection, alpha interferon

[33] Koh LK, Greenspan FS, Yeo PP. Interferon-alpha induced thyroid dysfunction: three clinical presentations and a review of the literature. Thyroid 1997;7(6):891–896. [34] Okanoue T, Sakamoto S, Itoh Y, Minami M, Yasui K, Sakamoto M, Nishioji K, Katagishi T, Nakagawa Y, Tada H, Sawa Y, Mizuno M, Kagawa K, Kashima K.et al. Side effects of high-dose interferon therapy for chronic hepatitis C. J Hepatol 1996;25(3):283–291. [35] Wong V, Fu AX, George J, Cheung NW. Thyrotoxicosis induced by alpha-interferon

[36] Gisslinger H, Gilly B, Woloszczuk W, Mayr WR, Havelec L, Linkesch W, Weissel M. Thyroid autoimmunity and hypothyroidism during long-term treatment with

[37] Scalzo S, Gengaro A, Boccoli G, Masciulli R, Giannella G, Salvo G, Marolla P, Carlini P, Massimini G, Holdener EE, et al. Primary hypothyroidism associated with interleukin-2 and interferon alpha-2 therapy of melanoma and renal carcinoma. Eur J Cancer

[38] Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol

[39] Tran HA, Jones TL, Ianna EA, Reeves GE. The natural history of interferon-alpha induced thyroiditis in chronic hepatitis C patients: a long term study. Thyroid Res

[40] Marazuela M, Garcia-Buey L, Gonzalez-Fernandez B, García-Monzón C, Arranz A, Borque MJ, Moreno-Otero R. Thyroid autoimmune disorders in patients with chronic hepatitis C before and during interferon-alpha therapy. Clin Endocrinol [Oxf]

[41] Deutsch M, Dourakis S, Manesis EK, Gioustozi A, Hess G, Horsch A, Hadziyannis S. Thyroid abnormalities in chronic viral hepatitis and their relationship to interferon alfa

therapy in chronic viral hepatitis. Clin Endocrinol [Oxf]. 2002;56(6):793–798.

recombinant interferon-alpha. Clin Exp Immunol 1992;90(3):363–367.

therapy and thyroid dysfunction. J Hepatol 1995;22(3):364–369.

Endocrinol Metab Clin North Am 2007;36(4):1051–1066.


[55] Vassilopoulou-Sellin R, Sella A, Dexeus FH, Theriault RL, Pololoff DA. Acute thyroid dysfunction [thyroiditis] after therapy with interleukin-2. Horm Metab Res 1992;24(9):434–438.

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 335

[69] Badros AZ, Siegel E, Bodenner D, Zangari M, Zeldis J, Barlogie B, Tricot G. Hypothyroidism in patients with multiple myeloma following treatment with

[70] Erdem F, Gundogdu M, Kiki I, Capoglu I. Autoimmune thyroiditis during thalidomide

[71] Chowta MN, Chowta NK. Hypothyroidism caused by thalidomide. Indian J Med Sci

[72] Mateos MV. Management of treatment-related adverse events in patients with multiple

[73] Gay F, Hayman SR, Lacy MQ, Buadi F, Gertz MA, Kumar S, Dispenzieri A, Mikhael JR, Bergsagel PL, Dingli D, Reeder CB, Lust JA, Russell SJ, Roy V, Zeldenrust SR, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Rajkumar SV. Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple

[75] Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary

[76] Figaro MK, Clayton W Jr, Usoh C, Brown K, Kassim A, Lakhani VT, Jagasia S. al. Thyroid abnormalities in patients treated with lenalidomide for hematological malignancies: results of a retrospective case review. Am J Hematol 2011;86(6):467–470. [77] Somers GF. Pharmacological properties of thalidomide [alpha-phthalimido glutarimide], a new sedative hypnotic drug. Br J Pharmacol Chemother 1960;15(1):111–

[78] Murdoch JM, Campbell GD. Antithyroid activity of N-phthalyl glutamic acid imide

[79] Giagounidis A, Fenaux P, Mufti GJ, Muus P, Platzbecker U, Sanz G, Cripe L, Von Lilienfeld-Toal M, Wells RA. Practical recommendations on the use of lenalidomide in the management of myelodysplastic syndromes. Ann Hematol 2008;87(5):345–352. [80] Ledford H. Melanoma drug wins US approval. Nature 2011;471(7340):561.

[81] Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated

[83] Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L, Lowy I, Solomon SR, Morris LE, Holland HK, Mason JR, Alyea EP, Soiffer RJ, Ball ED. CTLA4 blockade

antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 2005;23(35):8968–8977. [82] Min L, Vaidya A, Becker C. Thyroid autoimmunity and ophthalmopathy related to

melanoma biological therapy. Eur J Endocrinol 2011;164(2):303–307.

myeloma: a comparative analysis of 411 patients. Blood 2010;115(7):1343–1350. [74] List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J

thalidomide. Am. J. Med 2002;112(5):412–413.

2006;60(10):424–426.

Med 2006;355(14):1456–1465.

[K17]. Br Med J 1958;1(5062):84–85.

doi:10.1038/471561a

116.

treatment. Am J Hematol 2006;81(2):152. DOI: 10.1002/ajh.20480

myeloma. Cancer Treat Rev 2010;36(suppl 2):S24–S32.

systemic amyloidosis. Blood 2007;109(2):465–470.


[69] Badros AZ, Siegel E, Bodenner D, Zangari M, Zeldis J, Barlogie B, Tricot G. Hypothyroidism in patients with multiple myeloma following treatment with thalidomide. Am. J. Med 2002;112(5):412–413.

334 Thyroid Hormone

533.

1992;24(9):434–438.

1990;21(5):493–502.

[55] Vassilopoulou-Sellin R, Sella A, Dexeus FH, Theriault RL, Pololoff DA. Acute thyroid dysfunction [thyroiditis] after therapy with interleukin-2. Horm Metab Res

[56] Kragel AH, Travis WD, Feinberg L, Pittaluga S, Striker LM, Roberts WC, Lotze MT, Yang JJ, Rosenberg SA. Pathologic findings associated with interleukin-2-based immunotherapy for cancer: a postmortem study of 19 patients. Hum Pathol

[57] Pichert G, Jost LM, Zobeli L, Odermatt B, Pedia G, Stahel RA. Thyroiditis after treatment with interleukin-2 and interferon alpha-2a. Br J Cancer. 1990;62[1]:100–104. [58] Gemlo BT, Palladino MA Jr., Jaffe HS, Espevik TP, Rayner AA. Circulating cytokines in patients with metastatic cancer treated with recombinant interleukin 2 and lymphokine-

[59] Pang XP, Hershman JM, Chung M, Pekary AE. Characterization of tumor necrosis factor-alpha receptors in human and rat thyroid cells and regulation of the receptors by

[60] Franzke A, Peest D, Probst-Kepper M, Buer J, Kirchner GI, Brabant G, Kirchner H, Ganser A, Atzpodien J. Autoimmunity resulting from cytokine treatment predicts longterm survival in patients with metastatic renal cell cancer. J Clin Oncol 1999;17(2):529–

[61] Krouse RS, Royal RE, Heywood G, Weintraub BD, White DE, Steinberg SM, Rosenberg SA, Schwartzentruber DJ. Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma treated with interleukin-2 alone. J Immunother Emphasis

[62] Phan GQ, Attia P, Steinberg SM, White DE, Rosenberg SA. Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol

[63] Anderson KC. Lenalidomide and thalidomide: mechanisms of action—similarities and

[64] Kotla V, Goel S, Nischal S, Heuck C, Vivek K, Das B, Verma A. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol 2009;;2(8):36.

[65] Choueiri TK, Dreicer R, Rini BI, Elson P, Garcia JA, Thakkar SG, Baz RC, Mekhail TM, Jinks HA, Bukowski RM Phase II study of lenalidomide in patients with metastatic

[66] Bartlett JB, Tozer A, Stirling D, Zeldis JB. Recent clinical studies of the immunomodulatory drug [IMiD] lenalidomide. Br J Cancer 2005;93(6):613–619. [67] Ain KB, Lee C, Williams KD. Phase II trial of thalidomide for therapy of radioiodineunresponsive and rapidly progressive thyroid carcinomas. Thyroid 2007;17(7):663–670. [68] de Savary N, Lee R, Vaidya B. Severe hypothyroidism after thalidomide treatment. J R

activated killer cells. Cancer Res 1988;48(20):5864–5867.

thyrotropin. Endocrinology 1989;125(4):1783–1788.

differences. Semin Hematol 2005;42(4;suppl 4):S3–S8.

renal cell carcinoma. Cancer 2006;107(11):2609–2616.

Soc Med 2004;97(9):443. doi: 10.1258/jrsm.97.9.443

Tumor Immunol 1995;18(4):272–278.

2001;19(15):3477–3482.

doi:10.1186/1756-8722-2-36


with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood 2009;113(7):1581–1588.

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 337

[95] Fabbro D, Cowan-Jacob SW, Möbitz H, Martiny-Baron G. Targeting cancer with small-

[96] Lodish MB, Stratakis CA. Endocrine side effects of broad-acting kinase inhibitors.

[97] Brown RL. Tyrosine kinase inhibitor-induced hypothyroidism: incidence, etiology, and

[98] de Groot JW, Zonnenberg BA, Plukker JT, van Der Graaf WT, Links TP. Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther

[99] Kundra P, Burman KD. The effect of medications on thyroid function tests. Med Clin

[100] Gupta-Abramson V, Troxel AB, Nellore A, Puttaswamy K, Redlinger M, Ransone K, Mandel SJ, Flaherty KT, Loevner LA, O'Dwyer PJ, Brose MS. Phase II trial of sorafenib

[101] Schlumberger MJ, Elisei R, Bastholt L, Wirth LJ, Martins RG, Locati LD, Jarzab B, Pacini F, Daumerie C, Droz JP, Eschenberg MJ, Sun YN, Juan T, Stepan DE, Sherman SI. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol

[102] Sherman SI, Wirth LJ, Droz JP, Hofmann M, Bastholt L, Martins RG, Licitra L, Eschenberg MJ, Sun YN, Juan T, Stepan DE, Schlumberger MJ. Motesanib diphosphate

[104] Schröder-van der Elst JP, van der Heide D, DiStefano JJ 3rd, van der Bent C, Kaptein E, Visser TJ. Effects of 5, 5'-diphenylhydantoin on the metabolic pathway of thyroid

[105] De Luca F, Arrigo T, Pandullo E, Siracusano MF, Benvenga S, Trimarchi F. Changes in thyroid function tests induced by 2 month carbamazepine treatment in L-thyroxine-

[106] Takasu N, Takara M, Komiya I. Rifampin induced hypothyroidism in patients with

[107] Grossmann M, Premaratne E, Desai J, Davis ID. Thyrotoxicosis during sunitinib

[108] Faris JE, Moore AF, Daniels GH. Sunitinib [sutent]- induced thyrotoxicosis due to

[109] 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

[110] Mannavola D, Coco P, Vannucchi G, Coco P, Vannucchi G, Bertuelli R, Carletto M, Casali PG, Beck-Peccoz P, Fugazzola L. A novel tyrosine-kinase selective inhibitor,

treatment for renal cell carcinoma. Clin Endocrinol [Oxf] 2008;69(4):669–672.

in progressive differentiated thyroid cancer. N Engl J Med 2008;359(1):31–42. [103] Curran PG, DeGroot LJ. The effect of hepatic enzyme-inducing drugs on thyroid

molecular-weight kinase inhibitors. Methods Mol Biol 2012;795:1-34.

Endocr Relat Cancer. 2010;17(3):R233-44. doi: 10.1677/ERC-10-0082

in advanced thyroid cancer. J Clin Oncol 2008;26(29):4714–4719.

hormones and the thyroid gland. Endocr Rev 1991;12(2):135–150.

substituted hypothyroid children. Eur J Pediatr 1986;145(1-2):77–79.

destructive thyroiditis: a case report. Thyroid 2007;17(11):1147–1149.

inhibit thyroid peroxidase activity. Thyroid 2007;17(4):351–355.

hormone in rats. Eur. J. Endocrinol 1997;136(3):324–329.

Hashimoto's thyroiditis. N Engl J Med 2005;352(5):518–519.

2005;78(4):433–438.

2009;27(23):3794–3801.

North Am 2012;96(2):283-95.

management. Targ Oncol (2011) 6:217–226 DOI 10.1007/s11523-011-0197-2


http://meeting.ascopubs.org/cgi/content/abstract/26/15\_suppl/LBA9011.


[95] Fabbro D, Cowan-Jacob SW, Möbitz H, Martiny-Baron G. Targeting cancer with smallmolecular-weight kinase inhibitors. Methods Mol Biol 2012;795:1-34.

336 Thyroid Hormone

with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell

[84] Torino F, Barnabei A, De Vecchis L, Salvatori R, Corsello SM. Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new

[85] Dillard T, Yedinak CG, Alumkal J, Fleseriu M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: Serious immune related adverse events across a

[86] Chistiakov DA, Turakulov RI. CTLA-4 and its role in autoimmune thyroid disease. J

[87] Ribas A, Hauschild A, Kefford R, Punt CJ, Haanen JB, Marmol M, et al. Phase III, openlabel, randomized, comparative study of tremelimumab [CP-675,206] and chemotherapy [temozolomide [TMZ] or dacarbazine [DTIC]] in patients with advanced

[88] Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, Marshall MA, Gomez-Navarro J, Liang JQ, Bulanhagui CA. Phase II trial of tremelimumab [CP-675,206] in patients with advanced refractory or relapsed melanoma. Clin Cancer Res

[89] Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A & Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J

[90] Weber J, Thompson JA, Hamid O, Minor D, Amin A, Ron I, Ridolfi R, Assi H, Maraveyas A, Berman D, Siegel J, O'Day SJ. A randomized, double-blind, placebocontrolled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable

[91] Hodi FS, Friedlander PA, Atkins MB et al. A phase I trial of ipilimumab plus bevacizumab in patients with unresectable stage III or stage IV melanoma. J Clin Oncol

[92] Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Haworth LR, Levy C, Kleiner D, Mavroukakis SA, Yellin M, Rosenberg SA. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyteassociated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol.

[93] Di Giacomo AM, Biagioli M, Maio M. The emerging toxicity profiles of anti-CTLA-4

[94] Borodic G, Hinkle DM, Cia Y. Drug-induced graves disease from ctla-4 receptor

antibodies across clinical indications. Semin Oncol 2010;37(5):499-507.

suppression. Ophthal Plast Reconstr Surg. 2011; 27(4):e87-88.

http://meeting.ascopubs.org/cgi/content/abstract/26/15\_suppl/LBA9011.

transplantation. Blood 2009;113(7):1581–1588.

melanoma. J Clin Oncol 2008;26:9011.

2010;16(3):1042-1048.

2011;29(15 suppl):8511.

2005;12(12):1005-1016.

cause of a rare disease. Oncologist 2012;17(4):525-35.

spectrum of cancer subtypes. Pituitary 2010;13(1):29 –38.

Med 2010;363(8):711–723. doi:10.1056/NEJMoa1003466

stage III or IV melanoma. Clin Cancer Res 2009;15(17):5591–5598.

Mol Endocrinol. 2003;31(1): 21–36. doi: 10.1677/jme.0.0310021


sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 2007;92(9):3531–3534.

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 339

[123] Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, Morgan JA, Dychter SS, Larsen PR, Demetri GD, Alexander EK. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006;145(9):660–664. [124] Feldman DR, Martorella AJ, Robbins RJ, Motzer RJ. Re: hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst

[125] Wolter P, Stefan C, Decallonne B, Dumez H, Bex M, Carmeliet P, Schoffski P. The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation. Br

[126] 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?

[127] Riesenbeck LM, Bierer S, HoVmeister 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(6):807–813.

[128] Clement P WP, Stefan C, Decallonne B, Dumez H, Wildiers H, Schöffski P. J Clin

[129] Miyake H, Kurahashi T, Yamanaka K, Kondo Y, Muramaki M, Takenaka A, Inoue TA, Fujisawa M. Abnormalities of thyroid function in Japanese patients with metastatic renal cell carcinoma treated with sorafenib: a prospective evaluation. Urol Oncol

[130] Iavarone M, Perrino M, Viganò M, Beck-Peccoz P, Fugazzola L. Sorafenib-induced

[131] van Doorn L, Eskens FA, Visser TJ, van der Lugt A, Mathijssen RH, Peeters RP. Sorafenib induced thyroiditis in two patients with hepatocellular carcinoma. Thyroid

[132] Abdulrahman RM, Verloop H, Hoftijzer H, Verburg E, Hovens GC, Corssmit EP, Reiners C, Gelderblom H, Pereira AM, Kapiteijn E, Romijn JA, Visser TJ, Smit JW. Sorafenib-induced hypothyroidism is associated with increased type 3 deiodination. J

[133] Benjamin RS, Schöffski P, Hartmann JT, Van Oosterom A, Bui BN, Duyster J, Schuetze S, Blay JY, Reichardt P, Rosen LS, Skubitz K, McCoy S, Sun YN, Stepan DE, Baker L. Efficacy and safety of motesanib, an oral inhibitor of VEGF, PDGF, and Kit receptors, in patients with imatinib-resistant gastrointestinal stromal tumors. Cancer Chemother

[134] Brassard M, Rondeau G. Role of vandetanib in the management of medullary thyroid

[135] Robinson BG, Paz-Ares L, Krebs A, Vasselli J, Haddad R. Vandetanib [100 mg] in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin

J Cancer 2008;99(3):448–454. doi:10.1038/sj.bjc.6604497

Cancer 2011;117(3)::534–544. doi: 10.1002/cncr.25422.

destructive thyroiditis. Thyroid 2010;20(9):1043-1044.

cancer. Biologics 2012;6:59-66. doi: 10.2147/BTT.S24220

Endocrinol Metab 2010;95(6):2664–2671. doi: 10.1210/jc.2009-2461

Clin Endocrinol Metab 2010;95(8):3758-62.

2007;99(12):974–975.

DOI 10.1007/s00345-010-0627-2

2010;28(5):515–519.

2011;21(2):197-202.

Pharmacol 2011;68(1):69-77.

Oncol 2008;26(20 suppl): abstr 16145.


[123] Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, Morgan JA, Dychter SS, Larsen PR, Demetri GD, Alexander EK. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006;145(9):660–664.

338 Thyroid Hormone

Endocrinol Metab 2007;92(9):3531–3534.

antibodies. Thyroid 2008;18(7):809–812.

2010;20(3):243–244.

Endocrinol 2008;158(5):771–772.

10.1093/annonc/mdl112.

with sunitinib. J Natl Cancer Inst 2007;99(1):81–83.

function of FRTL-5 thyroid cells. Thyroid 2008;18(6):631–635.

markedly reduced vascularity. Thyroid 2010;20(3):323–326.

effects in human rectal cancer. Nat Med 2004;10(2):145–147.

in rectal cancer patients. J Clin Oncol 2005;23(31):8136–8139.

cell carcinoma treated with sorafenib. Ann Oncol 2008;19(2):265–268.

marker of irreversible thyroid dysfunction? Thyroid 2010;20(3):317–322.

sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin

[111] 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

[112] Salem AK, Fenton MS, Marion KM, Hershman JM. Effect of sunitinib on growth and

[113] Alexandrescu DT, Popoveniuc G, Farzanmehr H, Dasanu CA, Dawson N, Wartofsky L. et al. Sunitinib-associated lymphocytic thyroiditis without circulating antithyroid

[114] Tamaskar I, Bukowski R, Elson P, Ioachimescu AG, Wood L, Dreicer R, Mekhail T, Garcia J, Rini BI. Thyroid function test abnormalities in patients with metastatic renal

[115] 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. VEGF-dependent plasticity of fenestrated capillaries in the normal

adult microvasculature. Am J Physiol Heart Circ Physiol 2006;290(2):H560–H576. [116] Makita N, Miyakawa M, Fujita T, Iiri T. Sunitinib induces hypothyroidism with a

[117] 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

[118] Hershman JM, Liwanpo L. How does sunitinib cause hypothyroidism? Thyroid

[119] Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK. Direct evidence that the VEGF specific antibody bevacizumab has antivascular

[120] Willett CG, Boucher Y, Duda DG, di Tomaso E, Munn LL, Tong RT, Kozin SV, Petit L, Jain RK, Chung DC, Sahani DV, Kalva SP, Cohen KS, Scadden DT, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Shellito PC, Mino-Kenudson M, Lauwers GY. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase i trial

[121] Dora JM, Leie MA, Netto B, Fogliatto LM, Silla L, Torres F, Maia AL. Lack of imatinibinduced thyroid dysfunction in a cohort of non-thyroidectomized patients. Eur J

[122] de Groot JW, Links TP, van der Graaf WT. Tyrosine kinase inhibitors causing hypothyroidism in a patient on levothyroxine. Ann Oncol 2006;17(11):1719–1720. doi:


[136] Brassard M, Neraud B, Trabado S, Salenave S, Brailly-Tabard S, Borget I, Baudin E, Leboulleux S, Chanson P, Schlumberger M, Young J. Endocrine effects of the tyrosine kinase inhibitor vandetanib in patients treated for thyroid cancer. J Clin Endocrinol Metab 2011;96(9):2741–2749.

Thyroid Function Abnormalities in Patients Receiving Anticancer Agents 341

Sullivan L, Tran C, Humphreys BD, Penson RT. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 2009;20(33):5601-5606. [149] Sharma V, Hays WR, Wood WM, et al. Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary-thyroid axis. Endocrinology 2006;147(3):1438–1451. [150] Smith JW, Stokkel MP, Pereira AM, Romijn JA, Visser TJ. Bexarotene-induced hypothyroidism: bexarotene stimulates the peripheral metabolism of thyroid hormones.

[151] O'Connor P, Feely J. Clinical pharmacokinetics and endocrine disorders. Therapeutic

[152] Chen SY, Kao PC, Lin ZZ, Chiang WC, Fang CC. Sunitinib-induced myxedema coma.

[153] Collinson F, Vasudev N, Berkin L, Khan MM, Selby PJ, Brown JE. Sunitinib-induced severe hypothyroidism with cardiac compromise Med Oncol 2010;28(Suppl 1):S699-701.

[154] Di Lorenzo G, Autorino R, Bruni G, Cartenì G, Ricevuto E, Tudini M, Ficorella C, Romano C, Aieta M, Giordano A, Giuliano M, Gonnella A, De Nunzio C, Rizzo M, Montesarchio V, Ewer M, De Placido S. Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis. Ann Oncol

[155] Cristofanilli M, Yamamura Y, Kau SW, Bevers T, Strom S, Patangan M, Hsu L, Krishnamurthy S, Theriault RL, Hortobagyi GN. Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary

[156] Nelson M, Hercbergs A, Rybicki L, Strome M. Association between development of hypothyroidism and improved survival in patients with head and neck cancer. Arch

[157] 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

[158] Wolter P, Stefan C, Decallonne B, et al. Evaluation of thyroid dysfunction as a candidate surrogate marker for efficacy of sunitinib in patients [pts] with advanced

[159] Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, Suri KB, Levy C, Allen T, Mavroukakis S, Lowy I, White DE, Rosenberg SA. Ipilimumab [anti-CTLA4 antibody] causes regression of metastatic renal cell cancer associated with enteritis and

[160] Eisen T, Sternberg CN, Robert C, Mulders P, Pyle L, Zbinden S, Izzedine H, Escudier B. Targeted therapies for renal cell carcinoma: review of adverse event management

grade glioma: a phase I/II study. Anticancer Res 2003;23(1B):617–626.

renal cell carcinoma [RCC]. J Clin Oncol 2008;26(15S): abstract 5126.

J Clin Endocrinol Metab 2007;92(7):2496–2499.

Am J Emerg Med 2009;27(3):370.e1–370.e3.

breast carcinoma. Cancer 2005;103(6):1122–1128.

hypophysitis. J Immunother 2007;30(8):825–830.

strategies. J Natl Cancer Inst 2012;104(2):93-113.

Otolaryngol Head Neck Surg 2006;132(10):1041–1046.

doi:10.1007/s12032-010-9757-z.

2009;20(9):1535–1542.

implications. Clin Pharmacokinet 1987;13(6):345–364.


Sullivan L, Tran C, Humphreys BD, Penson RT. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 2009;20(33):5601-5606.

[149] Sharma V, Hays WR, Wood WM, et al. Effects of rexinoids on thyrotrope function and the hypothalamic-pituitary-thyroid axis. Endocrinology 2006;147(3):1438–1451.

340 Thyroid Hormone

Metab 2011;96(9):2741–2749.

ajpheart.00616.2005

cell carcinoma. J Clin Oncol 2009;20(27):4462-4468.

myeloid leukemia. Thyroid 2011; 20(11):1209–1214.

Hematol 2011;93(3):400–402.

[136] Brassard M, Neraud B, Trabado S, Salenave S, Brailly-Tabard S, Borget I, Baudin E, Leboulleux S, Chanson P, Schlumberger M, Young J. Endocrine effects of the tyrosine kinase inhibitor vandetanib in patients treated for thyroid cancer. J Clin Endocrinol

[137] Kelly RJ, Rixe O. Axitinib [AG-013736]. Recent Results Cancer Res 2010;184:33–44 [138] Fujiwara Y, Kiyota N, Chayahara N, Suzuki A, Umeyama Y, Mukohara T, Minami H. 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. 2012;30(3):1055-64. doi:10.1007/ s10637-011-9637-1 [139] Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J, Rosbrook B, Trask PC, Wood L, Dutcher JP. Phase II study of axitinib in sorafenib-refractory metastatic renal

[140] Baffert F, Le T, Sennino B, Thurston G, Kuo CJ, Hu-Lowe D, McDonald DM. Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol 2006;290(2):H547–H559. doi: 10.1152/

[141] 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. Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias. Blood 2007;109(5):2112–2120. doi: 10.1182/blood-2006-06-026377 [142] Manley PW, Drueckes P, Fendrich G, Furet P, Liebetanz J, Martiny-Baron G, Mestan J, Trappe J, Wartmann M, Fabbro D. Extended kinase profile and properties of the protein

[143] Kim TD, Schwarz M, Nogai H, Grille P, Westermann J, Plockinger U, Braun D, Schweizer U, Arnold R, Dorken B, le Coutre P. Thyroid dysfunction caused by secondgeneration tyrosine kinase inhibitors in Philadelphia chromosomepositive chronic

[144] Yoshizato T, Nannya Y, Yoshiki Y, Nakamura F, Imai Y, Ichikawa M, Kurokawa M. Nilotinib-induced hypothyroidism in a patient with chronic myeloid leukemia. Int J

[145] Ohanian M, Cortes J, Kantarjian H, Jabbour E. Tyrosine kinase inhibitors in acute and

[146] Wolter P, McCann L, Sternberg CN, Hutson TE, Mehmud F, Pandite LN, Schoffski P. Incidence of thyroid dysfunction in renal cell carcinoma [RCC] patients treated with

pazopanib in prospective clinical trials. J Clin Oncol 2011; (29 suppl); abstr 4633. [147] Goss GD, Arnold A, Shepherd FA, Dediu M, Ciuleanu TE, Fenton D, Zukin M, Walde D, Laberge F, Vincent MD, Ellis PM, Laurie SA, Ding K, Frymire E, Gauthier I, Leighl NB, Ho C, Noble J, Lee CW, Seymour L. Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC clinical trials group BR24 study. J Clin Oncol 2010;28(1):49–55. [148] Matulonis UA, Berlin S, Ivy P, Tyburski K, Krasner C, Zarwan C, Berkenblit A, Campos S, Horowitz N, Cannistra SA, Lee H, Lee J, Roche M, Hill M, Whalen C,

kinase inhibitor nilotinib. Biochim Biophys Acta 2010;1804(3):445–453.

chronic leukemias. Expert Opin Pharmacother 2012;13(7):927-938.


[161] Baskin HJ, Cobin RH, Duick DS, Gharib H, Guttler RB, Kaplan MM, Segal RL. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract 2002;8(6):457–469.

**Section 6** 

**Experimental Advances** 


**Section 6** 
