Advanced medullary thyroid cancer: Pathophysiology and management

Cancer Management and Research

Volumn 5, Issue 1, 2013, Pages 57-66

  Ferreira, Carla Vaz ^a   Siqueira, Débora Rodrigues ^a   Ceolin, Lucieli ^a   Maia, Ana Luiza ^a  

^a HOSPITAL DE CLÍNICAS DE PORTO ALEGRE   (Brazil)

Author keywords

Medullary thyroid carcinoma; Proto oncogene RET; Tyrosine kinase inhibitors

Indexed keywords

ANTINEOPLASTIC AGENT; AXITINIB; BETA CATENIN; CABOZANTINIB; IMATINIB; ISOPROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; MOTESANIB; PHOSPHATIDYLINOSITOL 3 KINASE; PLACEBO; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PROTEIN RET; PROTEIN TYROSINE KINASE INHIBITOR; SORAFENIB; STEM CELL FACTOR RECEPTOR; SUNITINIB; TIPIFARNIB; VANDETANIB; VASCULOTROPIN RECEPTOR;

ABDOMINAL PAIN; ACNE; ACUTE HEART FAILURE; ADVANCED CANCER; ALOPECIA; ANEMIA; ANOREXIA; ANTIANGIOGENIC ACTIVITY; ASPIRATION PNEUMONIA; BLOOD TOXICITY; CANCER INHIBITION; CARDIOTOXICITY; CELL ACTIVATION; CELL DIFFERENTIATION; CELL GROWTH; CELL MIGRATION; CELL PROLIFERATION; CELL SURVIVAL; CHEMOTHERAPY INDUCED EMESIS; CODON; COUGHING; DIARRHEA; DIFFERENTIATED THYROID CANCER; DRUG DOSE COMPARISON; DRUG ERUPTION; DRUG FATALITY; DRUG INDUCED HEADACHE; DRUG POTENTIATION; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; DRY SKIN; DYSPEPSIA; EARLY DIAGNOSIS; ENDOCRINE DISEASE; EPISTAXIS; EXON; EXTERNAL BEAM RADIOTHERAPY; FACE EDEMA; FATIGUE; GASTROINTESTINAL TOXICITY; GENETIC CODE; GERM LINE; HAND FOOT SYNDROME; HEART ARRHYTHMIA; HUMAN; HYPERTENSION; HYPOTHYROIDISM; INTRACELLULAR SIGNALING; LARYNX EDEMA; LEUKOPENIA; LUNG TOXICITY; MALAISE; MISSENSE MUTATION; MONOTHERAPY; MOUTH PAIN; NAUSEA; NEUTROPENIA; PATHOPHYSIOLOGY; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROGRESSION FREE SURVIVAL; PROTEINURIA; PROTO ONCOGENE; PRURITUS; QT PROLONGATION; RANDOMIZED CONTROLLED TRIAL (TOPIC); RESPIRATORY ARREST; RESPIRATORY FAILURE; RET GENE; REVIEW; SEPSIS; SKIN TOXICITY; SOMATIC MUTATION; STAPHYLOCOCCUS INFECTION; STOMATITIS; THROMBOCYTOPENIA; THYROID MEDULLARY CARCINOMA; THYROIDECTOMY; TREATMENT RESPONSE;

EID: 84877736920     PISSN: None     EISSN: 11791322     Source Type: Journal    
DOI: 10.2147/CMAR.S33105     Document Type: Review

References (96)

1. Hazard JB, Hawk WA, Crile G Jr. Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. J Clin Endocrinol Metab. 1959;19(1): 152-161.
2. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006;295(18):2164-2167.
3. Laure Giraudet A, Al Ghulzan A, Aupérin A, et al. Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol. 2008;158(2): 239-246.
4. Meijer JA, le Cessie S, van den Hout WB, et al. Calcitonin and carcinoembryonic antigen doubling times as prognostic factors in medullary thyroid carcinoma: a structured meta-analysis. Clin Endocrinol (Oxf). 2010;72(4):534-542.
5. Girelli ME, Nacamulli D, Pelizzo MR, et al. Medullary thyroid carcinoma: clinical features and long-term follow-up of seventy-eight patients treated between 1969 and 1986. Thyroid. 1998;8(6):517-523.
6. Modigliani E, Cohen R, Campos JM, et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'étude des tumeurs à calcitonine. Clin Endocrinol (Oxf). 1998;48(3):265-273.
7. Gilliland FD, Hunt WC, Morris DM, Key CR. Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program 1973-1991. Cancer. 1997;79(3):564-573.
8. Saad MF, Ordonez NG, Rashid RK, et al. Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine (Baltimore). 1984;63(6):319-342.
9. Steiner A, Goodman A, Powers S. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: multiple endocrine neoplasia, type 2. Medicine (Baltimore). 1968;47(5):371-409.
10. Pelizzo MR, Boschin IM, Bernante P, et al. Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Eur J Surg Oncol. 2007;33(4):493-497.
11. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET Mutation Consortium analysis. JAMA. 1996;276(19):1575-1579.
12. Mulligan LM, Marsh DJ, Robinson BG, et al. Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med. 1995;238(4): 343-346.
13. Decker RA, Peacock ML, Watson P. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotypephenotype correlation. Hum Mol Genet. 1998;7(1):129-134.
14. Gagel RF, Levy ML, Donovan DT, Alford BR, Wheeler T, Tschen JA. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med. 1989;111(10):802-806.
15. Machens A, Gimm O, Hinze R, Hoppner W, Boehm BO, Dralle H. Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. J Clin Endocrinol Metab. 2001;86(3):1104-1109.
16. Kebebew E, Ituarte PH, Siperstein AE, Duh Q, Clark OH. Medullary thyroid cancer. Curr Treat Options Oncol. 2000;1(4):359-367.
17. Farndon JR, Leight GS, Dilley WG, et al. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg. 1986;73(4):278-281.
18. Heshmati HM, Gharib H, van Heerden JA, Sizemore GW. Advances and controversies in the diagnosis and management of medullary thyroid carcinoma. Am J Med. 1997;103(1):60-69.
19. Elisei R, Cosci B, Romei C, et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab. 2008;93(3):682-687.
20. Moura MM, Cavaco BM, Pinto AE, et al. Correlation of RET somaticmutations with clinicopathological features in sporadic medullary thyroid carcinomas. Br J Cancer. 2009;100(11):1777-1783.
21. Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363(6428):458-460.
22. Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer. 2006;107(9):2134-2142.
23. Da Silva AM, Maciel RM, Da Silva MR, Toledo SR, De Carvalho MB, Cerutti JM. A novel germ-line point mutation in RET exon 8 (Gly(533) Cys) in a large kindred with familial medullary thyroid carcinoma. J Clin Endocrinol Metab. 2003;88(11):5438-5443.
24. Myers SM, Eng C, Ponder BA, Mulligan LM. Characterization of RET proto-oncogene 3′ splicing variants and polyadenylation sites: a novel C-terminus for RET. Oncogene. 1995;11(10):2039-2045.
25. Takahashi M, Asai N, Iwashita T, Isomura T, Miyazaki K, Matsuyama M. Characterization of the ret proto-oncogene products expressed in mouse L cells. Oncogene. 1993;8(11):2925-2929.
26. Milos IN, Frank-Raue K, Wohllk N, et al. Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC. TGG) mutation. Endocr Relat Cancer. 2008;15(4):1035-1041.
27. Frank-Raue K, Höppner W, Frilling A, et al. Mutations of the ret protooncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype. German Medullary Thyroid Carcinoma Study Group. J Clin Endocrinol Metab. 1996;81(5):1780-1783.
28. Verga U, Fugazzola L, Cambiaghi S, et al. Frequent association between MEN 2A and cutaneous lichen amyloidosis. Clin Endocrinol (Oxf). 2003;59(2):156-161.
29. Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET protooncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993;2(7):851-856.
30. Frank-Raue K, Rybicki LA, Erlic Z, et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat. 2011;32(1):51-58.
31. Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet. 1994;6(1):70-74.
32. Punales MK, Graf H, Gross JL, Maia AL. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003;88(6):2644-2649.
33. Gimm O, Marsh DJ, Andrew SD, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab. 1997;82(11):3902-3904.
34. Smith DP, Houghton C, Ponder BA. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene. 1997;15(10): 1213-1217.
35. Menko FH, van der Luijt RB, de Valk IA, et al. Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918. J Clin Endocrinol Metab. 2002;87(1):393-397.
36. Miyauchi A, Futami H, Hai N, et al. Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res. 1999;90(1):1-5.
37. Zedenius J, Larsson C, Bergholm U, et al. Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab. 1995;80(10):3088-3090.
38. Hofstra RM, Fattoruso O, Quadro L, et al. A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab. 1997;82(12): 4176-4178.
39. Bolino A, Schuffenecker I, Luo Y, et al. RET mutations in exons 13 and 14 of FMTC patients. Oncogene. 1995;10(12):2415-2419.
40. Dabir T, Hunter SJ, Russell CF, McCall D, Morrison PJ. The RET mutation E768D confers a late-onset familial medullary thyroid carcinoma only phenotype with incomplete penetrance: implications for screening and management of carrier status. Fam Cancer. 2006;5(2):201-204.
41. Eng C, Smith DP, Mulligan LM, et al. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene. 1995;10(3):509-513.
42. Eng C, Mulligan LM, Healey CS, et al. Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res. 1996;56(9):2167-2170.
43. Siqueira DR, Romitti M, da Rocha AP, et al. The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma. Endocr Relat Cancer. 2010;17(4):953-963.
44. Romei C, Elisei R, Pinchera A, et al. Somatic mutations of the ret protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence. J Clin Endocrinol Metab. 1996;81(4):1619-1622.
45. Ceolin L, Siqueira DR, Romitti M, Ferreira CV, Maia AL. Molecular basis of medullary thyroid carcinoma: the role of RET polymorphisms. Int J Mol Sci. 2012;13(1):221-239.
46. Elisei R, Cosci B, Romei C, et al. RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population. J Clin Endocrinol Metab. 2004;89(7):3579-3584.
47. Gimm O, Neuberg DS, Marsh DJ, et al. Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. Oncogene. 1999;18(6):1369-1373.
48. Robledo M, Gil L, Pollan M, et al. Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A. Cancer Res. 2003;63(8): 1814-1817.
49. Rocha AP, Magalhães PR, Maia AL, Maciel LZ. Genetic polymorphisms: implications in the pathogenesis of medullary thyroid carcinoma. Arq Bras Endocrinol Metab. 2007;5(51):723-730.
50. Scollo C, Baudin E, Travagli JP, et al. Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2003;88(5):2070-2075.
51. Brierley J, Tsang R, Simpson WJ, Gospodarowicz M, Sutcliffe S, Panzarella T. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid. 1996;6(4):305-310.
52. Nocera M, Baudin E, Pellegriti G, Cailleux AF, Mechelany-Corone C, Schlumberger M. Treatment of advanced medullary thyroid cancer with an alternating combination of doxorubicin-streptozocin and 5 FU-dacarbazine. Groupe d'Etude des Tumeurs à Calcitonine (GETC). Br J Cancer. 2000;83(6):715-718.
53. Ichihara M, Murakumo Y, Takahashi M. RET and neuroendocrine tumors. Cancer Lett. 2004;204(2):197-211.
54. Vieira JM, Santos SC, Espadinha C, et al. Expression of vascular endothelial growth factor (VEGF) and its receptors in thyroid carcinomas of follicular origin: a potential autocrine loop. Eur J Endocrinol. 2005;153(5):701-709.
55. Broekman F, Giovannetti E, Peters GJ. Tyrosine kinase inhibitors: multitargeted or single-targeted? World J Clin Oncol. 2011;2(2):80-93.
56. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000;103(2):211-225.
57. Therasse P, Arbuck SG, Eisenhauer EA, et al. 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(3):205-216.
58. Lam ET, Ringel MD, Kloos RT, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol. 2010;28(14):2323-2330.
59. Licitra L, Locati LD, Greco A, Granata R, Bossi P. Multikinase inhibitors in thyroid cancer. Eur J Cancer. 2010;46(6):1012-1018.
60. Machens A, Dralle H. Parenchymal versus nonparenchymal target lesion response in clinical trials for metastatic medullary thyroid cancer. J Clin Oncol. 2010;28(28):e534; author reply e535-e536.
61. Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res. 2002;62(24):7284-7290.
62. Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 2002;62(16):4645-4655.
63. Vitagliano D, De Falco V, Tamburrino A, et al. The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells. Endocr Relat Cancer. 2011;18(1):1-11.
64. Wells SA Jr, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010;28(5):767-772.
65. 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 Endocrinol Metab. 2010;95(6): 2664-2671.
66. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141.
67. Deshpande H, Roman S, Thumar J, Sosa JA. Vandetanib (ZD6474) in the treatment of medullary thyroid cancer. Clin Med Insights Oncol. 2011;5:213-221.
68. Carlomagno F, Guida T, Anaganti S, et al. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene. 2004;23:6056-6063.
69. Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29(19):2660-2666.
70. Schoffski P, Elisei R, Müller S, et al. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. J Clin Oncol. 2012; 30 Suppl:5508.
71. Polverino A, Coxon A, Starnes C, et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res. 2006;66(17):8715-8721.
72. Coxon A, Bready J, Kaufman S, et al. Anti-tumor activity of motesanib in a medullary thyroid cancer model. J Endocrinol Invest. 2011;35(2):181-190.
73. Schlumberger MJ, Elisei R, Bastholt L, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. 2009;27(23):3794-3801.
74. Bass MB, Sherman SI, Schlumberger MJ, et al. Biomarkers as predictors of response to treatment with motesanib in patients with progressive advanced thyroid cancer. J Clin Endocrinol Metab. 2010; 95(11):5018-5027.
75. Carlomagno F, Anaganti S, Guida T, et al. BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006;98(5):326-334.
76. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099-7109.
77. Frank-Raue K, Ganten M, Kreissl MC, Raue F. Rapid response to sorafenib in metastatic medullary thyroid carcinoma. Exp Clin Endocrinol Diabetes. 2011;119(3):151-155.
78. Ahmed M, Barbachano Y, Riddell A, et al. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. Eur J Endocrinol. 2011;165(2):315-322.
79. Hong DS, Cabanillas ME, Wheler J, et al. Inhibition of the Ras/Raf/ MEK/ERK and RET kinase pathways with the combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in medullary and differentiated thyroid malignancies. J Clin Endocrinol Metab. 2011;96(4):997-1005.
80. Koh YW, Shah MH, Agarwal K, et al. Sorafenib and Mek inhibition is synergistic in medullary thyroid carcinoma in vitro. Endocr Relat Cancer. 2012;19(1):29-38.
81. Broutin S, Ameur N, Lacroix L, et al. Identification of soluble candidate biomarkers of therapeutic response to sunitinib in medullary thyroid carcinoma in preclinical models. Clin Cancer Res. 2011;17(7):2044-2054.
82. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25(7):884-896.
83. Schueneman AJ, Himmelfarb E, Geng L, et al. SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res. 2003;63(14):4009-4016.
84. Cleary JM, Sadow PM, Randolph GW, et al. Neoadjuvant treatment of unresectable medullary thyroid cancer with sunitinib. J Clin Oncol. 2010;28(23):e390-e392.
85. Kelleher FC, McDermott R. Response to sunitinib in medullary thyroid cancer. Ann Intern Med. 2008;148(7):567.
86. Carr LL, Mankoff DA, Goulart BH, et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010;16(21):5260-5268.
87. Ravaud A, de la Fouchardiere C, Asselineau J, et al. Efficacy of sunitinib in advanced medullary thyroid carcinoma: intermediate results of phase II THYSU. Oncologist. 2010;15(2):212-213; author reply 214.
88. Inai T, Mancuso M, Hashizume H, et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004;165(1):35-52.
89. Cohen EE, Rosen LS, Vokes EE, et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol. 2008;26(29):4708-4713.
90. de Groot JW, Plaza Menacho I, Schepers H, et al. Cellular effects of imatinib on medullary thyroid cancer cells harboring multiple endocrine neoplasia Type 2A and 2B associated RET mutations. Surgery. 2006;139(6):806-814.
91. Frank-Raue K, Fabel M, Delorme S, Haberkorn U, Raue F. Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma. Eur J Endocrinol. 2007;157(2):215-220.
92. de Groot JW, Zonnenberg BA, van Ufford-Mannesse PQ, et al. A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2007;92(9):3466-3469.
93. Verbeek HH, Alves MM, de Groot JW, et al. The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cells. J Clin Endocrinol Metab. 2011;96(6):E991-E995.
94. Lenihan DJ, Cardinale DM. Late cardiac effects of cancer treatment. J Clin Oncol. 2012;30(30):3657-3664.
95. Sheffel R, Dora JM, Siqueira DR, Burttet LM, Cerski MR, Maia AL. Toxic cardiomyopathy leading to fatal acute cardiac failure related to vandetanib: a case report with histopathological analysis. Eur J Endocrinol. 2013;168:K51-K54.
96. 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 Oncol. 2009;6(4):219-228.