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Current Standards in Treatment of Radioiodine Refractory Thyroid Cancer

  • Head and Neck Cancer (J-P Machiels, Section Editor)
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Opinion Statement

Radioiodine refractory differentiated thyroid cancer (RAI-R DTC) is a challenging malignancy with limited prognosis and treatment options. Recently, clinical trials with targeted therapies have advanced the outlook of these patients, and inhibition of the vascular endothelial growth factor (VEGF) axis has led to the approval of small-molecule tyrosine kinase inhibitors (TKIs) for first-line treatment of radioiodine refractory disease. In addition to approved therapies (sorafenib and lenvatinib), other multi-targeted tyrosine kinase inhibitors that are commercially available have been recognized as viable treatment options for RAI-R DTC. Our preference is to initially use lenvatinib, given the dramatic progression-free survival (PFS) improvement versus placebo, with the caveat that 24 mg daily is not often tolerated and lower doses often used. In patients with BRAF V600E mutation, BRAF inhibitors are now considered for treatment, especially if patients are at high risk from antiangiogenic therapy. Research is continuing to evolve in identifying mechanisms related to radioiodine refractoriness, and trials are evaluating therapeutic molecules to overcome this resistance. Clinical care of patients with RAI-R DTC requires careful consideration of both patient and disease characteristics. Many patients with asymptomatic and indolent disease can be followed for years without treatment while others with high volume or rapidly progressive disease merit early intervention.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988–2005. Cancer. 2009;115:3801–7.

    Article  PubMed  Google Scholar 

  2. Howlader N NA, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA editors. SEER cancer statistics review, 1975–2012, National Cancer Institute. Bethesda, MD based on November 2014 SEER data submission, posted to the SEER web site, April 2015.

  3. Carling T, Udelsman R. Thyroid cancer. Annu Rev Med. 2014;65:125–37.

    Article  CAS  PubMed  Google Scholar 

  4. Enewold L, Zhu K, Ron E, et al. Rising thyroid cancer incidence in the United States by demographic and tumor characteristics, 1980–2005. Cancer Epidemiol Biomarkers Prev. 2009;18:784–91.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Nixon IJ, Whitcher MM, Palmer FL, et al. The impact of distant metastases at presentation on prognosis in patients with differentiated carcinoma of the thyroid gland. Thyroid. 2012;22:884–9.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006;91:2892–9.

    Article  CAS  PubMed  Google Scholar 

  7. Robbins RJ, Wan Q, Grewal RK, et al. Real-time prognosis for metastatic thyroid carcinoma based on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning. J Clin Endocrinol Metab. 2006;91:498–505.

    Article  CAS  PubMed  Google Scholar 

  8. Haugen BRM, Alexander EK, Bible KC, et al. American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2015.

  9. Schlumberger M, Tubiana M, De Vathaire F, et al. Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab. 1986;63:960–7.

    Article  CAS  PubMed  Google Scholar 

  10. Yen TC, Lin HD, Lee CH, et al. The role of technetium-99m sestamibi whole-body scans in diagnosing metastatic Hurthle cell carcinoma of the thyroid gland after total thyroidectomy: a comparison with iodine-131 and thallium-201 whole-body scans. Eur J Nucl Med. 1994;21:980–3.

    Article  CAS  PubMed  Google Scholar 

  11. American Thyroid Association Guidelines Taskforce on Thyroid N, Differentiated Thyroid C, Cooper DS, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19:1167–214.

    Article  Google Scholar 

  12. Spitzweg C, Morris JC. The sodium iodide symporter: its pathophysiological and therapeutic implications. Clin Endocrinol (Oxf). 2002;57:559–74.

    Article  CAS  Google Scholar 

  13. Spitzweg C, Harrington KJ, Pinke LA, et al. Clinical review 132: the sodium iodide symporter and its potential role in cancer therapy. J Clin Endocrinol Metab. 2001;86:3327–35.

    Article  CAS  PubMed  Google Scholar 

  14. Matuszczyk A, Petersenn S, Bockisch A, et al. Chemotherapy with doxorubicin in progressive medullary and thyroid carcinoma of the follicular epithelium. Horm Metab Res. 2008;40:210–3.

    Article  CAS  PubMed  Google Scholar 

  15. Shimaoka K, Schoenfeld DA, DeWys WD, et al. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer. 1985;56:2155–60.

    Article  CAS  PubMed  Google Scholar 

  16. Hofstra RM, Landsvater RM, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367:375–6.

    Article  CAS  PubMed  Google Scholar 

  17. Cohen Y, Xing M, Mambo E, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst. 2003;95:625–7.

    Article  CAS  PubMed  Google Scholar 

  18. Soares P, Trovisco V, Rocha AS, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene. 2003;22:4578–80.

    Article  CAS  PubMed  Google Scholar 

  19. Namba H, Nakashima M, Hayashi T, et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab. 2003;88:4393–7.

    Article  CAS  PubMed  Google Scholar 

  20. Kimura ET, Nikiforova MN, Zhu Z, et al. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 2003;63:1454–7.

    CAS  PubMed  Google Scholar 

  21. Xu X, Quiros RM, Gattuso P, et al. High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res. 2003;63:4561–7.

    CAS  PubMed  Google Scholar 

  22. Fukushima T, Suzuki S, Mashiko M, et al. BRAF mutations in papillary carcinomas of the thyroid. Oncogene. 2003;22:6455–7.

    Article  CAS  PubMed  Google Scholar 

  23. Kim TH, Park YJ, Lim JA, et al. The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer. 2012;118:1764–73.

    Article  CAS  PubMed  Google Scholar 

  24. Xing M, Westra WH, Tufano RP, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005;90:6373–9.

    Article  CAS  PubMed  Google Scholar 

  25. Liu Z, Hou P, Ji M, et al. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab. 2008;93:3106–16.

    Article  CAS  PubMed  Google Scholar 

  26. Wang Y, Hou P, Yu H, et al. High prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol-3-kinase/akt pathway in thyroid tumors. J Clin Endocrinol Metab. 2007;92:2387–90.

    Article  CAS  PubMed  Google Scholar 

  27. Hou P, Liu D, Shan Y, et al. Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clin Cancer Res. 2007;13:1161–70.

    Article  CAS  PubMed  Google Scholar 

  28. Ricarte-Filho JC, Ryder M, Chitale DA, et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res. 2009;69:4885–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Costa AM, Herrero A, Fresno MF, et al. BRAF mutation associated with other genetic events identifies a subset of aggressive papillary thyroid carcinoma. Clin Endocrinol (Oxf). 2008;68:618–34.

    Article  CAS  Google Scholar 

  30. Garcia-Rostan G, Zhao H, Camp RL, et al. ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. J Clin Oncol. 2003;21:3226–35.

    Article  CAS  PubMed  Google Scholar 

  31. Basolo F, Pisaturo F, Pollina LE, et al. N-ras mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression. Thyroid. 2000;10:19–23.

    Article  CAS  PubMed  Google Scholar 

  32. Volante M, Rapa I, Gandhi M, et al. RAS mutations are the predominant molecular alteration in poorly differentiated thyroid carcinomas and bear prognostic impact. J Clin Endocrinol Metab. 2009;94:4735–41.

    Article  CAS  PubMed  Google Scholar 

  33. Fukahori M, Yoshida A, Hayashi H, et al. The associations between RAS mutations and clinical characteristics in follicular thyroid tumors: new insights from a single center and a large patient cohort. Thyroid. 2012;22:683–9.

    Article  CAS  PubMed  Google Scholar 

  34. Nikiforova MN, Lynch RA, Biddinger PW, et al. RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab. 2003;88:2318–26.

    Article  CAS  PubMed  Google Scholar 

  35. Rivera M, Ricarte-Filho J, Knauf J, et al. Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns. Mod Pathol. 2010;23:1191–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Manenti G, Pilotti S, Re FC, et al. Selective activation of ras oncogenes in follicular and undifferentiated thyroid carcinomas. Eur J Cancer. 1994;30A:987–93.

    Article  CAS  PubMed  Google Scholar 

  37. Zhu Z, Gandhi M, Nikiforova MN, et al. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol. 2003;120:71–7.

    Article  CAS  PubMed  Google Scholar 

  38. Santarpia L, Myers JN, Sherman SI, et al. Genetic alterations in the RAS/RAF/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathways in the follicular variant of papillary thyroid carcinoma. Cancer. 2010;116:2974–83.

    Article  CAS  PubMed  Google Scholar 

  39. Dahia PL, Marsh DJ, Zheng Z, et al. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res. 1997;57:4710–3.

    CAS  PubMed  Google Scholar 

  40. Gustafson S, Zbuk KM, Scacheri C, et al. Cowden syndrome. Semin Oncol. 2007;34:428–34.

    Article  CAS  PubMed  Google Scholar 

  41. Garcia-Rostan G, Tallini G, Herrero A, et al. Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma. Cancer Res. 1999;59:1811–5.

    CAS  PubMed  Google Scholar 

  42. Garcia-Rostan G, Camp RL, Herrero A, et al. Beta-catenin dysregulation in thyroid neoplasms: down-regulation, aberrant nuclear expression, and CTNNB1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis. Am J Pathol. 2001;158:987–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fagin JA, Matsuo K, Karmakar A, et al. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest. 1993;91:179–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Donghi R, Longoni A, Pilotti S, et al. Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland. J Clin Invest. 1993;91:1753–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Murugan AK, Bojdani E, Xing M. Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem Biophys Res Commun. 2010;393:555–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hemerly JP, Bastos AU, Cerutti JM. Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. Eur J Endocrinol. 2010;163:747–55.

    Article  CAS  PubMed  Google Scholar 

  47. Murugan AK, Xing M. Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res. 2011;71:4403–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Murugan AK, Dong J, Xie J, et al. Uncommon GNAQ, MMP8, AKT3, EGFR, and PIK3R1 mutations in thyroid cancers. Endocr Pathol. 2011;22:97–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jo YS, Li S, Song JH, et al. Influence of the BRAF V600E mutation on expression of vascular endothelial growth factor in papillary thyroid cancer. J Clin Endocrinol Metab. 2006;91:3667–70.

    Article  CAS  PubMed  Google Scholar 

  50. Klugbauer S, Demidchik EP, Lengfelder E, et al. Molecular analysis of new subtypes of ELE/RET rearrangements, their reciprocal transcripts and breakpoints in papillary thyroid carcinomas of children after Chernobyl. Oncogene. 1998;16:671–5.

    Article  CAS  PubMed  Google Scholar 

  51. Rabes HM, Demidchik EP, Sidorow JD, et al. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res. 2000;6:1093–103.

    CAS  PubMed  Google Scholar 

  52. Santoro M, Thomas GA, Vecchio G, et al. Gene rearrangement and Chernobyl related thyroid cancers. Br J Cancer. 2000;82:315–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science. 2000;289:1357–60.

    Article  CAS  PubMed  Google Scholar 

  54. Eberhardt NL, Grebe SK, McIver B, et al. The role of the PAX8/PPARgamma fusion oncogene in the pathogenesis of follicular thyroid cancer. Mol Cell Endocrinol. 2010;321:50–6.

    Article  CAS  PubMed  Google Scholar 

  55. Dwight T, Thoppe SR, Foukakis T, et al. Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J Clin Endocrinol Metab. 2003;88:4440–5.

    Article  CAS  PubMed  Google Scholar 

  56. Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013;13:184–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Melillo RM, Castellone MD, Guarino V, et al. The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J Clin Invest. 2005;115:1068–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Haugen BR, Sherman SI. Evolving approaches to patients with advanced differentiated thyroid cancer. Endocr Rev. 2013;34:439–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xing M, Haugen BR, Schlumberger M. Progress in molecular-based management of differentiated thyroid cancer. Lancet. 2013;381:1058–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tufano RP, Teixeira GV, Bishop J, et al. BRAF mutation in papillary thyroid cancer and its value in tailoring initial treatment: a systematic review and meta-analysis. Medicine (Baltimore). 2012;91:274–86.

    Article  CAS  Google Scholar 

  61. Howell GM, Hodak SP, Yip L. RAS mutations in thyroid cancer. Oncologist. 2013;18:926–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Giordano TJ, Kuick R, Thomas DG, et al. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene. 2005;24:6646–56.

    Article  CAS  PubMed  Google Scholar 

  63. Kumagai A, Namba H, Mitsutake N, et al. Childhood thyroid carcinoma with BRAFT1799A mutation shows unique pathological features of poor differentiation. Oncol Rep. 2006;16:123–6.

    CAS  PubMed  Google Scholar 

  64. Palona I, Namba H, Mitsutake N, et al. BRAFV600E promotes invasiveness of thyroid cancer cells through nuclear factor kappaB activation. Endocrinology. 2006;147:5699–707.

    Article  CAS  PubMed  Google Scholar 

  65. Mesa Jr C, Mirza M, Mitsutake N, et al. Conditional activation of RET/PTC3 and BRAFV600E in thyroid cells is associated with gene expression profiles that predict a preferential role of BRAF in extracellular matrix remodeling. Cancer Res. 2006;66:6521–9.

    Article  CAS  PubMed  Google Scholar 

  66. Zerilli M, Zito G, Martorana A, et al. BRAF(V600E) mutation influences hypoxia-inducible factor-1alpha expression levels in papillary thyroid cancer. Mod Pathol. 2010;23:1052–60.

    Article  CAS  PubMed  Google Scholar 

  67. Riesco-Eizaguirre G, Rodriguez I, De la Vieja A, et al. The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Res. 2009;69:8317–25.

    Article  CAS  PubMed  Google Scholar 

  68. Knauf JA, Sartor MA, Medvedovic M, et al. Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFbeta signaling. Oncogene. 2011;30:3153–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Garcia-Rostan G, Costa AM, Pereira-Castro I, et al. Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res. 2005;65:10199–207.

    Article  CAS  PubMed  Google Scholar 

  70. Yu XM, Lo CY, Chan WF, et al. Increased expression of vascular endothelial growth factor C in papillary thyroid carcinoma correlates with cervical lymph node metastases. Clin Cancer Res. 2005;11:8063–9.

    Article  CAS  PubMed  Google Scholar 

  71. Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013;368:623–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Deandreis D, Al Ghuzlan A, Leboulleux S, et al. Do histological, immunohistochemical, and metabolic (radioiodine and fluorodeoxyglucose uptakes) patterns of metastatic thyroid cancer correlate with patient outcome? Endocr Relat Cancer. 2011;18:159–69.

    Article  CAS  PubMed  Google Scholar 

  73. Schlumberger M, Sherman SI. Clinical trials for progressive differentiated thyroid cancer: patient selection, study design, and recent advances. Thyroid. 2009;19:1393–400.

    Article  PubMed  Google Scholar 

  74. Gottlieb JA, Hill Jr CS. Chemotherapy of thyroid cancer with adriamycin. Experience with 30 patients. N Engl J Med. 1974;290:193–7.

    Article  CAS  PubMed  Google Scholar 

  75. Burgess MA HCJ: Chemotherapy in the management of thyroid cancer. In: Greenfield LD, editor. Thyroid Cancer. FL CRC Press, W. Palm Beach, 1978. p.233.

  76. Haugen BR. Management of the patient with progressive radioiodine non-responsive disease. Semin Surg Oncol. 1999;16:34–41.

    Article  CAS  PubMed  Google Scholar 

  77. 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;64:7099–109.

    Article  CAS  PubMed  Google Scholar 

  78. Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26:4714–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009;27:1675–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384:319–28. This important phase 3 trial was the first to demonstrate that a tyrosine kinase inhibitor had definitive clinical benefit for patients with RAI-R DTC. This should be paired with the below NEJM article on lenvatinib as the two definitive ph 3 trials demonstrating clinical benefit with sorafenib and lenvatinib in this situation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Matsui J, Funahashi Y, Uenaka T, et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008;14:5459–65.

    Article  CAS  PubMed  Google Scholar 

  82. Matsui J, Yamamoto Y, Funahashi Y, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer. 2008;122:664–71.

    Article  CAS  PubMed  Google Scholar 

  83. Okamoto K, Kodama K, Takase K, et al. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett. 2013;340:97–103.

    Article  CAS  PubMed  Google Scholar 

  84. Cabanillas ME, Schlumberger M, Jarzab B, et al. A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: a clinical outcomes and biomarker assessment. Cancer. 2015;121:2749–56.

    Article  CAS  PubMed  Google Scholar 

  85. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621–30. This represents the publication of standard of care changing data for the treatment of RAI-R DTC and as such is an essential read for anyone treating these patients. The magnitude of PFS difference is much greater than seen with the sorafenib RCT cited above.

    Article  PubMed  CAS  Google Scholar 

  86. Bible KC, Suman VJ, Molina JR, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010;11:962–72. This is an important phase 2 experience demonstrating that non’ BRAF targeting VEGF inhibitors can have meaningful clinical activity against RAI-R DTC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369:722–31.

    Article  CAS  PubMed  Google Scholar 

  88. 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;16:5260–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 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;15:212–3; author reply 214.

  90. Ravaud A DlFC, Courbon F, Asselineau J, Klein M, Nicoli-Sire P, et al. : Sunitinib in patients with refractory advanced thyroid cancer: the THYSU phase II trial. J Clin Oncol. 2008; 26(suppl) abstr 6058.

  91. 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;26:4708–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Locati LLL, Ou S-HI, et al. Phase 2 trial of axitinib for advanced thyroid cancer: preliminary activity results. [abstract PP17]. Eur Arch Otorhino- laryngol. 2012;269:1345.

    Google Scholar 

  93. Lupi C, Giannini R, Ugolini C, et al. Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab. 2007;92:4085–90.

    Article  CAS  PubMed  Google Scholar 

  94. Elisei R, Ugolini C, Viola D, et al. BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. J Clin Endocrinol Metab. 2008;93:3943–9.

    Article  CAS  PubMed  Google Scholar 

  95. Henderson YC, Shellenberger TD, Williams MD, et al. High rate of BRAF and RET/PTC dual mutations associated with recurrent papillary thyroid carcinoma. Clin Cancer Res. 2009;15:485–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kim KB, Cabanillas ME, Lazar AJ, et al. Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAF(V600E) mutation. Thyroid. 2013;23:1277–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dadu R, Shah K, Busaidy NL, et al. Efficacy and tolerability of vemurafenib in patients with BRAF(V600E)-positive papillary thyroid cancer: M.D. Anderson Cancer Center off label experience. J Clin Endocrinol Metab. 2015;100:E77–81. This article demonstrates the important preliminary data suggesting significant clinical utility of BRAF inhibitors in BRAF v600E mutant RAI-R DTC. see also reference 99.

    Article  CAS  PubMed  Google Scholar 

  98. Brose MSCM, Cohen EEW, et al. An open-label, multi-center phase 2 study of the BRAF inhibitor vemurafenib in patients with metastatic or unresectable papillary thyroid cancer (ptc) positive for the BRAF V600 mutation and resistant to radioactive iodine. Eur J Cancer. 2013;49 suppl 3:LBA28.

    Google Scholar 

  99. Falchook GS, Millward M, Hong D, et al. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. Thyroid. 2015;25:71–7. This article demonstrates the important preliminary data suggesting significant clinical utility of BRAF inhibitors in BRAF v600E mutant RAI-R DTC. see also reference 97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Dabrafenib with or without trametinib in treating patients with recurrent thyroid cancer. https://clinicaltrials.gov/ct2/show/NCT01723202. Accessed Jan 2016.

  102. Trametinib in increasing tumoral iodine incorporation in patients with recurrent or metastatic thyroid cancer. https://clinicaltrials.gov/ct2/show/NCT02152995. Accessed Jan 2016.

  103. Cabanillas ME, Brose MS, Holland J, et al. A phase I study of cabozantinib (XL184) in patients with differentiated thyroid cancer. Thyroid. 2014;24:1508–14. This article demonstrates early clinical data suggesting that multitargeted kinase inhibitors which target RET can be beneficial in patients with RAI-R- DTC. see also reference 104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13:897–905. This article demonstrates early clinical data suggesting that mutitargeted kinase inhibitors which target RET can be beneficial in patients with RAI-R- DTC. see also reference 103.

    Article  CAS  PubMed  Google Scholar 

  105. Pennell NA, Daniels GH, Haddad RI, et al. A phase II study of gefitinib in patients with advanced thyroid cancer. Thyroid. 2008;18:317–23.

    Article  CAS  PubMed  Google Scholar 

  106. Lim SM, Chang H, Yoon MJ, et al. A multicenter, phase II trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes. Ann Oncol. 2013;24:3089–94.

    Article  CAS  PubMed  Google Scholar 

  107. Hayes DN, Lucas AS, Tanvetyanon T, et al. Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin Cancer Res. 2012;18:2056–65.

    Article  CAS  PubMed  Google Scholar 

  108. Sherman SI, Wirth LJ, Droz JP, et al. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med. 2008;359:31–42.

    Article  CAS  PubMed  Google Scholar 

  109. Hingorani M, Spitzweg C, Vassaux G, et al. The biology of the sodium iodide symporter and its potential for targeted gene delivery. Curr Cancer Drug Targets. 2010;10:242–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Durante C, Puxeddu E, Ferretti E, et al. BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J Clin Endocrinol Metab. 2007;92:2840–3.

    Article  CAS  PubMed  Google Scholar 

  111. Knauf JA, Kuroda H, Basu S, et al. RET/PTC-induced dedifferentiation of thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase. Oncogene. 2003;22:4406–12.

    Article  CAS  PubMed  Google Scholar 

  112. Liu D, Hu S, Hou P, et al. Suppression of BRAF/MEK/MAP kinase pathway restores expression of iodide-metabolizing genes in thyroid cells expressing the V600E BRAF mutant. Clin Cancer Res. 2007;13:1341–9.

    Article  CAS  PubMed  Google Scholar 

  113. Mitsutake N, Knauf JA, Mitsutake S, et al. Conditional BRAFV600E expression induces DNA synthesis, apoptosis, dedifferentiation, and chromosomal instability in thyroid PCCL3 cells. Cancer Res. 2005;65:2465–73.

    Article  CAS  PubMed  Google Scholar 

  114. Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Cabezas MA, et al. The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I- targeting to the membrane. Endocr Relat Cancer. 2006;13:257–69.

    Article  CAS  PubMed  Google Scholar 

  115. Schmutzler C, Winzer R, Meissner-Weigl J, et al. Retinoic acid increases sodium/iodide symporter mRNA levels in human thyroid cancer cell lines and suppresses expression of functional symporter in nontransformed FRTL-5 rat thyroid cells. Biochem Biophys Res Commun. 1997;240:832–8.

    Article  CAS  PubMed  Google Scholar 

  116. Simon D, Korber C, Krausch M, et al. Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study. Eur J Nucl Med Mol Imaging. 2002;29:775–82.

    Article  CAS  PubMed  Google Scholar 

  117. Handkiewicz-Junak D, Roskosz J, Hasse-Lazar K, et al. 13-cis-retinoic acid re-differentiation therapy and recombinant human thyrotropin-aided radioiodine treatment of non-Functional metastatic thyroid cancer: a single-center, 53-patient phase 2 study. Thyroid Res. 2009;2:8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Coelho SM, Corbo R, Buescu A, et al. Retinoic acid in patients with radioiodine non-responsive thyroid carcinoma. J Endocrinol Invest. 2004;27:334–9.

    Article  CAS  PubMed  Google Scholar 

  119. Liu YY, Stokkel MP, Morreau HA, et al. Radioiodine therapy after pretreatment with bexarotene for metastases of differentiated thyroid carcinoma. Clin Endocrinol (Oxf). 2008;68:605–9.

    Article  CAS  Google Scholar 

  120. Kebebew E, Lindsay S, Clark OH, et al. Results of rosiglitazone therapy in patients with thyroglobulin-positive and radioiodine-negative advanced differentiated thyroid cancer. Thyroid. 2009;19:953–6.

    Article  CAS  PubMed  Google Scholar 

  121. Rosenbaum-Krumme SJ, Freudenberg LS, Jentzen W, et al. Effects of rosiglitazone on radioiodine negative and progressive differentiated thyroid carcinoma as assessed by (1)(2)(4)I PET/CT imaging. Clin Nucl Med. 2012;37:e47–52.

    Article  PubMed  Google Scholar 

  122. Rosenbaum-Krumme SJ, Bockisch A, Nagarajah J. Pioglitazone therapy in progressive differentiated thyroid carcinoma. Nuklearmedizin. 2012;51:111–5.

    Article  CAS  PubMed  Google Scholar 

  123. Rothenberg SM, McFadden DG, Palmer EL, et al. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res. 2015;21:1028–35.

    Article  CAS  PubMed  Google Scholar 

  124. Furuya F, Shimura H, Suzuki H, et al. Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin. Endocrinology. 2004;145:2865–75.

    Article  CAS  PubMed  Google Scholar 

  125. Kitazono M, Robey R, Zhan Z, et al. Low concentrations of the histone deacetylase inhibitor, depsipeptide (FR901228), increase expression of the Na(+)/I(−) symporter and iodine accumulation in poorly differentiated thyroid carcinoma cells. J Clin Endocrinol Metab. 2001;86:3430–5.

    CAS  PubMed  Google Scholar 

  126. Sherman EJ, Su YB, Lyall A, et al. Evaluation of romidepsin for clinical activity and radioactive iodine reuptake in radioactive iodine-refractory thyroid carcinoma. Thyroid. 2013;23:593–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. A phase II Trial of valproic acid in patients with advanced thyroid cancers of follicular cell origin https://clinicaltrials.gov/ct2/show/NCT01182285. Accessed Jan 2016.

  128. Blevins DP, Dadu R, Hu M, et al. Aerodigestive fistula formation as a rare side effect of antiangiogenic tyrosine kinase inhibitor therapy for thyroid cancer. Thyroid. 2014;24:918–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Gruber JJ, Colevas AD. Differentiated thyroid cancer: focus on emerging treatments for radioactive iodine-refractory patients. Oncologist. 2015;20:113–26.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Dadu R, Devine C, Hernandez M, et al. Role of salvage targeted therapy in differentiated thyroid cancer patients who failed first-line sorafenib. J Clin Endocrinol Metab. 2014;99:2086–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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;96:997–1005.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Sherman E HA, Fury M, Baxi SS, Haque S, Korte SH, et al.: A phase II study of temsirolimus/sorafenib in patients with radioactive iodine (RAI)-refractory thyroid carcinoma. J Clin Oncol. 2012;30(suppl) abstr 5514.

  133. Study of everolimus and sorafenib in patients with advanced thyroid cancer who progressed on sorafenib alone https://clinicaltrials.gov/ct2/show/NCT01263951. Accessed Jan 2016.

  134. Evaluating the combination of everolimus and sorafenib in the treatment of thyroid cancer https://clinicaltrials.gov/ct2/show/NCT01141309. Accessed Jan 2016.

  135. Combination of temsirolimus and sorafenib in the treatment of radioactive iodine refractory thyroid cancer https://clinicaltrials.gov/ct2/show/NCT01025453. Accessed Jan 2016.

  136. Hoftijzer H, Heemstra KA, Morreau H, et al. Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur J Endocrinol. 2009;161:923–31.

    Article  CAS  PubMed  Google Scholar 

  137. 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;165:315–22.

    Article  CAS  PubMed  Google Scholar 

  138. Cohen EE Phase 2 study of sunitinib in refractory thyroid cancer. J Clin Oncol. 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 26, No 15S (May 20 Supplement), 2008: 6025.

  139. Woyach JA, Kloos RT, Ringel MD, et al. Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma. J Clin Endocrinol Metab. 2009;94:164–70.

    Article  CAS  PubMed  Google Scholar 

  140. Piekarz R LV, Draper D, et al. : Phase I trial of romidepsin, a histone deacetylase inhibitor, given on days one, three and five in patients with thyroid and other advanced cancers. J Clin Oncol 2008; 26 (suppl): abstr 3571.

  141. Cediranib maleate with or without lenalidomide in treating patients with thyroid cancer. https://clinicaltrials.gov/ct2/show/NCT01208051. Accessed Jan 2016.

  142. Cabozantinib-S-malate in treating patients with refractory thyroid cancer. https://clinicaltrials.gov/ct2/show/NCT01811212. Accessed January 2016.

  143. A phase II trial of cabozantinib for the treatment of radioiodine (rai)-refractory differentiated thyroid carcinoma (DTC) in the first-line setting. https://clinicaltrials.gov/ct2/show/NCT02041260. Accessed Jan 2016.

  144. RAD001 for patients with radioiodine refractory thyroid cancer. https://clinicaltrials.gov/ct2/show/NCT00936858. Accessed Jan 2016.

  145. A trial of pasireotide and everolimus in adult patients with radioiodine-refractory differentiated and medullary thyroid cancer . https://clinicaltrials.gov/ct2/show/NCT01270321 . Accessed Jan 2016.

  146. Nintedanib (BIBF1120) in thyroid cancer. https://clinicaltrials.gov/ct2/show/NCT01788982. Accessed Jan 2016.

  147. Pazopanib hydrochloride in treating patients with advanced thyroid cancer. https://clinicaltrials.gov/ct2/show/NCT00625846. Accessed Jan 2016.

  148. Phase II study of the optimal scheme of administration of pazopanib in thyroid carcinoma. https://clinicaltrials.gov/ct2/show/NCT01813136. Accessed Jan 2016.

  149. AZD6244 in treating patients with papillary thyroid cancer that did not respond to radioactive iodine. https://clinicaltrials.gov/ct2/show/NCT00559949. Accessed Jan 2016.

  150. Sunitinib in treating patients with thyroid cancer that did not respond to iodine I 131 and cannot be removed by surgery. https://clinicaltrials.gov/ct2/show/NCT00381641. Accessed Jan 2016.

  151. Sutent adjunctive treatment of differentiated thyroid cancer (IIT Sutent). https://clinicaltrials.gov/ct2/show/NCT00668811. Accessed Jan 2016.

  152. Evaluation of efficacy, safety of vandetanib in patients with differentiated thyroid cancer (VERIFY). https://clinicaltrials.gov/ct2/show/NCT01876784. Accessed Jan 2016.

  153. A study of RO5185426 (vemurafenib) in patients with metastatic or unresectable papillary thyroid cancer positive for the BRAF V600 mutation. https://clinicaltrials.gov/ct2/show/NCT01286753. Accessed Jan 2016.

  154. Vemurafenib neoadjuvant trial in locally advanced thyroid cancer. https://clinicaltrials.gov/ct2/show/NCT01709292. Accessed Jan 2016.

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  1. Division of Medical Oncology, School of Medicine, Stanford University, Stanford, CA, 94305, USA

    Sujata Narayanan M.D. & A. Dimitrios Colevas M.D.

  2. Stanford Cancer Institute, Stanford University Medical Center, 875 Blake Wilbur Drive, Stanford, CA, 94305, USA

    A. Dimitrios Colevas M.D.

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  1. Sujata Narayanan M.D.
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Narayanan, S., Colevas, A.D. Current Standards in Treatment of Radioiodine Refractory Thyroid Cancer. Curr. Treat. Options in Oncol. 17, 30 (2016). https://doi.org/10.1007/s11864-016-0404-6

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