Medical Oncology

, 31:49 | Cite as

Advanced thyroid cancers: new era of treatment

  • Amrallah A. MohammedEmail author
  • Ayman EL-Shentenawy
Review Article


Since chemotherapy has been shown to be unsuccessful in case of advanced thyroid carcinomas, the research for new therapies is fundamental. Clinical trials of many tyrosine kinase inhibitors as well as anti-angiogenic inhibitors suggest that patients with thyroid cancer could have an advantage with new target therapy. Recently, Food and Drug Administration approved two targeted therapies, vandetanib and cabozantinib for the treatment of metastatic thyroid carcinomas with acceptable outcome. We summarized the results and the toxic effects associated with these treatments reported in clinical trials. Future trials should aim at combinations of targeted agents with or without other treatment modalities to obtain a more effective result in thyroid carcinoma treatment.


Targeted therapy Advanced thyroid cancer Tyrosine kinase inhibitors 


Conflict of interest

The authors certify that there is no actual or potential conflict of interest in relation to this article.


  1. 1.
    Deshpande H, Gettinger S, Sosa J. Axitinib. The evidence of its potential in the treatment of advanced thyroid cancer. Core Evid. 2010;4:43–8.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Moo-Young T, Traugott A, Moley J. Sporadic and familial medullary thyroid carcinoma: state of the art. Surg Clin North Am. 2009;89:1193–204.PubMedCrossRefGoogle Scholar
  3. 3.
    Leboullex S, Baudin E, Travagli J, Schlumberger M. Medullary thyroid carcinoma. Clin Endocrinal. 2004;61:299–310.CrossRefGoogle Scholar
  4. 4.
    Patel K, Shaha A. Poorly differentiated and anaplastic thyroid cancer. Cancer Control. 2006;13:119–28.PubMedGoogle Scholar
  5. 5.
    Droz J, Schlumberger M, Rougier P, Ghosn M, Gardet P, et al. Chemotherapy in metastatic nonanaplastic thyroid cancer: experience at the Institut Gustave-Roussy. Tumori. 1990;76:480–3.PubMedGoogle Scholar
  6. 6.
    Argiris A, Agarwala S, Karamouzis M, Burmeister L, Carty S. A phase II trial of doxorubicin and interferon alpha 2b in advanced, non medullary thyroid cancer. Invest New Drugs. 2008;26:183–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Kondo T, Ezzat S, Asa L. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006;6:292–306.PubMedCrossRefGoogle Scholar
  8. 8.
    Kimura E, Nikiforova M, Zhu Z, Knauf J, Fagin JA, et al. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RASBRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 2003;63:1454–7.PubMedGoogle Scholar
  9. 9.
    Elisei R, Cosci B, Romei C, Bottici V, Renzini G, et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10 years follow up study. J Clin Endocrinol Metab. 2007;93:682–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Hoffmann S, Wunderlich A, Celik I, Maschuw K, Hassan I, et al. Paneling human thyroid cancer cell lines for candidate proteins for targeted anti-angiogenic therapy. J Cell Biochem. 2006;98:954–65.PubMedCrossRefGoogle Scholar
  11. 11.
    Wasenius V, Hemmer S, Nupponen N, Franssila K, Joensuu J. MET receptor tyrosine kinase sequence alterations in differentiated thyroid carcinoma. Am J Surg Pathol. 2005;29:544–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Rugo H, Herbst R, Liu G, Park J, Kies M, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol. 2005;23:5474–83.PubMedCrossRefGoogle Scholar
  13. 13.
    Cohen E, Rosen S, Vokes E, Kies M, Forastiere A, 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):4713.Google Scholar
  14. 14.
    Kloos R, Ringel M, Knopp M, Hall N, King M, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009;27:1675–84.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Gupta-Abramson V, Troxel A, Nellore A, Puttaswamy K, Redlinger M, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26:4714–9.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Ravaud A, de la Fouchardiere C, Courbon F, Asselineau J, Klein M, et al. Sunitinib in patients with refractory advanced thyroid cancer: the THYSU phase II trial. J Clin Oncol. 2008;26:6058.Google Scholar
  17. 17.
    Cohen E, Needles B, Cullen K, Wong J, Wade J, et al. Phase 2 study of sunitinib in refractory thyroid cancer. J Clin Oncol. 2009;26:6025.Google Scholar
  18. 18.
    Goulart B, Carr L, Martins R, Kell E, Bauman J, et al. Phase II study of sunitinib in iodine refractory, well-differentiated thyroid cancer (WDTC) and metastatic medullary thyroid carcinoma (MTC). Proc Am Soc Clin Oncol. 2010;26:6062.Google Scholar
  19. 19.
    De Groot J, Plaza M, Schepers I, Drenth-Diephuis H, Osinga L, et al. Cellular effects of imatinib on medullary thyroid cancer cells harboring multiple endocrine neoplasia type 2A and 2B associated RET mutations. Surgery. 2006;139:806–14.PubMedCrossRefGoogle Scholar
  20. 20.
    Frank-Raue K, Fabel M, Delorme S, Haberkorn U, Raue F. Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma. Eur J Endocrinol. 2007;157:215–20.PubMedCrossRefGoogle Scholar
  21. 21.
    Sherman I, Wirth L, Droz J, Hofmann M, Bastholt L, et al. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med. 2008;359(31):42.Google Scholar
  22. 22.
    Bible K, Smallridge R, Maples W, Menefee M, et al. Phase II trial of pazopanib in progressive, metastatic, iodine-insensitive differentiated thyroid cancers. Proc Am Soc Clin Oncol. 2009;27:3521.Google Scholar
  23. 23.
    Bible K, Suman V, Molina J, Smallridge R, Maples W, et al. Multicenter phase 2 trial of pazopanib in metastatic and progressive medullary thyroid carcinoma: MC057H. J Clin Endocrinol Metab. 2014;25:2013–3713.Google Scholar
  24. 24.
    Hoffmann S, Glaser S, Wunderlich A, Lingelbach S, Dietrich C, et al. Targeting the EGF/VEGF-R system by tyrosine-kinase inhibitors a novel antiproliferative/antiangiogenic strategy in thyroid cancer. Langenbecks Arch Surg. 2006;391(589):596.Google Scholar
  25. 25.
    Wells S, Robinson B, Gagel R, Dralle J, Faquin M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized double-blind PIII trial. J Clin Oncol. 2012;30:134–41.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Schoffski P, Elisei P, Mülleret P, Shoffski P, Brose MS, 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;30:5508.Google Scholar
  27. 27.
    Kogan E, Rozhkova E, Seredin V, Paltsev M. Prognostic value of the expression of thyreoglobulin and oncomarkers (p53, EGFR, ret-oncogene) in different types of papillary carcinoma of the thyroid: clinicomorphological and immunohistochemical studies]. Arkh Patol. 2006;68:8–11.PubMedGoogle Scholar
  28. 28.
    Fury M, Solit D, Su Y, Rosen N, Sirotnak F, et al. A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2007;59:467–75.PubMedCrossRefGoogle Scholar
  29. 29.
    Pennell N, Daniels G, Haddad R, Ross D, Evans T, et al. A phase II study of gefitinib in patients with advanced thyroid cancer. Thyroid. 2008;18:317–23.PubMedCrossRefGoogle Scholar
  30. 30.
    Mitsiades C, Poulaki V, McMullan C, Negri J, Fanourakis G, et al. Novel histone deacetylase inhibitors in the treatment of thyroid cancer. Clin Cancer Res. 2005;11:3958–65.PubMedCrossRefGoogle Scholar
  31. 31.
    Kelly W, O’Connor O, Krug L, Chiao J, Heaney M, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol. 2005;23(3923):3931.Google Scholar
  32. 32.
    Woyach J, Kloos R, Ringel M, Arbogast D, Collamore M, et al. Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodinerefractory thyroid carcinoma. J Clin Endocrinol Metab. 2009;94(164):170.Google Scholar
  33. 33.
    Mrozek E, Kloos R, Ringel M, Kresy L, Snider P, et al. Phase II study of celecoxib in metastatic differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2006;91:2201–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Specht M, Tucker O, Hocever M, Gonzalez D, Teng L. Cyclooxygenase-2 expression in thyroid nodules. J Clin Endocrinol Metab. 2002;87:358–63.PubMedCrossRefGoogle Scholar
  35. 35.
    Liu Y, Morreau H, Kievit J, Romijn J, Carrasco N. Combined immunostaining with galectin-3, fibronectin-1, CITED-1, Hector Battifora mesothelial-1, cytokeratin-19, peroxisome proliferator-activated receptor-{gamma}, and sodium/iodide symporter antibodies for the differential diagnosis of non-medullary thyroid carcinoma. Eur J Endocrinol. 2008;158:375–84.PubMedCrossRefGoogle Scholar
  36. 36.
    Kebebew E, Lindsay S, Clark O, Woeber K, Hawkins R, et al. Results of rosiglitazone therapy in patients with thyroglobulin-positive and radioiodine-negative advanced differentiated thyroid cancer. Thyroid. 2009;19:953–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Tepmongkol S, Keelawat S, Honsawek S, Ruanqvejvorachai P. Rosiglitazone. Effect on radioiodine uptake in thyroid carcinoma patients with high thyroglobulin but negative total body scan: a correlation with the expression of peroxisome proliferator-activated receptor-gamma. Thyroid. 2008;18:697–704.PubMedCrossRefGoogle Scholar
  38. 38.
    Liu Y, van der Pluijm G, Karperien M, Stokkel MP, Pereira A, et al. Lithium as adjuvant to radioiodine therapy in differentiated thyroid carcinoma: clinical and in vitro studies. Clin Endocrinol (Oxf). 2006;64:617–24.CrossRefGoogle Scholar
  39. 39.
    Ain K, Lee C, Holbrook K, Dziba J, Williams D. Phase II study of lenalidomide in distantly metastatic, rapidly progressive, and radioiodine-unresponsive thyroid carcinomas: preliminary results. Proc Am Soc Clin Oncol. 2008;26:6027.Google Scholar
  40. 40.
    Mitsiades C, McMillin D, Kotoula V, Poulaki V, McMullan C, et al. Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro. J Clin Endocrinol Metab. 2006;91:4013–21.PubMedCrossRefGoogle Scholar
  41. 41.
    Dowlati A, Robertson K, Cooney M, Petros W, Stratford M, et al. A phase I pharmacokinetic and translational study of thenovel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer. Cancer Res. 2002;62:3408–16.PubMedGoogle Scholar
  42. 42.
    Cooney M, Savvides P, Agarwala S, Wasman J, Cooney M, et al. Phase II study of combrestatin A4 phosphate (CA4P) in patients with advanced anaplstic thyroid carcinoma (ATC). J Clin Oncol. 2006;24:3005.Google Scholar
  43. 43.
    Marsee D, Venkateswaran A, Tao H, Vadysirisack D, Zhang Z, et al. Inhibition of heat shock protein 90, a novel RET/PTC1-associated protein, increases radioiodide accumulation in thyroid cells. J Biol Chem. 2004;279:43990–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Hong D, Camacho L, Ng C, Janisch MJ, Ratain R, et al. Phase I study of tipifarnib and sorafenib in patients with biopsiable advanced cancers. Proc Am Soc Clin Oncol. 2007;25(18S):3549.Google Scholar
  45. 45.
    Gild M, Landa L, Ryder M, Ghossein R, Knauf J, et al. Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells. Endocr Relat Cancer. 2013;20(5):659–67.PubMedCrossRefGoogle Scholar
  46. 46.
    Spitzweg C. Gene therapy in thyroid cancer. Horm Metab Res. 2009;41:500–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Papewalis C, Wuttke M, Seissler J, Meyer Y, Kessler C, et al. Dendritic cell vaccination with xenogenic polypeptide hormone induces tumor rejection in neuroendocrine cancer. Clin Cancer Res. 2008;14:4298–305.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Oncology CenterKing Abdullah Medical City-Holy CapitalMakkahSaudi Arabia
  2. 2.Medical Oncology Department, Faculty of MedicineZagazig UniversityZagazigEgypt
  3. 3.Department of Clinical Oncology, Faculty of MedicineCairo UniversityGizaEgypt

Personalised recommendations