Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Differentiated thyroid cancer refractory to standard treatment: Chemotherapy

Steven I Sherman, MD
Section Editor
Douglas S Ross, MD
Deputy Editor
Jean E Mulder, MD


The treatment of most patients with differentiated thyroid cancer (DTC; both papillary [PTC] and follicular [FTC] histologies) includes surgery, thyroid hormone therapy, and selective use of radioactive iodine. When metastatic disease occurs, radioactive iodine can be curative in a minority of patients, and thyroid-stimulating hormone (TSH)-suppressive thyroid hormone therapy can help to slow the pace of the disease. In addition, external radiotherapy may be useful in some patients. (See "Differentiated thyroid cancer: Overview of management" and "Differentiated thyroid cancer: Radioiodine treatment" and "Differentiated thyroid cancer: External beam radiotherapy".)

However, for those patients with metastatic DTC that progresses despite radioiodine, TSH-suppressive thyroid hormone therapy, and external beam radiotherapy (EBRT), treatment options have historically been limited. New approaches based upon application of targeted chemotherapies are emerging as effective alternatives for progressive disease. Current and experimental chemotherapies for advanced DTC will be reviewed here. Chemotherapies for medullary and anaplastic thyroid cancers are discussed separately. (See "Medullary thyroid cancer: Chemotherapy and immunotherapy" and "Anaplastic thyroid cancer".)


For patients with metastatic differentiated thyroid cancer (DTC) that persists despite radioiodine, thyroid-stimulating hormone (TSH)-suppressive thyroid hormone therapy, and external radiotherapy, treatment options include observation, kinase inhibitors that primarily target angiogenesis, and traditional cytotoxic chemotherapy.

The availability of kinase inhibitors that can stabilize progressive metastatic disease has changed the standard approach to treating patients whose disease no longer responds to radioiodine and TSH-suppressive hormone therapy [1,2]. Although it may take many months before radiographic response becomes evident, targeting angiogenesis (and specifically vascular endothelial growth factor receptor [VEGFR] signaling pathways) has produced the most impressive clinical responses to date in DTC.

However, these drugs are disease-modifying agents, usually tumoristatic rather than tumoricidal, and no published study has demonstrated that these agents improve overall survival. In addition, these newer “targeted therapies” have significant toxicities and, therefore, it is important to limit the use of systemic treatments to patients at significant risk for morbidity or mortality due to progressive metastatic disease. Patients treated with systemic agents should have a baseline performance status sufficiently functional to tolerate these interventions, such as being ambulatory at least 50 percent of the day (Eastern Cooperative Oncology Group [ECOG] performance status 2 or better).

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jun 02, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on February 27, 2016).
  2. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016; 26:1.
  3. Bonadonna G, Monfardini S, De Lena M, et al. Phase I and preliminary phase II evaluation of adriamycin (NSC 123127). Cancer Res 1970; 30:2572.
  4. Gottlieb JA, Hill CS Jr. Chemotherapy of thyroid cancer with adriamycin. Experience with 30 patients. N Engl J Med 1974; 290:193.
  5. Carhill AA, Litofsky DR, Ross DS, et al. Long-Term Outcomes Following Therapy in Differentiated Thyroid Carcinoma: NTCTCS Registry Analysis 1987-2012. J Clin Endocrinol Metab 2015; 100:3270.
  6. Carhill AA, Cabanillas ME, Jimenez C, et al. The noninvestigational use of tyrosine kinase inhibitors in thyroid cancer: establishing a standard for patient safety and monitoring. J Clin Endocrinol Metab 2013; 98:31.
  7. Cabanillas ME, Hu MI, Durand JB, Busaidy NL. Challenges associated with tyrosine kinase inhibitor therapy for metastatic thyroid cancer. J Thyroid Res 2011; 2011:985780.
  8. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009; 9:28.
  9. Haugen BR, Sherman SI. Evolving approaches to patients with advanced differentiated thyroid cancer. Endocr Rev 2013; 34:439.
  10. Schlumberger M, Sherman SI. Clinical trials for progressive differentiated thyroid cancer: patient selection, study design, and recent advances. Thyroid 2009; 19:1393.
  11. Brose MS, Troxel AB, Redlinger M, et al. Effect of BRAFV600E on response to sorafenib in advanced thyroid cancer patients. J Clin Oncol (Meeting Abstracts) 2009; 27:6002.
  12. Sherman SI, Wirth LJ, Droz JP, et al. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med 2008; 359:31.
  13. 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; 92:205.
  14. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm434288.htm (Accessed on February 13, 2015).
  15. 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.
  16. Ball DW, Sherman SI, Jarzab B, et al. Lenvatinib treatment of advanced RAI-refractory differentiated thyroid cancer (DTC): Cytokine and angiogenic factor (CAF) profiling in combination with tumor genetic analysis to identify markers associated with response. J Clin Oncol 2012; 30 (suppl).
  17. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015; 372:621.
  18. 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.
  19. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376443.htm (Accessed on December 02, 2013).
  20. Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 2009; 27:1675.
  21. Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol 2008; 26:4714.
  22. 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.
  23. Schneider TC, Abdulrahman RM, Corssmit EP, et al. Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial. Eur J Endocrinol 2012; 167:643.
  24. 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.
  25. Brose MS, Nutting C, Shong YK, et al. Association between tumor BRAF and RAS mutation status and clinical outcomes in patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) randomized to sorafenib or placebo: sub-analysis of the phase III DECISION trial. ECCO/ESMO/ESTRO Annual Meeting; 2013; Amsterdam.
  26. Waguespack SG, Sherman SI, Williams MD, et al. The successful use of sorafenib to treat pediatric papillary thyroid carcinoma. Thyroid 2009; 19:407.
  27. Dubauskas Z, Kunishige J, Prieto VG, et al. Cutaneous squamous cell carcinoma and inflammation of actinic keratoses associated with sorafenib. Clin Genitourin Cancer 2009; 7:20.
  28. Kumar R, Knick VB, Rudolph SK, et al. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 2007; 6:2012.
  29. 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.
  30. Kim DW, Jo YS, Jung HS, et al. An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab 2006; 91:4070.
  31. Dawson SJ, Conus NM, Toner GC, et al. Sustained clinical responses to tyrosine kinase inhibitor sunitinib in thyroid carcinoma. Anticancer Drugs 2008; 19:547.
  32. Cohen EE, Needles BM, Cullen KJ, et al. Phase 2 study of sunitinib in refractory thyroid cancer. J Clin Oncol (Meeting Abstracts) 2008; 26.
  33. Ravaud A, de la Fouchardière F, Courbon F, et al. Sunitinib in patients with refractory advanced thyroid cancer: The THYSU phase II trial. J Clin Onc 2008; 26:6058.
  34. Carr L, Goulart B, Martins R, et al. Phase II trial of continuous dosing of sunitinib in advanced, FDG-PET avid, medullary thyroid carcinoma (MTC) and well-differentiated thyroid cancer (WDTC). J Clin Oncol (Meeting Abstracts) 2009; 27:6056.
  35. 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.
  36. 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.
  37. 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.
  38. Brose MS, Cabanillas ME, 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. ECCO/ESMO/ESTRO Annual Meeting; 2013; Amsterdam.
  39. Flaherty K, Puzanov I, Sosman J, et al. Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. J Clin Oncol (Meeting Abstracts) 2009; 27:9000.
  40. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012; 379:1893.
  41. 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.
  42. Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013; 368:623.
  43. 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.
  44. Lorch JH. A phase II study of everolimus in patients with aggressive RAI refractory (RAIR) thyroid cancer (TC). J Clin Oncol 2013; 31 (suppl).
  45. Sherman E. Phase II study of everolimus and sorafenib for the treatment of metastatic thyroid cancer. J Clin Oncol 2013; 31 (suppl).
  46. Brose MS, Cabanillas ME, Cohen EEW, et al. Clinical safety and activity from a phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions. Eur J Cancer 2017; 72:S148.
  47. Ain KB, Lee C, Williams KD. Phase II trial of thalidomide for therapy of radioiodine-unresponsive and rapidly progressive thyroid carcinomas. Thyroid 2007; 17:663.
  48. Ain KB, Lee C, Holbrook KM, et al. Phase II study of lenalidomide in distantly metastatic, rapidly progressive, and radioiodine-unresponsive thyroid carcinomas: preliminary results. J Clin Oncol (Meeting Abstracts) 2008; 26:6027.
  49. Mrozek E, Kloos RT, Ringel MD, et al. Phase II study of celecoxib in metastatic differentiated thyroid carcinoma. J Clin Endocrinol Metab 2006; 91:2201.
  50. Haugen BR. Management of the patient with progressive radioiodine non-responsive disease. Semin Surg Oncol 1999; 16:34.
  51. 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.
  52. Burgess MA, Hill CS Jr. Chemotherapy in the management of thyroid cancer. In: Thyroid Cancer, Greenfield LD (Ed), CRC Press, W. Palm Beach, FL 1978. p.233.
  53. Carter SK, Blum RH. New chemotherapeutic agents--bleomycin and adriamycin. CA Cancer J Clin 1974; 24:322.
  54. 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.
  55. Ain KB, Egorin MJ, DeSimone PA. Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group. Thyroid 2000; 10:587.
  56. Ikeda M, Tanaka K, Sonoo H, et al. [Docetaxel administration for radioiodine-resistant patients with metastatic papillary thyroid carcinoma]. Gan To Kagaku Ryoho 2007; 34:933.
  57. Williams SD, Birch R, Einhorn LH. Phase II evaluation of doxorubicin plus cisplatin in advanced thyroid cancer: a Southeastern Cancer Study Group Trial. Cancer Treat Rep 1986; 70:405.
  58. Argiris A, Agarwala SS, Karamouzis MV, et al. A phase II trial of doxorubicin and interferon alpha 2b in advanced, non-medullary thyroid cancer. Invest New Drugs 2008; 26:183.
  59. Biganzoli L, Gebbia V, Maiorino L, et al. Thyroid cancer: different outcomes to chemotherapy according to tumour histology. Eur J Cancer 1995; 31A:2423.
  60. Santini F, Bottici V, Elisei R, et al. Cytotoxic effects of carboplatinum and epirubicin in the setting of an elevated serum thyrotropin for advanced poorly differentiated thyroid cancer. J Clin Endocrinol Metab 2002; 87:4160.
  61. Matuszczyk A, Petersenn S, Voigt W, et al. Chemotherapy with paclitaxel and gemcitabine in progressive medullary and thyroid carcinoma of the follicular epithelium. Horm Metab Res 2010; 42:61.
  62. Zlock DW, Greenspan FS, Clark OH, Higgins CB. Octreotide therapy in advanced thyroid cancer. Thyroid 1994; 4:427.
  63. Kohlfuerst S, Igerc I, Gallowitsch HJ, et al. Is there a role for sandostatin treatment in patients with progressive thyroid cancer and iodine-negative but somatostatin-receptor-positive metastases? Thyroid 2006; 16:1113.
  64. Iten F, Muller B, Schindler C, et al. [(90)Yttrium-DOTA]-TOC response is associated with survival benefit in iodine-refractory thyroid cancer: long-term results of a phase 2 clinical trial. Cancer 2009; 115:2052.
  65. Batty N, Malouf GG, Issa JP. Histone deacetylase inhibitors as anti-neoplastic agents. Cancer Lett 2009; 280:192.
  66. Piekarz R, Luchenko V, 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; 26:3571.
  67. Sherman EJ, Fury MG, Tuttle RM, et al. Phase II study of depsipeptide (DEP) in radioiodine (RAI)-refractory metastatic nonmedullary thyroid carcinoma. J Clin Oncol (Meeting Abstracts) 2009; 27:6059.
  68. 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.