Thyroid cancer is the most common endocrine malignancy, with differentiated thyroid cancer (DTC) comprising ∼93% of all thyroid cancers. While most cases of DTC are curable with the use of surgery and radioactive iodine (RAI) ablation of the remaining thyroid remnant, prognosis is dire and treatment options limited when DTC becomes RAI-refractory (RAI-R). Standard cytotoxic chemotherapy has limited efficacy, making enrollment in clinical trials of novel targeted therapies the preferred treatment approach. Thus, we conducted a comprehensive systematic review of the clinical trial scientific literature with a focus on efficacy, safety, and economics to identify all potential treatment options that have been or are currently being evaluated for the treatment of RAI-R DTC.
Methods:
Embase.com (including Medline), Medline In-Process and other nonindexed citations, the Cochrane Libraries, ClinicalTrials.gov, and relevant recent conference proceedings were searched using predefined search criteria. Important inclusion criteria included English language, randomized controlled studies or interventional single-arm studies only, and studies of drug therapies only. Search results were screened utilizing the discretion of multiple researchers, and key data were abstracted.
Results:
Forty-five unique trials (16 full-text, 4 conference abstracts, and 25 ClinicalTrials.gov entries) were included in the clinical review. No studies that met criteria for inclusion in the economic review were identified. Among 20 trials with results available, all were Phase II and only one was randomized. The most commonly studied drugs were tyrosine kinase inhibitors (TKIs); other drugs included celecoxib, doxorubicin with interferon alpha-2b, rosiglitazone, selumetinib (AZD6244), thalidomide, VEGF trap, and vorinostat. Overall, efficacy and safety profiles were specific to treatment regimen, with objective response rates (ORR) ranging from 0% on gefitinib, rosiglitazone, VEGF trap, and vorinostat to 50% on lenvatinib, a TKI.
Conclusions:
Limited clinical research and no economic research has been conducted in RAI-R DTC. Certain treatments, notably TKIs, have shown promise in Phase II trials, and two Phase III randomized placebo-controlled trials are ongoing. New research on the economic and humanistic burden of RAI-R DTC must be paired with the clinical evidence currently in development to examine the existing burden and future promise in treating patients with RAI-R DTC.
Get full access to this article
View all access options for this article.
References
1.
American Cancer Society. Thyroid Cancer. www.cancer.org/acs/groups/cid/documents/webcontent/003144-pdf.pdf. 2013 February 26.
2.
NixonIJ, WhitcherMM, PalmerFL, TuttleRM, ShahaAR, ShahJP, PatelSG, GanlyI. 2012. The Impact of Distant Metastases at Presentation on Prognosis in Patients with Differentiated Carcinoma of the Thyroid Gland. Thyroid, 22:884–889.
3.
DuranteC, HaddyN, BaudinE, LeboulleuxS, HartlD, TravagliJP, CaillouB, RicardM, LumbrosoJD, De VathaireF, SchlumbergerM. 2006. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: Benefits and limits of radioiodine therapy. Journal of Clinical Endocrinology and Metabolism, 91:2892–2899.
4.
BergerA, EdelsbergJ, ChungK, NgyuyenA, StepanD, OsterG. 2007. Healthcare (HC) utilization, costs in patients (pts) with newly diagnosed metastatic thyroid cancer (MTC)Abstract presented at the 2007 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, June 1–5Abstract no. 17082.
5.
CooperDS, DohertyGM, HaugenBR, KloosRT, LeeSL, MandelSJ, MazzaferriEL, McIverB, PaciniF, SchlumbergerM, ShermanSI, StewardDL, TuttleRM. 2009. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 19:1167–1214.
6.
CapdevilaJ, ArgilesG, Rodriguez-FrexinosV, NunezI, TaberneroJ. 2010. New approaches in the management of radioiodine-refractory thyroid cancer: the molecular targeted therapy era. Discov Med, 9:153–162.
7.
SchlumbergerM, LacroixL, RussoD, FilettiS, JMB. 2007. Defects in iodide metabolism in thyroid cancer and implications for the follow-up and treatment of patients. Nat Clin Pract Endocrinol Metab, 3:260–269.
8.
SchlumbergerM, TubianaM, De VathaireF, HillC, GardetP, TravagliJ, FraguP, LumbrosoJ, CaillouB, ParmentierC. 1986. Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab, 63:960–967.
9.
CarterWB, TourtelotJB, SavellJG, LilienfeldH. 2011. New treatments and shifting paradigms in differentiated thyroid cancer management. Cancer Control, 18:96–103.
10.
Pharmacia & Upjohn Company Division of Pfizer Inc.Doxorubicin Hydrochloride for Injection: May 2010 [package insert]www.accessdata.fda.gov/drugsatfda_docs/label/2010/050467s070lbl.pdf. 2012 October 24.
11.
HaugenBR. 1999. Management of the patient with progressive radioiodine non-responsive disease. Seminars in surgical oncology, 16:34–41.
12.
ArgirisA, AgarwalaSS, KaramouzisMV, BurmeisterLA, CartySE. 2008. A phase II trial of doxorubicin and interferon alpha 2b in advanced, non-medullary thyroid cancer. Investigational New Drugs, 26:183–188.
13.
ShimaokaK, SchoenfeldDA, DewysWD, CreechRH, DecontiR. 1985. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer, 56:2155–2160.
14.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma v.3.2012. www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. 2012 October 24.
15.
ElsevierB.V.Embase: Journals Coverage. www.embase.com/info/what-is-embase/coverage. 2012 August 17.
16.
LeboulleuxS, BastholtL, KrauseT, de la FouchardiereC, TennvallJ, AwadaA, GómezJM, BonichonF, LeenhardtL, SouffletC, LicourM, SchlumbergerMJ. 2012. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. The Lancet Oncology, 13:897–905.
17.
ChenL, ShenY, LuoQ, YuY, LuH, ZhuR. 2011. Response to sorafenib at a low dose in patients with radioiodine-refractory pulmonary metastases from papillary thyroid carcinoma. Thyroid, 21:119–124.
18.
AhmedM, BarbachanoY, RiddellA, HickeyJ, NewboldKL, VirosA, HarringtonKJ, MaraisR, NuttingCM. 2011. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: A phase II study in a UK based population. Eur J Endocrinol, 165:315–322.
DuntasLH, VlassopoulouV, BoutsiadisA, MantzouE, AnapliotouM, TsatsoulisA. 2011. Sorafenib in the treatment of radioiodine refractory thyroid cancer. A multicenter phase II study. Abstract presented at the 35th Annual Meeting of the European Thyroid Association, Krakow, Poland, September 10–14Abstract no. P03.
21.
Gupta-AbramsonV, TroxelAB, NelloreA, PuttaswamyK, RedlingerM, RansoneK, MandelSJ, FlahertyKT, LoevnerLA, O'DwyerPJ, BroseMS. 2008. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol, 26:4714–4719.
22.
HoftijzerH, HeemstraKA, MorreauH, StokkelMP, CorssmitEP, GelderblomH, WeijersK, PereiraAM, HuijbertsM, KapiteijnE, RomijnJA, SmitJW. 2009. Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. Eur J Endocrinol, 161:923–931.
23.
BroseMS, TroxelAB, PuttaswamyK, MaC, KeefeSM, ChalainAA, FrakerDL, MandelSJ, LeeWM, FeldmanMD, LoevnerLA, O'DwyerPJ. 2009. Measurements of outcome of a phase II study of sorafenib for advanced thyroid cancer. Abstract presented at the 80th Annual Meeting of the American Thyroid Association, Palm Beach, FL, September 23–27Short call poster 27.
24.
KeefeSM, TroxelAB, RheeS, PuttaswamyK, O'DwyerPJ, LoevnerLA, MandelSJ, BroseMS. 2011. Phase II trial of sorafenib in patients with advanced thyroid cancer. Abstract presented at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, June 3–7Abstract no. 5562.
25.
CohenEEW, RosenLS, VokesEE, KiesMS, ForastiereAA, WordenFP, KaneMA, ShermanE, KimS, BycottP, TortoriciM, ShalinskyDR, LiauKF, CohenRB. 2008. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: Results from a phase II study. J Clin Oncol, 26:4708–4713.
26.
PennellNA, DanielsGH, HaddadRI, RossDS, EvansT, WirthLJ, FidiasPH, TemelJS, GurubhagavatulaS, HeistRS, ClarkJR, LynchTJ. 2008. A phase II study of gefitinib in patients with advanced thyroid cancer. Thyroid, 18:317–323.
27.
ShermanSI, JarzabB, CabanillasME, LicitraLF, PaciniF, MartinsR, RobinsonB, BallD, McCaffreyJ, ShahMH, BodennerD, AllisonR, NewboldK, EliseiR, O'BrienJP, SchlumbergerM. 2011. A phase II trial of the multitargeted kinase inhibitor E7080 in advanced radioiodine (RAI)-refractory differentiated thyroid cancer (DTC)Abstract presented at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, June 3–7Abstract no. 5503.
28.
ShermanSI, WirthLJ, DrozJP, HofmannM, BastholtL, MartinsRG, LicitraL, EschenbergMJ, SunYN, JuanT, StepanDE, SchlumbergerMJ. 2008. Motesanib diphosphate in progressive differentiated thyroid cancer. New England Journal of Medicine, 359:31–42.
29.
BibleKC, SumanVJ, MolinaJR, SmallridgeRC, MaplesWJ, MenefeeME, RubinJ, SiderasK, MorrisJC, McIverB, BurtonJK, WebsterKP, BieberC, TraynorAM, FlynnPJ, GohBC, TangH, IvySP, ErlichmanC. 2010. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: Results of a phase 2 consortium study. The Lancet Oncology, 11:962–972.
30.
CarrLL, MankoffDA, GoulartBH, EatonKD, CapellPT, KellEM, BaumanJE, MartinsRG. 2010. 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. Clinical Cancer Research, 16:5260–5268.
31.
ShermanEJ, HoAL, FuryMG, BaxiSS, HaqueS, KorteSH, Smith-MarroneS, XiaoH, GhosseinRA, FaginJA, PfisterDG. 2012. A phase II study of temsirolimus/sorafenib in patients with radioactive iodine (RAI)-refractory thyroid carcinoma. Abstract presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, June 1–5Abstract no. 5514.
32.
MrozekE, KloosRT, RingelMD, KrestyL, SniderP, ArbogastD, KiesM, MundenR, BusaidyN, KleinMJ, ShermanSI, ShahMH. 2006. Phase II study of celecoxib in metastatic differentiated thyroid carcinoma. J Clin Endocrinol Metab, 91:2201–2204.
33.
KebebewE, LindsayS, ClarkOH, WoeberKA, HawkinsR, GreenspanFS. 2009. Results of rosiglitazone therapy in patients with thyroglobulin-positive and radioiodine-negative advanced differentiated thyroid cancer. Thyroid, 19:953–956.
34.
HayesDN, LucasAS, TanvetyanonT, KrzyzanowskaMK, ChungCH, MurphyBA, GilbertJ, MehraR, MooreDT, SheikhA, HoskinsJ, HaywardMC, ZhaoN, O'ConnorW, WeckKE, CohenRB, CohenEEW. 2012. 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, 18:2056–2065.
35.
AinKB, LeeC, WilliamsKD. 2007. Phase II trial of thalidomide for therapy of radioiodine-unresponsive and rapidly progressive thyroid carcinomas. Thyroid, 17:663–670.
36.
ShermanEJ, HoAL, HaqueS, TuttleRM, GhosseinRA, SchoderH, BaumMS, KellyK, ChenAP, ShahaAR, PfisterDG. 2011. A phase II study of VEGF trap in patients with radioactive iodine (RAI)-refractory thyroid carcinoma. Abstract presented at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, June 3–7Abstract no. 5566.
37.
WoyachJA, KloosRT, RingelMD, ArbogastD, CollamoreM, ZwiebelJA, GreverM, Villalona-CaleroM, ShahMH. 2009. Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma. J Clin Endocrinol Metab, 94:164–170.
38.
OkenMM, CreechRH, TormeyDC, HortonJ, DavisTE, McFaddenET, CarbonePP. 1982. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol, 5:649–655.
39.
Dana–Farber Cancer Institute 2000–. RAD001 for patients with radioiodine refractory thyroid cancer. ClinicalTrials.gov[Internet]Bethesda, MD: National Library of Medicine (US)http://clinicaltrials.gov/ct2/show/NCT00936858(NLM Identifier: NCT00936858; cited August 17, 2012).
40.
Leiden University Medical Center 2000–. Everolimus in treating patients with progressive or recurrent unresectable, or metastatic thyroid cancer. ClinicalTrials.gov[Internet]Bethesda, MD: National Library of Medicine (US)http://clinicaltrials.gov/ct2/show/NCT01118065(NLM Identifier: NCT01118065; cited August 17, 2012).
41.
Memorial Sloan–Kettering Cancer Center 2000–. Evaluating the combination of everolimus sorafenib in the treatment of radioactive iodine refractory thyroid cancer. ClinicalTrials.gov[Internet]Bethesda, MD: National Library of Medicine (US)http://clinicaltrials.gov/ct2/show/NCT01141309(NLM Identifier: NCT01141309; cited August 17, 2012).
42.
Yonsei University 2000–. Everolimus in treating patients with locally advanced or metastatic thyroid cancer. ClinicalTrials.gov[Internet]Bethesda, MD: National Library of Medicine (US)http://clinicaltrials.gov/ct2/show/NCT01164176(NLM Identifier: NCT01164176; cited August 17, 2012).
43.
Emory University 2000–. A trial of pasireotide everolimus in adult patients with radioiodine-refractory differentiated, medullary thyroid cancer. ClinicalTrials.gov[Internet]Bethesda, MD: National Library of Medicine (US)http://clinicaltrials.gov/ct2/show/NCT01270321(NLM Identifier: NCT01270321; cited August 17, 2012).
44.
Bayer 2000–. Nexavar® versus placebo in locally advanced/metastatic RAI-refractory differentiated thyroid cancer. ClinicalTrials.gov[Internet]Bethesda, MD: National Library of Medicine (US)http://clinicaltrials.gov/ct2/show/NCT00984282(NLM Identifier: NCT-00984282; cited August 17, 2012).
45.
Memorial Sloan–Kettering Cancer Center 2000–. Combination of temsirolimus sorafenib in the treatment of radioactive iodine refractory thyroid cancer. ClinicalTrials.gov[Internet]Bethesda, MD: National Library of Medicine (US)http://clinicaltrials.gov/ct2/show/NCT01025453(NLM Identifier: NCT01025453; cited August 17, 2012).
46.
University Hospital Bordeaux 2000–. Thyroid cancer sunitinib (THYSU)ClinicalTrials.gov[Internet]Bethesda, MD: National Library of Medicine (US)http://clinicaltrials.gov/ct2/show/NCT00510640(NLM Identifier: NCT00510640; cited August 17, 2012).
47.
University of Chicago 2000–. Sunitinib in treating patients with thyroid cancer that did not respond to iodine I 131 and cannot be removed by surgery. ClinicalTrials.gov[Internet]Bethesda, MD: National Library of Medicine (US)http://clinicaltrials.gov/ct2/show/NCT00381641(NLM Identifier: NCT00381641; cited August 17, 2012).
48.
Washington Hospital Center 2000–. Sutent adjunctive treatment of differentiated thyroid cancer (IIT sutent)ClinicalTrials.gov[Internet]Bethesda, MD: National Library of Medicine (US)http://clinicaltrials.gov/ct2/show/NCT00668811(NLM Identifier: NCT00668811; cited August 17, 2012).
49.
Eisai Inc 2000–. A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial of lenvatinib (E7080) in 131I-refractory differentiated thyroid cancer. ClinicalTrials.govBethesda, MD: National Library of Medicine (US)http://clinicaltrials.gov/ct2/show/NCT01321554(NLM Identifier: NCT01321554; cited August 17, 2012).
50.
BusaidyNL, CabanillasME. 2012. Differentiated thyroid cancer: management of patients with radioiodine nonresponsive disease. J Thyroid Res, 2012Article ID 618985.
51.
KojicKL, KojicSL, WisemanSM. 2012. Differentiated thyroid cancers: a comprehensive review of novel targeted therapies. Expert Rev Anticancer Ther, 12:345–357.
52.
O'NeillCJ, OucharekJ, LearoydD, SidhuSB. 2010. Standard and emerging therapies for metastatic differentiated thyroid cancer. Oncologist, 15:146–156.
53.
PerezCA, ArangoBA, VelezM, RaezLE, SantosES. 2012. Emerging role of multikinase inhibitors for refractory thyroid cancer. Biologics, 6:257–265.
54.
BallD, ShermanS, JarzabB, CabanillasM, LicitraL, PaciniF, MartinsRG, RobinsonB, McCaffreyJC, ShahMH, BodennerD, AllisonR, NewboldK, EliseiR, SachdevP, KadowakiT, FunahashiY, O'BrienJP, SchlumbergerM. 2011. A Phase II Trial of the Multi-Targeted Kinase Inhibitor Lenvatinib (E7080) in Advanced Radioiodine (RAI)-Refractory Differentiated Thyroid Cancer (DTC): Correlation of Treatment Outcomes with Tumor Genetic Analysis, Serum Biomarkers and Pharmacokinetics. Abstract presented at the 81st Annual Meeting of the American Thyroid Association, Indian Wells, CA, October 26–30Oral Presentation 3.
55.
FukahoriM, YoshidaA, HayashiH, YoshiharaM, MatsukumaS, SakumaY, KoizumeS, OkamotoN, KondoT, MasudaM, MiyagiY. 2012. The associations between RAS mutations and clinical characteristics in follicular thyroid tumors: new insights from a single center and a large patient cohort. Thyroid, 22:683–689.
56.
HoAL, LeboeufR, GrewalRK, ShermanEJ, DeandreisD, PentlowKS, TuttleRM, FuryMG, Ricarte-FilhoJCM, PfisterDG, LarsonSM, FaginJA. 2012. Reacquisition of RAI uptake in RAI-refractory metastatic thyroid cancers by pretreatment with the MEK inhibitor selumetinib. Abstract presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, June 1–5Abstract no. 5509.
57.
Memorial Sloan–Kettering Cancer Center 2000–. Reacquisition of radioactive iodine (RAI) uptake of RAI-refractory metastatic thyroid cancers by pretreatment with the selective MEK inhibitor AZD6244. ClinicalTrials.gov[Internet]Bethesda, MD: National Library of Medicine (US)http://clinicaltrials.gov/ct2/show/NCT00970359(NLM Identifier: NCT00970359; cited August 17, 2012).
