Thyroid cancer, differentiated - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main DTC page for regimens that include active anticancer treatment.
=Adjuvant therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Leboulleux et al. 2022 (ESTIMABL2)	2013-2017 	Phase 3 (E-de-esc)	Radioiodine ablation	Non-inferior composite endpoint
No treatment after surgery.
====Preceding treatment====
*Thyroidectomy
===References===
#ESTIMABL2: Leboulleux S, Bournaud C, Chougnet CN, Zerdoud S, Al Ghuzlan A, Catargi B, Do Cao C, Kelly A, Barge ML, Lacroix L, Dygai I, Vera P, Rusu D, Schneegans O, Benisvy D, Klein M, Roux J, Eberle MC, Bastie D, Nascimento C, Giraudet AL, Le Moullec N, Bardet S, Drui D, Roudaut N, Godbert Y, Morel O, Drutel A, Lamartina L, Schvartz C, Velayoudom FL, Schlumberger MJ, Leenhardt L, Borget I. Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer. N Engl J Med. 2022 Mar 10;386(10):923-932. link to original article EuroPMC NCT01837745
##Update: Leboulleux S, Bournaud C, Chougnet CN, Lamartina L, Zerdoud S, Do Cao C, Catargi B, Dygai I, Kelly A, Barge ML, Vera P, Rusu D, Schneegans O, Roux J, Raymond P, Benisvy D, Eberle MC, Bidault S, Nascimento C, Bastie D, Giraudet AL, Bardet S, Le Moullec N, Roudaut N, Drui D, Godbert Y, Zalzali M, Drutel A, Morel O, Velayoudom FL, Al Ghuzlan A, Schlumberger M, Buffet C, Borget I. Thyroidectomy without radioiodine in patients with low-risk thyroid cancer: 5 years of follow-up of the prospective randomised ESTIMABL2 trial. Lancet Diabetes Endocrinol. 2025 Jan;13(1):38-46. Epub 2024 Nov 22. link to original article EuroPMC
=Advanced or metastatic disease, radioactive iodine-refractory=
==Placebo==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Leboulleux et al. 2012 (D4200C00079)	2007-2008 	Randomized Phase 2 (C)	Vandetanib 	Shorter PFSMedian PFS: 5.9 vs 11.1 mo(HR 1.59, 60% CI 1.35-1.85)
Brose et al. 2014 (DECISION) 	2009-2011 	Phase 3 (C) 	Sorafenib 	Shorter PFSMedian PFS: 5.8 vs 10.8 mo(HR 1.69, 95% CI 1.32-2.22)
Schlumberger et al. 2015 (SELECT) 	2011-08-05 to 2012-10-04	Phase 3 (C) 	Lenvatinib 	Shorter PFSMedian PFS: 3.6 vs 18.3 mo(HR 4.76, 99% CI 3.23-7.14)
Lin et al. 2022 (REALITY) 	2017-2020 	Phase 3 (C) 	Apatinib 	Seems to have shorter OSMedian OS: 29.9 vs NYR mo(HR 2.38, 95% CI 1.03-5.56)
Lin et al. 2023 (ZGDD3) 	2018-08-29 to 2021-02-28	Phase 3 (C) 	Donafenib 	Shorter PFS (primary endpoint)Median PFS: 6.4 vs 12.9 mo(HR 2.56, 95% CI 1.64-4.00)
Brose et al. 2021 (COSMIC-311) 	2019-02-27 to 2020-08-18	Phase 3 (C) 	Cabozantinib	Shorter PFS1 (co-primary endpoint)Median PFS: 1.9 vs 11 mo(HR 4.55, 96% CI 3.12-6.67)
1Reported efficacy for COSMIC-311 is based on the 2022 update.
No active antineoplastic treatment.
===References===
# D4200C00079: Leboulleux S, Bastholt L, Krause T, de la Fouchardiere C, Tennvall J, Awada A, Gómez JM, Bonichon F, Leenhardt L, Soufflet C, Licour M, Schlumberger MJ. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012 Sep;13(9):897-905. Epub 2012 Aug 14. link to original article EuroPMC NCT00537095
# DECISION: Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, de la Fouchardiere C, Pacini F, Paschke R, Shong YK, Sherman SI, Smit JW, Chung J, Kappeler C, Peña C, Molnár I, Schlumberger MJ; DECISION investigators. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014 Jul 26;384(9940):319-28. Epub 2014 Apr 24. link to original article link to PMC article EuroPMC NCT00984282
# SELECT: Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Habra MA, Newbold K, Shah MH, Hoff AO, Gianoukakis AG, Kiyota N, Taylor MH, Kim SB, Krzyzanowska MK, Dutcus CE, de las Heras B, Zhu J, Sherman SI. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015 Feb 12;372(7):621-30. link to original article EuroPMC NCT01321554
# COSMIC-311: Brose MS, Robinson B, Sherman SI, Krajewska J, Lin CC, Vaisman F, Hoff AO, Hitre E, Bowles DW, Hernando J, Faoro L, Banerjee K, Oliver JW, Keam B, Capdevila J. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021 Aug;22(8):1126-1138. Epub 2021 Jul 5. link to original article EuroPMC NCT03690388
##Update: Brose MS, Robinson BG, Sherman SI, Jarzab B, Lin CC, Vaisman F, Hoff AO, Hitre E, Bowles DW, Sen S, Oliver JW, Banerjee K, Keam B, Capdevila J. Cabozantinib for previously treated radioiodine-refractory differentiated thyroid cancer: Updated results from the phase 3 COSMIC-311 trial. Cancer. 2022 Dec 15;128(24):4203-4212. Epub 2022 Oct 19. Erratum in: Cancer. 2023 Mar 1;129(5):807. link to original article link to PMC article EuroPMC
#REALITY: Lin Y, Qin S, Li Z, Yang H, Fu W, Li S, Chen W, Gao Z, Miao W, Xu H, Zhang Q, Zhao X, Bao J, Li L, Ren Y, Lin C, Jing S, Ma Q, Liang J, Chen G, Zhang H, Zhang Y, Zhou X, Sang Y, Hou Z. Apatinib vs Placebo in Patients With Locally Advanced or Metastatic, Radioactive Iodine-Refractory Differentiated Thyroid Cancer: The REALITY Randomized Clinical Trial. JAMA Oncol. 2022 Feb 1;8(2):242-250. link to original article link to PMC article EuroPMC NCT03048877
#ZGDD3: Lin Y, Qin S, Yang H, Shi F, Yang A, Han X, Liu B, Li Z, Ji Q, Tang L, Deng Z, Ding Y, Fu W, Xie X, Li L, He X, Lv Z, Ma Q, Shen Z, Guo Z, Chen Z, Cui Y, Tan J, Gao Z, Jing S, Lu K, Luo X, Zhang Y, Fang Y, Li Z, Cheng Y, Lei S, Luan S, Chen G, Wang G, Wu L, Liu L. Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer. Clin Cancer Res. 2023 Aug 1;29(15):2791-2799. link to original article EuroPMC NCT03602495
Category:Thyroid cancer regimens
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Category:Head and neck cancers
Category:Null regimens