Thyroid cancer, differentiated - null regimens

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

1. 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 PubMed NCT01837745

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	Inferior PFS
Brose et al. 2014 (DECISION)	2009-2011	Phase 3 (C)	Sorafenib	Inferior PFS
Schlumberger et al. 2015 (SELECT)	2011-08-05 to 2012-10-04	Phase 3 (C)	Lenvatinib	Inferior PFS
Lin et al. 2022 (REALITY)	2017-2020	Phase 3 (C)	Apatinib	Seems to have inferior OS
Lin et al. 2023 (ZGDD3)	2018-08-29 to 2021-02-28	Phase 3 (C)	Donafenib	Inferior PFS (primary endpoint)
Brose et al. 2021 (COSMIC-311)	2019-02-27 to 2020-08-18	Phase 3 (C)	Cabozantinib	Inferior PFS

No active antineoplastic treatment.

References

1. 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 PubMed NCT00537095
2. 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 PubMed NCT00984282
3. 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 PubMed NCT01321554
4. 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 PubMed NCT03690388
5. 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 PubMed NCT03048877
6. 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 PubMed NCT03602495