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Sorafenib for the treatment of locally advanced or metastatic, differentiated thyroid carcinoma, refractory to radioactive iodine

KCE has read for you

Patriek Mistiaen, Nadia Benahmed

Main messages

The European network for Health Technology Assessment EUnetHTA published in March 2015 a systematic review on the clinical effectiveness of a new drug Sorafenib to treat patients with a radioactive iodine resistant differentiated thyroid cancer.
One randomized controlled trial was included in the review.
The review concluded that Sorafenib prolongs progression free survival compared to a placebo group, but no differences were found with regard to overall survival. The number of adverse events was larger in the Sorafenib than in the placebo group.

Background and scope

The EUnetHTA review
The overall objective of the EUnetHTA Joint Action is to foster collaboration and knowledge sharing between European public HTA agencies, with the aim of increasing the efficiency and quality of technology assessments and promoting their uptake in the national health policy decision-making processes. The present assessment is one of the pilot joint assessments using the EUnetHTA Core model® for Rapid Relative Effectiveness Assessment of pharmaceuticals (more info: www.eunethta.eu).

The objective of this EUnetHTA review1 was to assess the relative efficacy of Sorafenib (Nexavar®) in monotherapy compared to placebo for adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma, refractory to radioactive iodine.
The primary outcome used in the review was progression-free survival; other outcomes related to efficacy were: overall survival, time to progression, disease control rate, response rate and duration of response. Secondary outcomes were safety (adverse events) and health-related quality of life (HRQoL).

Thyroid cancer today in Belgium

The incidence of thyroid cancers, although relatively low, is increasing rapidly in most western countries.2 This growing incidence is due to many factors, including a better detection of early disease.2, 3
In Belgium the incidence of thyroid cancer in 2012 was 12.6/100 000 in women and 4.7 in men, totalling 961 new patients this year.
Differentiated thyroid cancer is the most frequent type. Surgery is the most common initial treatment together with radioiodine treatment.4 Survival rate at 10 years is above 90%. However about 10% of differentiated thyroid cancers become refractive to iodine treatment, and for these patients 10 year survival drops to 10%. Tyrosine kinase inhibitors seem to offer a promising new approach for treatment of differentiated thyroid cancer resistant to radioactive iodine. Sorafenib is one of those tyrosine kinase inhibitors that has been tested in a phase 3 trial.


The authors searched several databases and also grey literature and manufacturer sources up to October 2014. Only randomised controlled trials were considered. One trial5 was retrieved and included, in which 417 patients were enrolled; the review authors rated this trial as having low risk of bias.

This methodology was critically appraised by two KCE researchers using the AMSTAR instrument. This resulted in a 7/11 score, demonstrating moderate quality.



  • a better median progression free survival, which was 329 days (95% confidence interval [CI]: 278-393) in the Sorafenib group, compared with 175 days (95% CI: 160-238) in the placebo group;
  • no statistical difference in overall survival between Sorafenib group and placebo group;
  • a longer median time to progression in Sorafenib-treated patients than those randomised to placebo (11.1 months vs. 5.8 months, respectively; HR=0.56 95% CI: 0.43-0.72; p<0.0001);
  • a higher disease control rate in Sorafenib-treated patients than in the placebo-treated group (86.2% vs. 74.6%; p=0.0015; 95% CI: 80.6%-90.7%);
  • a larger response rate in the Sorafenib group (12.2%) than in the placebo group (0.5%); the difference between the groups was 11.8% (95% CI: 7.0%-16.5%; p<0.0001).


  • a higher frequency of adverse events (mainly skin and subcutaneous tissue disorders and gastrointestinal disorders) in the Sorafenib group (204 patients; 98.6%) than in the placebo group (183 patients; 87.6%);
  • a higher incidence of serious adverse events among Sorafenib-treated patients (37.2%) than in those treated with placebo (26.3%).

Quality of life

  • health-related quality of life (assessed at baseline, during treatment, and at the end of treatment) showed a small but statistically significant difference in favour of the placebo.


This EUnetHTA-review searched extensively for RCTs on Sorafenib for radioiodine refractory thyroid cancers, but could include only 1 placebo-controlled trial with 417 patients.
Sorafenib increases progression free survival by 5 months, but other efficacy endpoints showed less convincing or no improvement; moreover the trial showed that patients in the Sorafenib group experienced worse quality of life and encountered a larger number of (severe) adverse events.
Further research is warranted before its routine use in clinical practice.


1. EUnetHTA. Sorafenib for the treatment of progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine. ID: SA-[3]. EUnetHTA; 2015.
2. La Vecchia C, Malvezzi M, Bosetti C, Garavello W, Bertuccio P, Levi F, et al. Thyroid cancer mortality and incidence: a global overview. Int J Cancer. 2015;136(9):2187-95.
3. Van den Bruel A, Francart J, Dubois C, Adam M, Vlayen J, De Schutter H, et al. Regional variation in thyroid cancer incidence in Belgium is associated with variation in thyroid imaging and thyroid disease management. J Clin Endocrinol Metab. 2013;98(10):4063-71.
4. Huang TW, Lai JH, Wu MY, Chen SL, Wu CH, Tam KW. Systematic review of clinical practice guidelines in the diagnosis and management of thyroid nodules and cancer. BMC Med. 2013;11:191.
5. Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384(9940):319-28.

published on 16-11-2015