Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial

Reporter: J Taylor Whaley, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2013

Presenter: Marcia S. Brose, MD
Presenter's Affiliation: Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA

  • Thyroid cancer is fairly common, and is the 6th most common cancer in women; however, death due to thyroid cancer is uncommon, with fewer than 1500 deaths per year.
  • In recent years, the incidence of thyroid cancer, the most common type of endocrine cancer, has increased in both the United States and globally.
  • There are 3 major categories of thyroid cancer with differentiated being the most common type by far. Papillary, follicular, Hurthle cell, and undifferentiated types are all considered differentiated thyroid cancers.
  • Although the vast majority of thyroid cancers are small and curable by surgery and radioactive iodine, 5-10% of patients develop resistance with 2.5-3.5 year survival. Therefore, patients with locally advanced and metastatic radioactive iodine-refractory (RAI) tumors present a challenge that is associate with poor long-term survival.
  • For the past 40 years, no standard of care has existed. In fact, patients rarely saw medical oncologists because the only drug approved by the FDA for radioactive iodine-refractory disease was doxorubicin, considered too toxic for effective treatment.
    • There is thus a clear a need for novel therapeutics in this subset of patients.
    • Thyroid cancers are known to have a high rate of vascular endothelial growth factor (VEGF) expression and are highly vascular.
    • Sorafenib is an orally active, small molecular multi-kinase inhibitor of several kinases, including VEGFR1-3 and Raf kinases. It has shown promising clinical activity in single-arm phase II studies in radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). In those trials, 15-23% response rates were seen with median progression free survival of 12 months.
  • In preliminary results from another trial, 27% of patients with papillary and 43% of patients with follicular thyroid cancer had some response. Progression free survival was 84 weeks. Of 32 patients with progressive, radioiodine-negative differentiated thyroid cancer treated with sorafenib for 26 weeks, 25% of patients had a partial response, 34% had stable disease, and 22% had progressive disease. Median progression free survival was 14.5 months.
  • The current Phase III DECISION trial was undertaken to evaluate efficacy and safety of sorafenib as first line therapy for patients with advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer.

Materials and Methods

  • This was a double-blind, randomized, multicenter, and international phase III trial. Entry criteria were as follows:
    • Treatment naive and pathologically locally advanced or metastatic, radioactive iodine-refractory, differentiated thyroid cancer (papillary, follicular, Hurthle cell and poorly differentiated) who progressed in the preceding 14 months
    • Patients were not surgical or radiation candidates
    • ECOG PS 0-2
    • Adequate bone marrow and kidney function
    • No prior chemotherapy, tyrosine kinase inhibitors, or monoclonal antibodies that target VEGF
    • Patients were considered refractory if:
      • At least one lesion was shown to not uptake iodine
      • There was evidence of disease progression following RAI treatment
      • Patients had been treated with more than the lifetime cumulative dose of 600 mCi of RAI
    • Patients were randomized 1:1 to sorafenib 400 mg twice daily or placebo.
    • 89 centers participated in the trial
    • Placebo patients were allowed to receive sorafenib open-label upon progression.
    • The primary endpoint was progression-free survival (PFS) assessed every 8 wks by independent radiologic review using modified RECIST 1.0.
    • Secondary endpoints included overall survival (OS), response rate (RR; complete + partial response [PR]), duration of response, and safety.


    • A total of 417 patients were randomized (207 to sorafenib and 210 to placebo) 2004-09 with minimum follow-up of 24 months.
    • Median age was 63 years old. 52% of patients were female.
    • Tumor histology by independent assessment was 57% papillary, 25% follicular, and 10% poorly differentiated.
    • 96% of patients had metastatic disease; the most common target lesions were lung (71%), lymph node (40%), and bone (14%).
    • The primary endpoint was met: median PFS 10.8 months (sorafenib) vs 5.8 months (placebo); HR 0.58, p<0.0001, which is highly statistically significant.
    • Median OS has not been reached in either arm; 70% of placebo patients crossed over to start open-label sorafenib.
    • No complete responses have been documented.
    • RR (all PRs) in the sorafenib vs placebo arms was 12.2% and 0.5% (p<0.0001) and stable disease ? 6 months was 42% and 33%, respectively.
    • Median duration of response was 10 months.
    • Treatment was well-tolerated. The most common adverse events in the sorafenib arm included hand–foot skin reaction (20% Grade 3/4), diarrhea (6% Grade 3/4), alopecia, rash/desquamation (5% Grade 3/4), fatigue, weight loss and hypertension (10% Grade 3/4). One death in each arm was attributed to study drug.
    • A small percentage (4%) of patients on sorafenib developed second malignancies in the form of skin cancers, a known adverse event of the drug.
    • Eighteen percent of patients stopped sorafenib secondary to toxicity.
    • On the placebo arm, at 400 days, 25% of the patients did not progress.

    Author's Conclusions

    • The use of Sorafenib met its primary endpoint and improved progression free survival compared with placebo in patients with progressive RAI-refractory differentiated thyroid cancer.
    • Treatment was well-tolerated and consistent with the known sorafenib safety profile.
    • The DECISION trial is the first phase III trial of targeted agent for RAI refractory thyroid disease and is practice changing.

    Clinical Implications

    • The authors presented the DECISION trial, which is a randomized, placebo-controlled, phase III international study evaluating the use of Sorafenib for progressive RAI-refractory differentiated thyroid cancer. This is a new area of research for medical oncologists as there has previous been no standard of care for this disease.
    • This well-run phase III study changes the standard of care in progressive RAI-refractory differentiated thyroid cancer to include Sorafenib. The regimen was well-tolerated and provided significant benefit with clear efficacy.
    • It should be noted that 25% of patients on the placebo arm did not progress in the first year. For this reason, there appears to be a subset of patients that have indolent disease and may not need treatment; however, the ability to isolate which patients need treatment remains unclear.
    • Current studies are evaluating Lenvatinib, an alternate multi-kinase inhibitor. This trial has completed accrual. We will look forward to future phase III studies comparing the two drugs.


Smoothies for All Occasions
by OncoLink Editorial Team
May 24, 2016

From the National Cancer Institute