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.

From the National Cancer Institute