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Sorafenib Improves Progression-Free Survival in Some Patients with Metastatic Thyroid Cancer


Results from an international phase III trial show that sorafenib (Nexavar®) may benefit  patients with locally advanced or metastatic differentiated thyroid cancer that is no longer responding to treatment with radioactive iodine. Patients who were treated with sorafenib lived longer without their cancers getting worse than patients who received a placebo.


The Lancet, April 24, 2014. (See the journal abstract.)


Approximately 95 percent of thyroid cancers are classified as either the papillary or the follicular type, both of which arise from follicular cells of the thyroid. The cells of these tumors are well differentiated (that is, they appear similar to normal thyroid cells) and tend to grow more slowly than cells of the rarer, more aggressive medullary and anaplastic types of thyroid cancer. Both papillary and follicular thyroid cancers are considered highly treatable; they respond well to standard treatment, which includes surgery and radioactive iodine therapy.

A small percentage of patients with differentiated thyroid cancer, however, develop metastatic disease that does not respond to treatment with radioactive iodine (refractory disease). The treatment options for patients who develop radioactive iodine-refractory metastatic disease are very limited. No therapy has been shown to extend the survival of these patients; only 10 to 20 percent of patients with radioactive iodine-refractory metastatic disease are still alive 10 years after diagnosis.

Laboratory studies have identified several changes in tumor cells that are associated with the development and progression of thyroid cancer. These include mutations in the BRAF and RAS genes that lead to chronic activation of their protein products (cell growth-promoting kinases), and increased production of vascular endothelial growth factor (VEGF), a protein that stimulates the development of new blood vessels needed to support tumor growth, and its receptors, the VEGFRs.

Sorafenib, a drug approved by the Food and Drug Administration (FDA) to treat some patients with kidney and liver cancer, inhibits the activities of the VEGFR and B-RAF proteins. Moreover, several early-phase clinical trials suggested that sorafenib may be effective in treating patients with radioactive iodine-refractory metastatic thyroid cancer.

The Study

The randomized, double-blind, placebo-controlled DECISION trial enrolled 417 patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed in the prior 14 months. This international trial included patients with papillary, follicular, and poorly differentiated disease from Europe, Asia, and the United States.

Participants were randomly assigned to receive 400 mg of sorafenib taken orally twice daily or a placebo. Patients assigned to the placebo group whose disease progressed during the trial could "cross over" and receive sorafenib.

The primary endpoint of the trial was the length of time patients lived after starting treatment without their disease getting worse (progression-free survival), as assessed by independent review. Secondary endpoints included overall survival and objective response rate.

The trial was led by Marcia Brose, M.D., Ph.D., of the University of Pennsylvania Abramson Cancer Center. Bayer Healthcare Pharmaceuticals and Onyx Pharmaceuticals funded the trial.


Progression-free survival was statistically significantly longer in patients treated with sorafenib than in those who received a placebo: 10.8 months versus 5.8 months. This benefit in progression-free survival was observed regardless of patient age, the extent of disease, or the sites of metastases.

None of the patients had a complete response. The objective response rate—the percentage of patients whose tumors had measurable reductions in size following treatment—was 12 percent in the sorafenib group and less than 1 percent in the placebo group.

Overall survival did not differ between the patients treated with sorafenib and those who received a placebo. Among patients with no objective response, nearly 42 percent in the sorafenib group had stable disease for at least 6 months after beginning treatment, compared with 33 percent of those in the placebo group.

Approximately 70 percent of patients in the trial’s placebo group crossed over and began receiving sorafenib when their cancer began to progress.

Information on BRAF and RAS mutations in the patients' tumor tissue was available for 61 percent of all patients in the trial (126 patients in the sorafenib group and 130 patients in the placebo group). Mutations in these genes were not associated with longer progression-free survival in patients treated with sorafenib.

Nearly all of the patients treated with sorafenib experienced side effects. The side effects were mainly low-grade and included hand-foot skin reactions, diarrhea, skin rash, fatigue, and hair loss. Nevertheless, nearly two-thirds of patients in the sorafenib group had their treatment temporarily halted or the drug dose reduced, and nearly 19 percent stopped treatment altogether because of side effects.

Approximately 37 percent of the patients in the sorafenib group and 26 percent of the patients in the placebo group had a serious adverse event. Serious adverse events in the sorafenib group included the development of a second primary cancer, difficulty breathing, and pleural effusion. One death, caused by a heart attack, was also attributed to sorafenib.

On November 22, 2013, the FDA approved sorafenib for the treatment of patients with radioactive iodine-refractory metastatic differentiated thyroid cancer based on results from the DECISION trial.


Having a new FDA-approved drug for patients with radioactive iodine-refractory metastatic thyroid cancer "is good news for patients," said Electron Kebebew, M.D., an expert on endocrine cancers at NCI's Center for Cancer Research.

But, he noted, sorafenib can have substantial side effects and, in some patients with radioactive iodine-refractory metastatic thyroid cancer, the disease progresses slowly and immediate treatment may not be necessary. To help guide clinical decision making, he suggested, "it would have been good to know how rapidly the disease progressed in these patients, and whether those with the most rapidly progressive disease were more likely to respond to treatment given that there were no complete responses and only 12 percent had a partial response."

Although it is important to delay disease progression, Dr. Kebebew continued, it is unclear whether sorafenib improves overall survival. "That's important information to patients and clinicians," he said.


The results of the DECISION trial "establish a new standard of care for progressive radioactive iodine-refractory differentiated thyroid cancer," wrote Sigurdis Haraldsdottir, M.D., and Manisha Shah, M.D., of the Ohio State University Comprehensive Cancer Center, in an accompanying comment in The Lancet.

Because so many patients in the placebo group crossed over and began receiving sorafenib, they continued, the "absence of a benefit in overall survival is not surprising."

Overall, Drs. Haraldsdottir and Shah noted, the side effects seen in the DECISION trial were consistent with those experienced with sorafenib in other clinical trials. "[C]linicians should be aware of the class effects" of drugs like sorafenib that target multiple kinases, they cautioned.

These effects can include "rare serious toxicities such as bleeding, thromboembolism, bowel perforation, and left ventricle dysfunction," Drs. Haraldsdottir and Shah explained. "Close monitoring, early recognition, and management of adverse events are therefore essential when patients are being treated with sorafenib."

Finding the right balance between treatment and side effects is required when using sorafenib in these patients, Dr. Kebebew stressed. "You have to find a threshold," he said, "because when you’re looking at a drug with this side-effect profile, you may want to delay using it until the disease is progressing rapidly."

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