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Second-line Therapy with TKIs Improves Time to Progression for Refractory Thyroid Cancer

Fuerst, Mark

doi: 10.1097/01.COT.0000435379.90267.88

CHICAGO—Sequential therapy with the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib appears to be beneficial even in second-line or third-line therapy for patients with iodine-refractory differentiated thyroid carcinomas, according to a presentation here at the American Society of Clinical Oncology Annual Meeting (Abstract 6092).

“We can treat differentiated thyroid cancer patients with second-line TKI therapy with some progression-free survival (PFS). The benefits appear to be the same as first-line therapy,” Christelle de la Fouchardiere, MD, of the Department of Medical Oncology at Centre Léon Bérard in Lyon, France, said in an interview.

TKIs are currently used to treat patients with advanced iodine-refractory differentiated thyroid cancers. Sorafenib was the first such drug to receive approval by the Food and Drug Administration.



“Sometimes, patients are treated with an off-label TKI when a clinical trial is not available, or in second-line and third-line therapy,” she said.

The report was for the efficacy of “off-label” sorafenib and sunitinib treatments as first-line, second-line, and third-line therapy in metastatic differentiated thyroid cancer patients from the French TUTHYREF (TUmeurs THYroïdiennes REFractaires) network, including investigators from throughout France and Quebec. The primary endpoints of the trial were PFS and tumor response, according to sequential TKI treatments. The secondary endpoint was organ-specific metastatic site analysis.

The trial included 45 patients, mean age of 62, with advanced iodine-refractory differentiated thyroid cancer treated with off-label TKIs. The patients had papillary thyroid cancer (22 patients), follicular thyroid cancer (10 patients), and poorly differentiated thyroid cancer (13 patients).

A little more than half of the patients were treated with two lines of TKIs, and three patients received three lines of TKIs. Slightly more than half of the patients had received sorafenib, slightly less than one-quarter had received sunitinib (21.5%), and slightly less than one-quarter had received vandetanib (21.5%).

Partial responses were achieved by 29 percent of the 21 patients who had received first-line sorafenib. The partial response rate was 57 percent in the seven first-line sunitinib patients. There were no partial responses among the patients who had received second-line and third-line treatments.

However, “median PFS was similar in second-line as compared with first-line sorafenib or sunitinib treatment,” de la Fouchardiere said. First-line therapy with sorafenib led to a PFS of 7.6 months compared with 6.7 months in second-line therapy. Similarly, first-line therapy with sunitinib led to a 10.7-month PFS compared with 13.7 months in second-line therapy.

She pointed out that although the number of patients in this non-randomized trial is small, “these patients had many metastases and continued to respond to second-line therapy.” Liver metastases were the most responsive to treatment, followed by lung and lymph node metastases. Bone and pleural lesions were the most refractory to treatment, she noted.

In conclusion, de la Fouchardiere said, “Due to the small number of patients, we could not recommend a specific treatment sequence—for example, sorafenib and then sunitinib—over another—sunitinib and then sorafenib. But TKI therapy does appear to be beneficial in refractory differentiated thyroid cancer patients, even in second-line and third-line therapy, with similar PFS and stable disease as best response.”

She added: “We may need a clinical trial to compare the two drugs, as has been done in renal cancer. We now know we can use TKIs for two lines of treatment.”

Pazopanib is another drug that might be considered in combination with either sorafenib or sunitinib, she noted.

The message to practicing clinical oncologists is “to continue treatment after first-line therapy even after progression in differentiated thyroid cancer patients. The benefit for patients is about the same in second-line therapy as in first-line therapy.”

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‘Combinations May Be Particularly Helpful in Refractory Patients’

Vassiliki Papdimitrakopoulou, MD, Professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center, commented that “combinations of targeted therapies, notably sorafenib, may enhance activity and that combination strategies may be particularly useful in refractory patients.”

Phase II studies of TKIs in thyroid cancer have shown that both sorafenib and sunitinib can be effective in inducing responses, he noted. For example, a study of 30 patients with a mixture of differentiated, medullary, and anaplastic thyroid cancer who had disease progression for 12 months on other therapy found that many patients responded to sorafenib.

About one-quarter of patients had a partial response and another half had stabilized disease. The PFS of the patients was 76 weeks.

In another study, involving 33 patients with positron emission tomography-positive differentiated and medullary thyroid cancer, about one-third responded to sunitinib and about one-quarter of them had stable disease. The time to progression was 12.8 months. There may be an advantage to combine these two drugs for a better result, he said.

© 2013 by Lippincott Williams & Wilkins, Inc.
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