Treatment Advances for Metastatic Thyroid Cancer: Paradigm Shift Underway

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Thyroid cancer metastases / Science Source
Thyroid cancer metastases / Science Source

Significant advances have occurred in the treatment of thyroid cancer over the past few years, leading to a paradigm shift now in how healthcare professionals evaluate and manage their patients with advanced disease.

“We are most definitely in a new era.  There are new targeted therapies that are showing good effects, and there is no question that patients with advanced disease now have a range of new options to treat their disease,” said James Fagin, MD, Chief of Endocrinology Service at Memorial Sloan-Kettering Cancer Center, New York, NY.

Post-Radioactive Iodine Therapy Failure: Researching Alternatives

An estimated 56,000 new cases of thyroid cancer are diagnosed in the United States each year, and about 5% of patients eventually develop distant metastatic disease.  Dr. Fagin added that the 10-year survival rate for patients with metastatic tumors who fail to respond to radioactive iodine therapy (RAI), the most effective treatment for the disease, is approximately 10%. He and his colleagues have now found that an experimental agent called selumetinib may allow some patients with advanced thyroid cancer to overcome resistance to RAI.

Previous studies have shown that the ability of a cell to absorb RAI is controlled by the MAPK pathway. Dr. Fagin and his colleagues have found that selumetinib, an MAPK inhibitor, can reverse radioiodine resistance by inhibiting the signaling of genetic mutations in this pathway. (Related: Selumetinib Ups Radioiodine Uptake in Thyroid Cancer). The approach proved effective, especially in patients with thyroid cancers that contain mutations in this pathway.1  

Following a 5-day low-iodine diet, the researchers administered selumetinib to 20 patients with tumors resistant to RAI. After 4 weeks, patients underwent a diagnostic scan that measured how much RAI their tumors would absorb.  In eight patients, including five with an NRAS gene mutation, selumetinib increased iodine uptake enough to allow patients to undergo RAI therapy.

The researchers found that following RAI therapy, five patients had confirmed partial responses and three had stable disease.  In seven of the eight patients, outcomes remained unchanged during 6 months of follow-up.  The researchers found that all eight patients had a decreased level of serum thyroglobulin, a protein used to screen for advanced thyroid cancer, and none experienced serious side effects from selumetinib.

“The patients tended to be fatigued.  Some patients developed a rash and a few had diarrhea; however, all the patients managed to complete the 4 weeks of treatment. So, I would say overall [selumetinib] was quite well tolerated,” said Dr. Fagin in an interview with ChemotherapyAdvisor.com. The advantage with this therapeutic strategy, added Dr. Fagin, is that it appears to elicit a significant clinical effect with only a short course of therapy. 

Currently, a larger, international, multicenter phase 3 trial with selumetinib is underway to determine its effect on a broader range of advanced thyroid cancer subtypes.

Sorafenib Showing Promise in Locally Advanced and Metastatic Thyroid Cancer

A randomized phase 3 study has found that the targeted drug sorafenib (Nexavar®) may be able to stall disease progression by 5 months in patients with metastatic differentiated thyroid cancer that has progressed despite RAI therapy.2 This is the first time a kinase inhibitor had been assessed for this indication in a large clinical trial.  If approved by the U.S. Food and Drug Administration (FDA), sorafenib would become the first new active drug for this form of thyroid cancer in 40 years.

“After having no effective agents for this patient population, it is very exciting to have an oral agent that may significantly improve progression-free survival (PFS),” said Marcia Brose, MD, PhD, of the University of Pennsylvania, Philadelphia, PA, and lead author of the study.

Differentiated thyroid cancer is the most common subtype of thyroid cancer, and approximately 5% to 15% of patients with this type of thyroid cancer develop RAI resistance, according to Dr. Brose and her colleagues. Currently, the only approved treatment for these patients is doxorubicin, but it is rarely used due to its low efficacy and high toxicity. 

In this study, 417 patients (median age, 63 years) were randomly assigned to receive sorafenib or placebo.  All the patients had RAI-resistant differentiated thyroid cancer and were allowed to cross over to the sorafenib arm upon disease progression. The researchers found that the median PFS was 10.8 months in the sorafenib arm compared with 5.8 months in the placebo arm. 

Tumor shrinkage of 30% or greater was observed in 12.2% of patients in the sorafenib arm compared with 0.5% in the placebo arm.  Overall, 42% of the patients in the sorafenib arm had stable disease for 6 months or longer.2 

Combination Everolimus and Sorafenib May Benefit Patients with Metastatic Thyroid Cancer

Recently, researchers have been combining sorafenib with everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of metastatic thyroid cancer and have obtained promising results.3 The study showed that this drug combination was especially promising in Hurthle cell and medullary subgroups, two subgroups that had not previously responded well to sorafenib alone.

The Future of Thyroid Cancer Management

Loren Michel, MD, who is a thyroid cancer expert at Washington University School of Medicine, St. Louis, MO, said thyroid cancer is not one disease but actually several.  Dr. Michel noted that metastatic disease has been highly lethal with very limited treatment options until now.

“What we are witnessing is the payoff of decades of investment by the federal government in basic biomedical research. This has enabled researchers to identify the specific lesions and pathways driving tumor growth and pharmaceutical companies to use their knowledge of chemistry to target these pathways. The result: modern drugs that are more efficacious and less toxic than conventional chemotherapies,” Dr. Michel told ChemotherapyAdvisor.com.

John Olson, MD, Professor of Surgery and Chief of Surgical Oncology at the University of Maryland Medical Center, Baltimore, MD, has treated hundreds of patients with thyroid cancer.  According to Dr. Olson, it is unlikely that one agent will provide a complete cure for patients with metastatic disease.

He noted that additional treatment options have yet to be developed for use as second-line agents and beyond, but that may be changing.  “I think we are certainly getting pointed in that direction,” Dr. Olson said in an interview with ChemotherapyAdvisor.com.  “I think we are making incremental gains, but there is no magic bullet at the moment.”



References

1. Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013 Feb 14;368(7):623-32.

2. Brose MS, Nutting C, Jarzab B, et al.  Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial. J Clin Oncol 31, 2013 (suppl; abstr 4).

3. Sherman EJ, Ho AL, Fury MG, et al. Phase II study of everolimus and sorafenib for the treatment of metastatic thyroid cancer. J Clin Oncol 31, 2013 (suppl; abstr 6024).

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