Novel Agent Nixes Radioiodine Resistance in Thyroid Cancer

Roxanne Nelson

February 13, 2013

An investigational agent may allow some patients with metastatic thyroid cancer to overcome resistance to radioiodine, according to a new report from researchers at Memorial Sloan-Kettering Cancer Center in New York.

The product, selumetinib (under development by AstraZeneca) is being investigated in a number of different cancer types.

In this study, it was investigated in 20 patients with thyroid cancer who had been treated with radioiodine, but who had become resistant to the treatment.

Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients included in the study, with 8 reaching the dosimetry threshold for radioiodine therapy. Within this subgroup, 5 experienced a confirmed partial response and 3 had stable disease, and all 8 patients showed declines in serum thyroglobulin levels (mean reduction, 89%; P = .004).

The results are published in the February 14 issue of the New England Journal of Medicine.

Mainstay of Treatment

Radioiodine (iodine-131) is a mainstay of therapy for patients with metastatic thyroid cancer of follicular origin, but many have tumors that do not concentrate iodine. This results in radioiodine resistance and a poor prognosis. "There has been about 20 years of effort trying to overcome radioiodine resistance in metastatic thyroid cancers, but none have been successful," said senior author James A Fagin, MD, endocrinology service chief at Memorial Sloan-Kettering.

"This study is based on observations that we made in the lab, which showed that the different oncogenic events associated with thyroid cancer, that activate MAPK signaling, are directly responsible for decreasing the ability of the thyroid cancer cells to trap iodine," he said in an interview with Medscape Medical News. "So if we can block that particular pathway with drugs like selumetinib, you can alter that process."

The second important part of the study, he said, is use of technology for precise quantification of iodine uptake before and after selumetinib treatment in individual metastatic lesions (lesional dosimetry). In this study, the researchers used serial iodine-124 positron-emission tomography (PET)-computed tomography (CT) rather than traditional whole-body iodine-131 scintigraphy.

"We really proved in a convincing way that when you pretreat patients with selumetinib, we could see true measurable quantitative differences in the metastatic lesions before and after treatment," Dr. Fagin explained.

"The final point that really makes this an important study is that we were able to predict the amount of radiation that each tumor deposit would receive by using this quantitative dosimetry approach," he added. "We set a threshold and we were only going to treat patients with a therapeutic dose if they met that threshold, and all patients who met that had a good clinical response."

Study Details

In this study, Dr. Fagin and colleagues sought to determine if treatment with selumetinib could reverse radioiodine resistance in patients with metastatic thyroid cancer.

A total of 20 patients were referred to the study between August 2010 and December 2011 and were available for evaluation. Within this cohort, 5 patients (25%) had classic papillary thyroid cancer, 8 (40%) had tall-cell-variant papillary thyroid cancer, and 7 (35%) had poorly differentiated carcinoma.

After following a low-iodine diet for 5 days, patients underwent a thyrotropin alfa-stimulated iodine-124 PET-CT study and then received selumetinib at a dose of 75 mg given orally twice daily for 4 weeks. At 4 weeks, patients underwent a second iodine-124 PET-CT study, and discontinued the study if the second scan showed no increase in iodine uptake to a prespecified dosimetry threshold (predicted to be 2000 cGy or greater).

Patients continued to receive selumetinib and a low-iodine diet if the dosimetry threshold was met, and thyrotropin alfa-stimulated whole-body and blood dosimetry studies were performed to determine the maximum tolerable activity. When the maximum tolerable activity was determined, a therapeutic dose of iodine-131 was administered after stimulation with thyrotropin alfa. Selumetinib was then continued until 2 days after ingestion of therapeutic iodine-131.

There were 12 patients (60%) who had iodine-124 uptake that was new, increased, or both after treatment with selumetinib.

In 8 patients (40%), the second iodine-124 PET scan indicated that the absorbed radiation dose in the lesion would equal or exceed 2000 cGy with 300 mCi of radioiodine or less, and continued to receive selumetinib and therapeutic radioiodine.

All adverse events that could be attributed to selumetinib were grade 1 or 2, and this was consistent with events reported in larger studies, the researchers comment. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, which eventually progressed to acute leukemia.

Upcoming Trial

"There is going to be an international, multicenter phase III clinical trial of selumetinib that Memorial Sloan-Kettering will be leading," Dr. Fagin said. "We will hopefully begin enrolling later this year, and will include patients at an earlier stage of the disease."

This study was conducted in patients with metastatic disease, but the upcoming trial will be a cohort of patients who have undergone a total thyroidectomy and are considered to be at high risk. "We know that this population doesn't respond well to radioactive iodine," he said. "Our goal is to use selumetinib as an adjuvant therapy, and send more patients into remission and hopefully cure them."

The study was supported by grants from the American Thyroid Association, The Society of Memorial Sloan-Kettering Cancer Center, the National Institutes of Health, AstraZeneca, and Genzyme.

N Engl J Med. 2013;368:623-632. Abstract