Tuesday, April 16, 2013

Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer — NEJM

Now this sounds interesting!  I hope the study is expanded.


Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium–iodide symporter and uptake of iodine. Their effects in humans are not known.


We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib.


Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients withBRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia.


Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.)
Supported by grants from the American Thyroid Association, the Society of Memorial Sloan-Kettering Cancer Center, the National Institutes of Health (RO1-CA50706 and RO1-CA72598), AstraZeneca, and Genzyme, as well as funding from the Lefkofsky Family, Margot Rosenberg Pulitzer, Byrne, and J. Randolph Hearst foundations. The iodine-124 PET studies were supported in part by a grant from the In-Vivo Cellular and Molecular Imaging Center (P50 086438-10). Dr. Domínguez was supported in part by a grant from Pontificia Universidad Católica de Chile and Becas Chile (76100021), and Dr. Deandreis by a grant from Fondation de France (2010-12521).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the research study staff, particularly Susan Korte, Alex F. Mak, Brynna Lipson, Donna Lisa, and Lisa Cox, R.N.


From the Head and Neck Oncology Service (A.L.H., E.J.S., D.G.P.) and the Endocrinology Service (R.L., R.M.T., J.A.F.), Department of Medicine, and the Departments of Radiology (R.K.G., D.D., S.H., S.G., S.M.L.), Medical Physics (K.S.P., P.B.Z.), Pathology (R.A.G.), and Human Oncology and Pathogenesis (J.C.R.-F., J.M.D., J.A.F.), and the Epidemiology–Biostatistics (R.S.) and Molecular Pharmacology and Chemistry (S.M.L.) Programs, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York.
Address reprint requests to Dr. Fagin at the Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065.

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