Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer.
Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer.
复制标题
DOI：
10.1056/nejmoa1209288
复制
发表时间：
2013-02-14
期刊：
影响因子：
--
通讯作者：
Fagin JA
中科院分区：
文献类型：
--
作者：
Ho AL;Grewal RK;Leboeuf R;Sherman EJ;Pfister DG;Deandreis D;Pentlow KS;Zanzonico PB;Haque S;Gavane S;Ghossein RA;Ricarte-Filho JC;Domínguez JM;Shen R;Tuttle RM;Larson SM;Fagin JA
在甲状腺癌的小鼠模型，选择性有丝分裂因素激活的蛋白激酶（MAPK）途径中，对放射性碘的转移性癌（碘131）与预后不良有关。碘在人类中的影响不知道。
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-发射断层扫描（PET）是在用Selumetinib治疗后4周（每天两次）进行的4周。 PET研究表明，可以将2000 CGY或更多CGY的碘131剂量递送到转移性病变或病变，当患者接受塞鲁前替尼时，给予治疗性放射碘。
在筛查研究的24名患者中，可以评估20个年龄。 Selumetinib增加了20例患者中的12例碘124次的摄取（BRAF突变患者中的4例，5例NRAS突变中的5例）。达到放射性碘治疗的剂量阈值，包括所有5例NRA突变患者。 。放射碘治疗后51周，进展为急性白血病。
Selumetinib在甲状腺疾病的甲状腺癌中产生碘摄入量的有意义，并保留了甲状腺癌的亚组。编号，NCT00970359。
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 with BRAF 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.)