Head and Neck Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY 10065, USA.
N Engl J Med. 2013 Feb 14;368(7):623-32. doi: 10.1056/NEJMoa1209288.
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.).
对放射性碘（碘-131）难治的转移性甲状腺癌预后不良。在甲状腺癌的小鼠模型中，选择性丝裂原活化蛋白激酶（MAPK）通路拮抗剂可增加钠碘转运体的表达和碘的摄取。其在人类中的效果尚不清楚。
我们进行了一项研究，以确定 MAPK 激酶（MEK）1 和 MEK2 抑制剂 selumetinib（AZD6244， ARRY-142886）是否可以逆转转移性甲状腺癌患者对放射性碘的耐药性。在用促甲状腺素 alfa 刺激后，在接受 selumetinib（75mg，每日两次）治疗前和 4 周后进行碘-124 正电子发射断层扫描（PET）剂量测定。如果第二次碘-124 PET 研究表明转移性病变或病变可接受 2000cGy 或更高剂量的碘-131，则在接受 selumetinib 治疗的同时给予放射性碘治疗。
在 24 名接受研究筛选的患者中，有 20 名可进行评估。中位年龄为 61 岁（范围为 44 至 77 岁），11 名男性。9 名患者的肿瘤有 BRAF 突变，5 名患者的肿瘤有 NRAS 突变。Selumetinib 增加了 20 名患者中的 12 名（4 名有 BRAF 突变的患者和 5 名有 NRAS 突变的患者）的碘-124 摄取。这 12 名患者中有 8 名达到了放射性碘治疗的剂量阈值，包括所有 5 名有 NRAS 突变的患者。在接受放射性碘治疗的 8 名患者中，5 名有确认的部分缓解，3 名有稳定的疾病；所有患者的血清甲状腺球蛋白水平均下降（平均下降 89%）。没有观察到研究人员归因于 selumetinib 的 3 级或更高级别的毒性作用。1 名患者在接受放射性碘治疗后 51 周以上被诊断为骨髓增生异常综合征，并进展为急性白血病。
Selumetinib 可使一组对放射性碘难治的甲状腺癌患者的碘摄取和保留量产生有临床意义的增加；在 RAS 突变疾病患者中，疗效可能更大。（由美国甲状腺协会和其他机构资助；ClinicalTrials.gov 编号，NCT00970359。）
