Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Thyroid. 2010 Sep;20(9):975-80. doi: 10.1089/thy.2010.0057.
Currently, there is no standard treatment for metastatic anaplastic thyroid cancer (ATC). DNA microarray analysis has shown platelet-dervived growth factor receptor (PDGFR) overexpression in ATC relative to well-differentiated thyroid cancer. In p53-mutated/deficient ATC cell lines, cABL is overexpressed, and selective inhibition of cABL results in a cytostatic effect. Imatinib inhibits tyrosine kinase activity of Bcr-ABL and PDGF. We hypothesize that patients with ATC that over-expresses PDGF receptors or cABL will respond to imatinib.
Patients with histologically confirmed ATC who had measurable disease and whose disease expressed PDGF receptors by immunohistochemistry were eligible for study. Imatinib was administered at 400 mg orally twice daily without drug holiday. Response to treatment was assessed every 8 weeks. Patients with complete response, partial responses, or stable disease were treated until disease progression. The study was terminated early due to poor accrual.
From February 2004 to May 2007, 11 patients were enrolled and were started on imatinib. At baseline, 4/11 had locoregional disease, 5/11 had distant metastases, and 2/11 had both. Nine of 11 had prior chemoradiation, and 7/11 had thyroidectomy. Eight of 11 were evaluable for response; 4 were excluded for lack of follow-up with radiologic evaluation. The overall response rates at 8 weeks were complete response 0/8, partial response 2/8, and stable disease 4/8. The median time to follow-up was 26 months (ranges 23-30 months). The rate of 6-month progression-free survival was 36% (95% confidence interval, 9%-65%). The rate of 6-month overall survival was 45% (95% confidence interval, 16%-70%). The most common grade 3 toxicity was edema in 25%; other grade 3 toxicities included fatigue and hyponatremia (12.5% each). There were no grade 4 toxicities or treatment related deaths.
Imatinib appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing patients with a rare malignancy at a single institution, further investigation of imatinib in ATC may be warranted in a multi-institutional setting.
目前，转移性间变性甲状腺癌（ATC）尚无标准治疗方法。DNA 微阵列分析显示，与分化良好的甲状腺癌相比，血小板衍生生长因子受体（PDGFR）在 ATC 中过度表达。在 p53 突变/缺失的 ATC 细胞系中，cABL 过度表达，选择性抑制 cABL 可产生细胞抑制作用。伊马替尼抑制 Bcr-ABL 和 PDGF 的酪氨酸激酶活性。我们假设，PDGF 受体或 cABL 过度表达的 ATC 患者将对伊马替尼有反应。
符合研究条件的患者为经组织学证实的 ATC 患者，且其疾病的免疫组织化学检查结果显示 PDGF 受体可测量。伊马替尼以 400mg 口服，每日两次，无药物假期。每 8 周评估一次治疗反应。完全缓解、部分缓解或病情稳定的患者在疾病进展前接受治疗。由于入组人数较少，该研究提前终止。
从 2004 年 2 月至 2007 年 5 月，共有 11 名患者入组并开始服用伊马替尼。基线时，4/11 例有局部区域疾病，5/11 例有远处转移，2/11 例同时存在。9/11 例患者有既往放化疗，7/11 例有甲状腺切除术。8/11 例可评估反应；4 例因缺乏放射学评估随访而被排除。8 周时的总体反应率为完全缓解 0/8，部分缓解 2/8，稳定疾病 4/8。中位随访时间为 26 个月（范围 23-30 个月）。6 个月无进展生存率为 36%（95%置信区间，9%-65%）。6 个月总生存率为 45%（95%置信区间，16%-70%）。最常见的 3 级毒性是水肿（25%）；其他 3 级毒性包括疲劳和低钠血症（各 12.5%）。无 4 级毒性或治疗相关死亡。
伊马替尼似乎对晚期 ATC 有效，且耐受性良好。由于在单一机构中招募罕见恶性肿瘤患者存在困难，可能需要在多机构环境中进一步研究伊马替尼在 ATC 中的应用。
