Cancer Genetics Unit, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
Nat Rev Endocrinol. 2011 Aug 23;7(10):617-24. doi: 10.1038/nrendo.2011.141.
Thyroid cancer typically has a good outcome following standard treatments, which include surgery, radioactive iodine ablation and treatment with TSH-suppressive levothyroxine. Thyroid cancers that persist or recur following these therapies have a poorer prognosis. Activation of mitogenic and angiogenic signaling pathways occurs in these cancers, and preclinical models have shown that inhibition of key kinase steps in these pathways can have antitumoral effects. Several of these kinase inhibitors have now been tested in phase II and phase III trials, with modestly encouraging results. Some promising data exist for the use of vandetanib (also known as ZD6474), motesanib, axitinib, cabozantinib (also known as XL184), sorafenib, sunitinib, pazopanib and lenvatinib (also known as E7080) in progressive thyroid cancer of medullary, papillary and follicular subtypes. These drugs are generally well-tolerated, although dose-limiting toxicities are common, and a few (probable) treatment-related deaths have been reported. Additional phase III trials will be needed to conclusively show that treatment benefit exceeds risk. Drug resistance can occur via activation of alternate mitogenic signals (pathway switching), as has been reported for the use of kinase inhibitors in other malignancies, such as melanoma. The hypothesis that combinations of kinase inhibitors targeting different pathways might produce better results is currently being tested in several clinical trials.
甲状腺癌在接受标准治疗后（包括手术、放射性碘消融和甲状腺刺激素抑制性左甲状腺素治疗）通常预后良好。这些治疗后持续存在或复发的甲状腺癌预后较差。这些癌症中存在有丝分裂原和血管生成信号通路的激活，临床前模型表明，抑制这些通路中的关键激酶步骤可产生抗肿瘤作用。目前已经在 II 期和 III 期临床试验中对几种这些激酶抑制剂进行了测试，结果略有令人鼓舞。在进展性甲状腺髓样癌、甲状腺乳头状癌和甲状腺滤泡癌中，使用凡德他尼（也称为 ZD6474）、莫特塞尼布、阿昔替尼、卡博替尼（也称为 XL184）、索拉非尼、舒尼替尼、帕唑帕尼和仑伐替尼（也称为 E7080）已有一些有前景的数据。这些药物通常耐受性良好，尽管常见剂量限制毒性，并且已经报道了一些（可能）与治疗相关的死亡。还需要进行额外的 III 期试验，以明确表明治疗益处超过风险。正如在其他恶性肿瘤（如黑色素瘤）中使用激酶抑制剂所报道的那样，通过激活替代有丝分裂原信号（途径转换）可能会发生耐药性。目前正在几项临床试验中测试针对不同途径的激酶抑制剂联合使用可能产生更好结果的假设。
