De Leo Simone, Trevisan Matteo, Fugazzola Laura
Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Piazzale Brescia, 20, 20149, Milan, Italy.
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
Thyroid Res. 2020 Nov 24;13(1):17. doi: 10.1186/s13044-020-00091-w.
Anaplastic thyroid cancer (ATC) is undoubtedly the thyroid cancer histotype with the poorest prognosis. The conventional treatment includes surgery, radiotherapy, and conventional chemotherapy. Surgery should be as complete as possible, securing the airway and ensuring access for nutritional support; the current standard of care of radiotherapy is the intensity-modulated radiation therapy; chemotherapy includes the use of doxorubicin or taxanes (paclitaxel or docetaxel) generally with platin (cisplatin or carboplatin). However, frequently, these treatments are not sufficient and a systemic treatment with kinase inhibitors is necessary. These include multitarget tyrosine kinase inhibitors (Lenvatinib, Sorafenib, Sunitinib, Vandetanib, Axitinib, Pazopanib, Pyrazolo-pyrimidine compounds), single target tyrosine kinase inhibitors (Dabrafenib plus Trametinib and Vemurafenib against BRAF, Gefitinib against EGFR, PPARγ ligands (e.g. Efatutazone), Everolimus against mTOR, vascular disruptors (e.g. Fosbretabulin), and immunotherapy (e.g. Spartalizumab and Pembrolizumab, which are anti PD-1/PD-L1 molecules). Therapy should be tailored to the patients and to the tumor genetic profile. A BRAF mutation analysis is mandatory, but a wider evaluation of tumor mutational status (e.g. by next-generation sequencing) is desirable. When a BRAF mutation is detected, treatment with Dabrafenib and Trametinib should be preferred: this combination has been approved by the Food and Drug Administration for the treatment of patients with locally advanced or metastatic ATC with BRAF mutation and with no satisfactory locoregional treatment options. Alternatively, Lenvatinib, regardless of mutational status, reported good results and was approved in Japan for treating unresectable tumors. Other single target mutation agents with fair results are Everolimus when a mutation involving the PI3K/mTOR pathway is detected, Imatinib in case of PDGF-receptors overexpression, and Spartalizumab in case of PD-L1 positive tumors. Several trials are currently evaluating the possible beneficial role of a combinatorial therapy in ATC. Since in this tumor several genetic alterations are usually found, the aim is to inhibit or disrupt several pathways: these combination strategies use therapy targeting angiogenesis, survival, proliferation, and may act against both MAPK and PI3K pathways. Investigating new treatment options is eagerly awaited since, to date, even the molecules with the best radiological results have not been able to provide a durable disease control.
间变性甲状腺癌（ATC）无疑是预后最差的甲状腺癌组织学类型。传统治疗方法包括手术、放疗和传统化疗。手术应尽可能彻底，确保气道安全并保证营养支持途径；目前放疗的标准治疗方法是调强放射治疗；化疗通常包括使用阿霉素或紫杉烷类（紫杉醇或多西他赛）以及铂类（顺铂或卡铂）。然而，这些治疗方法常常并不充分，因此需要使用激酶抑制剂进行全身治疗。这些抑制剂包括多靶点酪氨酸激酶抑制剂（乐伐替尼、索拉非尼、舒尼替尼、凡德他尼、阿昔替尼、帕唑帕尼、吡唑并嘧啶化合物）、单靶点酪氨酸激酶抑制剂（达拉非尼联合曲美替尼以及针对BRAF的维莫非尼、针对EGFR的吉非替尼、PPARγ配体（如依伐他汀）、针对mTOR的依维莫司、血管破坏剂（如福斯可林）以及免疫疗法（如抗PD - 1/PD - L1分子的斯帕妥珠单抗和帕博利珠单抗）。治疗应根据患者和肿瘤基因谱进行调整。BRAF突变分析是必需的，但更广泛地评估肿瘤突变状态（如通过二代测序）则更佳。当检测到BRAF突变时，应优先选择达拉非尼和曲美替尼进行治疗：这种联合用药已被美国食品药品监督管理局批准用于治疗局部晚期或转移性BRAF突变且局部区域治疗选择不佳的ATC患者。或者，无论突变状态如何，乐伐替尼都取得了良好效果，并在日本被批准用于治疗不可切除的肿瘤。其他取得一定效果的单靶点突变药物包括检测到PI3K/mTOR途径突变时使用的依维莫司、血小板衍生生长因子受体过表达时使用伊马替尼以及PD - L1阳性肿瘤时使用的斯帕妥珠单抗。目前有多项试验正在评估联合治疗在ATC中的潜在益处。由于在这种肿瘤中通常会发现多种基因改变，其目的是抑制或阻断多种途径：这些联合治疗策略使用针对血管生成、生存、增殖的治疗方法，可能同时作用于MAPK和PI3K途径。由于迄今为止，即使是放射学效果最佳的分子也未能实现持久的疾病控制，因此人们急切期待研究新的治疗方案。
