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甲状腺癌是最常见的头颈部内分泌系统肿瘤,近几十年来,它的发病率不断升高,位列美国女性肿瘤的第5位[1],引起人们的强烈关注。近30年,美国甲状腺癌的发病率增加了将近3倍[2]。Lim等[3]研究显示,在甲状腺癌发病率逐渐升高的同时,晚期甲状腺癌的病死率也有升高的趋势。甲状腺乳头状癌(papillary thyroid cancer,PTC)、甲状腺滤泡癌(follicular thyroid cancer,FTC)和嗜酸细胞肿瘤在一定程度上保留了甲状腺滤泡上皮的功能,称为分化型甲状腺癌(differentiated thyroid cancer,DTC),占甲状腺癌的90%以上。大多数DTC经规范化治疗[4]——手术、131I治疗、TSH抑制治疗后预后良好,5年生存率高达98%。然而,仍有一部分(<10%)DTC由于疾病侵袭性较强,很快出现远处转移。由于缺乏有效且持久的系统性治疗方法,这类患者预后较差,5年生存率低于50%,其精神健康及生存情况非常不理想,是甲状腺癌病死病例的主要部分[5]。DTC患者的病灶在无外源碘负荷干扰及TSH>30 mIU/L刺激时,131I治疗后全身显像出现下列情况之一[6]:病灶不能摄取碘、病灶部分摄取碘、病灶多次治疗逐渐丧失摄碘能力或病灶能够摄取碘但在一定时间内疾病出现进展,均称为放射性碘难治性分化型甲状腺癌(radioiodine refractory differentiated thyroid cancer,RR-DTC)。在精准医学的时代背景下,靶向治疗成为甲状腺癌治疗的研究热点。笔者旨在对RR-DTC的精准靶向治疗策略——药物靶向治疗、肽受体核素靶向治疗、局部精准治疗以及免疫治疗进行综述。
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随着分子病理学的发展,人们对甲状腺癌发病机制的研究取得了很大进展,肿瘤病理、基因改变、分子学改变等多种因素[7]均影响着甲状腺癌的疾病进程。研制针对甲状腺癌特定分子学改变的靶向治疗药物是治疗晚期甲状腺癌的主导方向。以丝苏氨酸蛋白激酶(v-raf murine sarcoma viral oncogene homolog B,BRAF)突变、血管内皮生长因子(vascular endothelial growth factor receptor,VEGFR)等分子改变和丝裂原活化蛋白激酶(mitogen activated protein kinase,MAPK)与磷脂酰肌醇-3-激酶(phosphatidylinositol-3- kinase,PI3K)信号通路改变[8-9]为治疗靶点的药物成为研究热点,多种药物已被研制并应用于试验性治疗。已批准和处于临床试验中的甲状腺癌靶向治疗药物见表1。
靶向治疗药物 靶点 研究阶段 PFS/月,ORR 酪氨酸激酶受体抑制剂 Sorafenib[10] RAF-1、RET、BRAF、VEGFR-2、VEGFR-3、PDGFR-β 2013.11获得FDA批准;2017.3获得CFDA批准,治疗RR-DTC 417例,5.0(10.8 vs. 5.8),
12.2% vs. 0.5%Lenvatinib[11] VEGFR1-3、FGFR1-4、PDGFR、RET、KIT 2015.2获得FDA批准治疗RR-DTC 392例,14.7(18.3 vs. 3.6),
64.8% vs. 1.5%Vandeanib[12] EGFR、VEGFR、RET 2011.4获得FDA批准治疗MTC 331例,11.2(30.5 vs. 19.3),
45% vs. 13%Cabozantinib[13] VEGFR1-2、RET、MET 2012.11获得FDA批准治疗MTC 330例,7.2(11.2 vs. 4),28% vs. 0% Apatinib[14] VEGFR Ⅱ;RR-DTC Sunitinib[15] PDGFR、EGFR、FLT-3、CSF-1R、KIT、RET、VEGFR1-2 Ⅱ;RR-DTC 57例,10.2,35.1% Axitinib[16] VEGFR1-3、PDGFR、KIT Ⅱ;RR-DTC 52例,16.1,30% Dovitinib[17] FGFR、VEGFR Ⅱ;RR-DTC 40例,5.4,20.5% Pazopanib[18] VEGFR-1、VEGFR-3、PDGFR、KIT Ⅱ;RR-DTC 37例,12,49% BRAF抑制剂 Vemurafenib[19] BRAF Ⅱ;RR-DTC 51例,15.6,35% Dabrafenib[20] BRAF Ⅰ;RR-DTC 14例,11.3,PR29%,SD43% MEK抑制剂 Selumetinib[21] MEK-1、MEK-2、RAS、BRAF V600E RR-DTC 注:表中,RAF-1:c-RAF原癌基因丝苏氨酸蛋白激酶-1;RET:RET原癌基因蛋白;BRAF:丝苏氨酸蛋白激酶;VEGFR:血管内皮生长因子受体;PDGFR:血小板衍生生长因子受体;KIT:C-KIT原癌基因酪氨酸激酶受体蛋白;MET:c-MET原癌基因蛋白;FGFR:纤维母细胞生长因子受体;EGFR:表皮生长因子受体;FLT-3:类酪氨酸激酶-3;CSF-1R:集落刺激因子1受体;MEK:甲乙酮;RAS:大鼠肉瘤原癌基因蛋白。FDA:美国食品药品监督管理局;CFDA:国家食品药品监督管理总局;RR-DTC:放射性碘难治性分化型甲状腺癌;MTC:甲状腺髓样癌。PFS:无进展生存期;PR:部分缓解;SD:病情稳定。 表 1 已批准和处于临床试验中的甲状腺癌靶向治疗药物
Table 1. Drugs for targeted treatment of thyroid cancer approved and in clinical trials
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TKI通过与酪氨酸激酶受体结合位点的ATP竞争性结合发挥其抗肿瘤活性。TKI不仅可以阻断体内的细胞信号通路,直接抑制肿瘤细胞的增殖,还可以作用于血管内皮生长因子受体等多种酪氨酸受体,阻断肿瘤新生血管的生成,间接抑制肿瘤细胞的生长,是研发TKI靶向治疗甲状腺癌的药理学基础[22]。目前美国食品药品监督管理局(food and drug administration,FDA)已经批准了4种用于甲状腺癌治疗的多靶点药物,索拉非尼(Sorafenib)[10]和乐伐替尼(Lenvatinib)[11]用于治疗RR-DTC,凡德他尼(Vandeanib)[12]和卡博替尼(Cabozantinib)[13]用于治疗甲状腺髓样癌(medullary thyroid carcinoma,MTC)。使用TKI对患者进行治疗有一定的不良反应[23]。在使用药物前,建议全面评估患者的健康状况,并谨慎使用TKI,以最大限度地发挥其益处,并尽量减少其不良反应。
2017年3月,我国国家食品药品监督管理总局批准索拉非尼用于RR-DTC的治疗。甲磺酸阿帕替尼(Apatinib)是第一个具有我国自主知识产权的小分子TKI,它可以高选择性地阻断VEGFR-2,从而抑制肿瘤血管内皮细胞的增殖,达到治疗肿瘤的目的[24]。Lin等[25]对10例服用阿帕替尼的RR-DTC患者进行随访研究,中位随访时间为7.9个月,结果显示,患者服药6周内血清学甲状腺球蛋白(thyroglobulin,TG)快速下降,8周内影像学病灶大小明显减小,之后TG和病灶大小均较稳定。停药后两周,观察到TG的反弹趋势,病灶大小未见明显变化。从血清学及结构影像学角度证实阿帕替尼的短期疗效显著,但其长期疗效及对患者生存的获益尚有待进一步的研究。
凡德他尼和卡博替尼对MTC的治疗已得到认可,但在RR-DTC的临床应用尚处于临床试验阶段。Leboulleux等[26]对145例RR-DTC患者进行的凡德他尼Ⅱ期研究显示,治疗组和安慰剂组无进展生存期(progression free survival,PFS)分别为11.1个月和5.9个月,其中PTC和FTC分别为16.2个月和7.7个月,且FTC组的TG无明显降低。因此,有学者认为,凡德他尼更适合于PTC的治疗[27]。Cabanillas等[14]对15例RR-DTC患者进行的卡博替尼Ⅰ期临床试验结果显示,53%的患者达到部分缓解(partial remission,PR)。此外,还有其他尚在实验阶段的TKI,如舒尼替尼(Sunitinib)[15]、阿西替尼(Axitinib)[16]、多韦替尼(Dovitinib)[17]及帕唑帕尼(Pazopanib)[18]等,它们是很有潜力的治疗RR-DTC药物,试验性疗效较好,且总体不良反应较轻。
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BRAF突变对肿瘤细胞的生长、增殖、侵袭、转移至关重要,其主要发生于黑色素瘤、结肠癌和甲状腺癌[28]。选择性BRAF抑制剂针对甲状腺癌的BRAF抑制剂的临床试验正在开展中。维罗非尼(Vemurafenib)和达拉非尼(Dabrafenib)是两种针对甲状腺癌的BRAF抑制剂,在临床研究中对于BRAF突变型的DTC疗效显著。Brose等[19]对51例BRAF突变型的RR-DTC患者行维罗非尼治疗,结果显示,PFS为15.6个月,客观缓解率为35%,且未经TKI治疗的患者的有效率高于以往接受过TKI治疗的患者。Falchook等[20]关于达拉非尼的Ⅰ期研究显示,14例BRAF突变的DTC患者中29% PR,43%病情稳定(stable disease,SD)。由于患者数量较少,需要扩大样本数量进行进一步的研究。
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传统的RR-DTC再分化治疗的主要药物是维甲酸类药物和PAX-8/PPAR-γ激动剂[29-30],但它们只在体外试验中被证实可以提高甲状腺癌细胞的摄碘率,临床研究并不是很理想。司美替尼(Selumetinib)是口服的小分子MAPK激酶(MEK1、MEK2)抑制剂,可以抑制MAPK信号通路的过度激活,提高细胞的摄碘能力,提高病灶对131I治疗的敏感性。Ho等[21]使用司美替尼联合131I的临床试验中,20例RR-DTC患者[9例BRAF突变,5例大鼠肉瘤(rat sarcoma,RAS)突变],其中12例(4例BRAF突变,5例RAS突变)摄碘能力增强,8例(5例RAS突变)达到131I治疗的剂量阈值。其中8例患者经131I治疗后,5例PR,3例SD。司美替尼明显改善了RR-DTC患者病灶的摄碘能力,且在RAS突变患者中的疗效更为显著。
碘难治性分化型甲状腺癌的精准靶向治疗进展
Research progress in accurate targeted therapy for radioiodine refractory differentiated thyroid cancer
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摘要: 甲状腺癌的发病率逐年上升,传统的治疗方法对于碘难治性分化型甲状腺癌的疗效有限。靶向治疗是近年来比较热门的新型治疗方法,在甲状腺癌的治疗上已取得一定研究成果。笔者就碘难治性分化型甲状腺癌的精准靶向治疗策略——药物靶向治疗、肽受体核素靶向治疗、局部精准治疗以及免疫治疗进行综述。
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关键词:
- 碘难治性分化型甲状腺癌 /
- 免疫疗法 /
- 靶向治疗 /
- 核素靶向治疗
Abstract: The incidence of thyroid cancer is increases year by year. Traditional treatment for radioiodine refractory differentiated thyroid cancer is limited.Targeted therapy is a popular new treatment method in recent years, and has achieved positive results in the treatment of thyroid carcinoma. This article reviews the accurate targeting therapy strategy of radioiodine refractory differentiated thyroid carcinoma, drug targeting therapy, peptide receptor radionuclide targeting therapy, local precise therapy and immunotherapy. -
表 1 已批准和处于临床试验中的甲状腺癌靶向治疗药物
Table 1. Drugs for targeted treatment of thyroid cancer approved and in clinical trials
靶向治疗药物 靶点 研究阶段 PFS/月,ORR 酪氨酸激酶受体抑制剂 Sorafenib[10] RAF-1、RET、BRAF、VEGFR-2、VEGFR-3、PDGFR-β 2013.11获得FDA批准;2017.3获得CFDA批准,治疗RR-DTC 417例,5.0(10.8 vs. 5.8),
12.2% vs. 0.5%Lenvatinib[11] VEGFR1-3、FGFR1-4、PDGFR、RET、KIT 2015.2获得FDA批准治疗RR-DTC 392例,14.7(18.3 vs. 3.6),
64.8% vs. 1.5%Vandeanib[12] EGFR、VEGFR、RET 2011.4获得FDA批准治疗MTC 331例,11.2(30.5 vs. 19.3),
45% vs. 13%Cabozantinib[13] VEGFR1-2、RET、MET 2012.11获得FDA批准治疗MTC 330例,7.2(11.2 vs. 4),28% vs. 0% Apatinib[14] VEGFR Ⅱ;RR-DTC Sunitinib[15] PDGFR、EGFR、FLT-3、CSF-1R、KIT、RET、VEGFR1-2 Ⅱ;RR-DTC 57例,10.2,35.1% Axitinib[16] VEGFR1-3、PDGFR、KIT Ⅱ;RR-DTC 52例,16.1,30% Dovitinib[17] FGFR、VEGFR Ⅱ;RR-DTC 40例,5.4,20.5% Pazopanib[18] VEGFR-1、VEGFR-3、PDGFR、KIT Ⅱ;RR-DTC 37例,12,49% BRAF抑制剂 Vemurafenib[19] BRAF Ⅱ;RR-DTC 51例,15.6,35% Dabrafenib[20] BRAF Ⅰ;RR-DTC 14例,11.3,PR29%,SD43% MEK抑制剂 Selumetinib[21] MEK-1、MEK-2、RAS、BRAF V600E RR-DTC 注:表中,RAF-1:c-RAF原癌基因丝苏氨酸蛋白激酶-1;RET:RET原癌基因蛋白;BRAF:丝苏氨酸蛋白激酶;VEGFR:血管内皮生长因子受体;PDGFR:血小板衍生生长因子受体;KIT:C-KIT原癌基因酪氨酸激酶受体蛋白;MET:c-MET原癌基因蛋白;FGFR:纤维母细胞生长因子受体;EGFR:表皮生长因子受体;FLT-3:类酪氨酸激酶-3;CSF-1R:集落刺激因子1受体;MEK:甲乙酮;RAS:大鼠肉瘤原癌基因蛋白。FDA:美国食品药品监督管理局;CFDA:国家食品药品监督管理总局;RR-DTC:放射性碘难治性分化型甲状腺癌;MTC:甲状腺髓样癌。PFS:无进展生存期;PR:部分缓解;SD:病情稳定。 -
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