Volume 43 Issue 6
Jan.  2020
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Research progress in accurate targeted therapy for radioiodine refractory differentiated thyroid cancer

  • 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.
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Research progress in accurate targeted therapy for radioiodine refractory differentiated thyroid cancer

    Corresponding author: Yali Cui, 13936500552@126.com
  • Department of Nuclear Medicine, Harbin Medical University Cancer Hospital, Harbin 150081, China

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.

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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。

1.   药物靶向治疗
  • 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。

    Table 1.  Drugs for targeted treatment of thyroid cancer approved and in clinical trials

  • 1.1.   酪氨酸激酶受体抑制剂(tyrosine kinase-linked receptor inhibitor,TKI)

  • 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。

  • 1.2.   BRAF抑制剂

  • 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。

  • 1.3.   甲乙酮(methyl ethyl ketone,MEK)抑制剂

  • 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。

2.   局部精准治疗
  • 对于脑、肺、肝及骨转移等远处转移出现症状及局部残留或复发病灶出现病情进展的甲状腺癌患者,局部精准治疗应优先于全身系统治疗[31-32]。体外放疗(立体定向放疗、调强放疗)、消融治疗[射频消融(radiofrequency ablation,RFA)、激光消融]等为常用的局部针对性治疗手段。2018版《持续、复发及转移性甲状腺癌诊疗指南》指出[6],放疗在RR-DTC的应用主要是局部姑息治疗,消融治疗目前仍是复发转移性甲状腺癌的补充治疗手段。通过局部治疗控制病情,延缓患者疾病进展的速度,减轻疼痛,提高患者的生存质量。

    体外照射的靶区根据病灶具体位置而定,剂量范围为50~70 Gy,可采用大分割短疗程或常规分割治疗[33]。照射的具体实施应根据患者的一般情况、外照射技术的选择、治疗耐受等因素综合考虑,通过积极的支持治疗、合理缩小照射范围、使用三维外照射技术等提高对转移灶的局部控制,尽可能降低不良反应发生率。Besic等[34]对3146例DTC患者的回顾性研究发现,其中91例DTC患者(FTC 27例、PTC 53例、Hürthle 11例)在其他治疗的基础上增加了颈部和纵隔的体外放疗,其中23例远处转移,38例局部转移,随访时间为6~308个月(PFS 61个月),5年和10年无病生存率分别为64%和48%。研究终止时,44例患者存活(28例完全缓解、16例带病生存),3例失访,34例死于甲状腺癌(29例远处转移、5例区域性转移),10例死于其他原因。体外放疗作为甲状腺癌的多种治疗方法之一,对复发的转移性DTC有长期的局部控制作用。

    2001年,Dupuy等[35]首次将RFA用于治疗131I不能清除的DTC复发灶,对32例复发性DTC患者行RFA治疗(31例患者共33个病灶仅行RFA治疗,1例患者共2个病灶行RFA治疗后再行手术治疗),结果显示,仅行RFA治疗的31个病灶完全消失,其余2个病灶体积缩小,33个病灶的最大直径和体积分别减少了93.2%和96.4%。RFA术在DTC复发灶的治疗上取得了良好效果,但尚缺乏大样本、前瞻性、随机对照研究,因此RFA治疗目前仍然是复发转移性DTC的补充治疗手段。

3.   肽受体放射核素靶向治疗
  • 肽受体放射性核素治疗(peptide receptor radionuclide therapy,PPRT)是指以生物活性肽受体为媒介,与放射性药物形成耦联的药物靶向治疗方法。目前,这种治疗在肿瘤的研究中取得了一定的进展,其中最为成功的是生长抑素受体(somatostatin receptor,SSTR)介导的靶向治疗,如以奥曲肽(octreotide,OC)、RC-160等生长抑素类似物作为载体,介导188Re、177Lu和90Y等放射性药物形成耦联物,进行靶向药物治疗[36] 。此外,应用生长抑素类似物(如OC、RC-160、P587等)作为标记配体进行肿瘤受体显像也是肿瘤(如内分泌肿瘤等)研究的热点,对于肿瘤的定位、诊断有很高的价值[37]

    甲状腺癌细胞(DTC和MTC较常见)可以表达SSTR,高表达生长抑素的甲状腺癌患者对OC有强烈的亲合力。68Ga标记的OC PET/CT显像可以检测残余肿瘤和(或)转移病灶SSTR的表达。对于生长抑素高表达的患者,可以选择肽受体放射性核素治疗,并用生长抑素显像(68Ga标记的OC)对治疗后患者进行疗效评价。生长抑素显像对患者治疗方法的选择和治疗效果的评价都是一种可靠的工具[38] 。Versari等[39]对41例RR-DTC患者行18F-FDG PET/CT检测复发病灶,行68Ga-DOTATOC PET/CT检测SSTR的表达。结果显示,24例患者的SSTR表达呈阳性,其中11例接受了90Y-DOTATOC治疗,肽受体放射性核素治疗诱导的控制率为63.64%(7/11)(2例PR、5例SD),持续时间为3.5~11.5个月。患者不良反应主要为恶心、乏力和暂时性血液学毒性。对于RR-DTC患者来说,PRRT毒性小、有效率高、患者生存率高,是一种很有前途的治疗方法。由此可见,肽受体核素靶向治疗在甲状腺癌方面有广阔的应用前景。

4.   肿瘤的免疫治疗
  • 免疫治疗是近十年来随着肿瘤与机体免疫应答的认识与应用发展起来的一种新的疗法。免疫治疗主要是在对肿瘤微环境及免疫细胞特定的相互作用认识的基础上,通过恢复不同免疫细胞的功能,提高其对肿瘤的抑制作用[40]。目前,免疫治疗是多种肿瘤的研究热点,其中,阻断和抑制免疫检查的研究是研究热点之一,在肺癌、黑色素瘤等多种肿瘤的研究中取得了良好的结果。

    免疫系统在对机体肿瘤反应、疾病的治疗和预后改善阶段均发挥重要作用。肿瘤细胞变异体逐渐逃离免疫系统的监测,导致肿瘤的生长及疾病的发生。在肿瘤的免疫监测过程中,肿瘤微环境中存在的抑制肿瘤的相关巨噬细胞(tumor associated macrophages,TAMs)为抗肿瘤M1表型,表达IL-1、IL-12和TNF-α,促进肿瘤的免疫控制。在肿瘤免疫逃逸阶段,TAMs的表型为M2表型,表达IL-10和CD 163,促进肿瘤的进展并抑制肿瘤的免疫消除[41]。T细胞表面免疫检查点分子[如程序性死亡受体-1(programmed cell death protein-1,Pd-1)、Tim-3、Lag-3和具有Ig和免疫受体酪氨酸抑制基序(im munoreceptor tyrosine-based inhibitory motif,IMIT)T细胞免疫蛋白及其相应配体(CD 80/86和程序性死亡受体-配体1( programmed cell death-Ligand 1,Pd-L1)/Pd-L2)在肿瘤细胞上的表达增加,导致免疫应答受到显著抑制[42]。调节性T细胞(regulatory T cells,Tregs)能够表达Pd-1和CTLA-4,通过免疫抑制作用促进肿瘤的生长与浸润。

    Mehnert等[43]研究发现,甲状腺肿瘤组织中的TAMs趋化剂集落刺激因子(colony stimulating factor ,CSF)-1和CC类趋化因子配体2(C-C motif chemokine ligand 2,CCL2)表达增高,可以靶向阻断CCL-2/CCR 2和CSF-1/CSF-1R通路,不仅能抑制M2表型TAMs的形成,还能促进其向M1抗肿瘤表型的再极化,是一种很有前途的甲状腺癌治疗方法。因此,抑制TAMs的聚集以增强抗肿瘤的免疫应答是许多正在进行的试验的研究方向。在临床实验01346358中[44],CSF-1R抗体LY 3022855被用于治疗晚期实体肿瘤,包括晚期甲状腺癌患者。

    在晚期、局部浸润性DTC、淋巴结转移和甲状腺未分化癌中发现的大量Tregs、CTLA-4和Pd-1相应配体的阻断抗体是肿瘤免疫治疗的新希望[45],它们通过阻断T细胞表面免疫检查点分子及其配体在肿瘤细胞的表达增强效应T细胞,并抑制肿瘤生长。抗CTLA-4类伊匹单抗(Ipilimumab)和玔尼单抗(Tremempumab)以及抗Pd-1类泼莱单抗(Pbrolizumab)和纳武单抗(Novilumab)被FDA批准用于治疗多种癌症,包括黑色素瘤、非小细胞肺癌和肾癌[40]。Zwaenepoel等[46]和Chowdhury等[47]研究表明,Pd-L1在甲状腺乳头状癌中的高表达与复发风险的增加有关,甲状腺癌Pd-L1 T细胞的增加提示这些检查点抑制剂在甲状腺癌中有潜在的应用价值。Topalian等[48]对22例甲状腺患者(18例为RR-DTC)行试验性治疗,结果显示2例PR,12例SD,18例出现轻度治疗相关的不良反应。

    目前,免疫治疗在甲状腺癌中的应用处于早期阶段,上述试验说明其在治疗RR-DTC方面有很好的应用前景,我们有理由相信免疫治疗未来会成为晚期甲状腺癌的一个治疗热点。

5.   结语
  • 目前,新的多酶抑制剂、BRAF抑制剂和MEK抑制剂等药物的发展以及局部精准治疗的应用,让甲状腺癌患者有了更多的治疗选择和更加精准的个性化治疗手段[49]。此外,肽受体核素治疗和免疫治疗相关药物尚在研制,值得我们进一步研究与期待。目前关于RR-DTC的靶向研究大多处于临床试验阶段,仍缺乏有力的证据证实其临床效果,因此,在靶向治疗前必须综合考虑潜在风险和获益。相信随着更多靶向治疗方案的出现,甲状腺癌的临床治疗会有突破性进展。

    利益冲突 本研究由署名作者按以下贡献声明独立开展,不涉及任何利益冲突。

    作者贡献声明 王新霞负责资料的查阅,论文的撰写及修改;马腾闯负责论文的修改;崔亚利负责研究方向的提出、论文的修订。

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