RAIR-DTC的靶向治疗药物
应用于RAIR-DTC的分子靶向治疗药物涵盖多种激酶抑制剂。多项随机、双盲、安慰剂对照Ⅱ～Ⅲ期临床试验证实索拉非尼（Sorafenib）、仑伐替尼（Lenvatinib）等激酶抑制剂可改善RAIRDTC的无进展生存（Progression-Free Survival， PFS），并延缓病情进展。有关索拉非尼作用于放射碘难治性局部进展及远处转移性甲状腺癌的全球多中心随机对照研究的Ⅲ期试验结果显示，与对照组比较，患者PFS延长，索拉非尼对该人群的疾病控制率达54.1%，73%的患者病灶出现了不同程度的缩小。索拉非尼分别于2013年和2014年作为第一个用于进展期RAIR-DTC的靶向药物被美国FDA及欧洲EMA批准。在药物使用方法上，推荐采用400mg/次，每天2次。值得注意的是，由于试验设计及副反应等因素，至今的临床试验研究结果均未提示患者总生存（Overall Survival， OS）及生活质量（Quality of Life， QOL）的获益，使得临床工作中靶向治疗指征的把握、患者的筛选以及治疗过程中病情的监测评估显得尤为关键。因此，仅对常规治疗无效且处于进展状态的晚期RAIR-DTC患者推荐使用这类药物，同时建议核医学、肿瘤学、内科学等多学科协作，及时处置药物不良反应并监测病情变化。
对于索拉非尼等初始激酶抑制剂治疗失败的患者，如果没有发生严重不良反应，应考虑正在开展临床试验的二线分子靶向药物。目前，越来越多旨在用于进展性晚期RAIR-DTC的新型靶向药物正处在临床试验阶段。在甲状腺癌中，BARFV600E基因突变是PTC最常见的且最具特异性的基因改变，且BARF激酶抑制剂已被批准用于BRAF突变型黑色素瘤的治疗。因此BARF激酶抑制剂是否可改善处于进展状态的晚期RAIR-DTC患者的预后也备受关注。除此之外，MEK激酶抑制剂和其他信号转导通路也引起国内外学者的关注。
（1）激酶抑制剂的副作用：乏力、腹泻、恶心、呕吐、食欲减退、高血压、手足反应、肝功能受损、出血、血栓栓塞、QTc延长、心力衰竭、消化道瘘、肠穿孔等。不良反应不同程度地影响了患者的生活质量，2/3患者需要因此而减少药量，约20%患者需要终止治疗，出血、栓塞、心力衰竭等严重不良反应甚至可引起死亡。
（2）激酶抑制剂的停药指征：通常情况下，只要患者获益大于药物副作用带来的弊端就应继续治疗。对于转移病灶显著缓解后的缓慢进展，在总体病情稳定且药物不良反应可控的前提下，应继续靶向药物治疗。治疗过程中应密切观察患者基本生命体征及可能出现的副作用，并定期采用CT和（或）MRI等影像学、Tg等血清学监测进行动态病情评估。应注意有时候患者只是出现局部或单个病灶的进展，在这种情况下，应在维持靶向治疗的同时实施局部治疗。比如，对于肺转移病灶缩小或减少而单个骨转移病灶进展的患者，应在激酶抑制剂治疗的同时对骨转移灶加用定向放射治疗。如出现以下情况，则可考虑终止治疗：①RAIR-DTC患者经分子靶向治疗后RECIST疗效评价仍判定为PD。②RAIR-DTC患者经分子靶向治疗后Tg未见下降或反而上升。③治疗过程中因出现严重的药物不良反应而不能耐受继续治疗者。综上所述，靶向药物通过改善PFS、延缓疾病进展、为处于进展状态的晚期RAIR-DTC患者带来了希望。
RAIR-DTC 的治疗一直是甲状腺癌治疗的难点，及时、准确诊断是后续治疗的关键。这些患者的治疗应结合外科、病理科、核医学科、放疗科、肿瘤内科等多学科团队的协同综合治疗。目前靶向治疗药物显示出良好的应用前景，相信靶向治疗不久将改变甲状腺癌尤其是晚期放射碘难治性甲状腺癌的综合治疗策略及格局。
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