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肝癌分子靶向治疗面面观:从一线二线治疗决策到综合性全程管理

2019-09-23 佚名 肿瘤资讯

随着医学的进步和技术水平的提高,目前肝癌的治疗已经进入精准治疗和多学科联合治疗的时代。在这一背景下,分子靶向药物在肝癌治疗中的地位如何?一线治疗如何决策?如何对治疗后进展进行评估?肝癌治疗未来将走向何方?

随着医学的进步和技术水平的提高,目前肝癌的治疗已经进入精准治疗和多学科联合治疗的时代。在这一背景下,分子靶向药物在肝癌治疗中的地位如何?一线治疗如何决策?如何对治疗后进展进行评估?肝癌治疗未来将走向何方?

早诊早治,新药研发,肝癌治疗疗效获显着提升

肝癌是我国的一个常见恶性肿瘤,发病率位居第三且居高不下。随着乙肝疫苗接种的普及,未来的10~20年发病率应该会有所下降。肝癌的治疗在近些年取得了一定进展,主要是诸如手术、消融等根治性治疗的进展。根治性手术的疗效之所以较前明显提高,主要是得益于早期诊断和综合治疗的进步。由于国家在医疗保险、体格检查及高危人群筛查上的投入,使得早期肝癌的检出率得以提高,从而间接促进了肝癌根治性治疗疗效的提高。而对于中晚期肝癌,由于分子靶向药物如索拉非尼、瑞戈非尼、仑伐替尼以及免疫检查点抑制剂的出现,使晚期肝癌的系统性治疗疗效提高,而中期肝癌经导管动脉栓塞化疗(TACE)联合全身系统治疗也成为可能,从而使疗效得到进一步提升。

判断耐药或进展:影像学是主要手段,生物标志物仅做参考

索拉非尼、仑伐替尼及化疗均是卫健委《原发性肝癌诊疗规范》所推荐的标准治疗。然而,这些治疗手段或多或少都会在治疗的过程中出现耐药,或患者的病情出现进展。目前判断患者出现耐药或者进展的主要手段依旧是影像学,并利用RECIST标准来进行评估。

在进行耐药或进展判定时,当然也会将生物标志物纳入参考,例如:在肿瘤标志物中,甲胎蛋白下降和再升高,所代表的临床意义是不同的。然而,最主要的手段仍旧是影像学。其中因由是肿瘤标志物和影像学表现并不完全一致,肿瘤标志物在缓慢升高的同时,影像学可能仍旧表现为稳定。

进展背景决定是否更换治疗药物

在一线治疗进展后,当然应该及时更换二线治疗药物。然而在临床实践中,由于患者的进展背景不一,还应具体问题具体分析:第一种,进展表现得极为缓慢,此时不一定需要换药,例如一线使用索拉非尼或者仑伐替尼时出现缓慢进展,然而这两种药副作用轻,继续使用患者仍然可能获益;第二种,药物剂量过低导致进展,比如在用药过程中因副作用导致药物减量,那么在副作用减轻或耐受后应考虑对药物剂量进行调整恢复,则患者使用该药可能仍然有效。

由于索拉非尼这一类的TKI类药物的耐药和进展机制与肺癌的分子靶向药不同,因此,在考虑是否更换药物时,不能进行简单的考量。当然,就原则而言,如果患者在一线治疗时出现进展,则应及时更换二线治疗药物。瑞戈非尼是美国FDA及我国国家食品药品监督局所批准的二线治疗药物,RESORCE研究中,一线索拉非尼序贯二线瑞戈非尼治疗后,患者的中位生存期可以达到26个月,这在以前是难以想象的。

分子靶向药物出现进展毋需进行二次影像评估

在影像学的表现上,分子靶向治疗和免疫治疗后出现的进展表现不同。免疫治疗可能出现假性进展的情况,因此需要二次影像学评估,而分子靶向治疗除了要考虑缓慢进展和药物剂量过低导致进展的特殊情况外,如果在影像学上第一次出现进展,则应该更换二线的瑞戈非尼进行治疗。

晚期肝癌全程管理:依据适应证选择适宜的治疗手段

就肝癌而言,总的治疗原则是综合治疗或多学科治疗的理念。局部治疗和全身治疗的主要适应证还是有区别的,局部治疗主要用于早期肝癌,分子靶向药物和免疫检查点抑制剂这些系统治疗主要用于晚期肝癌。然而,在做出具体的治疗决策时,虽然适应证是考量的依据,但并非系统治疗就不能应用于早期肝癌。而在进行晚期肝癌治疗时,如患者病灶相对局限,在使用分子靶向药物进行系统治疗的前提下,依旧可以接受局部治疗。比如肝癌肺转移的患者,如果肝癌局部病灶的负荷较大,可以通过介入消融等局部治疗减少肿瘤负荷,再加上全身系统治疗,患者生存获益会更大。但并非所有的晚期患者均可选择局部治疗,其依据是患者的病灶是否相对局限,是否以全身治疗为前提,是否能使患者最终获益。

免疫微环境复杂,临床需要综合的治疗手段

在最初的研究中,免疫检查点抑制剂的数据令人振奋,患者的客观缓解率相比以往的系统治疗得到提高,因此,FDA已将免疫检查点抑制剂批准为肝癌的二线治疗。然而,在后续的KEYNOTE-240和Checkmate 459研究中,免疫检查点抑制剂的表现均差强人意。Checkmate 459研究是免疫检查点抑制剂与索拉非尼进行头对头比较的研究,研究结果为阴性,没有达到预期。这说明单一免疫检查点抑制剂的临床获益十分有限。由于免疫抑制性细胞及多条免疫检查点途径的存在,使得人体内的免疫微环境变得非常复杂,目前使用的免疫检查点抑制剂仅针对PD-1或CTLA-4,对于整个免疫微环境而言远远不够,此时,就需要联合治疗策略。目前开展的临床试验数据已经表明免疫治疗联合分子靶向治疗,可以显着提高临床疗效。推而广之,在临床实践中,除了与系统治疗联合外,免疫治疗是否亦可联合消融、射频、放疗等局部治疗手段,让患者能有进一步获益,也有待进一步探索。

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    2019-09-23 留走人康

    肝癌,接下来就要细分了,对于体质好的病人,能否将PD-1类+抗血管新生+放疗等相结合,甚至有必要用TACE进行减负

    0

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