盘点 2023｜陈敏山教授：2023年肝癌治疗研究进展

盘点2023 肝癌治疗研究进展

原发性肝癌（以下简称肝癌）是我国排名第二位常见恶性肿瘤也是第二位肿瘤致死病因。近年来在国内外专家学者的共同努力下，肝癌临床治疗选择已经发生了显著变革，涌现出了多种药物和治疗策略，明显提升了肝癌患者的疗效和长期生存。其中以疾病为中心，以外科手术切除为主导的多学科诊疗制度更是得到了国内诸多中心的广泛认可并在临床实践中不断推广和完善。在此，我们将对2023年肝癌围手术期治疗及晚期系统治疗的重要进展做简单回顾。

首先，2023年AASLD肝癌诊疗指南和2023年美国NCCN肝癌诊疗指南首次扩大了肝癌手术切除适应症，指南推荐超BCLC A期标准的多发病灶患者，部分BCLC B期和Vp1、Vp2型门静脉癌栓的患者或经严格筛选的Child-Pugh B级的肝癌患者可在经验丰富的较大的肝脏中心、经多学科讨论后考虑行手术切除。需要指出的是，外科手术适应症的扩大的同时，需要加强围术期治疗手段才能保证高复发风险的肝癌患者能够切实在手术切除中获益。2023年肝癌围术期的相关转化治疗、新辅助及术后辅助治疗方面都取得了许多进展。

1 转化治疗

今年在ESMO会议上发布了一项来自天津医科大学肿瘤医院的前瞻性II期临床试验（NCT05166772），HAIC联合多纳非尼和信迪利单抗一线治疗不可切除肝癌的转化成功率达64.3%（18/28），中位无进展生存期（PFS）为10.2个月。同样，信迪利单抗联合仑伐替尼一线治疗不可切除肝癌具有良好的疗效及安全性，转化成功率也能达到51%，其中47%的患者接受了肝切除术。需要注意的是，提高晚期不可切除肝癌患者的长期预后，并不是单纯实现根治性切除，对于部分转化效果好，分期下降达到技术上和肿瘤学可切除标准的患者，如何决策下一步治疗方案是现阶段亟需循证的问题,目前正在进行的TALENTop研究拟评估肝切除在阿替利珠单抗联合贝伐珠单抗治疗后的合并大血管侵犯的肝癌患者中的有效性和安全性，以探索肝切除在中晚期肝癌患者转化治疗后的价值和意义，结果值得我们期待。

2 肝癌的新辅助治疗

ASCO会议公布了一项由我中心牵头在国内7家中心开展的III期、前瞻性、随机对照临床试验（NCT03851913）探讨术前新辅助FOLFOX-HAIC对于可手术切除的超出米兰标准的BCLC A/B期肝癌患者的疗效及安全性。该研究从循证医学的角度，提供了高水平的证据证明了术前新辅助FOLFOX-HAIC能为超米兰标准的可切除BCLC A/B期肝癌患者带来生存获益，为手术疗效欠佳的患者探索出了一种安全有效的治疗策略，更新了术前新辅助治疗的理念。不仅如此，目前已有替雷利珠单抗联合仑伐替尼、卡瑞利珠单抗联合阿帕替尼用于可切除、高复发风险的肝细胞癌围手术期治疗的前瞻性II期临床研究，都展现出了令人鼓舞的疗效和良好的耐受性。2023年ESMO会议上还报道了一项立体定向放疗联合替雷利珠单抗新辅助治疗可切除肝癌的Ib期研究（Notable-HCC）的中期结果，为新辅助治疗增加了一项潜在可行的选择。

3 肝癌的辅助治疗

2023年ASCO会议上已公布初期结果的，来自中山大学肿瘤防治中心郭荣平教授团队的一项FOLFOX-HAIC用于合并微血管侵犯肝癌术后辅助治疗的多中心III期研究表明术后辅助FOLFOX-HAIC显著改善了微血管侵犯肝癌患者的无病生存期。另一项备受瞩目的针对术后辅助治疗的多中心、随机对照、III期临床研究（Imbrave050）结果表明在根治性切除或消融术后复发风险较高的患者中，接受阿替利珠单抗联合贝伐单抗辅助治疗能显著改善患者的无复发生存状态，且安全性可控。不仅如此，IMbrave050也是首个报告阳性结果的肝癌术后辅助药物治疗相关的III期临床研究，或将成为一种指导临床、改变实践的辅助治疗新选择，然而仍需要更长的随访期，以更全面地评估获益及风险情况。

4 系统治疗药物

系统治疗药物同样在今年获得了许多成果，今年发表在Lancet的一项III期临床试验结果显示对于不可切除的肝细胞癌患者，与索拉非尼相比，卡瑞利珠单抗联合阿帕替尼在改善无进展生存期和总生存期方面表现出显著优势，并且具有良好的安全性，有望开启中晚期肝癌一线药物治疗新格局。除此之外，2023年ASCO会议公布了MORPHEUS-Liver研究的部分结果，该Ib/II期研究结果显示在阿替利珠单抗和贝伐珠单抗基础上加用Tiragolumab可获得更高的ORR和更长的PFS，且未观察到新的安全信号，三联药物治疗或可成为中晚期肝癌一线治疗的新选择。

5 免疫治疗

今年ESMO Asia大会更新了HIMALAYA这一III期研究的4年总生存率情况，也是迄今为止III期不可切除肝癌研究中最长的随访时间及前所未有的3年和4年OS率进一步强化了我们对双免方案有效性和安全性的认知。另外，卡度尼利单抗作为首个获批上市的国产靶向PD-1/CTLA-4的双抗药物，其联合仑伐替尼一线治疗晚期肝细胞癌，具有良好的抗肿瘤活性和尚可接受的安全性。

6 多学科联合治疗

一项由中山大学肿瘤防治中心陈敏山教授团队在ESMO Aisa会议上公布了经皮热消融联合替雷利珠单抗治疗BCLC A期或B期肝癌患者安全性的相关结果。经皮热消融联合替雷利珠单抗显示出了可接受的安全性和耐受性，相关疗效评估结果将在未来公布，让我们拭目以待。不仅如此，中山大学肿瘤防治中心赵明教授牵头的FOLFOX-HAIC联合度伐利尤单抗治疗伴严重门静脉癌栓（Vp3/Vp4）的晚期肝癌患者的前瞻性单臂II期试验（DurHope）在2023 ESMO年会壁报展示了中期结果，不仅收获了良好的安全性，而且取得了预期的临床效果。对于TACE治疗，EMERALD-1研究（NCT 03778957）是一项随机、双盲、安慰剂对照的多中心Ⅲ期研究显示度伐利尤单抗加TACE加贝伐珠单抗的联合治疗显著改善了受试者的PFS，OS。

7 放疗联合药物治疗

今年发表在Clinical Cancer Research杂志上的一项前瞻性研究结果显示，立体定向放疗联合卡瑞利珠单抗和阿帕替尼一线治疗伴门静脉癌栓的肝癌具有较好的疗效及安全性。

综上所述，围手术期治疗的快速发展给原本无手术机会或手术效果欠佳的患者带来了福音，但肝癌的治疗方法繁多，不同分期的肿瘤选择不同的治疗模式，且不同的治疗模式又涉及不同学科，从免疫单药时期到如今靶免联合局部治疗再加免疫增敏药物的新进展，导致了标准治疗理念的多样性。在治疗选择上，我们需要综合考虑病情和病人的个体差异，追求多学科、多方法的平衡，集中力量解决临床上遇到的难题，通过临床试验研究进一步明确获益人群，提高治疗效果，切实可行地改善肝癌患者的预后生存和提高患者的生活质量，推动我国肝癌临床诊疗水平的有效提升。

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