分子和免疫治疗时代的肝细胞癌局部疗法

StephenW

Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma

    Josep M. Llovet, Thierry De Baere, Laura Kulik, Philipp K. Haber, Tim F. Greten, Tim Meyer & Riccardo Lencioni

Nature Reviews Gastroenterology & Hepatology volume 18, pages293–313(2021)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality and has an increasing incidence worldwide. Locoregional therapies, defined as imaging-guided liver tumour-directed procedures, play a leading part in the management of 50–60% of HCCs. Radiofrequency is the mainstay for local ablation at early stages and transarterial chemoembolization (TACE) remains the standard treatment for intermediate-stage HCC. Other local ablative techniques (microwave ablation, cryoablation and irreversible electroporation) or locoregional therapies (for example, radioembolization and sterotactic body radiation therapy) have been explored, but have not yet modified the standard therapies established decades ago. This understanding is currently changing, and several drugs have been approved for the management of advanced HCC. Molecular therapies dominate the adjuvant trials after curative therapies and combination strategies with TACE for intermediate stages. The rationale for these combinations is sound. Local therapies induce antigen and proinflammatory cytokine release, whereas VEGF inhibitors and tyrosine kinase inhibitors boost immunity and prime tumours for checkpoint inhibition. In this Review, we analyse data from randomized and uncontrolled studies reported with ablative and locoregional techniques and examine the expected effects of combinations with systemic treatments. We also discuss trial design and benchmarks to be used as a reference for future investigations in the dawn of a promising new era for HCC treatment.
Key points

    Locoregional treatments for hepatocellular carcinoma (HCC) are aimed at eliminating or reducing tumoural viability, delaying progression and ultimately extending overall survival; options include local ablative techniques and intra-arterial techniques.

    Radiofrequency ablation is considered the standard treatment option among local ablative techniques for very early stage tumours (<2 cm) and for tumours at early stages not suitable for surgical therapies.

    Transarterial chemoembolization is established as the standard of care for intermediate-stage lesions (multinodular liver-only disease in asymptomatic patients with compensated liver function) leading to median survivals of 25–30 months.

    The role of radioembolization and stereotactic body radiotherapy is still to be defined, and further trials are required to delineate a patient subset deriving benefit from these treatments.

    No systemic therapy tyrosine kinase inhibitor has been able to improve survival when tested in combination with locoregional treatment but there is rationale for combination therapies with immunotherapy in HCC.

    Single-agent and combination therapies are being investigated in randomized controlled trials both in an adjuvant setting and combined with intra-arterial therapies, and results are expected to change HCC management within the next 5 years.

StephenW

分子和免疫治疗时代的肝细胞癌局部疗法

    Josep M.Llovet，Thierry De Baere，Laura Kulik，Philipp K.Haber，Tim F.Greten，Tim Meyer和Riccardo Lencioni

自然评论，胃肠病和肝病，第18卷，第293–313页（2021），引用本文

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抽象的

肝细胞癌（HCC）是与癌症相关的死亡率的第四大诱因，并且在全球范围内发病率不断上升。局部区域疗法（定义为影像学指导的肝肿瘤定向手术）在50％至60％的HCC的管理中起着主导作用。射频是早期局部消融的主要手段，而经动脉化学栓塞（TACE）仍然是中期HCC的标准治疗方法。还探索了其他局部消融技术（微波消融，冷冻消融和不可逆电穿孔）或局部区域疗法（例如放射栓塞和立体定向人体放射疗法），但尚未改变数十年前建立的标准疗法。这种认识目前正在改变，几种药物已被批准用于晚期HCC的管理。分子治疗在辅助治疗以及与TACE的中间阶段联合策略后主导了佐剂试验。这些组合的基本原理是合理的。局部疗法可诱导抗原和促炎性细胞因子释放，而VEGF抑制剂和酪氨酸激酶抑制剂可增强免疫力并引发肿瘤以抑制检查点。在本综述中，我们分析了采用消融和局部治疗技术报告的随机和非对照研究的数据，并研究了全身治疗联合治疗的预期效果。我们还将讨论试验设计和基准，以期在有希望的HCC治疗新时代来临之际为将来的研究提供参考。
关键点

    肝细胞癌（HCC）局部治疗旨在消除或降低肿瘤生存力，延缓进展并最终延长整体生存期；选项包括局部消融技术和动脉内技术。

    射频消融被认为是局部消融技术中针对极早期肿瘤（<2cm）和不适合手术治疗的早期肿瘤的标准治疗选择。

    经动脉化学栓塞治疗已被确立为中期病灶（无症状肝功能补偿的无症状患者的多结节性仅肝病）的治疗标准，导致中位生存期为25-30个月。

    放射栓塞和立体定向放射疗法的作用尚待确定，还需要进一步的试验来描述从这些治疗中获益的患者亚群。

    与局部治疗联用时，尚无全身疗法酪氨酸激酶抑制剂能够提高生存率，但在肝癌中采用联合疗法与免疫疗法是合乎逻辑的。

    在辅助治疗以及与动脉内治疗相结合的随机对照试验中，正在对单药和联合疗法进行研究，预计结果将在未来5年内改变HCC的管理。