修回日期: 2026-07-08
接受日期: 2026-07-24
在线出版日期: 2026-08-28
原发性肝癌的诊疗正在由单一学科、单一手段逐步转向以精准分期为基础的多学科诊疗和多模式联合治疗. 就我国临床实践而言, 中国肝癌分期(China national liver cancer staging system, CNLC)兼顾患者肝肿瘤负荷、肝功能和体能状态, 更能反映我国原发性肝癌尤其是肝细胞癌(hepatocellular carcinoma, HCC)患者的诊疗情况. 本文以CNLC分期为主线, 围绕手术切除、经动脉化疗栓塞术(transarterial chemoembolization, TACE)、TACE+消融、手术切除+TACE+消融、靶向免疫、系统治疗: TACE+靶向免疫及肝移植七种核心治疗策略, 对处于不同分期患者的适用人群、决策依据、联合路径及预后特点进行综述. 总体来说, CNLC Ⅰ期的治疗目标以根治为主, 手术切除、消融及肝移植构成其主要根治性手段; CNLC Ⅱ期以TACE为基础, 但联合消融或联合系统治疗正在重塑中期不可切除肝癌的全新治疗格局; CNLC Ⅲ期更强调系统治疗与转化治疗, 部分患者经局部治疗与靶向免疫协同后可获得再次手术切除机会. 未来, 基于肿瘤生物学行为、影像学反应和生物标志物的分层决策, 将进一步推动原发性肝癌综合治疗从"分期"走向"分期+生物学". 本文论述对象以HCC为主, 并以"分期-决策-联合路径-预后"为临床整合主线; 对每种治疗方式均强调适用人群、动态转换节点、联合目的及可比较的预后终点, 避免将单一研究结果或替代终点直接外推为普遍获益.
核心提要: 原发性肝癌治疗正从"单一分期决策"迈向"CNLC分期、肝功能与肿瘤生物学"共同指导的多学科诊疗全程管理, 其中经动脉化疗栓塞术联合靶向免疫为中晚期患者转化切除、延长生存带来新的突破.
引文著录: 李佳毅, 张国顺, 张颖, 李奕萱, 王素颖, 梅冬雪, 辛英瑛, 石峥, 蒋美钰, 韩超. 原发性肝癌分级分阶段诊治中的决策与多学科多模式联合治疗及预后的研究进展. 世界华人消化杂志 2026; 34(8): 616-629
Revised: July 8, 2026
Accepted: July 24, 2026
Published online: August 28, 2026
The diagnosis and treatment of primary liver cancer are shifting from single-disciplinary, single-modality approaches toward multidisciplinary management and multimodal combination therapy based on precise staging. In the context of clinical practice in China, the China National Liver Cancer (CNLC) staging system incorporates tumor burden, liver function, and performance status, and therefore more accurately reflects the clinical characteristics and management of Chinese patients with primary liver cancer, particularly hepatocellular carcinoma (HCC). Using the CNLC staging system as its framework, this review focuses on seven core therapeutic strategies-surgical resection, transarterial chemoembolization (TACE), TACE combined with ablation, surgical resection combined with TACE and ablation, targeted therapy and immunotherapy, TACE combined with targeted therapy and immunotherapy, and liver transplantation-and summarizes their target populations, decision-making criteria, combination pathways, and prognostic characteristics across different disease stages. Overall, the primary therapeutic goal for CNLC stage I disease is curative treatment, with surgical resection, ablation, and liver transplantation constituting the principal curative modalities. For CNLC stage II disease, TACE remains the mainstay of treatment; however, its combination with ablation or systemic therapy is reshaping the treatment landscape for unresectable intermediate-stage HCC. Management of CNLC stage III disease places greater emphasis on systemic and conversion therapies, and selected patients may become eligible for subsequent surgical resection following the synergistic use of locoregional therapy, targeted therapy, and immunotherapy. In the future, stratified decision-making based on tumor biological behavior, imaging response, and biomarkers is expected to further advance the comprehensive management of primary liver cancer from a "stage-based" approach toward an integrated "stage-plus-biology" paradigm. This review focuses primarily on HCC and adopts a clinically integrated framework of "staging-decision-making-combination pathways-prognosis". For each treatment modality, particular emphasis is placed on appropriate patient selection, dynamic transition points, the objectives of combination therapy, and comparable prognostic endpoints, thereby avoiding the inappropriate generalization of findings from individual studies or the direct extrapolation of surrogate endpoints to universal clinical benefit.
- Citation: Li JY, Zhang GS, Zhang Y, Li YX, Wang SY, Mei DX, Xin YY, Shi Z, Jiang MY, Han C. Decision-making in primary liver cancer: Advances in grading and staging diagnosis, multidisciplinary and multimodal therapy, and prognosis evaluation. Shijie Huaren Xiaohua Zazhi 2026; 34(8): 616-629
- URL: https://www.wjgnet.com/1009-3079/full/v34/i8/616.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v34.i8.616
核心提要: 原发性肝癌治疗正从"单一分期决策"迈向"CNLC分期、肝功能与肿瘤生物学"共同指导的多学科诊疗全程管理, 其中经动脉化疗栓塞术联合靶向免疫为中晚期患者转化切除、延长生存带来新的突破.
原发性肝癌是我国常见且致死率较高的恶性肿瘤, 其中肝细胞癌(hepatocellular carcinoma, HCC)占绝大多数. 由于我国原发性肝癌患者常合并乙型肝炎相关慢性肝病和肝硬化, 且初诊时中晚期比例较高, 因此其临床决策不能仅依据肿瘤解剖学分期, 还必须同时评估肝功能、门静脉高压、体能状态以及潜在的后续治疗路径[1]. 近年来, 随着局部治疗[2]、抗血管生成治疗和免疫检查点抑制剂的发展[3], 原发性肝癌治疗已由"单一治疗选择"转向"分级分阶段诊治中的多学科多模式协同"[4]. 在这一背景下, 中国肝癌分期(China national liver cancer staging system, CNLC)体系不断更新[1], 并将手术、局部治疗、系统治疗、转化治疗和肝移植纳入统一框架, 更符合我国临床实践[5]. 本文以HCC为主要讨论对象, 对不同治疗方法在各分期中的角色、适应证及预后证据进行系统梳理.
研究对象与文章定位: 鉴于不同病理类型在生物学行为和治疗证据上存在显著差异, 本文所称"原发性肝癌"在具体诊疗决策、临床试验和预后证据讨论中均以HCC为核心; 胆管细胞癌及混合型肝癌不作为本文治疗推荐的考虑对象. 本文属于叙述性临床决策综述, 旨在整合可用于多学科诊疗(multi-disciplinary treatment, MDT)讨论的证据, 而非提出新的实验性机制假说.
总体上, CNLC Ⅰ期强调根治性治疗, 目标是获得长期无瘤生存[1]; CNLC Ⅱ期兼顾局部控制与根治可能性, 需要在"可切除"与"不可切除但可强化局部治疗"之间进行动态判断[5]; CNLC Ⅲ期则更突出系统治疗和转化治疗的价值, 对于存在血管侵犯但无肝外转移、肝功能尚可的患者, 治疗目标并非单纯姑息, 而是争取降期、转化和延长生存[6]; 对于终末期或全身状况差的患者, 则应重视症状控制与生活质量维护[4]. 需要注意的是, 不同研究报告的生存数据常受入组标准、肝功能背景、病因谱及后续治疗影响, 因此各种治疗方式的预后指标不宜做简单横向比较.
原发性肝癌的治疗决策应由肝胆外科、肿瘤内科、介入科、影像科、放疗科、病理科及移植团队共同完成[1]. MDT评估的核心维度包括: 肿瘤数目、最大径和分布[5]; 是否存在门静脉或肝静脉癌栓; 是否合并肝外转移[6]; Child-Pugh分级、ALBI分级及门静脉高压情况[4]; 未来残肝体积与肝储备[2]; 甲胎蛋白(alpha-fetoprotein, AFP)等肿瘤标志物及其动态变化[7]; 既往经动脉化疗栓塞术(transarterial chemoembolization, TACE)反应、是否存在TACE不适合或TACE难治[8]; 以及患者对手术、移植和系统治疗的耐受性与意愿[1]. 因此, 所谓"分阶段诊治"并非将某一分期机械对应某一种治疗, 而是在分期框架内不断调整治疗顺序和联合方式[5].
"肝癌分期"用于识别肿瘤负荷、血管侵犯、肝外转移和肝功能背景所限定的预后基线; "分级分阶段诊治"是将该预后基线转化为治疗优先级、治疗时序和再评价节点的临床策略; MDT则是完成可切除性判定、局部与全身治疗组合、并发症控制以及患者偏好整合的实施机制. 三者并非并列概念, 而构成"分期定边界-策略定路径-MDT促落实"的连续过程[1,4,5,9](图1).
本文将每一种治疗方式均置入同一决策链: ①先判断能否达到根治性治疗目标; ②对不可根治但肝内病灶为主者, 判断局部治疗的可及性、预期获益及肝功能代价; ③对存在TACE不适合、血管侵犯、肝外转移或局部治疗后早期进展者, 及时转入系统治疗或局部-系统联合并评估转化机会; ④以总生存期(overall survival, OS)、无进展生存期(progression-free survival, PFS)、无复发生存期(recurrence-free survival, RFS)、客观缓解率(objective response rate, ORR)、转化切除率、移植脱落率、肝功能维持和主要不良反应作为不同场景下的结局指标, 而不以单一替代终点概括全部预后(表1和表2, 图2).
| CNLC分期 | 临床场景(简要) | 主要治疗目标 | 优先推荐策略 | 关键决策要点/预后提示 |
| CNLC Ⅰa | 单发肿瘤≤5 cm; 无血管侵犯/肝外转移 | 根治、长期无瘤生存 | 手术切除; 不适合切除者可行消融; 合并明显肝硬化/门脉高压者评估肝移植 | 优先争取根治; 兼顾残肝体积、肝功能与病灶位置 |
| CNLC Ⅰb | 单发>5 cm, 或2-3个结节且均≤3 cm | 根治优先, 兼顾复发风险控制 | 手术切除优先; 部分患者可选择消融或肝移植 | 术后复发风险高于Ia; 关注微血管 侵犯、AFP及病理高危因素 |
| CNLC Ⅱa | 2-3个结节, 且至少1个>3 cm | 根治机会筛选/强化局部控制 | 可切除者优先手术; 不可切除者TACE±消融; 必要时转化治疗后再评估切除 | MDT综合判断病灶分布、门脉高压、未来残肝与消融可及性 |
| CNLC Ⅱb | ≥4个结节; 以肝内病灶为主 | 疾病控制、延缓进展、争取降期/转化 | TACE为基础; 可选TACE+消融或 TACE+系统治疗; 必要时桥接/降期至移植或切除 | 避免机械重复TACE; 每次治疗后复评TACE适合性、肝功能及影像反应 |
| CNLC Ⅲa | 存在大血管侵犯; 无或少量肝外转移 | 延长生存、提高缓解率、争取转化切除 | 系统治疗为基础; 可联合TACE/HAIC/放疗等局部治疗; 少数降期成功者可切除/消融 | 重点看OS、ORR、转化切除率及安全性, 而非仅看PFS或缩瘤 |
| CNLC Ⅲb | 肝外转移为主, 或晚期 全身播散风险高 | 延长生存、症状控制、生活质量维护 | 系统治疗为主; 局部治疗用于肝内主导病灶或症状控制的选择性场景 | 不将局部治疗普遍化; 根据肿瘤负荷、症状和肝功能个体化选择 |
| CNLC Ⅳ | Child-Pugh C和/或PS 3-4等终末期场景 | 支持治疗、缓解症状 | 最佳支持治疗、营养支持、并发症管理、姑息照护 | 强调生活质量与患者意愿; 仅在个体化前提下考虑抗肿瘤治疗 |
| 框架 | 主要定位 | 分层/决策依据 | 对手术/根治治疗的态度 | 对中期HCC的处理 | 对晚期HCC的处理 | 临床特点与适用提示 |
| CNLC | 中国分期治疗推荐一体化框架 | 肿瘤负荷、血管侵犯、肝外转移、肝功能、PS | 相对更积极; 强调切除、消融、移植及转化后根治机会 | TACE为基础, 但更强调联合治疗、转化治疗和动态再评估 | 系统治疗为基础; 部分肝内主导或血管侵犯患者可联合局部治疗 | 更贴近中国HBV相关HCC和中晚期占比较 高的实践环境 |
| BCLC | 分期一预后一治疗链接框架 | 肿瘤分期、肝功能、PS, 并强调治疗阶段 迁移 | 对切除适应证相对严格; 早期患者优先根治治疗 | 经典推荐为TACE; 同时强调中期异质性和不可治疗进展后的转换 | 系统治疗为主, 基于高等级随机证据选择一线方案 | 国际影响最大, 适合作为证据基准与临床 试验对照框架 |
| AASLD | 美国临床实践指导(非独立分期体系) | 总体沿用BCLC思路, 并结合证据等级、移植和监测策略 | 强调切除、消融和移植的规范选择; 重视桥接/降期至移植 | 以TACE等局部治疗为主; 对TACE不适合/难治者及时转系统治疗 | 系统治疗为核心, 重视免疫联合方案与后线序贯管理 | 更强调循证等级与 美国临床可及性; 多与BCLC策略衔接解读 |
| EASL | 欧洲临床实践指南(与BCLC紧密衔接) | 以BCLC为主轴, 结合影像、肝功能、MDT和局部治疗适用性 | 强调MDT下个体化选择根治治疗; 对切除边界和移植筛选较谨慎 | 强调中期异质性、TACE适合性与从局部转向系统治疗的时机 | 系统治疗为主; 重视循证的一线免疫联合与后线治疗序贯 | 更突出MDT、影像标准化与欧洲指南一致性, 适于国际比较 |
手术切除仍是原发性肝癌获得长期生存乃至治愈的核心手段, 前提是能够实现根治性切除且保留足够残肝功能[10]. 从学术逻辑上看, 手术切除不仅是一种局部治疗方式, 更是整个综合治疗链条中的"中心节点": 对于早期患者, 它是首选根治方案[11]; 对于中晚期患者, 它常常又是转化治疗努力争取的最终目标[12].
在CNLC Ⅰ期及部分肿瘤负荷较低的Ⅱ期患者中, 手术切除通常应被优先评估[1]. 对于单发病灶、外周型病变或肿瘤直径较大的早期患者, 手术切除在局部控制和远期复发方面一般优于单纯消融[13]. 多项指南和综述一致认为, 选择合适病例后, 早期HCC肝切除后的5年总生存率可达到60%-80%[14]. 对于CNLC Ⅱa期以及部分病灶局限于同一肝段或同侧半肝的Ⅱb期患者, 若肝功能和残肝条件允许, 仍可通过解剖性切除[15]、联合局部消融或分次手术获得根治机会[2].
在CNLC Ⅲ期患者中, 手术不应被常规化使用, 但也不应被简单排除[1]. 对于门静脉癌栓范围有限、病灶主要局限于半肝、肝功能良好的患者, 经MDT讨论后可考虑切除联合取栓[16], 部分门静脉癌栓患者也可以从切除策略中获益[17], 尤其是在接受术前转化治疗并获得影像学降期患者中, 手术可能显著改善远期结局[18]. 不过, 这类患者的获益高度依赖临床经验、手术安全性和后续辅助治疗[19].
从预后角度看, 手术切除后的长期结局受分期、肿瘤生物学行为和复发风险共同影响[20]. 微血管侵犯[21]、多发病灶、肿瘤大于5 cm、AFP持续升高以及背景肝病活动度高, 均提示术后复发风险增加[22]. 故对于高危复发患者, 可在规范随访基础上, 结合病理分期考虑联合TACE[23]、临床试验或系统治疗[24], 对于伴门静脉癌栓或微血管侵犯等高危亚组, 联合证据来自临床研究[25]、随机研究[26]、倾向评分分析[27]和Meta分析[28], 及术后肝动脉灌注化疗(hepatic arterial infusion chemotherapy, HAIC)等策略[29,30], 但目前围手术期辅助策略仍在持续演进中, 需避免一刀切的使用[31].
TACE是中期原发性肝癌最经典、证据最充分的局部治疗方式之一[8]. 其基本机制在于利用肝癌主要由肝动脉供血的特点, 将化疗药物和栓塞材料选择性送达肿瘤供血动脉, 从而实现局部高药物浓度和缺血坏死[32]. 在CNLC框架下, TACE最重要的定位并不是"所有中晚期患者都可重复实施的标准程序", 而是中期不可切除HCC的治疗基础, 并可作为桥接、降期或联合治疗的平台[1].
对于CNLC Ⅰ期而不适合手术或消融的患者, TACE可作为替代或桥接治疗, 但并不应轻易替代根治性治疗[1]. 对于CNLC Ⅱ期、尤其是多发结节但无主干门静脉侵犯、肝功能较好的患者, TACE仍是标准基础治疗[8]. 经典随机研究及后续系统评价提示, TACE相较于对症支持治疗能够改善生存[33], 部分研究显示2年生存率可由约11%提高至31%左右[34], 系统评价也支持TACE在不可切除HCC中的生存获益[35]. 在技术层面, 传统TACE与载药微球TACE在总体疗效上差异并不稳定, 但后者在部分研究中显示出更低的全身毒性和更可控的药物释放过程[32].
对于CNLC Ⅲ期患者, TACE的应用更需要选择性[1]. 若存在较好的侧支循环、肿瘤负荷或以肝内病灶为主且肝功能尚可, TACE仍可用于局部减瘤、症状控制或为后续联合系统治疗创造条件[36]; 但对于主干门静脉完全阻塞、胆红素明显升高或反复TACE后肝功能下降的患者, 则应警惕治疗相关肝衰竭风险[8]. 现代指南更强调"TACE适合性"与"TACE难治"概念: 若连续TACE后仍无法获得客观缓解, 或治疗间隔缩短、肝功能恶化, 则应及时转入系统治疗而非机械重复介入[5].
从预后看, TACE治疗后中位总生存期常见于20-30 mo区间[37], 但该数据明显受患者选择影响[8]. 对中期肿瘤负荷较低、肝功能好的患者, 其获益最为明确[35]; 而对血管侵犯明显或肝外转移患者, 单纯TACE的长期获益有限, 更适合作为联合治疗的一部分[36].
需要注意的是TACE是否继续重复, 不宜以固定次数作为唯一依据, 而应在每次治疗后结合改良实体瘤疗效评价标准(modified response evaluation criteria in solid tumors, mRECIST)影像反应、残余活性肿瘤分布、Child-Pugh变化、胆红素和腹水、治疗间隔、门静脉侵犯或肝外转移进行再评价. 当连续治疗仍缺乏有意义的肿瘤控制, 或肝功能储备下降使下一次栓塞的风险超过预期获益时, 应及时由MDT讨论转入系统治疗、局部系统联合或支持治疗, 而非机械重复介入[5,8,38].
TACE联合局部消融(主要包括射频消融和微波消融)是"局部强化治疗"的典型代表, 其理论基础在于: TACE先行减少肿瘤血供, 可削弱热沉效应并增加消融边界的有效性[8]; 而消融又可弥补TACE难以彻底杀灭残余活性肿瘤的局限[39]. 因此, 该组合特别适用于单发但直径偏大、或结节数有限而单纯消融难以完整覆盖的患者[40].
在CNLCⅠ期患者中, 若肿瘤直径接近或超过单纯消融的理想范围, 而患者又不适合手术, TACE+消融可作为重要替代方案[11]. 既往研究提示[41], 对于较大肿瘤, 联合治疗在局部控制率和远期生存方面优于单纯消融; 有研究报道联合治疗1、3、5年总生存率分别约为94%、69%和46%, 优于单纯消融组[42]. 在CNLCⅡ期中, 对于2-3个结节、最大径处于"消融可及但单独消融不够稳妥"的患者, 该策略亦可作为介于手术与单纯TACE之间的折中方案[43].
从临床决策角度看[44], TACE+消融的价值并不在于"取代手术", 而在于为不适合切除或希望保留更多肝实质的患者提供接近根治的局部治疗机会. 尤其对于高龄、合并基础肝病、病灶位置较深但仍可穿刺到达的患者, 联合治疗有助于兼顾肿瘤控制与安全性[39]. 另一方面, 该模式也常被用于肝移植等待期的桥接治疗和部分降期治疗[7].
预后方面, TACE+消融在严格选择人群中可获得优于单纯TACE或单纯消融的局部控制效果, 但其长期生存仍受到多灶性、复发及肝病进展的影响[40]. 因此, 治疗后影像学随访和复发后再治疗策略同样决定最终结局[45].
TACE+消融的优势更应以局部肿瘤控制、完全坏死率、术后复发率、RFS及OS的综合表现评价, 而不是仅以单次影像缩小率判断. 对于肿瘤位置高危、肝功能边缘或多灶性明显的患者, 联合治疗的局部获益可能被穿刺风险、肝实质损失和后续复发所抵消. 因此, 应在可达到安全消融边界且不延误根治性切除的前提下实施, 慎重做出决策.
手术切除、TACE和消融三者联合, 体现的是"以根治为导向的多模式整合"思想[2]. 此类策略通常用于肿瘤负荷复杂、双侧分布、多中心发生、邻近重要血管或胆管, 难以单一方式完全处理的患者. 其本质不是简单叠加治疗次数, 而是在不同治疗方式之间进行功能互补: 手术用于去除主瘤或大体的肿瘤负荷, 消融用于处理深部、小卫星灶或保肝需求较高区域的病灶, TACE则用于术前降期、术后辅助或残余病灶控制[23].
在CNLC Ⅱ期患者中, 如果病灶分布不适合一次性广泛切除, 但存在"主病灶可切、边缘或对侧小病灶可消融"的解剖条件, 则可考虑切除联合术中或术后消融, 以提高总体清除率并减少不必要的肝实质去除[2]. 对于术后病理提示微血管侵犯、肿瘤负荷较大或存在高复发风险者, 辅助TACE在中国人群中有一定应用基础, 尤其在乙肝相关HCC中被认为可能降低早期复发风险[26].
在CNLC Ⅲ期或"边界可切除"患者中, 这一多模式路径更多体现为转化治疗后的"综合收尾": 先以TACE或HAIC联合系统治疗降低肿瘤活性[46], 再行切除; 对残余难处理灶辅以消融; 术后根据复发风险决定是否追加TACE[27]或系统治疗[29]. 现有证据提示[47], 这一策略可使部分原本不可切除患者重新获得根治机会, 但其证据来源仍以回顾性研究和中心经验为主, 需在高水平肝癌治疗中心实施.
从预后看, 多模式联合治疗的核心价值在于提升"治疗完成度"和"可切除率", 而非保证所有患者都获得同等长期生存[12]. 对于成功转化并完成手术的患者, 部分研究报道5年总生存率可超过50%, 但这一结果高度依赖患者筛选[48]. 故临床上更应强调"精准联合", 而不是"越多越好"的治疗累加[1].
对边界可切除或初始不可切除患者, 转化成功的判断不应只依据最长径缩小, 而应同时确认残余肿瘤活性、血管侵犯范围、术后残肝大小、技术性R0可切除性及全身治疗相关肝损伤. 建议以mRECIST动态影像反应、AFP下降趋势和肝储备稳定性作为是否进入切除或消融阶段的重要信号. 一旦获得可切除窗口, 应及时由外科、介入和肿瘤内科共同确认治疗时序, 避免因无终点的联合治疗错失根治机会[1,38].
以抗血管生成药物联合免疫检查点抑制剂为代表的靶向免疫治疗, 已成为不可切除或晚期HCC系统治疗的核心方向[3]. 其治疗逻辑在于, 肿瘤血管异常和免疫抑制微环境是HCC进展的重要生物学基础, 抗血管生成治疗可重塑免疫抑制性微环境并增强免疫治疗反应[49], 二者具有明确的协同潜力[50]. 不同免疫联合方案的相对疗效仍需结合Meta分析和相关证据的更新[51,52].
在CNLC Ⅱ期患者中, 当肿瘤呈弥漫浸润型、多灶广泛分布, 或者评估为TACE不适合或多次TACE后获益有限时, 应尽早转入系统治疗, 而不宜无限期坚持局部介入[53]. 对于CNLC Ⅲ期尤其伴大血管侵犯或肝外转移的患者, 靶向免疫更是治疗基础[3]. 目前证据最充分的一线方案包括阿替利珠单抗联合贝伐珠单抗(T+A方案)[3], 以及度伐利尤单抗联合曲美木单抗(STRIDE方案)[54], 两者均在Ⅲ期研究中显示出较索拉非尼更优的总生存获益[55]. 在中国临床实践中, 部分程序性死亡蛋白1(programmed cell death protein 1, PD-1)抑制剂联合小分子酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)方案也积累了Ⅱ期研究和真实世界数据[56], 多纳非尼等TKI研究也提供了证据[57], 及帕博利珠单抗二线治疗证据, 但其证据等级和适用边界仍需结合指南更新谨慎把握[58].
靶向免疫在转化治疗中的价值尤其值得关注[12]. 对于初始不可切除但未出现广泛肝外播散的CNLC Ⅲ期患者, 靶向免疫可作为转化治疗基础方案, 并与HAIC、TACE或放疗等局部治疗联合, 以提高客观缓解率和后续切除率[46]. 不过, 转化成功并不意味着治疗终点的提前到来, 何时评估可切除、何时停药、术后是否继续维持治疗, 仍需依据影像学、AFP动态和手术风险综合判断[59]. 部分研究进一步表明[48], 达到完全缓解或药物停用状态的患者仍需在治疗框架下动态随访.
从预后层面看, 靶向免疫显著改写了晚期HCC的一线治疗结局, 使部分患者由"短期控瘤"转向"长期生存"成为可能[3]. 索拉非尼相关研究构成了晚期HCC系统治疗早期基础[60], 仑伐替尼则提供了一线TKI替代选择[53]; 在序贯治疗中, 瑞戈非尼[61]、卡博替尼[62]和雷莫芦单抗[63]等证据构成后线方案基础. 免疫治疗方面, 纳武利尤单抗研究提示疗效存在明显个体差异[64], Ⅲ期比较研究也提示不同人群获益并不完全一致[65]; 联合免疫治疗为既往治疗后患者提供了新证据[66], 长期随访有助于理解持续获益和安全性[67]. 消化道出血风险、肝炎病毒再激活及肝功能波动均需严密监测[68], Child-Pugh B患者更需审慎评估[69]. 因此, 系统治疗的开展同样离不开MDT支持[1].
除T+A和STRIDE方案外, CARES-310研究显示卡瑞利珠单抗联合阿帕替尼组的中位无进展生存期显著长于索拉非尼组[5.6 mo vs 3.7 mo, 危险比(hazard ratio, HR) = 0.52], 同时中位总生存期同样长于索拉非尼组(22.1 mo vs 15.2 mo, HR = 0.62); CheckMate 9DW研究显示纳武利尤单抗联合伊匹木单抗相较仑伐替尼或索拉非尼显著改善了总生存期, 可带来OS获益(中位OS 23.7 mo vs 20.6 mo, HR = 0.79)[70,71]. 但这些研究的对照方案、入组人群、病因构成和后续治疗并不完全一致, 不能据此进行跨试验疗效排名. 方案选择应优先结合出血风险及抗血管内皮生长因子(vascular endothelial growth factor, VEGF)禁忌、免疫相关不良反应风险、自身免疫病或器官移植史、病毒复制状态、肝功能、体能状态和本地获批适应证; 任何监管状态均需以治疗所在地最新指南为准.
TACE与靶向免疫的结合, 是近年来原发性肝癌治疗最受关注的进展之一[72]. 该策略的理论基础较为清晰: TACE造成肿瘤坏死后可释放肿瘤抗原, 增强抗肿瘤免疫原性[8]; 与此同时, TACE后缺氧可诱导VEGF上调, 促进残余肿瘤新生血管形成, 而抗血管生成药物有望逆转这一变化[49]; 免疫检查点抑制剂则进一步放大抗肿瘤免疫反应[50]. 因此, 这一组合体现了"局部减瘤+全身调控"的双重优势[2]. 既往TACE联合索拉非尼研究为局部治疗联合系统治疗提供了重要基础[73], TACTICS研究则进一步推动了联合模式的证据积累[74].
在CNLC Ⅱ期不可切除、非转移性HCC中, LEAP-012研究提供了目前等级较高的循证依据[75]. 该Ⅲ期随机研究显示, TACE联合仑伐替尼+帕博利珠单抗较TACE联合安慰剂可显著延长无进展生存期(中位PFS 14.6 mo vs 10.0 mo)(HR = 0.66, 95%CI: 0.51-0.84), 并提高ORR(47% vs 33%),而总生存虽呈数值改善趋势, 但在当次分析时尚未达到统计学显著性[75]. 基于这些数据, 仑伐替尼加帕博利珠单抗联合TACE可能是不可切除、非转移性HCC患者的一种新治疗选择. 同时, 帕博利珠单抗(抗PD-1)在2024年被美国食品药品监督管理局和中国国家药品监督管理局药品审评中心批准作为二线单药疗法, 用于接受过除含PD-1或程序性死亡配体1抑制剂方案以外的先前全身治疗的HCC患者[58]. 更严谨的表达是: TACE+靶向免疫为中期不可切除HCC提供了强有力的新证据, 正在推动TACE单药模式向联合模式转变, 而不是对所有中期患者"完全替代"传统策略[75].
在CNLC Ⅲ期患者中, TACE或HAIC联合靶向免疫更多承担转化治疗任务[12]. 对于以肝内病灶和局限性血管侵犯为主、无广泛肝外转移的患者, 该策略有望提高缓解率并为后续切除创造条件[46]. 已有研究和综述提示, 此类联合治疗在部分人群中可获得较高ORR, 但现阶段证据仍以单臂研究、回顾性队列为主, 病例选择偏倚较大, 因此仍需更多前瞻性研究明确其最佳人群、治疗时序与终点设置[47].
从预后看, TACE+靶向免疫最大的意义在于提升"从局部控制走向全程管理"的可能性[72]. 对中期患者, 它可能延缓进展并减少单纯反复TACE带来的肝功能损伤[74]; 对部分晚期患者, 它则有望成为转化桥梁[12]. 然而, 这一策略的安全性管理同样复杂, 包括肝功能波动、栓塞后综合征、高血压、蛋白尿、免疫性肝炎等, 需在经验丰富的临床团队中实施[75].
EMERALD-1研究显示[76], 在栓塞可及的不可切除HCC中, 度伐利尤单抗+贝伐珠单抗+TACE较TACE使中位PFS由8.2 mo延长至15.0 mo(HR = 0.77); 而度伐利尤单抗+TACE未显示同等PFS优势. 该结果支持"免疫+抗VEGF+TACE"作为特定患者的可选强化策略, 但不应直接将PFS改善等同于已经证实的OS改善, 也不应据此忽略治疗相关肝功能波动、出血、高血压、蛋白尿以及免疫性肝炎等风险. 对所有TACE联合方案, 仍应以可栓塞性、肝储备、门静脉血流、肿瘤分布、患者偏好和可行性为前提, 并在治疗前明确下一步转换或停治标准[76](表3).
| 分组联合策略 | 关键研究(PubMed) | 适用场景 | 主要预后结果 | 安全性与证据解读 | |
| 1 | TACE+消融 | Peng等[83], 2013(RCT) | 肝内局限、病灶>3 cm或单纯 消融边界不足; 不宜手术但希望强化局部控制者 | 优于单纯TACE或单纯RFA; 代表研究提示局部控制和OS改善, TACE-RFA组和RFA组4年OS(61.8% vs 45.0%) | 主要风险为栓塞后综合征、穿刺并发症、热损伤; 适合"接近根治"的局部强化场景 |
| 2 | 切除+辅助TACE(±局灶消融) | Wei等[26], 2018(RCT); Wang等[84], 2018; Esagian等[85], 2021(Meta分析) | 高复发风险术后患者, 如MVI、多灶、肿瘤较大、HBV相关HCC | 以RFS和OS改善为主, 但并非所有切除后患者均获益 | 证据更偏向亚洲/乙肝相关人群; 需警惕肝功能损伤, 强调选择性应用 |
| 3 | 阿替利珠单抗+贝伐珠单抗 | IMbrave150, Cheng等[86], (2022更新) | 不可切除或晚期HCC一线治疗 | OS 19.2 mo vs 13.4 mo; PFS 6.9 mo vs 4.3 mo(对比索拉非尼) | 需关注出血、高血压、蛋白尿及免疫性肝炎; 已成为重要一线标准方案之一 |
| 4 | 曲美木单抗+度伐利尤单抗(STRIDE) | Himalaya, Abou-Alfa等[54], 2022 | 不可切除或晚期HCC一线治疗; 抗VEGF不适宜者可考虑 | OS 16.4 mo vs 13.8 mo(对比索拉非尼); PFS优势不突出 | 双免疫方案可带来OS获益, 但需警惕免疫相关不良反应 |
| 5 | 卡瑞利珠单抗+阿帕替尼 | CARES-310, Qin等[71], 2023 | 不可切除HCC一线治疗, 尤其是中国/亚洲实践中具有代表性 | OS 22.1 mo vs 15.2 mo; PFS 5.6 mo vs 3.7 mo(对比索拉非尼) | 需关注高血压、蛋白尿、手足综合征及免疫不良反应; 为中国方案提供强证据 |
| 6 | TACE+索拉非尼 | TACTICS, Kudo等[74], 2020; TACTICS最终分析Kudo等[72], 2022 | 中期不可切除HCC; 作为"TACE联合系统治疗"奠基模式 | PFS显著延长(约25.2 mo vs 13.5 mo)OS呈改善趋势但证据相对有限 | 提示联合系统治疗可减少无效重复TACE, 但并非免疫时代最终答案 |
| 7 | TACE+仑伐替尼+帕博利珠单抗 | LEAP-012, Kudo等[75], 2025 | 不可切除、非转移性中期HCC | PFS 14.6 mo vs 10.0 mo; ORR 47% vs 33%; OS在当次分析时尚未达到统计学显著 | 为中期HCC联合模式提供高等级新证据; 但"PFS改善"不应直接等同"OS已确证" |
| 8 | TACE+度伐利尤单抗+贝伐珠单抗 | EMERALD-1, Sangro等[76], 2025 | 可栓塞的不可切除HCC | PFS 15.0 mo vs 8.2 mo (对比TACE); OS尚未确证; 度伐利尤单抗+TACE未显示同等PFS优势 | 需关注出血、高血压、蛋白尿和免疫性肝炎; 三联强化策略需要严格筛选人群 |
肝移植是原发性肝癌最具"病灶清除+基础肝病纠正"双重意义的根治性治疗方式[77]. 对合并肝硬化、门静脉高压或肝功能失代偿的早期HCC患者而言, 肝移植相较单纯肝切除更能同时解决肿瘤与致癌土壤问题[11]. 因此, 肝移植在原发性肝癌综合治疗中的地位并非边缘性补充, 而是经过严格筛选后的优先根治方案之一[1].
从决策上看, 符合米兰标准的患者仍是肝移植最经典的获益人群, 其5年总生存率通常可达70%-80%[77]. 随着降期理念的发展, 部分初始超出米兰标准但经TACE、消融或放疗等桥接/降期治疗后达到可接受范围、且肿瘤生物学行为良好的患者, 也可在严格评估后进入移植通道[78]. 相比单纯以肿瘤大小和数目为依据, 现代移植决策更强调AFP水平、治疗反应和等待期稳定性等"生物学筛选指标"[7]. 对于超出米兰标准的患者, 降期后稳定性和筛选质量尤为关键[79].
在等待移植期间, TACE、消融乃至立体定向放疗均可作为桥接治疗, 以减少等待期进展和脱落风险[80]. 对于部分CNLC Ⅱ期甚至超出传统标准但成功降期的患者, 移植仍可能带来长期生存获益[78]. 但必须指出, 移植机会受供肝资源、等待时间、基础肝病状态及中心经验等多因素限制, 因此其临床应用具有明显的资源依赖性和选择性[81].
从预后角度看, 肝移植后的长期结局不仅受术前分期影响, 更与肿瘤生物学行为密切相关[82]. 对桥接或降期后稳定进入移植的患者, 治疗反应本身即可视作一种"生物学筛选"[79]. 因此, 在讨论肝移植时, 不能仅强调标准本身, 还应重视桥接或降期策略, 及等待期管理对预后的影响[7].
移植候选者的评估应由"静态肿瘤负荷"转向"静态标准+动态生物学行为": 桥接或降期后的mRECIST反应、AFP下降或持续升高、等待期稳定性、肝功能失代偿进展速度和肝外进展均影响移植获益. 对出现治疗后进展、AFP持续异常升高或肝外病灶等证据的患者, 应及时复核移植适宜性; 对稳定降期并维持肝功能者, 治疗反应本身可作为优先排序和预后沟通的重要信息[7,38].
原发性肝癌分级分阶段诊治的核心, 不在于为每一期患者预设单一答案, 而在于依据CNLC分期、肝功能与肿瘤生物学特征, 在MDT框架下为患者选择最合适的治疗路径. 总体上, 手术切除仍是早期及部分中期患者的首要根治手段; TACE仍是中期不可切除HCC的重要治疗基础, 但其价值越来越体现在联合平台而非单独反复使用; TACE+消融和手术切除+TACE+消融代表了局部强化与个体化保肝并重的思路; 靶向免疫改变了晚期HCC的一线系统治疗格局; 系统治疗: TACE+靶向免疫则显示出延缓进展和提高转化潜力的前景; 肝移植仍是严格筛选患者最具根治意义的选择之一.
未来研究需要进一步回答以下问题: 第一, 如何以生物标志物、影像学和动态AFP变化提高转化治疗和移植筛选的准确性; 第二, 如何界定TACE不适合、TACE难治以及何时由局部治疗切换至系统治疗; 第三, 如何优化围手术期和围移植期的辅助治疗策略; 第四, 如何在临床诊疗中建立以长期生存和生活质量为导向的全程管理模式. 可以预见的是, 随着指南更新和高质量临床研究积累, 原发性肝癌的综合治疗将更加精准, 也将更加重视"阶段性最优"向"全程最优"的转变.
基于上述证据, 本文提出以下建议: 第一, 任何阶段均先评估能否以切除、消融或移植实现根治, 而不因分期标签放弃可行的根治机会; 第二, 局部治疗应以"获益大于肝功能代价"为前提, 出现TACE不适合、无效或肝储备下降信号时应及时转换; 第三, 靶向免疫及其与TACE、HAIC、放疗等联合的价值, 应分别依据OS、PFS、ORR和转化切除率进行考虑, 并以影像学反应、AFP动态和肝功能维持决定后续治疗, 而非将所有联合方案泛化为同等获益; 第四, 对于拟行TACE治疗的患者, 应进行审慎、个体化的综合评估. TACE并非适用于所有HCC患者, 其获益与肿瘤负荷、最大肿瘤直径及数目、血管侵犯情况、肝功能储备、体能状态、门静脉血流及既往治疗史等因素密切相关. 尤其对于肿瘤体积较大、肝内病灶广泛、肝功能储备不足或存在明显血流动力学风险的患者, 应充分权衡潜在抗肿瘤获益与肝功能失代偿、肝衰竭等治疗相关风险, 避免因过度或反复栓塞造成不可逆肝损伤. 在治疗决策上宜秉持相对保守原则, 经多学科团队讨论后选择合适人群, 并根据治疗反应及时调整或转换治疗策略.
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学科分类: 胃肠病学和肝病学
手稿来源地: 河北省
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科学编辑: 刘继红 制作编辑:张砚梁