修回日期: 2026-07-31
接受日期: 2026-08-18
在线出版日期: 2026-10-28
肝门部胆管癌(hilar cholangiocarcinoma, HCCA)是胆道系统最常见的恶性肿瘤, 根治性R0切除为其首选治疗方案. 其起病隐匿, 多数患者初诊时因肿瘤局部浸润、远处转移或肝脏代偿功能不足而丧失手术时机. 转化治疗旨在通系统性干预将初始不可切除者转化为可切除状态, 其适用人群为经多学科诊疗评估确认为技术性或功能性不可切除者. 本文系统梳理了HCCA转化治疗的核心策略, 包括以吉西他滨联合顺铂为基础的化疗方案升级、立体定向体放射治疗的局部控瘤潜力、HER2等靶点的精准靶向治疗探索, 以及联合治疗的挑战, 成为转化治疗的重要参考. 在此基础上, 分析了联合疗法在疗效异质性、手术最佳时机、患者手术意愿等方面的核心挑战, 指出当前HCCA转化治疗证据多源于前瞻性队列与个案研究, 缺乏高质量随机对照试验验证. 未来研究需聚焦于明确转化治疗的最佳方案与适宜人群, 建立统一的可切除性评估体系, 并探索可预测疗效的生物标志物, 以推动个体化精准治疗的发展.
核心提要: 肝门部胆管癌转化治疗以GC方案联合免疫(如durvalumab)、立体定向体放射治疗局部控瘤及HER2靶向治疗最具前景, 但疗效异质性、手术时机与患者意愿构成主要挑战. 亟需随机对照试验验证最佳方案, 建立统一可切除评估体系, 并探索程序性死亡配体-1、循环肿瘤DNA等生物标志物, 推动个体化精准转化.
引文著录: 牛海鹏, 王石. 肝门部胆管癌转化治疗的现状与展望. 世界华人消化杂志 2026; 34(10): 806-815
Revised: July 31, 2026
Accepted: August 18, 2026
Published online: October 28, 2026
Hilar cholangiocarcinoma (HCCA) is the most common malignancy of the biliary tract, for which radical R0 resection remains the cornerstone of curative-intent treatment. However, due to its insidious onset, the majority of patients are precluded from surgery at the time of initial diagnosis, primarily because of locoregional tumor infiltration, distant metastasis, or insufficient hepatic functional reserve. Conversion therapy-defined as systematic interventions aimed at rendering initially unresectable disease amenable to R0 resection-is indicated for patients deemed technically or functionally unresectable after multidisciplinary team evaluation. This review systematically outlines the core strategies currently employed in HCCA conversion therapy, including optimized gemcitabine-plus-cisplatin-based chemotherapy regimens, the potential role of stereotactic body radiotherapy in achieving local tumor control, emerging precision therapies targeting HER2, and the inherent complexities associated with combination regimens. Building on this foundation, we analyze major clinical challenges, including heterogeneity in treatment response, uncertainty regarding the optimal timing of surgery, and patient willingness to undergo major resection. At present, the evidence supporting conversion therapy in HCCA is derived predominantly from prospective cohort studies and case series, with a notable paucity of high-quality randomized controlled trials. Future research should prioritize the identification of optimal conversion regimens and suitable patient candidates, the establishment of a standardized and reproducible resectability assessment framework, and the exploration of predictive biomarkers to facilitate individualized precision therapy.
- Citation: Niu HP, Wang S. Conversion therapy for hilar cholangiocarcinoma: Advances and obstacles. Shijie Huaren Xiaohua Zazhi 2026; 34(10): 806-815
- URL: https://www.wjgnet.com/1009-3079/full/v34/i10/806.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v34.i10.806
核心提要: 肝门部胆管癌转化治疗以GC方案联合免疫(如durvalumab)、立体定向体放射治疗局部控瘤及HER2靶向治疗最具前景, 但疗效异质性、手术时机与患者意愿构成主要挑战. 亟需随机对照试验验证最佳方案, 建立统一可切除评估体系, 并探索程序性死亡配体-1、循环肿瘤DNA等生物标志物, 推动个体化精准转化.
肝门部胆管癌(hilar cholangiocarcinoma, HCCA), 也称Klatskin瘤, 起源于肝门周围胆管(肝总管、左右肝管及其汇合部胆管上皮细胞)的恶性肿瘤, 其为胆道恶性肿瘤的最常见类型(40%-60%)[1-3]. HCCA的相关危险风险因素包括原发性硬化性胆管炎、胆管囊肿、寄生虫感染(如肝吸虫)、肝结石、胆石病、毒素(如Thorotrast造影剂)以及糖尿病、酒精、吸烟和肥胖等[4-6]. HCCA的流行病学显示, 其发病率虽有增长, 但死亡率趋于平稳或下降. HCCA发病率在过去20年中以年均1.2%的速度增长[6]. 从全球流行病学角度看, HCCA发病率存在显著地域差异[2]. 欧美、澳大利亚发病率仅0.35/10万-2/10万; 而肝胆吸虫流行区域(中国、韩国、泰国)发病率显著偏高, 泰国东北部可达85/10万[7]. 中国作为胆道恶性肿瘤高负担国家, 胆道恶性肿瘤(含HCCA)发病率存在显著城乡和东西差异, 城市地区粗发病率为4.94/10万, 农村地区为2.83/10万; 东部发达地区(4.57/10万)显著高于中部(2.99/10万)和西部(3.16/10万)[8]. 随着过去几十年来, 腹腔镜胆囊切除术的日益普及, HCCA死亡率在全球多个地区趋于平稳或下降[9].
目前最有效治疗HCCA的方法仍是外科手术行R0切除. 由于HCCA起病隐匿, 早期诊断困难, 常在疾病显著进展时方可确诊, 严重限制治疗策略的选择, 并导致患者预后不良[10]. 多项国际大型研究表明[7,11], 约70%因血管受累(门静脉/肝动脉包绕)、双侧胆管广泛浸润(Bismuth-Corlette Ⅳ型)、远处转移或未来剩余肝体积(future liver remnant, FLR)不足而丧失手术机会. 英国全国CAPBIL研究显示[9], 初次评估时仅32%的HCCA患者接受根治性切除, 其余68%接受姑息治疗或支持治疗. 美国纪念斯隆-凯特琳癌症中心的数据进一步表明, 在拟行根治性手术的HCCA患者中经腹腔镜探查后仅42%最终完成R0切除, 其余58%因腹腔种植、肝内转移或解剖学不可切除因素而中止[11]. 但接受根治性手术的患者5年生存率不足40%, 且复发率较高, 仍预后不理想[12,13]. 这组数据明确表明HCCA患者可能从有效的转化治疗中获益.
随着多学科诊疗(multidisciplinary team, MDT)深入发展和系统治疗策略多元化, 化疗、靶向治疗、免疫治疗及其联合方案在改善患者生存预后取得良好效果. 转化治疗旨在利用积极干预措施管理或逆转肿瘤进展, 实现将不可切除的HCCA转变为可切除状态[14,15]. 转化治疗有助于提高适合R0切除患者的比例, 并延长其长期生存率[16-18]. 目前HCCA转化治疗证据多源于前瞻性队列与个案积累, 仍需高质量随机对照试验(randomized controlled trial, RCT)明确转化治疗方案能否改善患者的中位总生存期(overall survival, mOS)和无进展生存期(progression-free survival, PFS)[18-21]. 随着治疗方法的优化, 未来研究应聚焦于明确HCCA最有效的转化治疗方案及合理的患者筛选标准, 以提高适合根治性切除患者比例, 从而显著改善其长期生存结局.
HCCA的围手术期系统治疗, 存在三个密切相关但本质不同的概念[2,3,15,18]: (1)新辅助治疗: 适用于初始评估为可切除的HCCA患者, 在计划性根治手术前给予系统治疗. 其治疗终点为: 提高R0切除率; 清除微小转移灶、降低术后复发率; 筛选肿瘤生物学行为良好的患者(对治疗敏感者)接受手术, 避免短期内快速进展者承受不必要的手术创伤; (2)交界可切除新辅助治疗: 适用于介于明确可切除与明确不可切除之间的交界可切除HCCA患者. 这类患者的肿瘤在解剖学上接近可切除标准, 但存在以下一项或多项风险因素: 单侧门静脉或肝动脉可疑受累(可尝试重建); FLR处于临界值(正常肝25%-30%, 硬化肝<40%); 区域淋巴结可疑转移但未超出根治清扫范围. 其治疗终点与转化治疗有所重叠, 但核心差异在于, 交界可切除患者通过较短周期(通常2-4周期)的系统治疗, 目标是降期至可切除状态而非从不可切除翻转为可切除; 和(3)不可切除转化治疗: 适用于初始明确不可切除的局部晚期HCCA患者. 其治疗终点为: 通过单纯系统治疗或联合局部治疗使肿瘤显著降期, 达到技术上可R0切除、FLR满足要求、且无新发远处转移的标准.
转化治疗法最初用于肝细胞癌(hepatocellular carcinoma, HCC)患者, 通过联合治疗减轻肿瘤负荷, 使患者适合手术切除[22]. 其逐渐在HCCA领域受到关注, 但与其他胃肠恶性肿瘤中转化治疗相比, HCCA转化率较低[23]. 目前晚期胆道肿瘤一线治疗吉西他滨联合顺铂(GC方案), 其客观缓解率(objective response rate, ORR)仅为15%-25%之间, 且中位PFS低于6 mo[11]. 系统性和局部区域治疗的进步让部分患者有机会通过转化治疗获得R0切除, 改善预后. 面对FLR不足的患者, 联合门静脉栓塞术(portal vein embolization, PVE)和肝静脉栓塞术能迅速提高HCCA患者的FLR肥大和切除率, 术后90 d未出现死亡病例, 中位mOS约为20.2个月[24]. 此外, 晚期HCCA患者在替雷利珠单抗加仑伐替尼和GEMOX方案进行转化治疗, R0切除率为33%(P = 0.15), ORR为33%(P = 0.71)[17]. 转化治疗通过系统治疗、靶向治疗、免疫疗法以及扩大患者FLR等积极治疗方式使不可切除转变为可切除, 在延长疗效方面具有显著潜力. 相比之下, 姑息治疗核心在于胆道引流通畅并提升生活质量, 主要手段包括经皮经肝胆道引流术/经皮经肝穿刺胆道支架置入术、经内镜鼻胆管引流术、胆道支架引流及胆道手术引流, 其用于晚期HCCA患者, 对肿瘤本身的治疗效果较差[25]. 因此, 如何确定HCCA的不可切除和患者选择至关重要.
转化治疗的患者筛选, 建议综合四个维度进行可切除性评估[2,3,26]: (1)从解剖学维度, 通过计算机断层扫描、核磁共振成像及磁共振胰胆管成像评估胆管受累范围(Bismuth-Corlette分型)、判断是否存在远处转移(器官、腹膜和远处淋巴结等)、血管侵犯程度(门静脉或肝动脉的可切除性)及FLR占比情况(正常肝≥25%-30%, 硬化或化疗后≥40%); (2)从生物学维度, 观察患者肿瘤标志物动态变化[糖类抗原19-9(carbohydrate antigen 19-9, CA19-9)、癌胚抗原]、循环肿瘤DNA(circulating tumor DNA, ctDNA)、肿瘤分化程度及分子亚型; (3)从功能学维度, 进行吲哚菁绿清除试验、肝脏弹性成像、美国东部肿瘤协作组体力状况评分(Eastern Cooperative Oncology Group Performance Status, ECOG)体力状况评分, 其中0-1分适合强化方案; 和(4)最后由胆道外科、肿瘤内科、放疗科、影像科、病理科及介入科专家共同决策(MDT), 综合判断肿瘤对胆管及邻近区域组织内的累及情况, 以及胆管、血管结构可否保持完整或重建, 达标后方可进入转化治疗路径[2,3,26-29]. 目前HCCA中转化治疗的适应症尚无明确标准, 该框架的核心优势在于将"不可切除"从单一解剖学定义升级为多维动态评估, 避免因单一维度判断偏差而错失转化机会[26].
2010年ABC-02研究[30]确立吉西他滨联合顺铂(GC方案)为晚期胆道系统肿瘤的一线治疗, 其ORR达26%, 成为后续新药研发的重要对照基准. 2023-2024年报道了三种三联方案: GC+S-1(替吉奥, 替加氟-吉美嘧啶-奥替拉西钾)、GC+durvalumab[一种抗编程性死亡配体-1(programmed death ligand-1, PD-L1)抗体]和GC+pembrolizumab[一种抗程序性死亡1(programmed death 1, PD-1)抗体], ORR为27%-42%(GC, 15%-29%), 肿瘤控制率为75%-85%(GC, 62%-83%), 不良事件略有增加, R0切除率约为22.9%[31]. 上述三联方案相较于GC方案, ORR提升了约10%-15%, 但R0切除率提升幅度相对有限(约5%-10%). Dong等[18]报告71例接受吉西他滨+顺铂+白蛋白紫杉醇(GCN/GAP方案)后, ORR达50.0%, 疾病控制率(disease control rate, DCR)达94.1%, 转化切除率为47.9%, 切除者mOS高达68.7 mo对比未切除者24.4 mo(P<0.001)[15]. 一项回顾性研究[32]评估了新辅助化疗在局部晚期HCCA的疗效. 术前接受新辅助联合化疗使肿瘤降期并提高肿瘤的切除率, 但未显著延长无病生存期和总生存期. Kuriyama等[33]表明吉西他滨联合替吉奥让局部晚期切除率达30.0%. 一项病例报告报道[34], 初始不可切除的Bismuth-Corlette Ⅳ型HCCA患者通过吉西他滨+奥沙利铂(GemOx方案)联合免疫检查点抑制剂方案, 显示肿瘤显著退缩, 使根治性切除成为可能. 在评估化疗转化方案时, R0切除率是比ORR更具临床决策价值的终点指标. 仍需RCT证明新辅助治疗是否能改善患者的总生存期和PFS(表1).
立体定向体放射治疗(stereotactic body radiotherapy, SBRT)能够在精确的解剖区域施加高剂量辐射, 同时尽可能减少危机器官的伤害, 在HCC及胆管癌局部控制中展现出显著优势[35,36]. 对于传统消融难以实施肿瘤, SBRT有效诱导肿瘤退缩并缓解血管包绕, 为后续手术创造条件. STRONG Ⅱ期研究[37](NCT06493734)作为辅助转化研究, 1年局部肿瘤控制率为80%(95%CI), 提示了SBRT可以局部有效控制HCCA肿瘤生长并保持或改善患者生活质量的能力. 一项回顾性研究提示[38], 对于局部晚期胆管癌患者使用SBRT可以有效控制肿瘤生长. 2025年中国专家共识指出[3], 在系统性治疗后疾病稳定(stable disease, SD)或部分缓解(partial response, PR)但仍未达到切除标准者, 联合SBRT作为局部强化可能进一步提升转化成功率. 但需注意放疗后手术的时机, 目前建议SBRT后至少间隔4 wk再行手术评估[34]. SBRT对于转化治疗有着很大的潜力, 但目前仅有少量前瞻性和回顾性研究, 需RCT进一步探讨其SBRT与系统治疗的联合应用是否有助于转化治疗.
随着高通量测序技术的普及, 晚期胆道癌诊疗已进入精准治疗时代, HCCA主要为HER2突变、NTRK融合突变和RET融合突变, 其临床研究[2,3]均为早期试验, 均为后线治疗, 但由于临床数据获益良好, 用于HCCA治疗.
约15%的HCCA出现HER2基因中的改变(扩增、过表达或突变), 这使HER2成为HCCA最具转化潜力的靶向治疗靶点[39,40]. 目前主要有联合使用抗HER2单克隆抗体曲妥珠单抗和帕妥珠单抗、HER2抗体药物偶联物曲妥珠单抗-德鲁昔单抗、曲妥珠单抗与改良FOLFOX方案联合使用、双特异性抗HER2抗体扎尼达单抗以及曲妥珠单抗与图卡替尼联合使用等不同HER2抑制策略, 其ORR在23%至47%之间, PFS为4.0-5.5 mo, 中位mOS为7.1-10.9 mo[40-45]. 值得注意的是, HER2抑制剂目前处于早期临床试验阶段. HERIZON-BTC-01研究[40](n = 80 HER2+ BTC)显示扎尼达单抗(zanidatamab)的ORR达41.3%(95%CI: 30.4-52.8), mOS为15.5 mo. 然而, 目前尚无专门针对HER2靶向治疗用于HCCA转化治疗的RCT数据. 对于一线免疫+化疗进展后检出可靶向突变的患者, 可选择相应靶向药物作为二线转化尝试[2].
NTRK基因融合、RET融合在胆管癌的发生率均低于1%[40,46]. 针对NTRK融合突变的患者, 主要使用恩曲替尼(entrectinib)和拉罗替尼(larotrectinib), ORR可达57%-75%[43]. 针对RET融合突变的患者, 主要有普拉替尼(pralsetinib)和塞普替尼(selpercatinib)[2,3]. 虽NTRK基因融合、RET融合不作为常规筛查标志物, 但相关临床试验显示在具有突变基因的患者中获益明显. 高度微卫星不稳定/错配修复缺陷(MSI-H/dMMR)在全部胆管癌中占比<5%, KEYNOTE-168(KEYNOTE-158)Ⅱ期篮子研究表明[43], 其ORR为40.9%, mOS为24.3 mo, 可用作临床治疗靶点(表2).
随着肿瘤免疫研究的进展, 越来越多的研究聚焦于PD-1、其配体(PD-L1)抑制剂. 研究表明[47], PD-L1在HCCA组织中呈显著异质性表达, 不仅存在于肿瘤细胞膜上, 亦广泛分布于肿瘤相关成纤维细胞及髓系来源抑制细胞等基质成分中. PD-1及其配体PD-L1抑制剂已在HCC治疗中确立重要地位, 但胆管癌现有的免疫治疗方案尚未实现突破性进展[15]. TOPAZ-1研究结果显示[48], durvalumab与GC联合使用延长了无法切除晚期胆管癌患者的生存期, 手术切除组3年mOS率68.5%对比未手术组17.6%(P = 0.026), R0切除率达91.3%. 一项Ⅲ期RCT(KEYNOTE-966)证实[49], 在晚期胆管癌的治疗中, 帕博利珠单抗联合吉西他滨/顺铂可显著延长患者mOS 12.7 mo. TOPAZ-1和KEYNOTE-966临床试验[18]确认了针对PD-1和PD-L1的免疫检查点抑制剂与化疗联合治疗晚期胆管癌的疗效. 值得注意的是, 一项专门针对胆道恶性肿瘤的研究(n = 21, 含4例HCCA)[19]表明, 卡瑞利珠单抗(camrelizumab)联合化疗的ORR达38.1%, 其中HCCA亚组TNM降期率50%, 转化切除率为25%. 此外, ZSAB-TransGOLP Ⅱ期前瞻性研究[17]证实替雷利珠单抗(tislelizumab)联合仑伐替尼和GEMOX的ORR为33%, 转化R0切除率为33%. 针对HCCA, 其治疗方案的差异会影响结果的可比性和可靠性, 需进一步RCT研究, 减少偏倚(表3).
| 联合方案 | 研究类型 | ORR(%) | DCR(%) | R0切除率 | 转化切除率 | mOS | 循证等级 |
| GC+Durvalumab[48] | Phase Ⅲ RCT | 26.7 | 85.3 | 91 | 46 | 12.9 mo | 1A |
| GC+Pembrolizumab[49] | Phase Ⅲ RCT | 29 | 83 | 数据有限 | 数据有限 | 12.7 mo | 1A |
| GEMOX+Len+Pembro[50] | 回顾性 | 38-55 | 78.9-87.5 | 数据有限 | 8.5 | 17.3 mo | 3 |
| PD-1/L1+TKIs±Chemo[51] | 回顾性 | 22-40 | 70-80 | 91.3 | 12 | 28.5 mo | 3 |
| S-1+nab-PTX+Camrelizumab[19] | 回顾性 | 38.1 | 50 | 25 | 25 | 个案报道 | 3 |
| Tislelizumab+Len+GEMOX[17] | Ⅱ期前瞻性 | 33 | - | 33 | 33 | - | 2B |
与化疗、靶向或免疫的肿瘤降期不同, 扩大FLR属于功能性不可切除的转化治疗, 两者可序贯或联合应用. 肝切除术后肝衰竭(posthepatectomy liver failure, PHLF)发生在大范围肝切除术后, 其导致术后高死亡率, 而充足的FLR是降低PHLF风险的关键因素[48]. 随着对于疾病研究不断深入, 联合肝脏离断及门脉结扎的分次肝切除术(associating liver partition and portal vein ligation for staged hepatectomy, ALPPS)被应用于HCCA患者, 这种两期肝切除术, 在第一阶段将有占位侵犯的肝脏与正常肝组织离断并结扎患侧门静脉, 与PVE相比, 可以促进FLR的快速肥大. 在FLR不足的情况下, ALPPS使患者有可能完全切除肿瘤, 并有助于降低围手术期发病率[50]. 改良ALPPS技术使FLR体积倍增时间缩短至9.3±2.1 d(传统PVE 21.5±4.3 d), 术后90 d死亡率降低至8.2%(vs PVE组15.6%, P = 0.04)[51]. 尤其高肿瘤切除性和FLR肥厚的快速诱导潜力, 对于HCCA可以考虑ALPPS[52]. 但其在转化治疗中的潜力, 还需展开进一步研究.
光动力疗法(photodynamic therapy, PDT)是一种新兴的姑息治疗方法, 涉及静脉注射对恶性细胞具有亲和力的光敏剂. 给药后, 特定波长的光激活光敏剂, 诱导肿瘤细胞坏死[53]. 目前, PDT作为非切除性闭合胸结的姑息治疗辅助, 配合胆道支架治疗. 临床数据显示, PDT可显著改善恶性梗阻性黄疸患者的胆道通畅率, 延长支架通畅时间达6-9 mo[54]. 一项研究[55]证实了PDT作为新辅助疗法的安全性, 证明其在将肿瘤从不可切除降级到可切除方面具有疗效. 与传统治疗相比, PDT在减少对正常组织的损伤和消除小病灶方面具有优势. 但PDT+支架置入后, 患者可能需要长期服用抗凝药物, 会导致凝血功能异常; 同时PDT后的局部炎症反应或组织修复也会引发胆管炎和胆管狭窄[56]. 这些结果表明, 需要大规模的RCT来证实其疗效, 应慎重选择PDT的适合人群.
转化后手术评估时机是MDT的核心决策之一. 2025年中国专家共识提出以下标准化评估流程[2,3]: ①启动阶段: 转化治疗2-4 wk期后进行首次MDT评估, 基于RECIST 1.1/mRECIST/iRECIST标准行影像学再评估, 同步检测CA19-9和ctDNA动态变化(Grade B, 100%一致); ②延续阶段: 若PR且体力状况(performance status, PS)良好(ECOG 0-1), 继续治疗至4-6周期后再次MDT评估可切除性; ③停药窗口: 化疗停药3-6 wk, PD-1/PD-L1抑制剂停药2-4 wk, 小分子酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)停药≥2 wk, 大分子抗血管药物(如贝伐珠单抗bevacizumab)停药>6 wk后方可安全手术(Grade C, 95.4%一致); ④未能转化者: SD/PR但仍不可切除或疾病进展转为二线方案、靶向治疗或临床试验(Grade B, 97.7%一致). 当前最大挑战包括: 部分患者经有效转化治疗后因主观原因不愿接受手术(倾向于维持现状); RECIST标准可能低估免疫治疗的延迟效应和假性进展; 缺乏可靠的生物标志物(如ctDNA清除率、外周免疫细胞亚群动态变化)来预测转化成功概率[12].
联合疗法可以增强肿瘤细胞的免疫原性, 改变肿瘤环境, 显著提升疗效, 远超单药治疗. 一项研究表明[57], Lenvatinib/bevacizumab联合PD-1/PD-L1(sintilimab或camrelizumab)抑制剂(sintilimab或camrelizumab)及GEMOX在晚期胆道癌患者的ORR相比于单药有所上升. 但此为小样本单中心研究, 需要进一步研究更大前瞻性队列. 日本报道一份病例[58], 一例无法切除的HCCA接受durvalumab加GC方案治疗, 并成功实施转换手术, 术后十个月并未复发. 研究人员评估了吉西他滨、顺铂和纳布-紫杉醇治疗三联方案在肝外胆管癌的疗效, 显示出降低分期效果, 转换手术率约为20%[59].
在不良反应方面, 不同联合方案的安全性谱存在明显差异[51]. 免疫+化疗联合方案(TOPAZ-1/KEYNOTE-966)的总体Grade≥3不良事件率(adverse event, AE)为75%-79%, 主要不良事件为骨髓抑制(中性粒细胞减少23.5%)、乏力(13.6%)和恶心呕吐(7%-10%), 与单纯化疗的安全性谱基本一致[45,46]. 四联方案(局部区域治疗LRT+ICI+化疗+仑伐替尼)的Grade≥3 AE率为65.2%, 对比免疫+化疗的56.8%, 差异无统计学意义(P = 0.389), 且无治疗相关性死亡(Grade 5 AE)报告[53]. 肝动脉灌注化疗为主的方案肝毒性偏高(天门冬氨酸氨基转移酶/丙氨酸氨基转移酶升高14.5%-48%), 而PD-1+TKI为主的方案则以高血压(9.1%-42.9%)、手足综合征(8.6%-19%)为特征. 总体上, 在MDT指导下通过合理药物组合选择和密切不良反应监测, 联合方案可在不显著增加安全风险的前提下提高转化成功率.
然而, 有效转化治疗后进行手术干预的最佳时机仍不确定. 在实际环境中, 许多通过转化治疗实现有效肿瘤控制的患者往往不愿意接受手术, 更愿意维持现有状况[15]. 对于HCCA患者, MDT有助于确定手术和转化治疗的最佳时机[60]. 未来还需开展RCT研究, 以确定有效转化治疗的最佳时间, 并确定预测治疗效果的合适生物标志物(图1).
HCCA 转化治疗是改善不可切除患者预后、提升R0切除率的核心手段, 近年来随着化疗方案的优化、精准靶向的探索及免疫联合治疗的突破, 其临床应用价值与疗效得到显著提升. 短期内需开展以R0切除率为主要终点的多中心前瞻性研究, 同时建立标准化可切除性评估体系(解剖学、生物学、功能学、MDT综合), 并通过前瞻性研究建立标准化停药窗口方案, 优化转化后手术时机.
未来需在前瞻性队列的基础上, 设计以R0切除率+OS为共同主要终点的Ⅲ期RCT. 同时整合基因组学、转录组学、蛋白质组学及影像组学数据, 构建可预测个体患者转化治疗获益概率的决策模型, 并在现有PD-1/PD-L1抑制剂基础上, 探索双免疫检查点抑制、双特异性抗体及嵌合抗原受体T细胞治疗在转化治疗中的应用前景, 推动个体化精准转化治疗的实现.
基于中国医疗资源分布不均的现实, 建议建立"三级医院MDT中心-区域医疗中心-基层医院"三级联动转化诊疗网络. 基层医院负责初筛和转诊, 区域中心负责MDT评估和治疗实施, 三级医院负责复杂手术和临床研究. 推动远程MDT会诊平台的普及, 使偏远地区患者获得同质化的转化评估机会; 开展HCCA转化治疗的RWS, 充分利用中国病例资源优势, 快速积累转化治疗证据; 依托中国临床试验注册中心, 建立覆盖全国中心的HCCA转化治疗前瞻性注册研究, 系统收集转化方案、ORR、R0切除率、OS及生活质量数据, 为指南更新提供本土化高质量证据.
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学科分类: 胃肠病学和肝病学
手稿来源地: 内蒙古自治区
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科学编辑: 刘继红 制作编辑:张砚梁