修回日期: 2026-05-07
接受日期: 2026-05-25
在线出版日期: 2026-05-28
结直肠癌腹膜转移(peritoneal metastasis from colorectal cancer, CRC-PM)预后较差, 约5%-15%的患者发生同时性转移, 20%左右出现异时性转移, TNM分期归为M1c. 早期常无症状, 晚期可表现为腹水、肠梗阻. 在全身治疗有效的前提下, 根据肿瘤负荷, 临床上主要采取肿瘤细胞减灭术联合腹腔热灌注化疗为重要治疗措施的综合治疗方案. 临床评估依赖影像学(计算机断层扫描、磁共振成像等)、血清肿瘤标志物[癌胚抗原、糖类抗原19-9、癌抗原125等联合检测]及肿瘤负荷评分(腹膜癌指数、腹膜表面疾病严重程度评分、RAS突变联合腹膜表面疾病严重程度评分、生物学评分系统等评分系统). 近年出现的新兴治疗手段如腹腔加压气溶胶化疗、免疫治疗、全身化疗对该疾病展现出一定潜力. 本文拟对CRC-PM的综合治疗进展进行综述, 从而加深临床医师对结直肠癌腹膜转移的认识, 为精准化治疗路径的制定与临床研究设计提供参考.
核心提要: 本综述综合了关于结直肠癌腹膜转移(peritoneal metastasis from colorectal cancer, CRC-PM)多模式治疗策略的最新证据, CRC-PM是一种具有挑战性且历史上预后不佳的疾病. 我们讨论了术前评估工具, 包括影像学、生物标志物和预后评分系统; 已建立的疗法, 如减瘤手术和腹腔热灌注化疗; 以及新兴方法, 如加压腹腔内气溶胶化疗、全身化疗、靶向治疗. 通过突出临床进展、局限性和未来方向, 本工作旨在指导精准治疗并改善CRC-PM患者的预后, 关注外科肿瘤学中多学科治疗中的关键领域.
引文著录: 曹宇奇, 吴清彬, 王自强, 孟文建. 结直肠癌腹膜转移多学科诊疗进展: 从精准评估到综合治疗. 世界华人消化杂志 2026; 34(5): 404-416
Revised: May 7, 2026
Accepted: May 25, 2026
Published online: May 28, 2026
Peritoneal metastasis from colorectal cancer (CRC-PM) carries a poor prognosis. It occurs synchronously in approximately 5%-15% of patients and metachronously in about 20%, and is classified as TNM stage M1c. Early-stage disease is often asymptomatic, while late-stage manifestations include ascites and bowel obstruction. Under the premise of effective systemic therapy, a multimodal treatment approach centered on cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is clinically adopted based on tumor burden. Clinical evaluation relies on imaging (computed tomography, magnetic resonance imaging, etc.), serum tumor markers (combined detection of carcinoembryonic antigen, carbohydrate antigen 19-9, cancer antigen 125, etc.), and tumor burden scoring systems (Peritoneal Cancer Index, Peritoneal Surface Disease Severity Score, RAS-Peritoneal Surface Disease Severity Score, Biological Score of Colorectal Peritoneal Metastasis, etc.). Emerging therapeutic modalities in recent years, such as pressurized intraperitoneal aerosol chemotherapy, immunotherapy, and systemic chemotherapy, have shown certain potential for the treatment of this disease. This article reviews the progress in multimodal therapy for CRC-PM, aiming to deepen clinicians' understanding of this condition and provide a reference for the development of precision treatment strategies and clinical research design.
- Citation: Cao YQ, Wu QB, Wang ZQ, Meng WJ. Advances in multimodal therapy for peritoneal metastasis from colorectal cancer. Shijie Huaren Xiaohua Zazhi 2026; 34(5): 404-416
- URL: https://www.wjgnet.com/1009-3079/full/v34/i5/404.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v34.i5.404
核心提要: 本综述综合了关于结直肠癌腹膜转移(peritoneal metastasis from colorectal cancer, CRC-PM)多模式治疗策略的最新证据, CRC-PM是一种具有挑战性且历史上预后不佳的疾病. 我们讨论了术前评估工具, 包括影像学、生物标志物和预后评分系统; 已建立的疗法, 如减瘤手术和腹腔热灌注化疗; 以及新兴方法, 如加压腹腔内气溶胶化疗、全身化疗、靶向治疗. 通过突出临床进展、局限性和未来方向, 本工作旨在指导精准治疗并改善CRC-PM患者的预后, 关注外科肿瘤学中多学科治疗中的关键领域.
结直肠癌(colorectal cancer, CRC)作为全球发病率位列第三的消化系统肿瘤, 其腹膜播散转移发生率仅次于肝脏和肺. 流行病学数据显示, 约5%-15% CRC患者会发生同时性腹膜转移(peritoneal metastasis, PM), 20%左右会发生异时性PM. 根据国际TNM分期标准, 此类病例被归入M1c分期范畴, 临床上多采用姑息性治疗策略. 但相较于单纯肝肺转移患者, 该群体中位生存期显著缩短且预后更为不良[1]. 值得关注的是, 随着各种综合治疗手段的进展, CRC-PM患者的临床结局已呈现出改善趋势. 既往的研究表明[2], 肿瘤细胞减灭术(cytoreductive surgery, CRS)联合腹腔热灌注化疗(hyperthermic intraperitoneal chemotherapy, HIPEC)的协同应用, 可提高CRC-PM患者的生存率. 近年来, 随着腹腔局部治疗技术的创新, 新型干预手段如腹腔加压气溶胶化疗(pressurised intraperitoneal aerosol chemotherapy, PIPAC)以及靶向性生物治疗如MOC31PE抗毒素开始应用于CRC-PM患者, 并取得了一定成效[3]. 本文拟对CRC-PM的综合治疗进行综述, 为精准化治疗路径的制定与临床研究设计提供参考.
CRC-PM的影像学评估是临床诊断体系中的核心环节. 目前临床常用技术包括计算机断层扫描(computed tomography, CT)、磁共振成像(magnetic resonance imaging, MRI)及正电子发射断层显像(positron emission tomography/computed tomography, PET/CT)等复合成像技术. 影像学评估不仅承担病灶检出功能, 更直接影响腹膜癌指数(peritoneal cancer index, PCI)估算以及CRS可切除性判断和MDT治疗路径选择[4]. 多层螺旋CT因其经济优势及快速成像特点, 现已成为CRC-PM的主要和首选检查方式, 其诊断PM癌的灵敏度和特异度分别为68%和88%[5], 且灵敏度随着转移灶的增大显著增加, 但其对小体积、等密度、肠系膜皱襞处及弥漫浸润型PM灶的敏感性有限, 容易低估实际PCI, 尤其在病灶直径<5 mm或合并黏液性成分时更为明显[4,5]. 相较之下, MRI凭借多参数成像及优越的软组织分辨率, 诊断敏感度提升至92%, 特异性维持在85%, 在PM范围评估方面较CT更具优势. 其中弥散加权成像(diffusion-weighted imaging, DWI)通过显示肿瘤组织受限扩散信号, 可提高浆膜面、小肠系膜、盆腔及膈下微小病灶的可见性[4,6]. 与CT相比, 对比增强MRI联合DWI更适用于CT结果不明确、疑似局部复发以及拟行CRS/HIPEC患者的术前分层. 但MRI检查时间较长, 易受呼吸运动和肠蠕动影响, 且不同中心扫描方案和阅片经验差异较大; 炎症、良性淋巴结和部分正常组织的限制性扩散也可能导致假阳性[7]. 因此, MRI可提高术前评估精度, 但不能替代术中探查对PCI的最终确认.
18氟代脱氧葡萄糖(F-18 fluorodeoxyglucose, 18F-FDG)PET/CT优势在于提供全身代谢信息, 尤其适用于肿瘤标志物升高但CT或MRI阴性、结果不一致, 或术前需排除腹膜外转移的患者[4]. PET-CT对CRC腹膜播散的检测能力突出, 其敏感性与特异性分别可达89.6%及90.9%, 特别是对于肠系膜和小肠转移灶的定位更有优势[8], 但对印戒细胞癌和黏液腺癌的诊断准确率较差[9,10]. 但18F-FDG PET/CT对印戒细胞癌、黏液腺癌和亚厘米病灶的敏感性不足, 肠道、肝包膜、膈肌及泌尿系统生理摄取也会影响腹膜局部病灶显示和PCI估算[9-11]. 近年来, 核素标记的成纤维细胞活化蛋白抑制剂PET/CT受到关注. 成纤维细胞活化蛋白(fibroblast activation protein, FAP)显像靶向肿瘤相关成纤维细胞表面的FAP, 肠道和肝脏生理摄取相对较低, 因此在腹膜种植、肠壁受累和小肠系膜病灶中可能获得更高肿瘤背景比[12,13]. Xi等[14]比较56例疑似复发CRC患者的68Ga-FAPI PET/CT与18F-FDG PET/CT后发现, 68Ga-FAPI PET/CT在复发灶、腹膜相关淋巴结转移及肠壁种植灶检出方面敏感性更高, 并可更准确评估PCI. 另一项CRC-PM研究显示[13], 18F-FAPI-42 PET/CT在PM检出中的敏感性、阴性预测值和准确性均优于18F-FDG PET/CT, 影像学PCI也更接近术中PCI, 尤其有助于评估右上腹、上腹部和小肠区域病灶. 但FAPI PET/CT在炎症、纤维化、术后瘢痕和造口相关组织中可能出现假阳性, 仍需结合CT、MRI、腹腔镜探查及病理结果综合判断.
PET/MRI可整合代谢、解剖和DWI功能信息, 理论上有助于提高微小腹膜病灶检出率和影像学PCI评估准确性[11,15]. 既往研究显示[15], PET/MRI在部分PM患者中较单独PET、MRI或常规CT具有更高综合诊断价值, 并可能改变治疗决策; 同时, 其辐射暴露低于PET/CT, 更适合需要多次随访的患者. 但PET/MRI受设备可及性、费用、检查时间和标准化不足限制, 目前仍需前瞻性多中心研究明确其临床价值.
人工智能(artificial intelligence, AI)和影像组学为CRC-PM无创评估提供了新工具. 2025年一项系统综述和荟萃分析纳入24项PM影像AI研究[16], 用于判断PM存在与否的模型合并曲线下面积(area under the curve, AUC)为0.84, 敏感度为0.75, 特异度为0.80. 在CRC-PM研究中[17], 基于CT的临床-影像组学联合模型预测PM的AUC为0.855, 优于单纯临床模型和单纯影像组学模型; 基于PET/CT的影像组学增强深度学习模型预测同时性CRC-PM的外部验证AUC达0.885. 但目前相关模型多为回顾性研究[16-18], 仍存在样本量有限、外部验证不足、扫描方案不统一及可解释性较弱等问题. 因此, AI目前更适合作为筛选高风险患者、提示进一步检查和减少术前PCI低估的辅助工具.
影像学仍是CRC-PM诊断和分期的基础, 但对微小种植灶、黏液性病灶及弥漫性小肠系膜受累的识别存在局限. 因此, 血清肿瘤标志物更适合作为影像学评估的补充, 用于提示隐匿性PM风险、监测治疗反应及辅助判断肿瘤生物学活性. 在CRC-PM的临床管理中, 血清肿瘤标志物的联合检测具有重要的辅助评估及动态监测价值, 目前推荐癌胚抗原(carcinoembryonic antigen, CEA)、糖类抗原19-9(carbohydrate antigen 19-9, CA19-9)和癌抗原125(cancer antigen 125, CA125)的多指标联合分析. CEA可以辅助判断肿瘤的侵袭程度. 腹水CEA水平在腹膜细胞学阴性的患者与复发和PM复发显著相关[19]. 另外, CRC患者CEA/PCI比值越低, 中位总生存期(overall survival, OS)(56 mo vs 24 mo)和无复发生存期(recurrence-free survival, RFS)(13 mo vs 9 mo)就越长, 特别是PCI≤10的患者(OS, 72 mo vs 30 mo; RFS, 21 mo vs 10 mo). 升高的CEA/PCI比值也是一个独立的OS和RFS不良预后因素(危险比分别为1.85和1.58). 这种新的评估方法将肿瘤活性和负荷作为一个单一指标, 因此提供了一个更加准确的肿瘤生物学行为的评估[20]. CA19-9水平可反映腹腔积液或原发肿瘤的增殖活性. CA19-9浓度升高与更深的肿瘤浸润、腹膜和淋巴结转移相关. 患者CA199≥74 U/mL发生腹膜种植的风险是CA199<74 U/mL患者的2.9倍. 血清CA19-9水平高和腹水CEA水平高分别与腹膜冲洗细胞学阳性和腹膜癌形成有关, 都是重要的预测因子[21-23]. CA125可反映腹膜刺激、腹水形成和腹膜受累风险, 但并非恶性PM的特异性标志物. CA125可由浆膜来源的间皮细胞表达, 肝硬化腹水、心力衰竭、结核性腹膜炎、子宫内膜异位症及其他炎症性浆膜腔积液均可导致其升高[24]. 在CRC患者中, CA125升高与腹膜播散风险相关, Huang等[25]研究提示其较CEA更有助于预测腹膜播散, 但该结果应理解为风险提示, 而非确诊依据. 在接受CRS/HIPEC治疗的CRC-PM患者中, CA125>16 U/mL主要用于预后分层, 提示患者可能存在更强腹膜反应或更差肿瘤生物学行为[26].
总体而言, CEA、CA19-9和CA125均不能单独用于确诊CRC-PM. 其临床价值在于联合动态监测, 并与CT、MRI、PET/CT、腹水细胞学、腹腔镜探查及PCI评估共同用于诊断补充和治疗分层.
CRC-PM的肿瘤负荷量化评估体系主要由PCI和腹膜表面疾病严重程度评分(Peritoneal Surface Disease Severity Score, PSDSS)构成.
PCI评分作为经典量化工具, 由Jacquet等[27]于1996年描述. PCI通过将腹腔划分为13个解剖区域进行病灶计数与大小分级, 各区域的评分之和即为总PCI评分, 总分范围0-39分. 在肿瘤减灭术的围手术期管理中, PCI评分具有双重临床意义: 术前评估为筛选适宜接受CRS+HIPEC的潜在获益人群, 术后评估作为独立预测患者远期生存结局的关键指标[28,29]. 既往的研究显示[30,31], PCI≤10分、11-20分及≥21分患者的五年OS呈显著梯度下降趋势(分别为53%、23%与12%). 基于此, 多不建议PCI≥21分患者接受CRS+HIPEC联合治疗. 然而, PCI评分机制仅反映转移灶数量及大小, 未考虑转移灶解剖位置对手术可切除性的影响, 如小肠广泛受累或者肠系膜受侵、肝门浸润或者胰腺受侵等复杂情况均可能影响手术可切除性, 因而其也存在固有的临床局限性. PSDSS系统最初由Pelz等[32]描述, 该系统整合了临床症状学评估、腹膜癌指数及原发肿瘤组织病理特征三项参数. PSDSS一共分为四期, Ⅰ期: 2-3分, Ⅱ期: 4-7分, Ⅲ期: 8-10分, Ⅳ期: >10分[33]. 该分期系统展现出对PM患者生存预后的独立预测价值, 能够预测CRS/HIPEC治疗患者的生存结局. 同时该评分也可用来筛选适宜接受CRS/HIPEC治疗的患者. 值得注意的是, PSDSS的构建尚未纳入肿瘤分子生物学特征指标, 这也在一定程度上限制了其预后评估效能. 基于此局限性, 2019年Arjona-Sanchez等[34]研究证实, RAS基因突变状态是CRS/HIPEC治疗后患者OS的独立预测因素, 并据此对原评分系统进行补充, 提出RAS-PSDSS改良评估体系. RAS-PSDSS系统优于单独的PSDSS评分系统, 且在术前对CRS/HIPEC治疗后患者预期OS提供快速可行的评估. Schneider等基于PCI、N分期、G分级和RAS/RAF基因状态进一步设立了CRC-PM生物学评分系统(Biological Score of Colorectal Peritoneal Metastasis, BIOSCOPE). 该评分系统分为4个风险人群: BIOSCOPE A(0分), 表示无风险(PCI<10、N0、G1-2、RAS/RAF野生型); BIOSCOPE B(1-3分); BIOSCOPE C(4-7分); BIOSCOPE D(≥8分). BIOSCOPE评分越高, 患者预后越差. BIOSCOPE进一步改进上述2个评分系统, 为评估CRC-PM患者的病情状况、判断预后和治疗决策提供了更好的指导. 近年来, AI也被用于术前预测腹膜肿瘤负荷和CRS可完成性. Lin等[35]2025年多中心研究纳入186例CRC-PM患者, 基于增强CT和临床病理参数建立深度学习模型, 预测CRS能否实现完全减灭, 内部验证AUC为0.900, 3个外部验证队列AUC分别为0.906、0.960和0.933. 该模型有助于术前识别更可能从CRS获益的患者, 但小肠系膜受累、广泛粘连、既往手术史、营养状态和体能储备仍难以完全由模型判断[35].
总体而言, PCI评分系统被广泛应用, 仍然是CRC-PM患者选择CRS手术的标准, 对于术前评估和患者预后判断非常重要. PSDSS、RAS-PSDSS和BIOSCOPE可补充分子及病理信息, AI模型则可能提高术前可切除性判断的准确性. 多维度评估有助于减少无效开腹和过度治疗, 提高CRS/HIPEC患者选择的精准度. 基于以上综合评估, CRC-PM患者可经MDT讨论后进入分层治疗路径, 见图1.
CRS是一个复杂的手术, 包括切除腹膜和受累内脏, 尽可能地达到消除所有肉眼可见的病变. 临床实践中采用细胞减灭完全性评分(completeness of cytoreduction, CC)评估减灭程度[36], 该分级标准包含: CC-0(无肉眼残留灶)、CC-1(残留灶<2.5 mm)、CC-2(残留灶2.5-25 mm)、CC-3(残留灶>25 mm或不可切除病灶). 研究证实[37], 对于接受CRS治疗的CRC-PM患者, 手术彻底性是影响其预后的最强独立变量, 当实现肉眼无残留病灶时, 患者五年生存率可高达51%[38]. CRS的可行性受多重因素制约, 包括PM负荷(通过PCI指数量化)、原发肿瘤生物学特性及淋巴结受累状况、肝脏转移状态及RAS基因变异情况等. 既往研究[39]建议PCI评分<20作为CRS适应证, 而目前建议将筛选标准限定于PCI<12分群体, PCI评分>17则通常不建议行CRS治疗. 然而, CRS的争议主要在于手术指征的把握. 通常情况下, 除了切除腹膜外, 也要切除胆囊, 大网膜, 卵巢, 阑尾, 甚至是子宫, 脾, 肝包膜, 胃, 部分小肠等器官(图2). 尽管CRS给PM患者带来生存获益, 但广泛切除带来的创伤常导致术后并发症总体发生率超过20%, 涵盖吻合口瘘、脓毒血症、肠梗阻、胰腺炎、循环系统栓塞事件及二次手术干预等临床问题[40]. 因此, 病例筛选需综合评估手术获益与风险, 通过标准规范的治疗体系来降低发病及死亡率.
CRS围术期管理需依赖外科、麻醉、营养、康复和重症医学协作. 基于本中心实践经验, 需特别强调围手术期容量调控的关键地位, 尤其是在手术过程中. 围手术期液体管理不仅关乎循环系统稳态维持, 更直接影响HIPEC阶段的治疗安全性及实施效果. 在肿瘤减灭过程中, 因广泛腹腔创面引发的液体丢失速率可达8-12 mL/kg/h, 因此需要足够的液体输注. 目前认为, 限制性补液策略可在保证组织灌注良好与循环稳定的前提下, 避免容量过负荷, 降低高危患者术后并发症发生率及致死风险[41]. 容量管理建议遵循以下原则: 优先选择胶体液(如人血白蛋白)可有效维持胶体渗透压、抑制腹腔渗出, 同时规避羟乙基淀粉潜在的急性肾损伤风险[42]; 晶体液输注需严格限制总量, 推荐使用平衡盐溶液, 避免大量使用生理氯化钠溶液, 以预防电解质紊乱(如高氯性酸中毒)及组织水肿对消化系统重建的影响[43,44]. 最后, 需警惕围术期凝血功能障碍风险, 建议无禁忌者全程联合机械预防与抗凝药物干预, 能有效降低静脉血栓栓塞事件及继发性肺循环栓塞发生率.
需要进一步指出的是, 严重术后并发症并非单纯影响短期恢复, 还可能影响长期结局, 研究显示[45,46]Clavien-Dindo Ⅲ级及以上并发症与CRS/HIPEC后生存受损相关. 因此, CRS并非范围越大越好, 只有在不显著增加不可接受风险的前提下, 彻底减灭才可能真正获益. 在生活质量方面, 既往系统综述显示, CRS/HIPEC后患者总体生活质量通常在术后早期明显下降, 尤其表现为体力、功能状态和胃肠道症状恶化, 但多数患者可在术后6-12 mo逐渐恢复至基线水平[47]. 一项纳入216例患者的前瞻性研究同样显示[48], CRS后生活质量在术后1-6 mo下降, 至12 mo恢复至术前基线, 而造口、手术时间过长及疾病复发是影响生活质量恢复的重要因素. 近期加拿大研究也提示[49], 年龄、性别、术后系统治疗、复发状态、家庭支持和心理因素均会影响术后12个月内的生活质量轨迹.
对于PCI较低、可预期达到CC-0/1且体能状态良好的患者, 积极CRS更可能带来OS和生活质量的双重获益; 而对于PCI过高、小肠或肠系膜根部广泛受累、营养状态差者, 即使技术上可行, 过度追求完全减灭也可能以术后并发症和生活质量下降为代价[46,50]. 因此, 未来CRC-PM外科治疗评价不应仅以OS或无进展生存期(progression-free survival, PFS)作为终点, 还应纳入无造口生存, 无严重并发症生存, 功能恢复时间和患者报告结局, 从而更准确地反映CRS的真实临床价值[47,49]. 需要提及的是, 对于是否合并肝肺转移也是CRS/HIPEC决策中的重要因素, 但不应简单作为能否手术的绝对标准. 总体而言, 腹膜外转移提示疾病具有系统播散倾向, 预后较差; Baratti等[51]研究显示, 有腹膜外疾病史的患者5年OS为16.5%, 明显低于单纯PM患者的52.0%. 但对于数量有限、可局部处理且系统治疗后稳定的肝转移患者, 部分研究[52]提示仍可能从CRS/HIPEC联合肝转移局部治疗中获益; 系统综述显示, 此类患者合并平均OS为26.4 mo, 3年OS率为34%, 5年OS率为25%, 但并发症发生率高于单纯PM患者. 而稳定肺转移的影响可能相对较小, 一项研究显示[53], 合并稳定肺转移者与单纯PM者接受CRS/HIPEC后的3年OS分别为68%和71%, 差异无统计学意义.
CRS的彻底性是CRC-PM患者获得长期生存的关键基础. 然而, 即使达到CC-0/1切除, 腹腔内仍可能存在肉眼不可见的游离癌细胞或微小残留病灶, 这也是术后腹膜复发的重要原因. 基于这一理论, HIPEC被引入作为CRS后的区域强化治疗手段. HIPEC通过精准控温技术(41-43 ℃)将含化疗药液体循环注入患者腹腔, 维持60-90 min. 其作用机制包括: 高温增强化疗药穿透力并诱导肿瘤细胞热损伤, 同时通过持续循环清除游离癌细胞, 形成"热疗+化疗+机械冲刷"三重治疗效应, 通过此种治疗方法, 达到靶向消灭残留微观病变的目标. HIPEC最常用的药物包括丝裂霉素Ｃ、奥沙利铂、铂类等. 对于符合以下指征的CRC-PM患者: (1)经影像学或腹腔镜探查确认可实现R0切除或肉眼肿瘤完全清除(CC0-1级); (2)经影像学等检查排除肝肺等远处转移, 可推荐在CRS后实施治疗性HIPEC[54-56].
从证据演进看, CRS/HIPEC的争议不应被简单概括为有效或无效, 而应分为两个层面理解, 其一, 较单纯系统治疗而言, 以完全肿瘤细胞减灭为目标的局部根治策略能否改善CRC-PM患者预后; 其二, 在高质量CRS已实现肉眼完全减灭的前提下, HIPEC是否仍能提供独立的获益[50,57,58]. 早期Verwaal等[59]研究显示, CRS联合丝裂霉素C为基础的HIPEC较系统治疗可显著延长患者生存期, 奠定了CRS/HIPEC在选择性CRC-PM患者中的治疗地位. 但该研究所用系统治疗方案相对陈旧, 且围术期死亡率较高, 因此其阳性结果更能说明局部治疗策略的价值, 而不能完全界定HIPEC本身在现代治疗体系中的独立作用. 随后的多项临床证据显示[60,61], 相较于单纯系统性化疗, CRS联合HIPEC可进一步改善此类患者的生存结局. 基于此,《肿瘤细胞减灭术加腹腔热灌注化疗的国际建议》将CRS+HIPEC治疗策略作为CRC-PM的推荐治疗[62].
PRODIGE-7研究进一步将争议焦点推进至完全CRS之后是否需要常规追加HIPEC. 该研究显示[55], CRS+HIPEC组与单纯CRS组中位OS分别为41.7 mo和41.2 mo, 差异无统计学意义, 而HIPEC组60 d内3级以上并发症发生率更高. 这一结果提示, CRC-PM长期获益的核心仍是能否完成高质量CRS, 而非所有患者均需常规联合HIPEC. 但PRODIGE-7采用30 min奥沙利铂灌注方案, 部分患者既往已接受奥沙利铂治疗, 可能影响HIPEC疗效. 其亚组分析提示PCI 11-15分患者可能存在获益信号, 说明HIPEC更可能适用于中等腹膜负荷且微小残留风险较高的患者.
预防性或辅助性HIPEC的证据同样存在分歧. PROPHYLOCHIP-PRODIGE 15研究显示[58,63], 在高危患者中实施系统性二次探查手术联合奥沙利铂HIPEC并未改善DFS; COLOPEC研究5年随访亦未证实奥沙利铂HIPEC可在总体人群中显著改善预后. 与此不同, HIPECT4研究显示[64], 对于术前诊断为局部进展期结肠癌的患者, 完全切除后联合丝裂霉素C HIPEC可提高3年局部区域控制率, 但DFS和OS尚未显示显著改善, 因此其意义更接近于降低腹腔局部复发风险, 而非已被证实能够转化为长期生存获益. GECOP-MMC研究正在评估完全CRS后追加MMC-HIPEC能否降低结肠癌PM患者的腹膜复发风险, 其设计可部分回应PRODIGE-7后关于奥沙利铂短时程方案能否代表所有HIPEC方案的疑问[65]. EFFIPECv5研究则比较标准奥沙利铂HIPEC与奥沙利铂/伊立替康HIPEC联合术后24h氟尿嘧啶(fluorouracil, 5-FU)早期腹腔化疗(early postoperative intraperitoneal chemotherapy, EPIC)的疗效, 并将复发、并发症和生活质量纳入随访终点[66]. 围绕HIPEC药物、剂量和灌注时长的争议, 仍需前瞻性研究进一步回答.
近年来也开展了许多围绕辅助或预防性HIPEC以及HIPEC方案优化相关的前沿研究(表1). 但目前仍提示CRS/HIPEC争议的实质在于现有研究在人群选择、药物种类、灌注时长、治疗时机、终点设置及围手术期系统治疗方面高度异质. 从临床决策角度看, 低PCI且可实现CC-0/1切除者可能主要获益于高质量CRS, 中等PCI且存在腹腔微小残留高风险者可考虑选择性联合HIPEC, 而PCI过高、小肠或肠系膜根部广泛受累、腹膜外病灶不可控或肿瘤生物学侵袭性强的患者, 则不宜接受高风险CRS/HIPEC[50]. 2025年CRC-PM共识进一步强调, 患者应尽早转诊至腹膜表面肿瘤专科中心接受MDT评估; 对于同时性CRC-PM, 治疗策略不宜过度强调直接CRS, 而应结合系统治疗反应、腹膜负荷、原发灶症状及可切除性制定综合策略[57].
| 年份 | 研究名称及注册号 | 研究对象 | 随机分组 | 主要研究终点 |
| 2023 | HIPECT4; NCT02614534 | 局部进展期结肠癌, cT4N0-2M0, 腹膜复发高风险人群 | 根治性切除+丝裂霉素C HIPEC vs 单纯根治性切除 | 3年局部区域控制率 |
| 2024 | COLOPEC; NCT02231086 | T4或穿孔性结肠癌, 腹膜转移高风险人群 | 辅助奥沙利铂HIPEC+系统辅助化疗 vs 单纯系统辅助化疗 | 腹膜无转移生存 |
| 2024 | EFFIPEC/EFFIPECv5; NCT04861558 | 可接受CRS-HIPEC的CRC-PM患者 | 标准奥沙利铂HIPEC vs 奥沙利铂/伊立替康HIPEC+术后24 h 5-FU EPIC | 复发相关结局 |
| 2024 | PIPOX02; NCT06681038 | 晚期CRC腹膜转移患者 | 标准系统治疗 vs 标准系统治疗+奥沙利铂PIPAC | PFS |
| 2024 | Intraperitoneal LSTA1 in CRS-HIPEC; NCT06216561 | 接受CRS-HIPEC的腹膜表面恶性肿瘤患者, 包含非黏液性CRC-PM | CRS-HIPEC+LSTA1 vs CRS-HIPEC | 安全性和药物递送相关指标 |
| 2025 | CAIRO6; NCT02758951 | 可切除孤立性CRC-PM患者 | 围手术期系统治疗+CRS-HIPEC vs 直接CRS-HIPEC | OS |
| 2025 | GECOP-MMC; NCT05250648 | 结肠癌腹膜转移, PCI≤20, 预期可完全CRS人群 | 完全CRS+系统治疗+丝裂霉素C HIPEC vs 完全CRS+系统治疗 | 腹膜复发 |
| 2025 | MMC vs Melphalan CRS-HIPEC; NCT03073694 | 结直肠或高级别阑尾来源腹膜表面肿瘤患者 | RS-HIPEC中丝裂霉素C vs 美法仑 | 90 d围手术期并发症和死亡率 |
CRC-PM具有腹腔局部进展和潜在系统播散并存的特点, 因此全身治疗不仅用于不可切除患者的疾病控制, 也可用于术前筛选肿瘤生物学行为, 争取转化切除机会及降低术后复发风险. 如何在CRS/HIPEC前后合理安排全身治疗, 是CRC-PM综合管理中的另一关键问题, 且新辅助化疗在CRC-PM中的价值仍存在争议. 常用新辅助化疗方案包括FOLFOX、FOLFIRI、CAPOX、XELIRI等[67]. 一项纳入12项临床研究(样本总量2463例)的荟萃分析显示[68], 对于CRC-PM患者, 接受新辅助化疗与直接手术相比, 术中及术后并发症发生率、死亡率等指标上未见统计学差异, 且短期生存数据(1、3年DFS; 3年OS)无明显区别, 但患者5年OS及DFS获得显著提升. 尽管各研究间存在一定异质性, 但结果表明新辅助治疗可作为潜在治疗策略纳入临床决策体系. 那新辅助化疗进一步联合CRS+HIPEC, 其临床价值又如何呢？CAIRO6研究探讨了在CRS/HIPEC基础上联合围手术期全身化疗能否进一步改善疗效, 结果显示研究组(新辅助化疗＋CRS/HIPEC)的影像学缓解率为28%, 病理显著缓解率为38%, 并发症发生率(33%)并不显著高于对照组(单纯CRS/HIPEC)(22%, P>0.05), 这提示新辅助化疗似乎是安全、有效的. 进一步地, 新辅助全身化疗联合靶向治疗, 在CRS/HIPEC基础上能否进一步改善疗效, Ceelen等[69]的研究结果显示联合贝伐珠单抗治疗可将OS延长至27 mo(95%CI: 20.8-33.2). 同样, 在转化治疗方面, Loupakis等[70]的研究显示, 对初始无法手术的PM病例, 四药强化方案(FOLFOXIRI: 5-FU/亚叶酸/奥沙利铂/伊立替康)联合贝伐珠单抗对比三药方案(FOLFIRI: 5-FU/伊立替康)联合相同靶向药物, 可分别使15% vs 12%的患者获得手术机会. 但另外一方面, Eveno等[71]的研究结果显示新辅助治疗联合贝伐珠单抗也使不良事件发生率增加达1倍(34% vs 19%, P = 0.020). CAIRO6研究是目前CRC-PM领域比较具代表性的多中心随机研究之一, 其设计初衷是比较围手术期系统治疗联合CRS/HIPEC与直接CRS/HIPEC在可切除孤立性CRC-PM患者中的疗效[72]. 2025年ASCO公布的Ⅲ期结果显示[73], 围手术期系统治疗未能较直接CRS/HIPEC显著改善OS, 但可延长PFS, 同时90 d主要术后并发症发生率有所增加. 这一结果提示, 围手术期化疗的意义可能并非简单使OS获益, 而更可能体现在延缓进展, 筛选肿瘤生物学行为等方面[73]. 另外, 术后通过系统性给药进行辅助化疗, 可能是降低术后复发和转移的有效手段. 一项观察性队列研究纳入393例患者[74], 探讨术后辅助化疗对同时性孤立性CRC-PM切除术后的价值, 倾向性评分匹配后的结果显示辅助化疗组的OS明显高于密切随访组(39.2% vs 24.8%, P = 0.006). 总体而言, 围手术期全身治疗对于CRC-PM患者肿瘤学和安全性的价值, 值得进一步的研究证实.
2011-11, PIPAC被引入作为腹膜恶性肿瘤新的腹腔内化疗方式, 其通过将化疗药物加压后以气溶胶的形式送入腹腔, 实现药物在腹膜表面的高覆盖性沉积, 提升药物对癌细胞的直接接触面积及组织穿透深度, 从而克服传统腹腔灌注化疗的药物分布缺陷. 目前PIPAC主要用于以下临床场景: (1)难治性PM癌如常规静脉化疗失败、继发药物抵抗性、合并顽固性腹腔积液, 以及肿瘤生物学特征高危的病例; (2)肿瘤负荷超出CRS完全切除阈值, 或无法耐受CRS/HIPEC的群体; (3)转化治疗探索: 法国里昂的一项回顾性研究数据表明[75], 经严格筛选的初始不可切除患者, 重复PIPAC治疗可诱导部分病例病灶退缩, 从而获得后续CRS/HIPEC治疗机会.
PIPAC现有两种主流腹腔给药方案: DDP联合多柔比星或L-OHP单药方案, 患者需至少接受3次重复PIPAC治疗, 每次间隔6-8 wk. Alyami等[3]整合45项临床研究数据分析显示, CRC-PM患者经PIPAC干预后的缓解率为71%-86%, 中位生存期达15.7 mo, 治疗相关不良事件发生率维持在12%-15%, 且重复治疗未导致生活质量显著下降. CRC-PIPAC研究显示[76], PIPAC-OX单药用于不可切除CRC-PM时, 可观察到生化反应、病理反应和腹水反应, 但未见明确影像学缓解, 中位PFS和OS分别为3.5 mo和8.0 mo, 提示单药PIPAC的抗肿瘤效应有限. CRC-PIPAC-Ⅱ研究[77]采用一线姑息性全身治疗与奥沙利铂电沉积增强PIPAC(electrostatic precipitation PIPAC, ePIPAC)交替应用, 主要治疗相关不良事件发生率为35%, 未发生治疗相关死亡, 且多数患者出现病理反应. 这一结果提示, PIPAC更可能在全身治疗基础上发挥局部强化作用, 而非替代系统治疗.
总体而言, PIPAC目前更适合定位为不可切除CRC-PM患者的区域控制和转化探索手段. 对于已具备完全CRS条件的患者, 仍应优先评估以CRS为核心的局部治疗路径; 对于肿瘤负荷较高, 症状明显或系统治疗后疾病稳定但仍不可切除者, PIPAC可作为延缓腹膜进展、控制腹水和争取后续转化机会的补充选择. 未来研究需进一步明确适用人群、标准化给药方案、与全身治疗的最佳时序.
近年来, 越来越多的研究开始探索免疫治疗在CRC-PM治疗中的应用. 免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)是目前研究最广泛的免疫治疗方法之一. 在CRC-PM的治疗中, ICIs主要针对程序性死亡受体1(programmed death 1, PD-1)及其配体PD-L1, 以及细胞毒性T淋巴细胞相关抗原4(cytotoxic T-lymphocyte antigen-4, CTLA-4)[78,79]. 一项针对微卫星高度不稳定型(microsatellite instability-high, MSI-H)CRC-PM患者的研究显示[80], 接受免疫治疗的患者在两年OS方面达到64.2%, 而化疗组仅为54.1%(P<0.05). 这项研究纳入了15322名患者, 其中819名(11.6%)为MSI-H. 研究结果表明, 免疫治疗显著提高了MSI-H CRC-PM患者的生存率.
然而, CRC-PM分子层面常呈现CMS4相关特征, 表现为间质成分丰富、上皮-间质转化活跃、肿瘤相关成纤维细胞和髓系细胞参与的免疫抑制微环境明显, 这也解释了其对传统化疗及单药免疫治疗反应相对有限的原因, 而对于微卫星稳定型(microsatellite stable, MSS)患者, 单一ICIs的效果较为有限[81]. 为了提高治疗效果, 研究者们正在探索联合治疗策略, 包括PD-1/PD-L1抑制剂联合CTLA-4抑制剂、抗血管生成治疗、MEK/TGF-β通路抑制、放疗或腹腔局部治疗等, 以期通过促进抗原释放、改善T细胞浸润和重塑基质-髓系免疫抑制微环境, 提高MSS型CRC-PM的免疫应答[82]. Botensilimab(Fc增强型抗CTLA-4抗体)联合balstilimab(PD-1抗体)在复发/难治性MSS型转移性CRCⅠ期研究中显示出可管理的安全性和一定持久抗肿瘤活性, 为MSS型患者突破免疫耐受提供了新的探索方向, 但其在PM亚组中的真实获益仍需进一步验证[82]. 双特异性抗体是CRC免疫治疗的重要前沿方向. CEA-CD3双特异性T细胞衔接抗体西比萨他单抗可同时结合肿瘤细胞表面CEA和T细胞CD3ε, 从而诱导T细胞对CEA阳性肿瘤细胞的杀伤; 2024年两项Ⅰ期研究显示[83], 西比萨他单抗单药或联合阿替利珠单抗在CEA阳性实体瘤中具有一定抗肿瘤活性, 但总体缓解率有限且高级别不良事件发生率较高, 提示其未来价值可能依赖更精准的患者筛选和联合治疗策略.
除免疫治疗外, 分子靶向治疗也应纳入CRC-PM精准治疗框架, 但目前相关证据主要来源于转移性CRC总体人群, PM亚组仍需进一步验证. 对于BRAF V600E突变患者, BREAKWATER Ⅲ期研究显示[84], 恩考芬尼联合西妥昔单抗及mFOLFOX6一线治疗较标准治疗显著延长PFS和OS, 为此类高危分子亚型患者的诱导或转化治疗提供了新的依据. 对于KRAS G12C突变患者, KRYSTAL-1研究显示[85]阿达格拉西布联合西妥昔单抗在既往治疗后的KRAS G12C突变转移性CRC中具有明确抗肿瘤活性; CodeBreaK 300 Ⅲ期研究进一步证实[86], 索托拉西布联合帕尼单抗较研究者选择的标准后线治疗可显著改善PFS. 对于RAS野生型、HER2阳性患者, MOUNTAINEER Ⅱ期研究显示[87]图卡替尼联合曲妥珠单抗在化疗耐药的HER2阳性、RAS野生型不可切除或转移性CRC中具有持久缓解和可接受的安全性, 为HER2阳性CRC-PM患者的后线精准治疗提供了可借鉴依据.
另外, 新型免疫治疗策略, 包括嵌合抗原受体T细胞(chimeric antigen receptor T-cell immunotherapy, CAR-T)治疗在CRC-PM的治疗中显示出潜力. 一项针对claudin18.2的重定向CAR-T细胞治疗在后线胃肠道肿瘤中表现良好[88], 为实体瘤的细胞治疗带来了新的希望. 肿瘤疫苗是另一种正在研究的免疫治疗方法[89], 旨在激发肿瘤浸润淋巴细胞的增加, 从而增强免疫系统对肿瘤抗原的反应. 在CRC-PM的治疗中, 肿瘤疫苗被认为是诱导实体瘤微环境中特异性肿瘤免疫的一种潜在方法[90]. 然而, 目前肿瘤疫苗在临床应用中仍面临诸多挑战, 如单一抗原靶向、免疫原性弱、脱靶效应及免疫反应受损等[91]. 研究者们也正在探索利用纳米技术来增强免疫治疗的效果. 一项研究[92]开发了一种基于脂质体的递送系统, 包含Toll样受体激动剂resiquimod(R848), 用于在腹膜腔内定位以增强对癌症的免疫反应. 这项研究在小鼠模型中显示, DSTAP-R848显著上调了腹膜液中的α-干扰素, 并在与奥沙利铂联合使用时有效抑制了结直肠肿瘤在CT26小鼠腹膜内的进展. 除此以外, 研究发现, CRC-PM的肿瘤微环境对免疫治疗的效果有重要影响. 一项研究[93]通过单细胞测序分析了CRC-PM患者的原发肿瘤、转移灶及外周血样本, 发现CRC-PM生态系统具有独特的免疫抑制模式, 主要由SPP1+肿瘤相关巨噬细胞和THBS2+基质癌相关成纤维细胞组成的基质-髓系微环境主导. 这种基质-髓系相互作用可能是CRC-PM患者对ICIs产生耐药的主要机制. 深入研究CRC-PM的肿瘤微环境, 特别是基质-髓系相互作用, 以开发针对性的免疫调节策略[93]. 通过这些研究方向, 我们有望在未来几年内取得突破性进展, 为CRC-PM患者提供更有效的免疫治疗策略.
CRC-PM的治疗已从姑息化疗发展为以CRS/HIPEC为核心的综合模式. CRS的彻底性是预后的决定因素, 但手术创伤大、并发症高, 需严格筛选患者. PRODIGE-7研究提示, HIPEC的生存获益主要集中于PCI 11-15的中等负荷人群, 低负荷(≤10)患者单纯CRS可能足够, 未来应基于PCI和分子分型实施分层治疗. 全身化疗在围术期和转化治疗中有一定价值, 但受限于PM灶血供差、药物渗透不足及RAS/BRAF突变等分子异质性. PIPAC为难治性或无法手术者提供了新选择, 但仍需标准化方案和高级别证据. 免疫治疗对MSI-H患者效果显著, 而MSS患者占绝大多数, 其独特的基质-髓系免疫抑制微环境是主要耐药机制, 靶向该网络的联合策略是未来的突破方向. 未来有望通过建立区域诊疗中心和多学科协作体系, 优化围术期管理, 将CRC-PM转变为可控、甚至可治愈的慢性疾病.
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学科分类: 胃肠病学和肝病学
手稿来源地: 四川省
同行评议报告学术质量分类
A级 (优秀): A
B级 (非常好): B
C级 (良好): 0
D级 (一般): D
E级 (差): 0
科学编辑: 刘继红 制作编辑:张砚梁