结直肠癌肝转移诊断和综合治疗指南（2025版）

Chinese guidelines for the diagnosis and comprehensive treatment of colorectal liver metastases (2025 edition)

摘要

为进一步规范和提升我国结直肠癌肝转移的诊疗水平，《结直肠癌肝转移诊断和综合治疗指南（2025版）》在以往版本基础上，结合近年来国内外研究进展和临床经验，进行了系统更新。新版指南在优化诊断流程、加强多学科团队协作的基础上，全面升级了治疗策略，涵盖可达到无疾病证据状态（NED）患者的外科手术、辅助与新辅助治疗，及无法达到NED状态患者的综合治疗方案；同时拓展了基因检测内容，引入多种局部毁损新技术，强调规范随访与长期管理，力求实现治疗个体化、精准化，最终改善患者预后。指南旨在为全国医疗机构在结直肠癌肝转移的临床实践中提供循证、实用的参考依据。

Abstract

To further standardize and improve the management of colorectal liver metastases (CRLM) in China, the Chinese guidelines for the diagnosis and comprehensive treatment of colorectal cancer liver metastases(2025 edition) have been systematically updated based on previous versions and the latest international and domestic evidence. The updated guideline refines diagnostic pathways, strengthens multidisciplinary team collaboration, and comprehensively upgrades therapeutic strategies-including surgical resection, neoadjuvant and adjuvant treatments for patients eligible for no evidence of disease (NED) status, and systemic therapy for those who are not. It also expands the scope of genetic testing, incorporates innovative local ablative therapies, and emphasizes standardized follow-up and long-term management. The guideline aims to promote individualized and precision-based treatment, ultimately improving clinical outcomes and patient survival. It serves as a practical, evidence-based reference for healthcare providers managing CRLM across China.

关键词

结直肠肿瘤 / 肿瘤转移 / 诊疗准则

Key words

Colorectal Neoplasms / Neoplasm Metastasis / Practice Guideline

肝脏是结直肠癌血行转移最主要的靶器官，结直肠癌肝转移（colorectal cancer liver metastases）是结直肠癌治疗的重点和难点之一^[1-2]。约有15%~25%结直肠癌患者在确诊时即合并有肝转移，而另15%~25%的患者在结直肠癌原发灶根治术后发生肝转移，其中绝大多数（80%~90%）的肝转移灶初始无法获得根治性切除^[3]。肝转移也是结直肠癌患者最主要的死亡原因^[4-5]，未经治疗的肝转移患者的中位生存期仅6.9个月，无法切除患者的5年生存率低于5%^[6]，而肝转移灶能完全切除[或可以达到无疾病证据（no evidence of disease，NED）状态]患者的中位生存期达35~60个月，5年总体生存率可达40%~57%^[7-11]。研究表明，有一部分最初肝转移灶无法根除的患者经治疗后可以转化为可切除或达到NED状态。因此，通过多学科团队（multidisciplinary team，MDT）对结直肠癌肝转移患者进行全面地评估，个性化地制定治疗目标，开展相应的综合治疗，以预防结直肠癌肝转移的发生、提高肝转移灶手术切除率和5年生存率^[12-13]。

为了提高我国结直肠癌肝转移的诊断和综合治疗水平，受卫生部临床重点学科项目资助（2008—2010年），中华医学会外科分会胃肠外科学组和结直肠外科学组、中国抗癌协会大肠癌专业委员会自2008年起联合编写了《结直肠癌肝转移诊断和综合治疗指南》（草案），以指导我国结直肠癌肝转移的诊断和治疗，并于2010年、2013年先后进行了两次修订。2016年、2018年、2020年、2023年联合中国医师协会外科医师分会结直肠外科医师委员会、中国医疗保健国际交流促进会转移肿瘤治疗学分会和结直肠病分会、中国临床肿瘤学会结直肠癌专家委员会、中国医师协会结直肠肿瘤专业委员会、中国医师协会肛肠医师分会肿瘤转移委员会、中华医学会肿瘤学分会结直肠肿瘤学组、中国医师协会外科医师分会等多次共同修订了《指南》。2025年再次共同总结国内外先进经验和最新进展修订本《指南》。（本文中出现的推荐级别、循证医学证据分类的界定，详见附录1；本《指南》对结直肠癌肝转移的诊断、预防、外科手术和其他综合治疗提出的建议，请各地医院根据实际情况予以应用，诊疗流程详见附录2）。

1 结直肠癌肝转移的诊断与随访

1.1 结直肠癌肝转移的定义

按照国际共识，同时性肝转移（synchronous liver metastases）是指结直肠癌确诊前或确诊时发现的肝转移；而结直肠癌根治术后发生的肝转移称为异时性肝转移（metachronous liver metastases）^[14]。本指南为便于诊疗策略的制定，将按照“结直肠癌确诊时合并肝转移”和“结直肠癌根治术后发生肝转移”两方面阐述。

1.2 结直肠癌确诊时肝转移的诊断常规

对已确诊结直肠癌的患者，除血清CEA、CA19-9等肿瘤标志物检查、病理分期评估外，应常规进行肝脏超声和腹部CT增强等影像检查筛查及诊断肝脏转移瘤。对于超声或CT影像高度怀疑但不能确诊的患者可加行血清甲胎蛋白、肝脏超声造影和肝脏MRI增强检查^[15-16]（1a类证据，A级推荐），肝脏细胞特异性造影剂增强MRI检查对于发现1 cm的微小病灶准确率更高，有条件时可考虑（2a类证据，B级推荐）。PET/CT或PET/MRI检查不作为常规推荐，可在病情需要时酌情应用^[17-18]（2a类证据，B级推荐）。

肝脏病灶的经皮针刺活检仅限于病情需要时应用^[19]。

结直肠癌手术中必须常规探查肝脏以进一步排除肝转移的可能^[20]，对可疑的肝脏结节可行术中超声检查，必要时考虑同步切除或术中活检^[6]（3a类证据，B级推荐）。

1.3 结直肠癌根治术后肝转移的监测

结直肠癌根治术后，应对患者定期随访^[21-23]，了解有无肝转移或其他远处转移的发生。(1) 每3~6个月进行1次病史询问、体格检查、肝脏超声检查和检测血清CEA、CA19-9等适当的肿瘤标志物，持续2年，以后每6个月1次直至满5年^[24]（1a类证据，A级推荐），5年后每年1次。(2) Ⅱ期和Ⅲ期的结直肠癌患者，建议每年进行1次胸/腹/盆腔CT增强检查，共3~5年^[25]（1b类证据，A级推荐），以后每1~2年1次。对于超声或CT影像高度怀疑肝转移瘤但不能确诊的患者应加行肝脏MRI等检查，并建议在随访过程中保持影像检查方法的一致性。PET/CT检查不作常规推荐。(3) 术后1年内应进行电子结肠镜的检查，若发现异常，需在1年内复查^[26]；如无异常则推荐术后第3年复查，以后每5年1次。如果患者发病年龄50岁或确诊Lynch综合征则应适当增加电子结肠镜的检查频率。对于结直肠癌原发灶切除术前因梗阻等原因未完成全结肠镜检查的患者，应在术后3~6个月内完成首次电子结肠镜检查^[26]（1a类证据，A级推荐）。

1.4 结直肠癌肝转移灶达到NED后的随访

结直肠癌肝转移灶达到NED后，对患者也应进行密切的随访，了解有无肝转移复发或出现其他远处转移的可能。(1) 建议术后2年内每3个月随访血清CEA、CA19-9和其他适当的肿瘤标志物，以后第3~5年内每6个月随访1次（1a类证据，A级推荐），5年后每年1次。(2) 术后2年内每3个月进行1次腹/盆腔CT增强检查或肝脏MRI增强检查，必要时肝脏细胞特异性造影剂增强MRI检查。以后每6~12个月进行1次，共5年^[25]（1a类证据，A级推荐），5年后每年1次。不推荐常规PET/CT或PET/MRI检查。(3) 其他随访内容和频次参照结直肠癌原发灶根治术后的随访进行。

1.5 结直肠癌及其肝转移的相关基因检测

1.5.1 错配修复基因（MMR）/微卫星不稳定性（MSI）检测

推荐结直肠癌患者均进行检测^[27-30]（1a类证据，A级推荐），以便更精准地制定治疗策略，尤其是对免疫检查点抑制剂的应用至关重要。采用PCR+毛细管电泳法比较肿瘤组织与正常组织中微卫星序列长度的差异检测微卫星状态，是MSI检测的金标准^[31-32]。免疫组化检测MMR的蛋白表达（包括MLH1、MSH2、MSH6和PMS2），因简便快捷已成为目前最常用的检测方式，可达到与PCR检测90%~95%以上的一致率^[33]。另外，经过验证合格的二代测序法（next-generation sequencing，NGS）也可用于MSI检测。

1.5.2 RAS检测

推荐所有结直肠癌肝转移的患者均进行KRAS第2、3、4外显子以及NRAS第2、3、4外显子的检测^[34-36]。RAS基因是否突变不仅具有预后意义^[37-39]，更是预测抗EGFR治疗有效性的重要生物标志物^[40-41]（1a类证据，A级推荐）。尤其强调具体突变位点的检测，如KRAS G12C或G12D等突变还有助于后线治疗对新型靶向药物的选择^[42-43]。

1.5.3 BRAF检测

推荐结直肠癌肝转移患者进行BRAF^V600E突变检测^[44-45]，作为预后的评估指标^[46-48]（1b类证据，A级推荐）以及疗效预测因子，以指导治疗方案选择。

1.5.4 HER2检测

在标准治疗失败的转移性结直肠癌患者中抗HER2治疗逐渐受到重视，建议转移性结直肠癌患者进行HER2检测^[49]，为晚期患者后线治疗的临床决策提供依据（2b类证据，B级推荐）。另外，HER2过表达或扩增提示患者可能对抗EGFR单抗治疗反应不佳。

1.5.5 其他

NGS检测肿瘤突变负荷^[50]、DNA聚合酶epsilon和delta 1（POLE/POLD1）^[51]、神经营养因子受体酪氨酸激酶（NTRK）融合基因^[52]、转染原癌基因（RET）重排、间质表皮转化因子（c-Met）等，均可作为潜在的预测免疫检查点抑制剂治疗或靶向药物治疗疗效的生物标志物^[53-54]。结直肠癌原发灶和肝转移灶的基因状态大多无差别^[55-57]，对于无法获取肿瘤组织进行检测时可考虑液态活检技术^[58]（2b类证据，B级推荐）。有研究发现基于循环肿瘤DNA（ctDNA）指导的微小残留病灶（minimum residual disease，MRD）评估可有效提示结直肠癌患者接受治疗后的治愈情况，因此MRD有助于判断预后和制定下一步治疗策略，目前还在不断完善中，仍需要更多循证医学证据^[53,59-60]。

2 结直肠癌肝转移的预防

2.1 结直肠癌原发灶根治性切除术

根治性手术切除结直肠癌病灶是迄今为止结直肠癌最有效的治愈方法，也是预防肝转移发生的重要环节。(1) 结肠癌根治性手术范围包括肿瘤全部及其两端足够肠段和周围可能被浸润的组织和器官以及相关系膜、主要供应血管和淋巴引流区，具体手术方式依照肿瘤部位不同而异，但均应遵循完整结肠系膜切除（complete mesocolic excision，CME）原则。(2) 直肠癌根治性手术范围应包括肿瘤全部及其两端足够肠段、周围可能被浸润的组织和器官以及相关的肠系膜和淋巴结。直肠中下段的肿瘤应遵循全直肠系膜切除（total mesorectal excision，TME）原则。(3) 术中发现存在切除范围外的可疑转移淋巴结，应进行术中活检或切除。

2.2 结直肠癌确诊时无肝转移（及其他远处转移）的新辅助治疗

术前通过新辅助治疗控制未被影像学检测到的微小转移灶，可以最大程度地减少根治性手术后的远处转移^[61]。

2.2.1 中低位直肠癌的新辅助治疗（注：高位直肠癌，即肿瘤下缘距肛缘10 cm以上者，其新辅助治疗参照结肠癌）

(1) 对于dMMR/MSI-H患者，现有研究^[62-64]表明：免疫检查点抑制剂治疗后效果较好，大多可以免除手术或/和放化疗，仅需观察等待。目前数据显示短期结果理想，长期结果有待观察。(2) 对于pMMR/MSS/MSI-L患者，术前诊断为T3期及以上或任何T、淋巴结阳性的直肠癌，在不伴有明显出血、梗阻症状、无穿孔以及其他远处转移等情况时，应用放化疗或放疗或化疗^[65-66]。另外，已有多项研究^[67-69]发现，新辅助放化疗或放疗联合/序贯免疫检查点抑制剂治疗，可获得更好的病理客观缓解，且安全性不受影响。局部进展期直肠癌还可实施全程新辅助治疗（total neoadjuvant treatment，TNT）^[70]，将直肠癌术后辅助化疗也提至术前应用，即术前进行新辅助化疗和同步放化疗，可获得更高的完全缓解率，有助于器官保留，还可以降低远处转移发生，改善长期生存^[71-74]（1a类证据，A级推荐）。(3) 肝动脉和肿瘤区域动脉联合灌注化疗，对于术前分期Ⅲ期，且不伴有出血、梗阻症状或无穿孔的患者，在有条件的单位可考虑应用。5-氟尿嘧啶（5-FU）（或其前体药物）并可联合奥沙利铂，经肝动脉、肿瘤区域动脉分别灌注，化疗后7~10 d施行根治性切除术。目前的临床研究表明该方案虽不能明显降期，但对Ⅲ期结直肠癌患者有预防肝转移的作用^[75]，建议在有条件的单位开展，不作为常规推荐。

2.2.2 结肠癌的新辅助治疗

pMMR/MSS/MSI-L的结肠癌的新辅助治疗尚无明确的循证医学证据，对于术前判断为Ⅲ期的患者可考虑肝动脉和肿瘤区域动脉联合灌注化疗，以减少肝转移的发生^[75]，不作为常规推荐。有研究发现，dMMR/MSI-H的结肠癌患者，应用免疫检查点抑制剂新辅助治疗可获得较为理想的病理客观缓解，从而改善生存。

2.3 无转移结直肠癌患者术中门静脉化疗、腹腔化疗

对于该治疗方案的探讨目前有了一些令人鼓舞的数据^[76]，如能联合术后辅助化疗，将可以减少肝转移的发生。但这一结果仍需进一步临床研究证实，故不作为常规手段推荐，临床研究可关注。

2.4 无转移结直肠癌患者根治术后的辅助治疗

对于Ⅲ期结肠癌，术后辅助化疗能延长5年无病生存率及总生存率^[77]。因此，Ⅲ期结肠癌患者在手术治疗后应进行3~6个月的辅助化疗，可选择的治疗方案有：FOLFOX、CapeOX、5-FU/LV或卡培他滨单药（1a类证据，A级推荐）。

pMMR/MSS/MSI-L的Ⅱ期患者如不存在复发转移高危因素（T4、组织分化差、肿瘤周围淋巴管神经侵犯、肠梗阻或T3伴有局部穿孔、切缘不确定或阳性、淋巴结活检数量少于12枚），术后两药联合的辅助化疗在许多临床研究中获益不显著，故建议接受临床观察和随访^[78]（1b类证据，A级推荐），或建议5-FU单药治疗。但对于高危Ⅱ期患者应予以辅助化疗，方案参照Ⅲ期患者^[79-80]（2a类证据，B级推荐）。

dMMR/MSI-H的Ⅱ期患者无论是否存在高危因素均可接受临床观察和随访，但T4患者是否需辅助化疗目前尚有争议^[81]。dMMR/MSI-H的Ⅱ/Ⅲ期患者，术后是否使用免疫检查点抑制剂作为辅助治疗仍存在争议。

T3及以上和任何T、淋巴结阳性的中低位直肠癌患者如术前没有进行放化疗，术后辅助化疗或放化疗能提高3年无病生存率及降低局部复发率^[82]，但对于能否减少直肠癌肝转移方面研究有限，和辅助治疗的结合方式也需更多临床试验验证。术前接受过放疗或联合放化疗的患者，术后也应接受辅助治疗，但尚无充分的循证医学证据。

总而言之，结直肠癌肝转移最有效的预防方式就是规范化治疗结直肠癌。

3 MDT在结直肠癌肝转移诊治中的作用

对于肿瘤性疾病，MDT治疗模式是有效的手段^[83]，因此建议结直肠癌肝转移的患者均进入MDT治疗模式^[84-85]（1a类证据，A级推荐）。结直肠癌的MDT以患者为中心，成员应包括结直肠外科/胃肠外科、肝脏外科、肿瘤内科、放疗科、放射介入科、放射和超声影像科、病理科及其他相关专业有一定资质的医生^[86]。MDT治疗模式可以减少个体医生做出的不完善决策^[87]，其重要作用还包括：(1) 更精准的基因分子分型；(2) 更精确的疾病分期；(3) 减少治疗混乱和延误；(4) 更个性化的评估体系和治疗；(5) 更好的治疗衔接；(6) 更高的生活质量；(7) 最佳的临床和生存获益；(8) 最优的卫生经济学^[88-89]。

MDT根据患者的体力状况、年龄、器官功能、合并症和肿瘤的分子病理特征等进行评估，针对不同的治疗目标，给予患者最合理的检查和最恰当的综合治疗方案^[90]（1a类证据，A级推荐）。

3.1 患者全身状况较差的处理

患者全身状况较差，不适合进行高强度治疗时，建议单药（或联合靶向药物）、减量的两药方案或最佳支持治疗，以提高生活质量并尽量延长生存时间。如全身情况好转，可以再进行高强度治疗。

3.2 适合高强度治疗患者的治疗策略

3.2.1 可切除肝转移灶

这类患者治疗目的是获得治愈^[91]。应该围绕手术治疗进行相应的新辅助和/或辅助治疗，以降低手术后复发的风险。肝转移灶是否可以R₀切除的判断应由肝外科、肿瘤外科、影像科专家联合进行。肝转移灶可以R₀切除，但手术切除难度较大时也应积极联合其他肿瘤局部毁损手段（如射频消融或/和立体定向放疗等），以达到NED状态^[92]。

3.2.2 初始不可切除但有望转化者

这类患者的治疗目的主要是最大程度地缩小瘤体或增加残肝体积，应采用最积极的综合治疗，即转化治疗。对于dMMR/MSI-H患者：排除禁忌证后，应首选免疫检查点抑制剂治疗，包括单药或两药治疗^[93-95]。对于pMMR/MSS/MSI-L患者：(1) 结直肠癌确诊时合并无法达到NED的肝转移：① 结直肠癌原发灶存在出血、梗阻症状或穿孔时，应先行切除结直肠癌原发病灶，继而进行系统性化疗[或加用肝动脉灌注化疗（HAIC）]，并可联合应用分子靶向药物治疗（1b类证据，A级推荐）。治疗后每6~8周进行肝脏超声检查和CT增强检查并依据RECIST标准予以评估。临床重大决策时建议MRI增强检查。如果肝转移灶转变成可切除或有望NED时，适当时机予以手术治疗和/或其他肿瘤局部毁损手段；如果肝转移灶仍不能达到NED，则继续进行综合治疗。② 结直肠癌原发灶无出血、梗阻症状及无穿孔时可以行系统性化疗（或加用HAIC），并可联用分子靶向治疗（1c类证据，B级推荐）。每6~8周评估1次，如果转移灶转化成可切除或有望NED时，即手术治疗（一期同步切除或分阶段切除原发病灶和肝转移灶）或手术联合其他肿瘤局部毁损手段；如果肝转移灶仍不能达到NED，则视具体情况手术切除结直肠癌原发病灶，术后继续对肝转移灶进行综合治疗。此类患者也可选择先行切除结直肠癌的原发病灶，继而进一步治疗，具体方案同上。③ 局部晚期直肠癌合并同时性肝转移，需兼顾直肠癌局部治疗和全身治疗，可长程同步放化疗序贯化疗或联合免疫检查点抑制剂治疗，也可短程放疗联合化疗或联合免疫检查点抑制剂治疗，现有研究结果更倾向于选择后者^[96-97]。(2) 结直肠癌根治术后发生的无法达到NED的肝转移：① 采用5-FU/LV（或卡培他滨）联合奥沙利铂或/和伊立替康的两药或三药方案作为一线化疗，并可加用分子靶向治疗，或联用HAIC^[98]（1b类证据，A级推荐）。对5-FU类药物不耐受的患者可考虑使用雷替曲塞（2b类证据，B级推荐）。② 在肝转移发生前12个月内使用过奥沙利铂为基础的化疗作为辅助治疗的患者，应采用FOLFIRI方案^[99]；化疗结束后12个月以上发生肝转移，仍可采用FOLFOX或CapeOX化疗方案，并可加用分子靶向药物治疗，或联用HAIC（3a类证据，B级推荐）。治疗后每6~8周检查肝脏超声、CT增强检查予以评估，临床重大决策时建议MRI增强检查。肝转移灶转为可切除或可以达到NED的患者，即应接受肝转移灶切除手术或手术联合其他肿瘤局部毁损手段，术后再予以辅助化疗；如果肝转移灶仍不能达到NED，则应继续进行综合治疗。

3.2.3 始终无法切除或达到NED者

这类患者以控制疾病进展为目的进行治疗，应该采用较为积极的联合治疗。对于结直肠癌原发灶无出血、梗阻症状及无穿孔时合并始终无法达到NED的肝转移灶的患者是否应该切除原发灶目前仍有争议^[100-101]。因此，需要MDT综合考虑肿瘤和患者情况，进行个体化决策，是否切除原发灶。

总之，正如多项真实世界研究所证实，多次MDT评估不仅对全身治疗有反应的结直肠癌肝转移患者有价值，而且对最初认为永远无法手术切除的患者也有价值^[100,102]。

4 结直肠癌肝转移灶的手术及其他毁损治疗

4.1 手术治疗

手术完全切除肝转移灶仍是目前能治愈结直肠癌肝转移的最佳方法^[103-106]，故符合条件的患者均应在适当的时候接受手术治疗。部分最初肝转移灶无法切除的患者经治疗后转化为可切除病灶时也应适时接受手术治疗。

4.1.1 手术适应证和禁忌证

(1) 适应证：是否适合手术切除的标准一直在演变，但主要应从以下三个方面来判断（2a类证据，B级推荐）：① 结直肠癌原发灶能够或已经根治性切除；② 根据肝脏解剖学基础和病灶范围，肝转移灶可完全（R₀）切除，且要求保留足够的功能性肝组织（肝脏残留容积≥30%~40%），采用三维CT、吲哚菁绿、3D数字成像技术等有助于评估残肝体积^[107-109]；③ 患者全身状况允许，没有不可切除或毁损的肝外转移病变，或仅为肺部结节性病灶，但不影响肝转移灶切除决策。随着技术的进步，肝转移灶的大小、数目、部位等已不再是影响判断结直肠癌肝转移患者是否适宜手术的单一决定因素。另外，当前的文献资料已经将切缘不足1 cm^[110]、可切除的肝门淋巴结转移^[111-112]、可切除的肝外转移病灶（包括肺、腹腔）^[113]等也纳入了适宜手术切除的范畴（4类证据，C级推荐）。(2) 禁忌证^[6,111,114]（3a类证据，B级推荐）：① 结直肠癌原发灶不能取得根治性切除；② 出现不适合局部处理的肝外转移；③ 预计术后残余肝脏容积不够；④ 患者全身状况不能耐受手术。

4.1.2 结直肠癌确诊时合并肝转移的手术治疗

(1) 结直肠癌原发灶和肝转移灶一期同步切除：在结直肠癌原发灶切除难度较小、肝转移灶小且多位于周边或局限于半肝，肝切除量低于60%，肝门部淋巴结、腹腔或其他远处转移均可手术切除的患者可建议一期同步切除^[115-116]。有研究认为一期同步切除肝转移灶和原发结直肠癌病灶手术的并发症发生率和死亡率可能高于二期分阶段手术^[117-118]，故患者的选择上应较为慎重，尤其是需要在两切口下完成的同步手术。急诊手术由于缺少完备的术前检查资料和较高的感染发生机会，不推荐原发结直肠癌和肝脏转移病灶一期同步切除^[119]（2c类证据，B级推荐）。(2) 结直肠癌原发灶和肝转移灶二期分阶段切除：术前评估不能满足一期同步切除条件的患者，可以先手术切除结直肠癌原发病灶，二期分阶段切除肝转移灶，时机选择在结直肠癌根治术后4~6周；若在肝转移灶手术前进行系统性治疗，肝转移灶的切除可延至原发灶切除后3个月内进行。可根治的复发性结直肠癌伴有可切除肝转移灶的治疗按结直肠癌确诊时合并肝转移处理，但倾向于进行二期分阶段切除肝转移灶。不可切除的结直肠癌肝转移经转化治疗转化为可切除后，倾向于进行二期分阶段切除结直肠癌原发灶和肝转移灶^[100]。先切除肝转移灶、再切除结直肠原发灶的“肝优先模式”（liver first approach）也已开展应用，其手术的并发症发生率、死亡率和5年生存率均与传统模式的二期分阶段切除相同^[120-121]（3b类证据，B级推荐）。

4.1.3 结直肠癌根治术后发生肝转移的手术治疗

既往结直肠原发灶为根治性切除且不伴有原发灶复发，肝转移灶能完全切除且肝切除量低于70%（无肝硬化者），应予以手术切除肝转移灶，也可考虑先行新辅助治疗（3b类证据，B级推荐）。诊断结直肠癌根治术后发生肝转移应当有两项以上的影像学检查依据，包括肝脏超声或超声造影、CT及MRI增强等，必要时可结合PET/CT或PET/MRI检查以确定病变的范围和有无肝外转移，从而避免不必要的手术治疗^[122]。

4.1.4 肝转移灶手术方式的选择（3b类证据，B级推荐）

(1) 肝转移灶切除后至少保留3根肝静脉中的1根且残肝容积≥40%（同时性肝切除）或≥30%（异时性肝切除）。转移灶的手术切除应符合R₀原则，切缘至少1 mm^[123-124]。(2) 如是局限于左半或右半肝的较大肝转移灶且无肝硬化者，可行规则的半肝切除。(3) 肝转移手术时采用术中超声或超声造影检查，有助于发现术前影像学检查未能诊断的肝转移病灶。肝脏微创手术切除比例逐渐增多，显示出更好的短期结局。而且，使用人工智能影像进行肝脏手术精准规划应用也日益增多。(4) 应用门静脉选择性的栓塞（PVE）或结扎（PVL）可以使肝转移灶切除术后预期剩余肝脏代偿性增大，增加手术切除的可能。此方法被用于预计手术切除后剩余肝脏体积不足30%的肝转移患者。对于那些剩余肝脏体积在30%~40%，并且接受了强烈化疗而有肝实质损伤的患者，同样也可从中得益^[125]（4类证据，C级推荐）。联合肝脏离断和门静脉结扎的二步肝切除术（associating liver partition and portal vein ligation for staged hepatectomy，ALPPS）可使残留肝脏的体积在较短时间内明显增大而获得更多Ⅱ期肝切除的机会，但此手术复杂，并发症发生率及死亡率均高于传统肝切除，故建议在严格选择的患者中由经验丰富的肝脏外科医师实施手术^[126]。放射性同时门静脉和肝静脉栓塞（radiological simultaneous portohepatic vein embolization，RASPE），又称肝静脉剥夺术^[127]（liver venous deprivation，LVD），对比单纯门静脉栓塞和联合肝脏离断和ALPPS^[128]，不仅可使残余肝迅速增生，而且并发症发生率和死亡率低于ALPPS^[129]，具有操作简捷、创伤小、安全等优点，但仍需更多研究进一步评价，临床研究可关注。放射性微球选择性内放射治疗（selective internal radiotherapy，SIRT）是兼具控制肿瘤和增大残余肝体积的临床治疗手段。研究综述显示，钇-90 SIRT用于单侧肝叶SIRT后1~9个月，对侧肝叶平均增大29%~57%，肿瘤控制良好，有利于随后的肝转移切除手术^[130-131]。(5) 对于经过肝切除、局部消融治疗、系统性化疗、介入治疗、分子靶向治疗、免疫检查点抑制剂治疗等多种方法的联合或序贯治疗仍无法达到NED但仍局限于肝转移的患者，如对全身化疗有反应，肝移植联合全身治疗，显著提高总体生存率，可酌情谨慎选择^[132-134]。

4.1.5 肝转移灶切除术后复发和肝外转移灶的切除

在全身状况和肝脏条件允许的情况下，对于可切除的肝转移灶术后的复发病灶，经MDT讨论后，可再次选择手术切除或其他局部治疗，文献报道显示其手术并发症发生率和死亡率并不高于第1次肝转移灶的切除，而且可获得相同的术后生存率^[102,135]（3b类证据，B级推荐）。同样，在患者全身状况允许时，如果肺^[136]和腹腔^[137]等的肝外转移病灶可完全切除，也应进行同步或分阶段切除（3b类证据，B级推荐）。

4.2 可以达到NED状态的肿瘤局部毁损治疗

除了手术切除肝转移灶外，有些治疗手段（如射频消融、微波消融和放射治疗）也能使病灶发生彻底毁损，所以对于手术切除难度较大的个别肝转移灶应积极联合此类手段，以使更多的患者有机会达到NED状态，提高5年生存率^[138]。

射频消融高效破坏肝转移灶肿瘤细胞，使用方便，安全性好，具有创伤小、可重复等优势^[139-141]。可作为肝病灶手术切除的重要补充，达到NED状态。建议应用时选择肝转移灶最大直径3 cm且1次消融最多5枚。但局部复发率偏高，不作为可切除病灶的首选推荐。也有研究表明，肝转移灶较小的患者，消融治疗和手术切除的长期生存相当。此外，对于一般情况不适宜或不愿意接受手术治疗的可切除结直肠癌肝转移患者也可以考虑射频消融治疗，但应注意避免肝外热损伤、针道转移、感染和消融不彻底等问题。

微波消融可处理直径5 cm的肝转移灶，也可处理贴近重要血管的肝转移灶^[141]。快速高温消融使肿瘤周边微血管凝固，减少卫星灶残留风险，显著降低大病灶复发率。微波消融深部肝转移灶，也可作为手术切除主要肝转移灶的重要补充。

对于转移灶数目≤3个，肿瘤最大直径≤6 cm的肝内转移灶，立体定向放射治疗（SBRT）可以取得较好的局部控制率。对于直径≤3 cm的肝寡转移灶，SBRT可取得媲美于射频消融的局部控制率；对于直径3 cm的肝转移灶，SBRT疗效优于射频消融，是首选的非手术局部治疗手段^[142-143]。

5 可达到NED状态结直肠癌肝转移的新辅助及辅助治疗

5.1 新辅助治疗

对可达到NED的结直肠癌肝转移患者可考虑进行新辅助治疗，主要基于以下几方面原因：(1) 新辅助化疗提供了“窗口期”，观察有无新的无法切除的转移灶的出现，减少没有必要的手术。(2) 新辅助治疗可增加R₀手术的机会，增加术后残余肝脏的体积。(3) 新辅助化疗可作为评价化疗方案敏感性的依据，指导术后化疗方案的选择。(4) 新辅助化疗的疗效，可作为患者预后评估的一个指标。(5) 新辅助化疗结合辅助化疗，可能改善接受治愈性手术患者的预后。

新辅助治疗在应用时也应关注如下情况的发生：(1) 化疗可能会造成肝脏损伤：如与奥沙利铂治疗相关的肝窦阻塞综合征^[144]；与伊立替康治疗相关的脂肪变性和脂肪性肝炎等^[145]，这些损害均可能增加肝切除术后并发症的发生^[146-147]。(2) 影像学检查消失的转移灶术中仍应积极探查^[148-149]，例如术中超声造影等^[150]，若病灶有残存，应积极切除；若病灶消失而无法精确定位者应慎重考虑是否切除^[151-152]。(3) 转移灶进展致使无法达到NED。

5.1.1 结直肠癌确诊时合并肝转移的新辅助治疗

在原发灶无出血、梗阻症状或无穿孔时，除肝转移灶在技术上切除容易且不存在不良预后因素的患者[如临床危险评分（clinical risk score，CRS）3]外，可考虑应用新辅助治疗^[153-156]（2a类证据，B级推荐），尤其是肝转移灶体积较大、转移灶数量较多或存在原发灶淋巴结可疑转移的患者。对于dMMR/MSI-H的患者，免疫检查点抑制剂应作为首选的新辅助治疗^[157]。对于pMMR/MSS/MSI-L的患者，系统性化疗的方案包括FOLFOX、FOLFIRI、CapeOX或FOLFOXIRI^[157-159]，可否联合分子靶向治疗目前仍有争议，同时也可以考虑联合HAIC^[160-163]。为减少化疗对肝脏手术的不利影响，新辅助化疗原则上不超过6个周期^[79,164-166]（1a证据，A级推荐），一般建议2~3个月内完成并进行手术^[167-168]。

5.1.2 结直肠癌根治术后发生的肝转移的新辅助治疗

对于dMMR/MSI-H的患者，免疫检查点抑制剂应作为首选的新辅助治疗。对于pMMR/MSS/MSI-L的原发灶切除术后未接受过化疗的患者，或者发现肝转移12个月前已完成化疗的患者，可采用新辅助治疗（方法同上），时间2~3个月^[164,169]（2a证据，B级推荐）。而肝转移发现前12个月内接受过化疗的患者，一般认为新辅助化疗作用可能较为有限，宜直接切除肝转移灶，继而术后辅助治疗^[170]（2a类证据，B级推荐）。也可考虑更换化疗方案进行新辅助化疗^[149,162]，或术前联合HAIC。

5.2 肝转移灶切除术后的辅助治疗

建议肝转移灶完全切除的患者接受术后辅助化疗^[171-172]，特别是没有进行过术前化疗及辅助化疗的患者，多数推荐手术前后的化疗时间总长不超过6个月（2c类证据，B级推荐）。对于术前接受过HAIC且有效的患者，术后也可考虑同时联合HAIC^[173-176]。经过术前化疗（包括联合分子靶向药物）证实有效的方案，术后如无禁忌应该作为首选的辅助治疗方案。

6 无法达到NED状态结直肠癌肝转移的综合治疗

对于无法达到NED的结直肠癌肝转移的综合治疗包括系统性化疗和介入化疗、分子靶向治疗、免疫检查点抑制剂治疗以及针对肝脏病灶的局部治疗如消融治疗、无水酒精注射、放射治疗等，治疗方案的选择应基于对患者治疗前的精确评估。

部分初诊无法达到NED的肝转移患者，经过系统的综合治疗后，即转化治疗，可转为适宜手术切除^[177-178]或达到NED。其术后5年生存率与初始肝转移灶手术切除的患者相似^[179-180]，此类患者应当采取较为积极的诱导方案，应用有效的强烈化疗，并考虑联合HAIC及分子靶向药物治疗。

对于肝转移灶始终无法达到NED的患者，综合治疗也可明显延长中位生存期，控制疾病快速进展，明显改善生存质量^[181-184]。因此，积极的综合治疗对于适合强烈治疗的晚期结直肠癌肝转移患者同样意义重大。

6.1 dMMR/MSI-H患者

相较于标准化疗±靶向治疗，一线应用免疫检查点抑制剂帕博利珠单抗等PD-1单抗或纳武利尤单抗PD-1单抗联合伊匹木单抗CTLA-4单抗免疫检查点抑制剂治疗可明显提高疾病控制率和转化切除率^[185-186]，应作为首选。

多项研究^[187-190]表明，单药或两药免疫检查点抑制剂治疗用于二线及三线治疗显示出令人鼓舞的效果。对于未使用过该类治疗的dMMR/MSI-H患者可以优先选择免疫检查点抑制剂。

6.2 pMMR/MSS/MSI-L患者

6.2.1 系统性化疗和HAIC

化疗开始前应充分评估患者的身体状况和肿瘤分期，事先规划好患者的后续治疗和预计有严重化疗毒性反应时剂量和方案的调整。开始治疗时必须考虑患者的分类（详见“3 MDT在结直肠癌肝转移诊治中的作用”节）、化疗的安全性以及将来手术或/和局部病灶毁损治疗的可能性。

(1) 初始化疗：① 对于肝转移灶有潜在NED可能的患者进行转化治疗至关重要。转移灶出现的早期退缩（early tumor shrinkage，ETS）更是预后的重要指标之一^[191-193]。5-FU/LV（或卡培他滨）联合奥沙利铂或/和伊立替康的化疗方案具有较高的转化切除率（1b类证据，A级推荐），应该作为首选的化疗方案。化疗联合分子靶向药物可以进一步提高转化率^[194-195]（1b类证据，A级推荐）。现有的研究数据显示，化疗联合贝伐珠单抗有良好的疾病控制率和转化切除率^[196]，而RAS野生型患者还可以采用化疗联合西妥昔单抗治疗^[197-198]（1b类证据，A级推荐）。有数据^{[179,197,199]}提示，对于RAS野生型的结直肠癌肝转移患者，抗EGFR治疗的疗效与肿瘤部位存在相关性。原发灶位于左半结肠（脾曲至直肠）肝转移患者使用抗EGFR单抗在客观缓解率和总生存上优于抗VEGF单抗，而原发灶位于右半结肠（回盲部至脾曲）肝转移患者，抗EGFR单抗在客观反应率上优于抗VEGF单抗，但总体生存不如抗VEGF单抗。以FOLFOXIRI为代表的三药化疗方案也有较高的切除转化率^[200-202]，在分子靶向药物无法使用且综合患者年龄、体能状况及肝功能状态等因素均适宜的情况下应该作为首选，但该方案的不良反应较多，应予以关注。目前三药化疗方案联合贝伐珠单抗的研究有了较好的临床数据^[202-205]，可在选择性的患者中谨慎地应用^{[182,201,204]}（2b类证据，B级推荐）。还有研究发现三药化疗联合抗EGFR单抗比单纯三药化疗有更高的客观缓解率，能潜在提高R₀切除率，改善总体生存^[199-200]（2b类证据，B级推荐）。也有研究发现三药化疗联合抗EGFR单抗，与两药化疗联合抗EGFR单抗，并没有显著改善客观缓解率，也没有提高转化切除率或长期生存，且相关毒性增加。BRAF的状态是重要的预后指标，BRAF^V600E突变的结直肠癌肝转移患者大多预后较差，有数据提示对该类患者化疗联合抗EGFR治疗的获益比较有限^[206]。因此对BRAF^V600E突变的结直肠癌肝转移患者，初始治疗采用三药化疗联合抗VEGF单抗，或者BRAF抑制剂+抗EGFR单抗±MEK抑制剂，或者BRAF抑制剂+伊立替康+抗EGFR单抗。② 对于肝转移灶始终无法达到NED的患者，5-FU/LV（或卡培他滨）联合奥沙利铂或伊立替康的化疗方案是首选，也可以联合分子靶向药物治疗^{[172,182,207]}（2b类证据，B级推荐）。含奥沙利铂和伊立替康的三药化疗尽管有较高的反应率，但毒性也较大，是否应在此类患者中应用尚不明确。

(2) 诱导化疗后病情缓解或稳定，但肝转移灶仍无法R₀切除：可考虑进入维持治疗（如采用毒性较低的5-FU/LV或卡培他滨单药，均可联合贝伐珠单抗）^[208-212]或单独使用贝伐珠单抗^[213]或暂停化疗，以降低持续高强度联合化疗的毒性反应^[213-214]。

(3) 初始化疗病情进展后的化疗选择：① FOLFOX（或CapeOX）方案±分子靶向治疗，如果病情进展后可以考虑改用FOLFIRI（或mXELIRI^[215]）方案；FOLFIRI方案±分子靶向治疗，如果病情进展可考虑改用FOLFOX（或CapeOX）方案，仍可考虑与分子靶向药物的联合^[216-218]；二线方案也可选用曲氟尿苷替匹嘧啶联合贝伐珠单抗。如果病情第二次进展，可以使用曲氟尿苷替匹嘧啶±贝伐珠单抗^[219-220]或瑞戈非尼^[221]或呋喹替尼^[222]或西妥昔单抗^[223-224]（未用过此类药者，仅限RAS野生型）或最佳支持治疗^[61]（2a类证据，B级推荐）。② 5-FU/LV联合分子靶向治疗后如果病情进展，应改用FOLFOX、FOLFIRI或CapeOX（均可联合分子靶向治疗），病情再次进展时推荐瑞戈非尼或呋喹替尼或曲氟尿苷替匹嘧啶±贝伐珠单抗或进行最佳支持治疗^[225]（3b类证据，B级推荐）。③ 对于三线失败后的治疗目前尚无标准方案。据文献报道联合抗BRAF^V600E（既往未使用过该方案的伊立替康+抗EGFR+BRAF抑制剂，或抗EGFR+BRAF抑制剂±MEK抑制剂）的治疗方案^{[44-45,226-228]}、抗HER2治疗（HER2阳性患者）^[229-232]、KRAS G12C抑制剂+西妥昔单抗（KRAS G12C突变患者）都能起到一定作用，但考虑到上述药物的适应证和可及性问题，仅建议在临床研究中谨慎使用，不作常规推荐。

(4) 肝转移为主的肿瘤负荷较大且药物治疗效果不明显的患者，或者难治性患者或者不能耐受系统治疗的患者：可在适当时机联合应用HAIC、肝动脉化疗栓塞（TACE）、药物洗脱微球动脉化疗栓塞（DEB-TACE）、钇-90 SIRT等，有助于延长疾病无进展时间和总体生存期^[233-239]，但是单独应用这些治疗并不比全身化疗更具优势。

6.2.2 局部毁损治疗

对于无法手术切除的肝转移灶，应根据其位置、治疗目标、治疗相关并发症及患者自身情况，在系统性化疗基础上选择适当的局部毁损工具以加强局部病灶的控制，具体应由MDT进行决策并结合患者意愿。其他治疗方法包括无水酒精瘤内注射、局部放射性粒子植入和中医中药治疗等，仅可作为综合治疗的一部分，不推荐单独使用。

参考文献

[1] Siegel RL, Wagle NS, Cercek A, et al. Colorectal cancer statistics, 2023[J]. CA Cancer J Clin, 2023, 73(3):233-254. doi:10.3322/caac.21772 .

[2] Eng C, Yoshino T, Ruíz-García E, et al. Colorectal cancer[J]. Lancet, 2024, 404(10449):294-310. doi:10.1016/S0140-6736(24)00360-X .

[3] Vibert E, Canedo L, Adam R. Strategies to treat primary unresectable colorectal liver metastases[J]. Semin Oncol, 2005, 32(6 ):33-39. doi:10.1053/j.seminoncol.2005.07.015 .

[4] Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020[J]. CA Cancer J Clinicians, 2020, 70(3):145-164. doi:10.3322/caac.21601 .

[5] Cohen R, Raeisi M, Chibaudel B, et al. Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: an ARCAD pooled analysis[J]. Eur J Cancer, 2024, 207:114160. doi:10.1016/j.ejca.2024.114160 .

[6] Stewart CL, Warner S, Ito K, et al. Cytoreduction for colorectal metastases: liver, lung, peritoneum, lymph nodes, bone, brain. When does it palliate, prolong survival, and potentially cure?[J]. Curr Probl Surg, 2018, 55(9):330-379. doi:10.1067/j.cpsurg.2018.08.004 .

[7] de Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients[J]. Ann Surg, 2009, 250(3):440-448. doi:10.1097/SLA.0b013e3181b4539b .

[8] Margonis GA, Sergentanis TN, Ntanasis-Stathopoulos I, et al. Impact of surgical margin width on recurrence and overall survival following R0 hepatic resection of colorectal metastases: a systematic review and meta-analysis[J]. Ann Surg, 2018, 267(6):1047-1055. doi:10.1097/SLA.0000000000002552 .

[9] Giuliante F, Ardito F, Vellone M, et al. Role of the surgeon as a variable in long-term survival after liver resection for colorectal metastases[J]. J Surg Oncol, 2009, 100(7):538-545. doi:10.1002/jso.21393 .

[10] Padmanabhan C, Nussbaum DP, D'Angelica M. Surgical management of colorectal cancer liver metastases[J]. Hematol Oncol Clin North Am, 2025, 39(1):1-24. doi:10.1016/j.hoc.2024.08.011 .

[11] Morris VK, Kennedy EB, Baxter NN, et al. Treatment of metastatic colorectal cancer: ASCO guideline[J]. J Clin Oncol, 2023, 41(3):678-700. doi:10.1200/JCO.22.01690 .

[12] Timmerman RD, Bizekis CS, Pass HI, et al. Local surgical, ablative, and radiation treatment of metastases[J]. CA Cancer J Clin, 2009, 59(3):145-170. doi:10.3322/caac.20013 .

[13] Lv Y, Feng QY, Wei Y, et al. Benefits of multi-disciplinary treatment strategy on survival of patients with colorectal cancer liver metastasis[J]. Clin Transl Med, 2020, 10(3):e121. doi:10.1002/ctm2.121 .

[14] Adam R, de Gramont A, Figueras J, et al. Managing synchronous liver metastases from colorectal cancer: a multidisciplinary international consensus[J]. Cancer Treat Rev, 2015, 41(9):729-741. doi:10.1016/j.ctrv.2015.06.006 .

[15] Görgec B, Hansen IS, Kemmerich G, et al. MRI in addition to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): an international, multicentre, prospective, diagnostic accuracy trial[J]. Lancet Oncol, 2024, 25(1):137-146. doi:10.1016/S1470-2045(23)00572-7 .

[16] Ichikawa S, Goshima S. Clinical significance of liver MR imaging[J]. Magn Reson Med Sci, 2023, 22(2):157-175. doi:10.2463/mrms.rev.2022-0100 .

[17] Monteil J, Le Brun-Ly V, Cachin F, et al. Comparison of 18FDG-PET/CT and conventional follow-up methods in colorectal cancer: a randomised prospective study[J]. Dig Liver Dis, 2021, 53(2):231-237. doi:10.1016/j.dld.2020.10.012 .

[18] Coenegrachts K, De Geeter F, ter Beek L, et al. Comparison of MRI (including SS SE-EPI and SPIO-enhanced MRI) and FDG-PET/CT for the detection of colorectal liver metastases[J]. Eur Radiol, 2009, 19(2):370-379. doi:10.1007/s00330-008-1163-y .

[19] Jones OM, Rees M, John TG, et al. Biopsy of resectable colorectal liver metastases causes tumour dissemination and adversely affects survival after liver resection[J]. Br J Surg, 2005, 92(9):1165-1168. doi:10.1002/bjs.4888 .

[20] Koshariya M, Jagad RB, Kawamoto J, et al. An update and our experience with metastatic liver disease[J]. Hepatogastroenterology, 2007, 54(80):2232-2239.

[21] Komborozos VA, Skrekas GJ, Pissiotis CA. The contribution of follow-up programs in the reduction of mortality of rectal cancer recurrences[J]. Dig Surg, 2001, 18(5):403-408. doi:10.1159/000050182 .

[22] Tsikitis VL, Malireddy K, Green EA, et al. Postoperative surveillance recommendations for early stage colon cancer based on results from the clinical outcomes of surgical therapy trial[J]. J Clin Oncol, 2009, 27(22):3671-3676. doi:10.1200/JCO.2008.20.7050 .

[23] Pfister DG, Benson AB 3rd, Somerfield MR. Clinical practice. Surveillance strategies after curative treatment of colorectal cancer[J]. N Engl J Med, 2004, 350(23):2375-2382. doi:10.1056/NEJMcp010529 .

[24] Locker GY, Hamilton S, Harris J, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer[J]. J Clin Oncol, 2006, 24(33):5313-5327. doi:10.1200/JCO.2006.08.2644 .

[25] Desch CE, Benson AB 3rd, Somerfield MR, et al. Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline[J]. J Clin Oncol, 2005, 23(33):8512-8519. doi:10.1200/JCO.2005.04.0063 .

[26] Rex DK, Kahi CJ, Levin B, et al. Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and US Multi-Society Task Force on Colorectal Cancer[J]. CA Cancer J Clin, 2006, 56(3):160-167. doi:10.3322/canjclin.56.3.160 .

[27] Moreira L, Balaguer F, Lindor N, et al. Identification of Lynch syndrome among patients with colorectal cancer[J]. JAMA, 2012, 308(15):1555-1565. doi:10.1001/jama.2012.13088 .

[28] Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (lynch syndrome) and microsatellite instability[J]. J Natl Cancer Inst, 2004, 96(4):261-268. doi:10.1093/jnci/djh034 .

[29] Buchanan DD, Clendenning M, Rosty C, et al. Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts[J]. J Gastroenterol Hepatol, 2017, 32(2):427-438. doi:10.1111/jgh.13468 .

[30] Mulet-Margalef N, Linares J, Badia-Ramentol J, et al. Challenges and therapeutic opportunities in the dMMR/MSI-H colorectal cancer landscape[J]. Cancers (Basel), 2023, 15(4):1022. doi:10.3390/cancers15041022 .

[31] Chen S, Watson P, Parmigiani G. Accuracy of MSI testing in predicting germline mutations of MSH2 and MLH1: a case study in Bayesian meta-analysis of diagnostic tests without a gold standard[J]. Biostatistics, 2005, 6(3):450-464. doi:10.1093/biostatistics/kxi021 .

[32] Hempelmann JA, Lockwood CM, Konnick EQ, et al. Microsatellite instability in prostate cancer by PCR or next-generation sequencing[J]. J Immunother Cancer, 2018, 6(1):29. doi:10.1186/s40425-018-0341-y .

[33] Stelloo E, Jansen AL, Osse EM, et al. Practical guidance for mismatch repair-deficiency testing in endometrial cancer[J]. Ann Oncol, 2017, 28(1):96-102. doi:10.1093/annonc/mdw542 .

[34] Modest DP, Ricard I, Heinemann V, et al. Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group[J]. Ann Oncol, 2016, 27(9):1746-1753. doi:10.1093/annonc/mdw261 .

[35] Therkildsen C, Bergmann TK, Henrichsen-Schnack T, et al. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: a systematic review and meta-analysis[J]. Acta Oncol, 2014, 53(7):852-864. doi:10.3109/0284186X.2014.895036 .

[36] Schirripa M, Cremolini C, Loupakis F, et al. Role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer[J]. Int J Cancer, 2015, 136(1):83-90. doi:10.1002/ijc.28955 .

[37] Brudvik KW, Mise Y, Chung MH, et al. RAS mutation predicts positive resection margins and narrower resection margins in patients undergoing resection of colorectal liver metastases[J]. Ann Surg Oncol, 2016, 23(8):2635-2643. doi:10.1245/s10434-016-5187-2 .

[38] Passot G, Chun YS, Kopetz SE, et al. Prognostic factors after resection of colorectal liver metastases following preoperative second-line chemotherapy: Impact of RAS mutations[J]. Eur J Surg Oncol, 2016, 42(9):1378-1384. doi:10.1016/j.ejso.2016.02.249 .

[39] Margonis GA, Buettner S, Andreatos N, et al. Anatomical resections improve disease-free survival in patients with KRAS-mutated colorectal liver metastases[J]. Ann Surg, 2017, 266(4):641-649. doi:10.1097/SLA.0000000000002367 .

[40] Sorich MJ, Wiese MD, Rowland A, et al. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials[J]. Ann Oncol, 2015, 26(1):13-21. doi:10.1093/annonc/mdu378 .

[41] Mao C, Yang ZY, Hu XF, et al. PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis[J]. Ann Oncol, 2012, 23(6):1518-1525. doi:10.1093/annonc/mdr464 .

[42] Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C[J]. N Engl J Med, 2023, 388(1):44-54. doi:10.1056/NEJMoa2212419 .

[43] Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C[J]. N Engl J Med, 2023, 389(23):2125-2139. doi:10.1056/NEJMoa2308795 .

[44] Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer[J]. N Engl J Med, 2019, 381(17):1632-1643. doi:10.1056/NEJMoa1908075 .

[45] Van Cutsem E, Huijberts S, Grothey A, et al. Binimetinib, encorafenib, and cetuximab triplet therapy for patients with BRAF V600E-mutant metastatic colorectal cancer: safety lead-In results from the phase Ⅲ BEACON colorectal cancer study[J]. J Clin Oncol, 2019, 37(17):1460-1469. doi:10.1200/JCO.18.02459 .

[46] Guren TK, Thomsen M, Kure EH, et al. Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-Ⅶ study[J]. Br. J. Cancer, 2017, 116(10):1271-1278. doi:10.1038/bjc.2017.93 .

[47] Sinicrope FA, Shi Q, Allegra CJ, et al. Association of DNA mismatch repair and mutations in BRAF and KRAS with survival after recurrence in stage Ⅲ colon cancers: a secondary analysis of 2 randomized clinical trials[J]. JAMA Oncol, 2017, 3(4):472-480. doi:10.1001/jamaoncol.2016.5469 .

[48] Pikoulis E, Margonis GA, Andreatos N, et al. Prognostic role of BRAF mutations in colorectal cancer liver metastases[J]. Anticancer Res, 2016, 36(9):4805-4811. doi:10.21873/anticanres.11040 .

[49] Guler I, Askan G, Klostergaard J, et al. Precision medicine for metastatic colorectal cancer: an evolving era[J]. Expert Rev Gastroenterol Hepatol, 2019, 13(10):919-931. doi:10.1080/17474124.2019.1663174 .

[50] Allgäuer M, Budczies J, Christopoulos P, et al. Implementing tumor mutational burden (TMB) analysis in routine diagnostics-a primer for molecular pathologists and clinicians[J]. Transl Lung Cancer Res, 2018, 7(6):703-715. doi:10.21037/tlcr.2018.08.14 .

[51] Ambrosini M, Rousseau B, Manca P, et al. Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer[J]. Ann Oncol, 2024, 35(7):643-655. doi:10.1016/j.annonc.2024.03.009 .

[52] Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy[J]. Nat Rev Clin Oncol, 2018, 15(12):731-747. doi:10.1038/s41571-018-0113-0 .

[53] Kojitani Y, Takeda M. Current status of precision medicine in colorectal cancer in Japan[J]. Int J Mol Sci, 2025, 26(11):5029. doi:10.3390/ijms26115029 .

[54] Lin KX, Istl AC, Quan D, et al. PD-1 and PD-L1 inhibitors in cold colorectal cancer: challenges and strategies[J]. Cancer Immunol Immunother, 2023, 72(12):3875-3893. doi:10.1007/s00262-023-03520-5 .

[55] Artale S, Sartore-Bianchi A, Veronese SM, et al. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer[J]. J Clin Oncol, 2008, 26(25):4217-4219. doi:10.1200/JCO.2008.18.7286 .

[56] Etienne-Grimaldi MC, Formento JL, Francoual M, et al. K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy[J]. Clin Cancer Res, 2008, 14(15):4830-4835. doi:10.1158/1078-0432.CCR-07-4906 .

[57] Knijn N, Mekenkamp LM, Klomp M, et al. KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients[J]. Br J Cancer, 2011, 104(6):1020-1026. doi:10.1038/bjc.2011.26 .

[58] Ho HY, Chung KK, Kan CM, et al. Liquid biopsy in the clinical management of cancers[J]. Int J Mol Sci, 2024, 25(16):8594. doi:10.3390/ijms25168594 .

[59] Kawashima M, Yamada T, Miyasaka T, et al. Impact of minimal residual disease on early recurrence of liver metastatic colorectal cancer[J]. Cancer Sci, 2025, 116(5):1366-1374. doi:10.1111/cas.16442 .

[60] Parikh AR, Chee BH, Tsai J, et al. Minimal residual disease using a plasma-only circulating tumor DNA assay to predict recurrence of metastatic colorectal cancer following curative intent treatment[J]. Clin Cancer Res, 2024, 30(14):2964-2973. doi:10.1158/1078-0432.CCR-23-3660 .

[61] Chau I, Chan S, Cunningham D. Overview of preoperative and postoperative therapy for colorectal cancer: the European and United States perspectives[J]. Clin Colorectal Cancer, 2003, 3(1):19-33. doi:10.3816/CCC.2003.n.009 .

[62] Yu JH, Liao LE, Xiao BY, et al. Long-term outcomes of dMMR/MSI-H rectal cancer treated with anti-PD-1-based immunotherapy as curative-intent treatment[J]. J Natl Compr Canc Netw, 2024, 22(3):e237096. doi:10.6004/jnccn.2023.7096 .

[63] Gervaso L, Ciardiello D, Oliveira RA, et al. Immunotherapy in the neoadjuvant treatment of gastrointestinal tumors: is the time ripe?[J]. J Immunother Cancer, 2024, 12(5):e008027. doi:10.1136/jitc-2023-008027 .

[64] Zhou L, Yang XQ, Zhao GY, et al. Meta-analysis of neoadjuvant immunotherapy for non-metastatic colorectal cancer[J]. Front Immunol, 2023, 14:1044353. doi:10.3389/fimmu.2023.1044353 .

[65] Schrag D, Shi Q, Weiser MR, et al. Preoperative treatment of locally advanced rectal cancer[J]. N Engl J Med, 2023, 389(4):322-334. doi:10.1056/NEJMoa2303269 .

[66] Basch E, Dueck AC, Mitchell SA, et al. Patient-reported outcomes during and after treatment for locally advanced rectal cancer in the PROSPECT trial (alliance N1048)[J]. J Clin Oncol, 2023, 41(21):3724-3734. doi:10.1200/JCO.23.00903 .

[67] Yang L, Cui X, Wu F, et al. The efficacy and safety of neoadjuvant chemoradiotherapy combined with immunotherapy for locally advanced rectal cancer patients: a systematic review[J]. Front Immunol, 2024, 15:1392499. doi:10.3389/fimmu.2024.1392499 .

[68] Tsukada Y, Bando H, Inamori K, et al. Three-year outcomes of preoperative chemoradiotherapy plus nivolumab in microsatellite stable and microsatellite instability-high locally advanced rectal cancer[J]. Br J Cancer, 2024, 131(2):283-289. doi:10.1038/s41416-024-02730-7 .

[69] Gao Y, Wu A. Organ preservation in MSS rectal cancer[J]. Clin Colon Rectal Surg, 2023, 36(6):430-440. doi:10.1055/s-0043-1767710 .

[70] Cercek A, Roxburgh CSD, Strombom P, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer[J]. JAMA Oncol, 2018, 4(6):e180071. doi:10.1001/jamaoncol.2018.0071 .

[71] Petrelli F, Trevisan F, Cabiddu M, et al. Total neoadjuvant therapy in rectal cancer: a systematic review and meta-analysis of treatment outcomes[J]. Ann Surg, 2020, 271(3):440-448. doi:10.1097/SLA.0000000000003471 .

[72] Turri G, Ostuzzi G, Vita G, et al. Treatment of locally advanced rectal cancer in the era of total neoadjuvant therapy: a systematic review and network meta-analysis[J]. JAMA Netw Open, 2024, 7(6):e2414702. doi:10.1001/jamanetworkopen.2024.14702 .

[73] Socha J, Glynne-Jones R, Bujko K. Oncological risks associated with the planned watch-and-wait strategy using total neoadjuvant treatment for rectal cancer: a narrative review[J]. Cancer Treat Rev, 2024, 129:102796. doi:10.1016/j.ctrv.2024.102796 .

[74] Lin W, Li C, Clement EA, et al. Surgical outcomes in total neoadjuvant therapy for rectal cancer versus standard long-course chemoradiation: a systematic review and meta-analysis of randomized controlled trials[J]. Ann Surg, 2024, 279(4):620-630. doi:10.1097/SLA.0000000000006161 .

[75] Xu J, Zhong Y, Niu W, et al. Preoperative hepatic and regional arterial chemotherapy in the prevention of liver metastasis after colorectal cancer surgery[J]. Ann Surg, 2007, 245(4):583-590. doi:10.1097/01.sla.0000250453.34507.d3 .

[76] Chang W, Wei Y, Ren L, et al. Randomized controlled trial of intraportal chemotherapy combined with adjuvant chemotherapy (mFOLFOX6) for stage Ⅱ and Ⅲ colon cancer[J]. Ann Surg, 2016, 263(3):434-439. doi:10.1097/SLA.0000000000001374 .

[77] Sugihara K, Ohtsu A, Shimada Y, et al. Safety analysis of FOLFOX4 treatment in colorectal cancer patients: a comparison between two Asian studies and four Western studies[J]. Clin Colorectal Cancer, 2012, 11(2):127-137. doi:10.1016/j.clcc.2011.09.001 .

[78] Rodríguez-Moranta F, Saló J, Arcusa A, et al. Postoperative surveillance in patients with colorectal cancer who have undergone curative resection: a prospective, multicenter, randomized, controlled trial[J]. J Clin Oncol, 2006, 24(3):386-393. doi:10.1200/JCO.2005.02.0826 .

[79] André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage Ⅱ or Ⅲ colon cancer in the MOSAIC trial[J]. J Clin Oncol, 2009, 27(19):3109-3116. doi:10.1200/JCO.2008.20.6771 .

[80] Kuebler JP, Wieand HS, O'Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage Ⅱ and Ⅲ colon cancer: results from NSABP C-07[J]. J Clin Oncol, 2007, 25(16):2198-2204. doi:10.1200/JCO.2006.08.2974 .

[81] Baxter NN, Kennedy EB, Bergsland E, et al. Adjuvant therapy for stage Ⅱ colon cancer: ASCO guideline update[J]. J Clin Oncol, 2022, 40(8):892-910. doi:10.1200/JCO.21.02538 .

[82] Yu TK, Bhosale PR, Crane CH, et al. Patterns of locoregional recurrence after surgery and radiotherapy or chemoradiation for rectal cancer[J]. Int J Radiat Oncol Biol Phys, 2008, 71(4):1175-1180. doi:10.1016/j.ijrobp.2007.11.018 .

[83] Fennell ML, Das IP, Clauser S, et al. The organization of multidisciplinary care teams: modeling internal and external influences on cancer care quality[J]. J Natl Cancer Inst Monogr, 2010, 2010(40):72-80. doi:10.1093/jncimonographs/lgq010 .

[84] Nordlinger B, Vauthey JN, Poston G, et al. The timing of chemotherapy and surgery for the treatment of colorectal liver metastases[J]. Clin Colorectal Cancer, 2010, 9(4):212-218. doi:10.3816/CCC.2010.n.031 .

[85] Miller ED, Klamer BG, Cloyd JM, et al. Consideration of metastasis-directed therapy for patients with metastatic colorectal cancer: expert survey and systematic review[J]. Clin Colorectal Cancer, 2024, 23(2):160-173. doi:10.1016/j.clcc.2024.01.004 .

[86] Wright FC, De Vito C, Langer B, et al. Multidisciplinary cancer conferences: a systematic review and development of practice standards[J]. Eur J Cancer, 2007, 43(6):1002-1010. doi:10.1016/j.ejca.2007.01.025 .

[87] Jung SM, Hong YS, Kim TW, et al. Impact of a multidisciplinary team approach for managing advanced and recurrent colorectal cancer[J]. World J Surg, 2018, 42(7):2227-2233. doi:10.1007/s00268-017-4409-5 .

[88] Hernandez Dominguez O, Yilmaz S, Steele SR. Stage Ⅳ colorectal cancer management and treatment[J]. J Clin Med, 2023, 12(5):2072. doi:10.3390/jcm12052072 .

[89] Al Bitar S, El-Sabban M, Doughan S, et al. Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond[J]. World J Gastroenterol, 2023, 29(9):1395-1426. doi:10.3748/wjg.v29.i9.1395 .

[90] Karaoğlan BB, Öz DK, Araz MS, et al. Advancements in the management of synchronous colorectal liver metastases: a comprehensive review of surgical, systemic, and local treatment modalities[J]. Curr Oncol Rep, 2024, 26(7):791-803. doi:10.1007/s11912-024-01548-z .

[91] Swan PJ, Welsh FS, Chandrakumaran K, et al. Long-term survival following delayed presentation and resection of colorectal liver metastases[J]. Br J Surg, 2011, 98(9):1309-1317. doi:10.1002/bjs.7527 .

[92] Rahbari NN, Birgin E, Bork U, et al. Anterior approach vs conventional hepatectomy for resection of colorectal liver metastasis: a randomized clinical trial[J]. JAMA Surg, 2021, 156(1):31-40. doi:10.1001/jamasurg.2020.5050 .

[93] Ambrosini M, Manca P, Nasca V, et al. Epidemiology, pathogenesis, biology and evolving management of MSI-H/dMMR cancers[J]. Nat Rev Clin Oncol, 2025, 22(6):385-407. doi:10.1038/s41571-025-01015-z .

[94] Margalit O, Stemmer A, Chapin WJ, et al. Duration of immunotherapy in dMMR/MSI-H metastatic colorectal cancer patients[J]. Eur J Cancer, 2024, 212:114336. doi:10.1016/j.ejca.2024.114336 .

[95] Andre T, Elez E, Van Cutsem E, et al. Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer[J]. N Engl J Med, 2024, 391(21):2014-2026. doi:10.1056/NEJMoa2402141 .

[96] Bae HW, Kim HS, Yang SY, et al. Upfront chemotherapy and short-course radiotherapy with delayed surgery for locally advanced rectal cancer with synchronous liver metastases[J]. Eur J Surg Oncol, 2021, 47(11):2814-2820. doi:10.1016/j.ejso.2021.05.018 .

[97] Huang YY, Chen GW, Zhang X, et al. Pelvic radiotherapy in rectal cancer patients with synchronous potentially treatable liver metastases[J]. Cancer Rep (Hoboken), 2025, 8(1):e70122. doi:10.1002/cnr2.70122 .

[98] Datta J, Narayan RR, Kemeny NE, et al. Role of hepatic artery infusion chemotherapy in treatment of initially unresectable colorectal liver metastases: a review[J]. JAMA Surg, 2019, 154(8):768-776. doi:10.1001/jamasurg.2019.1694 .

[99] Kanani A, Veen T, Søreide K. Neoadjuvant immunotherapy in primary and metastatic colorectal cancer[J]. Br J Surg, 2021, 108(12):1417-1425. doi:10.1093/bjs/znab342 .

[100] Mattar RE, Al-Alem F, Simoneau E, et al. Preoperative selection of patients with colorectal cancer liver metastasis for hepatic resection[J]. World J Gastroenterol, 2016, 22(2):567-581. doi:10.3748/wjg.v22.i2.567 .

[101] Lin Q, Ding KF, Zhao R, et al. Preoperative chemotherapy prior to primary tumour resection for asymptomatic synchronous unresectable colorectal liver-limited metastases: The RECUT multicenter randomised controlled trial[J]. Eur J Cancer, 2023, 191:112961. doi:10.1016/j.ejca.2023.112961 .

[102] Kobayashi K, Inoue Y, Oba A, et al. Strategies for recurrent colorectal liver metastases based on prognostic factors and resectability: potential benefit of multidisciplinary treatment[J]. Ann Surg Oncol, 2025, 32(3):1729-1741. doi:10.1245/s10434-024-16491-3 .

[103] Akgül Ö, Çetinkaya E, Ersöz Ş, et al. Role of surgery in colorectal cancer liver metastases[J]. World J Gastroenterol, 2014, 20(20):6113-6122. doi:10.3748/wjg.v20.i20.6113 .

[104] Zhu DX, Ren L, Wei Y, et al. Outcome of patients with colorectal liver metastasis: analysis of 1, 613 consecutive cases[J]. Ann Surg Oncol, 2012, 19(9):2860-2868. doi:10.1245/s10434-012-2356-9 .

[105] Rengers T, Warner S. Surgery for colorectal liver metastases: anatomic and non-anatomic approach[J]. Surgery, 2023, 174(1):119-122. doi:10.1016/j.surg.2023.02.032 .

[106] Kataoka K, Takahashi K, Takeuchi J, et al. Correlation between recurrence-free survival and overall survival after upfront surgery for resected colorectal liver metastases[J]. Br J Surg, 2023, 110(7):864-869. doi:10.1093/bjs/znad127 .

[107] Khan AS, Garcia-Aroz S, Ansari MA, et al. Assessment and optimization of liver volume before major hepatic resection: Current guidelines and a narrative review[J]. Int J Surg, 2018, 52:74-81. doi:10.1016/j.ijsu.2018.01.042 .

[108] Bégin A, Martel G, Lapointe R, et al. Accuracy of preoperative automatic measurement of the liver volume by CT-scan combined to a 3D virtual surgical planning software (3DVSP)[J]. Surg Endosc, 2014, 28(12):3408-3412. doi:10.1007/s00464-014-3611-x .

[109] Takemura N, Ito K, Inagaki F, et al. Added value of indocyanine green fluorescence imaging in liver surgery[J]. Hepatobiliary Pancreat Dis Int, 2022, 21(4):310-317. doi:10.1016/j.hbpd.2021.12.007 .

[110] Yan TD, Padang R, Xia H, et al. Management of involved or close resection margins in 120 patients with colorectal liver metastases: edge cryotherapy can achieve long-term survival[J]. Am J Surg, 2006, 191(6):735-742. doi:10.1016/j.amjsurg.2005.05.055 .

[111] Pulitanò C, Bodingbauer M, Aldrighetti L, et al. Colorectal liver metastasis in the setting of lymph node metastasis: defining the benefit of surgical resection[J]. Ann Surg Oncol, 2012, 19(2):435-442. doi:10.1245/s10434-011-1902-1 .

[112] Margonis GA, Buettner S, Andreatos N, et al. Prognostic factors change over time after hepatectomy for colorectal liver metastases: a multi-institutional, international analysis of 1099 patients[J]. Ann Surg, 2019, 269(6):1129-1137. doi:10.1097/SLA.0000000000002664 .

[113] Zizzo M, Galeone C, Braglia L, et al. Long-term outcomes after surgical resection for synchronous or metachronous hepatic and pulmonary colorectal cancer metastases[J]. Digestion, 2020, 101(2):144-155. doi:10.1159/000497223 .

[114] Sharma S, Camci C, Jabbour N. Management of hepatic metastasis from colorectal cancers: an update[J]. J Hepatobiliary Pancreat Surg, 2008, 15(6):570-580. doi:10.1007/s00534-008-1350-x .

[115] Capussotti L, Ferrero A, Viganò L, et al. Major liver resections synchronous with colorectal surgery[J]. Ann Surg Oncol, 2007, 14(1):195-201. doi:10.1245/s10434-006-9055-3 .

[116] Wu Y, Mao A, Wang H, et al. Association of simultaneous vs delayed resection of liver metastasis with complications and survival among adults with colorectal cancer[J]. JAMA Netw Open, 2022, 5(9):e2231956. doi:10.1001/jamanetworkopen.2022.31956 .

[117] Hatwell C, Bretagnol F, Farges O, et al. Laparoscopic resection of colorectal cancer facilitates simultaneous surgery of synchronous liver metastases[J]. Colorectal Dis, 2013, 15(1):e21-e28. doi:10.1111/codi.12068 .

[118] Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings[J]. Ann Surg, 2012, 255(3):405-414. doi:10.1097/SLA.0b013e31824856f5 .

[119] Nanji S, MacKillop WJ, Wei XJ, et al. Simultaneous resection of primary colorectal cancer and synchronous liver metastases: a population-based study[J]. Can J Surg, 2017, 60(2):122-128. doi:10.1503/cjs.008516 .

[120] Gumiero JL, Oliveira BMS, Neto PAO, et al. Timing of resection of synchronous colorectal liver metastasis: a systematic review and meta-analysis[J]. J Surg Oncol, 2022, 126(1):175-188. doi:10.1002/jso.26868 .

[121] Milazzo M, Todeschini L, Caimano M, et al. Surgical resection in colorectal liver metastasis: an umbrella review[J]. Cancers (Basel), 2024, 16(10):1849. doi:10.3390/cancers16101849 .

[122] Pelosi E, Deandreis D. The role of 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) in the management of patients with colorectal cancer[J]. Eur J Surg Oncol, 2007, 33(1):1-6. doi:10.1016/j.ejso.2006.10.020 .

[123] Ayez N, Lalmahomed ZS, Eggermont AM, et al. Outcome of microscopic incomplete resection (R1) of colorectal liver metastases in the era of neoadjuvant chemotherapy[J]. Ann Surg Oncol, 2012, 19(5):1618-1627. doi:10.1245/s10434-011-2114-4 .

[124] Pandanaboyana S, White A, Pathak S, et al. Impact of margin status and neoadjuvant chemotherapy on survival, recurrence after liver resection for colorectal liver metastasis[J]. Ann Surg Oncol, 2015, 22(1):173-179. doi:10.1245/s10434-014-3953-6 .

[125] Adam R, Miller R, Pitombo M, et al. Two-stage hepatectomy approach for initially unresectable colorectal hepatic metastases[J]. Surg Oncol Clin N Am, 2007, 16(3):525-536. doi:10.1016/j.soc.2007.04.016 .

[126] Díaz Vico T, Granero Castro P, Alcover Navarro L, et al. Two stage hepatectomy (TSH) versus ALPPS for initially unresectable colorectal liver metastases: a systematic review and meta-analysis[J]. Eur J Surg Oncol, 2023, 49(3):550-559. doi:10.1016/j.ejso.2022.11.010 .

[127] Chebaro A, Buc E, Durin T, et al. Liver venous deprivation or associating liver partition and portal vein ligation for staged hepatectomy?: a retrospective multicentric study[J]. Ann Surg, 2021, 274(5):874-880. doi:10.1097/SLA.0000000000005121 .

[128] Abbasi A, Rahnemai-Azar AA, Merath K, et al. Role of associating liver partition and portal vein ligation in staged hepatectomy (ALPPS)-strategy for colorectal liver metastases[J]. Transl Gastroenterol Hepatol, 2018, 3:66. doi:10.21037/tgh.2018.09.03 .

[129] Bertens KA, Hawel J, Lung K, et al. ALPPS: challenging the concept of unresectability: a systematic review[J]. Int J Surg, 2015, 13:280-287. doi:10.1016/j.ijsu.2014.12.008 .

[130] Salem R, Garin E, Boucher E, et al. Optimal patient selection for yttrium-90 glass plus chemotherapy in the treatment of colorectal liver metastases: additional quality of life, efficacy, and safety analyses from the EPOCH study[J]. Oncologist, 2024, 29(8):681-689. doi:10.1093/oncolo/oyae128 .

[131] Azeredo-da-Silva ALF, de Jesus VHF, Agirrezabal I, et al. Selective internal radiation therapy using Y-90 resin microspheres for metastatic colorectal cancer: an updated systematic review and network meta-analysis[J]. Adv Ther, 2024, 41(4):1606-1620. doi:10.1007/s12325-024-02800-5 .

[132] Tabbal M, Alkhalifa AM, AlQattan AS, et al. Salvage liver transplantation after resection of colorectal cancer liver metastasis with favorable outcomes: a case report and review of the literature[J]. BMC Gastroenterol, 2021, 21(1):191. doi:10.1186/s12876-021-01778-6 .

[133] Adam R, Piedvache C, Chiche L, et al. Liver transplantation plus chemotherapy versus chemotherapy alone in patients with permanently unresectable colorectal liver metastases (TransMet): results from a multicentre, open-label, prospective, randomised controlled trial[J]. Lancet, 2024, 404(10458):1107-1118. doi:10.1016/S0140-6736(24)01595-2 .

[134] Ros J, Salva F, Dopazo C, et al. Liver transplantation in metastatic colorectal cancer: are we ready for it?[J]. Br J Cancer, 2023, 128(10):1797-1806. doi:10.1038/s41416-023-02213-1 .

[135] Takeda Y, Mise Y, Ito H, et al. Repeat resection for advanced colorectal liver metastases-does it have the potential for cure?[J]. World J Surg, 2022, 46(9):2253-2261. doi:10.1007/s00268-022-06616-8 .

[136] Kanzaki R, Higashiyama M, Oda K, et al. Outcome of surgical resection for recurrent pulmonary metastasis from colorectal carcinoma[J]. Am J Surg, 2011, 202(4):419-426. doi:10.1016/j.amjsurg.2010.08.016 .

[137] Carpizo DR, D'Angelica M. Liver resection for metastatic colorectal cancer in the presence of extrahepatic disease[J]. Ann Surg Oncol, 2009, 16(9):2411-2421. doi:10.1245/s10434-009-0493-6 .

[138] Hallemeier CL, Sharma N, Anker C, et al. American Radium Society Appropriate Use Criteria for the use of liver-directed therapies for nonsurgical management of liver metastases: Systematic review and guidelines[J]. Cancer, 2023, 129(20):3193-3212. doi:10.1002/cncr.34931 .

[139] van den Bemd BAT, Puijk RS, Keijzers H, et al. Mathematical 3D liver model for surgical versus ablative therapy treatment planning for colorectal liver metastases: recommendations from the COLLISION and COLDFIRE trial expert panels[J]. Radiol Imaging Cancer, 2024, 6(6):e240068. doi:10.1148/rycan.240068 .

[140] Li J, Pang C, Liu G, et al. Thermal ablation with and without adjuvant systemic therapy: a nationwide multicenter observational cohort study of solitary colorectal liver metastases[J]. Int J Surg, 2024, 110(7):4240-4248. doi:10.1097/JS9.0000000000001397 .

[141] Ceppa EP, Collings AT, Abdalla M, et al. SAGES/AHPBA guidelines for the use of microwave and radiofrequency liver ablation for the surgical treatment of hepatocellular carcinoma or colorectal liver metastases less than 5 cm[J]. Surg Endosc, 2023, 37(12):8991-9000. doi:10.1007/s00464-023-10468-1 .

[142] Lukovic J, Dawson LA. Stereotactic body radiation therapy for colorectal cancer liver metastases[J]. J Gastrointest Oncol, 2024, 15(4):1917-1925. doi:10.21037/jgo-22-1183 .

[143] Yu J, Kim DH, Lee J, et al. Radiofrequency ablation versus stereotactic body radiation therapy in the treatment of colorectal cancer liver metastases[J]. Cancer Res Treat, 2022, 54(3):850-859. doi:10.4143/crt.2021.674 .

[144] Zhu C, Ren X, Liu D, et al. Oxaliplatin-induced hepatic sinusoidal obstruction syndrome[J]. Toxicology, 2021, 460:152882. doi:10.1016/j.tox.2021.152882 .

[145] Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases[J]. J Clin Oncol, 2006, 24(13):2065-2072. doi:10.1200/JCO.2005.05.3074 .

[146] Gomez D, Malik HZ, Bonney GK, et al. Steatosis predicts postoperative morbidity following hepatic resection for colorectal metastasis[J]. Br J Surg, 2007, 94(11):1395-1402. doi:10.1002/bjs.5820 .

[147] Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy[J]. Ann Surg, 2008, 247(1):118-124. doi:10.1097/SLA.0b013e31815774de .

[148] Adam R, Wicherts DA, de Haas RJ, et al. Complete pathologic response after preoperative chemotherapy for colorectal liver metastases: myth or reality?[J]. J Clin Oncol, 2008, 26(10):1635-1641. doi:10.1200/JCO.2007.13.7471 .

[149] Horgan PG. Surgical management of disappearing colorectal liver metastases (Br J Surg 2013; 100:1414-1420)[J]. Br J Surg, 2013, 100(11):1420. doi:10.1002/bjs.9219 .

[150] Barimani D, Kauppila JH, Sturesson C, et al. Imaging in disappearing colorectal liver metastases and their accuracy: a systematic review[J]. World J Surg Oncol, 2020, 18(1):264. doi:10.1186/s12957-020-02037-w .

[151] Leonard GD, Brenner B, Kemeny NE. Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma[J]. J Clin Oncol, 2005, 23(9):2038-2048. doi:10.1200/JCO.2005.00.349 .

[152] Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy[J]. Ann Surg, 2004, 240(4):644-658. doi:10.1097/01.sla.0000141198.92114.f6 .

[153] Poultsides GA, Servais EL, Saltz LB, et al. Outcome of primary tumor in patients with synchronous stage Ⅳ colorectal cancer receiving combination chemotherapy without surgery as initial treatment[J]. J Clin Oncol, 2009, 27(20):3379-3384. doi:10.1200/JCO.2008.20.9817 .

[154] Cheng XF, Zhao F, Chen D, et al. Current landscape of preoperative neoadjuvant therapies for initial resectable colorectal cancer liver metastasis[J]. World J Gastroenterol, 2024, 30(7):663-672. doi:10.3748/wjg.v30.i7.663 .

[155] Bernardi L, Roesel R, Aghayan DL, et al. Preoperative chemotherapy in upfront resectable colorectal liver metastases: New elements for an old dilemma?[J]. Cancer Treat Rev, 2024, 124:102696. doi:10.1016/j.ctrv.2024.102696 .

[156] Sarkar J, Attwood K, Schwarz RE. Perioperative chemotherapy is associated with superior overall survival in patients with synchronous colorectal liver metastases[J]. Ann Surg Oncol, 2023, 30(13):7986-7995. doi:10.1245/s10434-023-14302-9 .

[157] Li YJ, Tan LX, Chen N, et al. Neoadjuvant immunotherapy alone for patients with locally advanced and resectable metastatic colorectal cancer of dMMR/MSI-H status[J]. Dis Colon Rectum, 2024, 67(11):1413-1422. doi:10.1097/DCR.0000000000003290 .

[158] Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer[J]. J Clin Oncol, 2008, 26(11):1830-1835. doi:10.1200/JCO.2007.13.7679 .

[159] Parkin E, O'Reilly DA, Adam R, et al. The effect of hepatic steatosis on survival following resection of colorectal liver metastases in patients without preoperative chemotherapy[J]. HPB (Oxford), 2013, 15(6):463-472. doi:10.1111/hpb.12007 .

[160] Clancy TE, Dixon E, Perlis R, et al. Hepatic arterial infusion after curative resection of colorectal cancer metastases: a meta-analysis of prospective clinical trials[J]. J Gastrointest Surg, 2005, 9(2):198-206. doi:10.1016/j.gassur.2004.07.004 .

[161] Kemeny N, Eid A, Stockman J, et al. Hepatic arterial infusion of floxuridine and dexamethasone plus high-dose Mitomycin C for patients with unresectable hepatic metastases from colorectal carcinoma[J]. J Surg Oncol, 2005, 91(2):97-101. doi:10.1002/jso.20286 .

[162] Kemeny N, Jarnagin W, Paty P, et al. Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer[J]. J Clin Oncol, 2005, 23(22):4888-4896. doi:10.1200/JCO.2005.07.100 .

[163] Zaidi MY, Nussbaum DP, Hsu SD, et al. Hepatic artery infusion for unresectable colorectal cancer liver metastases: Palliation and conversion[J]. Surgery, 2023, 174(2):428-430. doi:10.1016/j.surg.2023.04.025 .

[164] Kishi Y, Zorzi D, Contreras CM, et al. Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases[J]. Ann Surg Oncol, 2010, 17(11):2870-2876. doi:10.1245/s10434-010-1166-1 .

[165] Hoogteijling TJ, Abu Hilal M, Zimmitti G, et al. Impact of neoadjuvant chemotherapy on short-term outcomes after simple and complex minimally invasive minor hepatectomy for colorectal liver metastases: a propensity-score matched and coarsened exact matched study[J]. Eur J Surg Oncol, 2024, 50(6):108309. doi:10.1016/j.ejso.2024.108309 .

[166] Tepelenis K, Pappas-Gogos G, Ntellas P, et al. The role of preoperative chemotherapy in the management of synchronous resectable colorectal liver metastases: a meta-analysis[J]. Curr Oncol, 2023, 30(5):4499-4511. doi:10.3390/curroncol30050340 .

[167] Benoist S, Nordlinger B. The role of preoperative chemotherapy in patients with resectable colorectal liver metastases[J]. Ann Surg Oncol, 2009, 16(9):2385-2390. doi:10.1245/s10434-009-0492-7 .

[168] Choti MA. Chemotherapy-associated hepatotoxicity: do we need to be concerned?[J]. Ann Surg Oncol, 2009, 16(9):2391-2394. doi:10.1245/s10434-009-0512-7 .

[169] Samantas E, Dervenis C, Rigatos SK. Adjuvant chemotherapy for colon cancer: evidence on improvement in survival[J]. Dig Dis, 2007, 25(1):67-75. doi:10.1159/000099172 .

[170] Benoist S, Nordlinger B. Neoadjuvant treatment before resection of liver metastases[J]. Eur J Surg Oncol, 2007, 33():S35-S41. doi:10.1016/j.ejso.2007.09.022 .

[171] Adam R, Bhangui P, Poston G, et al. Is perioperative chemotherapy useful for solitary, metachronous, colorectal liver metastases?[J]. Ann Surg, 2010, 252(5):774-787. doi:10.1097/SLA.0b013e3181fcf3e3 .

[172] Schwarz RE, Berlin JD, Lenz HJ, et al. Systemic cytotoxic and biological therapies of colorectal liver metastases: expert consensus statement[J]. HPB (Oxford), 2013, 15(2):106-115. doi:10.1111/j.1477-2574.2012.00558.x .

[173] De Greef K, Rolfo C, Russo A, et al. Multisciplinary management of patients with liver metastasis from colorectal cancer[J]. World J Gastroenterol, 2016, 22(32):7215-7225. doi:10.3748/wjg.v22.i32.7215 .

[174] Goéré D, Benhaim L, Bonnet S, et al. Adjuvant chemotherapy after resection of colorectal liver metastases in patients at high risk of hepatic recurrence: a comparative study between hepatic arterial infusion of oxaliplatin and modern systemic chemotherapy[J]. Ann Surg, 2013, 257(1):114-120. doi:10.1097/SLA.0b013e31827b9005 .

[175] House MG, Kemeny NE, Gönen M, et al. Comparison of adjuvant systemic chemotherapy with or without hepatic arterial infusional chemotherapy after hepatic resection for metastatic colorectal cancer[J]. Ann Surg, 2011, 254(6):851-856. doi:10.1097/SLA.0b013e31822f4f88 .

[176] Kemeny NE, Jarnagin WR, Capanu M, et al. Randomized phase Ⅱ trial of adjuvant hepatic arterial infusion and systemic chemotherapy with or without bevacizumab in patients with resected hepatic metastases from colorectal cancer[J]. J Clin Oncol, 2011, 29(7):884-889. doi:10.1200/JCO.2010.32.5977 .

[177] Abdalla EK. Commentary: radiofrequency ablation for colorectal liver metastases: do not blame the biology when it is the technology[J]. Am J Surg, 2009, 197(6):737-739. doi:10.1016/j.amjsurg.2008.06.029 .

[178] Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial[J]. Lancet Oncol, 2010, 11(1):38-47. doi:10.1016/S1470-2045(09)70330-4 .

[179] Adam R. Chemotherapy and surgery: new perspectives on the treatment of unresectable liver metastases[J]. Ann Oncol, 2003, 14():ii13-ii16. doi:10.1093/annonc/mdg731 .

[180] Goldberg RM, Sargent DJ, Morton RF, et al. Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: a North American Intergroup Trial[J]. J Clin Oncol, 2006, 24(21):3347-3353. doi:10.1200/JCO.2006.06.1317 .

[181] Cals L, Rixe O, François E, et al. Dose-finding study of weekly 24-h continuous infusion of 5-fluorouracil associated with alternating oxaliplatin or irinotecan in advanced colorectal cancer patients[J]. Ann Oncol, 2004, 15(7):1018-1024. doi:10.1093/annonc/mdh259 .

[182] Falcone A, Ricci S, Brunetti I, et al. Phase Ⅲ trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest[J]. J Clin Oncol, 2007, 25(13):1670-1676. doi:10.1200/JCO.2006.09.0928 .

[183] Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study[J]. J Clin Oncol, 2004, 22(2):229-237. doi:10.1200/JCO.2004.05.113 .

[184] Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study[J]. J Clin Oncol, 2008, 26(21):3523-3529. doi:10.1200/JCO.2007.15.4138 .

[185] André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer[J]. N Engl J Med, 2020, 383(23):2207-2218. doi:10.1056/NEJMoa2017699 .

[186] Andre T, Amonkar M, Norquist JM, et al. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial[J]. Lancet Oncol, 2021, 22(5):665-677. doi:10.1016/S1470-2045(21)00064-4 .

[187] Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency[J]. N Engl J Med, 2015, 372(26):2509-2520. doi:10.1056/NEJMoa1500596 .

[188] Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase Ⅱ KEYNOTE-158 study[J]. J Clin Oncol, 2020, 38(1):1-10. doi:10.1200/JCO.19.02105 .

[189] Lenz HJ, Van Cutsem E, Luisa Limon M, et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase Ⅱ CheckMate 142 study[J]. J Clin Oncol, 2022, 40(2):161-170. doi:10.1200/JCO.21.01015 .

[190] Le DT, Kim TW, Van Cutsem E, et al. Phase Ⅱ open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: keynote-164[J]. J Clin Oncol, 2020, 38(1):11-19. doi:10.1200/JCO.19.02107 .

[191] Piessevaux H, Buyse M, Schlichting M, et al. Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab[J]. J Clin Oncol, 2013, 31(30):3764-3775. doi:10.1200/JCO.2012.42.8532 .

[192] Suzuki C, Blomqvist L, Sundin A, et al. The initial change in tumor size predicts response and survival in patients with metastatic colorectal cancer treated with combination chemotherapy[J]. Ann Oncol, 2012, 23(4):948-954. doi:10.1093/annonc/mdr350 .

[193] Ye LC, Wei Y, Zhu DX, et al. Impact of early tumor shrinkage on clinical outcome in wild-type-KRAS colorectal liver metastases treated with cetuximab[J]. J Gastroenterol Hepatol, 2015, 30(4):674-679. doi:10.1111/jgh.12847 .

[194] Alberts SR, Horvath WL, Sternfeld WC, et al. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase Ⅱ study[J]. J Clin Oncol, 2005, 23(36):9243-9249. doi:10.1200/JCO.2005.07.740 .

[195] Pernot S, Artru P, Mithieux F, et al. Complete pathological response of unresectable liver metastases from colorectal cancer after trans-arterial chemoembolization with drug-eluting beads loaded with irinotecan (DEBIRI) and concomitant systemic FOLFOX: a case report from the FFCD 1201 trial[J]. Clin Res Hepatol Gastroenterol, 2015, 39(6):e73-e77. doi:10.1016/j.clinre.2015.06.004 .

[196] Tang W, Ren L, Liu T, et al. Bevacizumab plus mFOLFOX6 versus mFOLFOX6 alone as first-line treatment for RAS mutant unresectable colorectal liver-limited metastases: the BECOME randomized controlled trial[J]. J Clin Oncol, 2020, 38(27):3175-3184. doi:10.1200/JCO.20.00174 .

[197] Ye LC, Liu TS, Ren L, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases[J]. J Clin Oncol, 2013, 31(16):1931-1938. doi:10.1200/JCO.2012.44.8308 .

[198] Hu H, Wang K, Huang M, et al. Modified FOLFOXIRI with or without cetuximab as conversion therapy in patients with RAS/BRAF wild-type unresectable liver metastases colorectal cancer: the FOCULM multicenter phase Ⅱ trial[J]. Oncologist, 2021, 26(1):e90-e98. doi:10.1634/theoncologist.2020-0563 .

[199] Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer[J]. N Engl J Med, 2009, 360(14):1408-1417. doi:10.1056/NEJMoa0805019 .

[200] Garufi C, Torsello A, Tumolo S, et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial[J]. Br J Cancer, 2010, 103(10):1542-1547. doi:10.1038/sj.bjc.6605940 .

[201] Souglakos J, Androulakis N, Syrigos K, et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase Ⅲ trial from the Hellenic Oncology Research Group (HORG)[J]. Br J Cancer, 2006, 94(6):798-805. doi:10.1038/sj.bjc.6603011 .

[202] Cremolini C, Antoniotti C, Rossini D, et al. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial[J]. Lancet Oncol, 2020, 21(4):497-507. doi:10.1016/S1470-2045(19)30862-9 .

[203] Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study[J]. Lancet Oncol, 2015, 16(13):1306-1315. doi:10.1016/S1470-2045(15)00122-9 .

[204] Stein A, Atanackovic D, Hildebrandt B, et al. Upfront FOLFOXIRI+bevacizumab followed by fluoropyrimidin and bevacizumab maintenance in patients with molecularly unselected metastatic colorectal cancer[J]. Br J Cancer, 2015, 113(6):872-877. doi:10.1038/bjc.2015.299 .

[205] Tomasello G, Petrelli F, Ghidini M, et al. FOLFOXIRI plus bevacizumab as conversion therapy for patients with initially unresectable metastatic colorectal cancer: a systematic review and pooled analysis[J]. JAMA Oncol, 2017, 3(7):e170278. doi:10.1001/jamaoncol.2017.0278 .

[206] Karapetis CS, Jonker D, Daneshmand M, et al. PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer: results from NCIC CTG/AGITG CO.17[J]. Clin Cancer Res, 2014, 20(3):744-753. doi:10.1158/1078-0432.CCR-13-0606 .

[207] Cleary JM, Tanabe KT, Lauwers GY, et al. Hepatic toxicities associated with the use of preoperative systemic therapy in patients with metastatic colorectal adenocarcinoma to the liver[J]. Oncologist, 2009, 14(11):1095-1105. doi:10.1634/theoncologist.2009-0152 .

[208] Esin E, Yalcin S. Maintenance strategy in metastatic colorectal cancer: a systematic review[J]. Cancer Treat Rev, 2016, 42:82-90. doi:10.1016/j.ctrv.2015.10.012 .

[209] Goey KKH, Elias SG, van Tinteren H, et al. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study[J]. Ann Oncol, 2017, 28(9):2128-2134. doi:10.1093/annonc/mdx322 .

[210] Hegewisch-Becker S, Graeven U, Lerchenmüller CA, et al. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial[J]. Lancet Oncol, 2015, 16(13):1355-1369. doi:10.1016/S1470-2045(15)00042-X .

[211] Simkens LH, van Tinteren H, May A, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group[J]. Lancet, 2015, 385(9980):1843-1852. doi:10.1016/S0140-6736(14)62004-3 .

[212] Stein A, Schwenke C, Folprecht G, et al. Effect of application and intensity of bevacizumab-based maintenance after induction chemotherapy with bevacizumab for metastatic colorectal cancer: a meta-analysis[J]. Clin Colorectal Cancer, 2016, 15(2):e29-e39. doi:10.1016/j.clcc.2015.12.005 .

[213] Sonbol MB, Mountjoy LJ, Firwana B, et al. The role of maintenance strategies in metastatic colorectal cancer: a systematic review and network meta-analysis of randomized clinical trials[J]. JAMA Oncol, 2020, 6(3):e194489. doi:10.1001/jamaoncol.2019.4489 .

[214] Aparicio T, Ghiringhelli F, Boige V, et al. Bevacizumab maintenance versus No maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase Ⅲ trial (PRODIGE 9)[J]. J Clin Oncol, 2018, 36(7):674-681. doi:10.1200/JCO.2017.75.2931 .

[215] Xu RH, Muro K, Morita S, et al. Modified XELIRI (capecitabine plus irinotecan) versus FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab, as second-line therapy for metastatic colorectal cancer (AXEPT): a multicentre, open-label, randomised, non-inferiority, phase 3 trial[J]. Lancet Oncol, 2018, 19(5):660-671. doi:10.1016/S1470-2045(18)30140-2 .

[216] Ducreux M, Malka D, Mendiboure J, et al. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000–05): an open-label, randomised, phase 3 trial[J]. Lancet Oncol, 2011, 12(11):1032-1044. doi:10.1016/S1470-2045(11)70199-1 .

[217] Koopman M, Antonini NF, Douma J, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase Ⅲ randomised controlled trial[J]. Lancet, 2007, 370(9582):135-142. doi:10.1016/S0140-6736(07)61086-1 .

[218] Seymour MT, Maughan TS, Ledermann JA, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial[J]. Lancet, 2007, 370(9582):143-152. doi:10.1016/S0140-6736(07)61087-3 .

[219] Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer[J]. N Engl J Med, 2015, 372(20):1909-1919. doi:10.1056/NEJMoa1414325 .

[220] Shitara K, Doi T, Dvorkin M, et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2018, 19(11):1437-1448. doi:10.1016/S1470-2045(18)30739-3 .

[221] Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial[J]. Lancet, 2013, 381(9863):303-312. doi:10.1016/S0140-6736(12)61900-X .

[222] Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial[J]. JAMA, 2018, 319(24):2486-2496. doi:10.1001/jama.2018.7855 .

[223] Bennouna J, Borg C, Delord JP, et al. Bevacizumab combined with chemotherapy in the second-line treatment of metastatic colorectal cancer: results from the phase Ⅱ BEVACOLOR study[J]. Clin Colorectal Cancer, 2012, 11(1):38-44. doi:10.1016/j.clcc.2011.05.002 .

[224] Iwamoto S, Hazama S, Kato T, et al. Multicenter phase Ⅱ study of second-line cetuximab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) in KRAS wild-type metastatic colorectal cancer: the FLIER study[J]. Anticancer Res, 2014, 34(4):1967-1973.

[225] Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer[J]. N Engl J Med, 2004, 350(23):2335-2342. doi:10.1056/NEJMoa032691 .

[226] Jin Z, Sinicrope FA. Advances in the therapy of BRAFV600E metastatic colorectal cancer[J]. Expert Rev Anticancer Ther, 2019, 19(9):823-829. doi:10.1080/14737140.2019.1661778 .

[227] Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study[J]. J Clin Oncol, 2021, 39(4):273-284. doi:10.1200/JCO.20.02088 .

[228] Kopetz S, Guthrie KA, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406)[J]. J Clin Oncol, 2021, 39(4):285-294. doi:10.1200/JCO.20.01994 .

[229] Meric-Bernstam F, Hurwitz H, Raghav KPS, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study[J]. Lancet Oncol, 2019, 20(4):518-530. doi:10.1016/S1470-2045(18)30904-5 .

[230] Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS Codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial[J]. Lancet Oncol, 2016, 17(6):738-746. doi:10.1016/S1470-2045(16)00150-9 .

[231] Siena S, Di Bartolomeo M, Raghav K, et al. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial[J]. Lancet Oncol, 2021, 22(6):779-789. doi:10.1016/S1470-2045(21)00086-3 .

[232] Suwaidan AA, Lau DK, Chau I. HER2 targeted therapy in colorectal cancer: New horizons[J]. Cancer Treat Rev, 2022, 105:102363. doi:10.1016/j.ctrv.2022.102363 .

[233] D'Angelica MI, Correa-Gallego C, Paty PB, et al. Phase Ⅱ trial of hepatic artery infusional and systemic chemotherapy for patients with unresectable hepatic metastases from colorectal cancer: conversion to resection and long-term outcomes[J]. Ann Surg, 2015, 261(2):353-360. doi:10.1097/SLA.0000000000000614 .

[234] Qi MD, Tao ZJ, Yu D, et al. Complications of transarterial radioembolization in hepatic malignancies: Pathophysiological insights and management paradigms[J]. Eur J Radiol, 2025, 190:112224. doi:10.1016/j.ejrad.2025.112224 .

[235] Kong YQ, Huang XY, Peng G, et al. Efficacy of first-line radiofrequency ablation combined with systemic chemotherapy plus targeted therapy for initially unresectable colorectal liver metastases[J]. Int J Hyperthermia, 2025, 42(1):2432988. doi:10.1080/02656736.2024.2432988 .

[236] Connell LC, Kemeny NE. Intraarterial chemotherapy for liver metastases[J]. Hematol Oncol Clin North Am, 2025, 39(1):143-159. doi:10.1016/j.hoc.2024.08.005 .

[237] Arnold D, Pereira PL, Iezzi R, et al. Transarterial chemoembolisation with irinotecan (irinotecan-TACE) as salvage or post-inductive therapy for colorectal cancer liver metastases: effectiveness results from the CIREL study[J]. ESMO Open, 2025, 10(3):104292. doi:10.1016/j.esmoop.2025.104292 .

[238] Swierz MJ, Storman D, Mitus JW, et al. Transarterial (chemo)embolisation versus systemic chemotherapy for colorectal cancer liver metastases[J]. Cochrane Database Syst Rev, 2024, 8(8):CD012757. doi:10.1002/14651858.CD012757.pub2 .

[239] Sugumar K, Stitzel H, Wu V, et al. Outcomes of hepatic artery-based therapies and systemic multiagent chemotherapy in unresectable colorectal liver metastases: a systematic review and meta-analysis[J]. Ann Surg Oncol, 2024, 31(7):4413-4426. doi:10.1245/s10434-024-15187-y .

基金资助

国家卫生健康委员会四大慢病重大专项基金资助项目(2024ZD0520300)