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中华移植杂志(电子版) ›› 2024, Vol. 18 ›› Issue (03) : 174 -180. doi: 10.3877/cma.j.issn.1674-3903.2024.03.006

综述

肝移植治疗不可切除结直肠癌肝转移的研究进展
艾贵生1, 杨健2, 蒋文涛3,†()   
  1. 1. 300192　天津医科大学一中心临床学院
    2. 300112　天津市第一中心医院肝移植科
    3. 300192　天津医科大学一中心临床学院；300112　天津市第一中心医院肝移植科；天津市肝癌分子诊断与治疗重点实验室
  • 收稿日期:2024-02-11 出版日期:2024-06-25
  • 通信作者: 蒋文涛
  • 基金资助:
    国家自然科学基金项目(81870444); 国家自然科学基金青年项目(82202399); 天津市卫生健康科技项目(TJWJ2022QN032); 天津市卫生健康委员会重点学科专项(TJWJ2022XK016); 细胞生态海河实验室创新基金(22HHXBJC00001)

Progress of liver transplantation for nonresectable colorectal liver metastases

Guisheng Ai1, Jian Yang2, Wentao Jiang3,†()   

  1. 1. The First Central Clinical School, Tianjin Medical University, Tianjin 300192, China
    2. Liver Transplantation Department, Tianjin First Center Hospital, Tianjin 300112, China
    3. The First Central Clinical School, Tianjin Medical University, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin 300112, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300112, China
  • Received:2024-02-11 Published:2024-06-25
  • Corresponding author: Wentao Jiang
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艾贵生, 杨健, 蒋文涛. 肝移植治疗不可切除结直肠癌肝转移的研究进展[J]. 中华移植杂志(电子版), 2024, 18(03): 174-180.

Guisheng Ai, Jian Yang, Wentao Jiang. Progress of liver transplantation for nonresectable colorectal liver metastases[J]. Chinese Journal of Transplantation(Electronic Edition), 2024, 18(03): 174-180.

结直肠癌是全球第4大常见恶性肿瘤，其肝转移发病率高，5年生存率仅为14%。早期关于肝移植治疗不可切除结直肠癌肝转移(NRCLM)的研究结果并不乐观。然而，随着外科技术和围手术期管理的进步，如何应用肝移植为NRCLM患者带来生存获益的问题重新受到关注。最近的研究表明，通过制订严格的受者选择标准，可以显著提高这些患者肝移植后的生存率。NRCLM肝移植术后肿瘤复发仍是一个重要问题，但最常见的转移部位是肺部，如果积极治疗，对总生存率的影响很小。供者肝脏的短缺是肝移植的一个主要限制因素，但这一问题可以通过使用扩展标准供者、活体肝移植和开发创新手术技术等策略得到缓解。总之，肝移植作为一种治疗NRCLM的方法前景广阔，但还需要更多的研究来完善相关技术和策略。

关键词: 肝移植, 不可切除结直肠癌肝转移, 受者选择, 化疗

Colorectal cancer is the fourth most common malignancy worldwide, with a high incidence of liver metastases and a 5-year survival rate of only 14%. Early studies on liver transplantation for the treatment of nonresectable colorectal liver metastases (NRCLM) were not promising. However, with advancement in surgical techniques and perioperative management, the question of how to apply liver transplantation to achieve survival benefits for patients with NRCLM has regained attention. Recent studies have shown that by establishing strict recipient selection criteria, the survival rate after liver transplantation for these patients can be significantly improved. Postoperative tumor recurrence remains a significant issue, but the most common site of metastasis is the lungs, which has a minimal impact on overall survival when treated aggressively. The shortage of donor livers is a major limitation for liver transplantation, but this issue can be alleviated by strategies such as using extended criteria donors, living donor liver transplantation, and developing innovative surgical techniques. Overall, liver transplantation as a treatment for NRCLM shows promising prospects, but more research is needed to refine the relevant techniques and strategies.

Key words: Liver transplantation, Nonresectable colorectal liver metastases, Recipient selection, Chemotherapy
表1 NRCLM行肝移植手术治疗的患者筛选标准及预后
项目名称 纳入标准 排除标准
SECA-Ⅰ[14] (1)原发肿瘤已行根治性切除；(2)ECOG评分0～1分；(3)至少行6周化疗；(4)行胸部、腹部和盆腔CT和PET-CT明确无肝外疾病。 (1)体质量下降>10%；(2)难以控制的感染(包括细菌、真菌和病毒感染)；(3)严重的心、肺、脑和肾等重要器官实质性病变；(4)难以控制的心理精神疾病；(5)难以戒除的酗酒或吸毒；(6)合并其他恶性肿瘤。
SECA-Ⅱ[16] (1)原发肿瘤经组织学确诊为结直肠腺癌；(2)明确无肝外转移或局部复发：①PET-CT扫描，②入组前4周内(胸部/腹部/盆腔)CT或MRI，③入组前12个月内结肠镜检查/结肠CT造影；(3)ECOG评分0～1分；(4)血红蛋白>10 g/dL，中性粒细胞>1.0×109/L，血小板>75×109/L，总胆红素<正常上限的2倍，血清肌酐<正常上限的1.25倍，白蛋白>正常下限，AST和ALT均<正常上限的5倍；(5)既往行根治手术，切缘阴性(直肠癌患者环周切缘≥2 mm)；(6)接受至少3个周期的化疗(6周治疗)，且根据RECIST标准病灶未增大；(7)签署知情同意书。 (1)过去6个月内体质量下降>10%；(2)BMI>30 kg/m2；(3)其他恶性肿瘤；(4)雷帕霉素过敏；(5)既往有肝外转移或局部复发；(6)原发性结直肠癌未接受标准治疗；(7)接受原发结直肠癌姑息性切除术；(8)妊娠或哺乳期妇女；(9)研究者的其他意见。
SECA-Ⅱ D组[17] (1)原发肿瘤组织学明确为结直肠腺癌；(2)明确无肝外转移或局部复发：①PET-CT扫描；②试验前4周内(胸部/腹部/盆腔)CT或MRI；③试验前12个月内结肠镜检查/结肠CT造影；(3)ECOG评分0～1分；(4)血红蛋白>10 g/dL，中性粒细胞>1.0×109/L，血小板>75×109/L，总胆红素<正常上限的2倍，血清肌酐<正常上限的1.25倍，白蛋白>正常下限，AST和ALT<正常上限的5倍；(5)既往行根治手术，切缘阴性(直肠癌患者环周切缘≥2 mm)；(6)签署知情同意书；(7)患者可以存在可切除的肺转移灶(<15 mm)；(8)未行进一步化疗的患者可纳入。如接受化疗，根据RECIST标准，应达到缓解或疾病稳定。 (1)过去6个月体质量下降>10%；(2)BMI>30 kg/m2；(3)其他恶性肿瘤；(4)雷帕霉素过敏；(5)最大肝转移灶直径>10 cm；(6)接受原发结直肠癌姑息性切除术；(7)妊娠或哺乳期妇女；(8)研究者的其他意见。
UKCoMET[18] (1)原发肿瘤组织学明确为结直肠腺癌，列入移植名单前至少3个月行根治切除，保证切缘阴性；(2)CT和肝脏MRI确定为孤立肝转移灶，且无法选择肝切除；(3)患者接受一线系统化疗，并在2年内具有至少30%的持续缓解；(4)列入移植名单前4周内，FDG PET-CT无肝外转移或局部复发迹象；(5)列入移植名单前4周内，CT和MRI扫描无肝外转移或局部复发；(6)列入移植名单前12个月内，结肠镜检查/结肠CT造影无局部复发；(7)对于T3或更高分期肿瘤，列入移植名单4周内行诊断性腹腔镜检查和/或腹盆腔MRI结合DWI明确无腹膜复发证据；(8)ECOG评分0～1分；(9)血红蛋白>10 g/dL，总胆红素<正常上限的5倍，血清肌酐<正常上限的1.25倍，白蛋白在正常范围内；(10)签署知情同意书。 (1)过去6个月内体质量下降>10%；(2)BMI>30 kg/m2；(3)存在其他恶性肿瘤(黑色素瘤除外)；(4)既往有肝外转移或局部复发；(5)癌胚抗原持续升高；(6)未接受原发性结直肠癌标准手术治疗；(7)原发结直肠癌接受姑息性切除术；(8)原发性肿瘤临床完全缓解，未行根治性切除术；(9)一线化疗期间疾病进展。
表2 国际肝胆胰协会共识关于NRCLM肝移植的受者选择标准[19]
标准类别 具体内容
临床选择标准 (1)NRCLM或原发灶切除后复发肝转移患者；
(2)首先接受原发肿瘤切除，且保证切缘阴性(直肠癌环周切缘大于1 mm)；
(3)系统治疗前初始病灶的大小和数量不作为判断患者是否行肝移植的标准，但对于多灶性或病灶较大(或二者兼有)的患者应谨慎选择；
(4)几乎无证据支持肝移植用于可切除性CRLM；
(5)对于初始表现或随后发展为肝外转移的NRCLM患者，无证据支持行肝移植。
生物学行为 (1)建议患者肝移植前接受桥接治疗(化疗为主)，并观察至少6个月的疗效，期间每隔2～3个月定期进行1次放射成像和癌胚抗原测定，接受桥接治疗期间若出现疾病进展的放射学或实验室检查证据，则是肝移植的禁忌证；
(2)从诊断出NRCLM到肝移植至少间隔1年。
影像学标准 (1)初始肝转移灶的可切除性应通过肝脏MRI或CT或两者联合评估；
(2)建议行高分辨率胸部CT检查以排除肺转移；
(3)18F-FDG PET-CT可评估代谢肿瘤体积和病灶总糖酵解量；代谢肿瘤体积为>70 cm3，病灶总糖酵解量为>260 g的患者应排除；
(4)18F-FDG PET-CT被推荐用于排除肝外转移灶，当临床怀疑程度高且术前PET成像不确定时，应考虑淋巴结穿刺采样；发现淋巴结阳性的患者不应行肝移植治疗。
病理标准 (1)排除原发肿瘤组织学为未分化腺癌和印戒细胞癌；
(2)相对排除原发肿瘤淋巴结N2转移的患者。
分子生物学标准 (1)必须对原发肿瘤和/或肝转移瘤进行BRAF和RAS突变以及微卫星不稳定性和错配修复状态分析；
(2)BRAF V600E突变的患者不应考虑行肝移植；
(3)RAS基因突变并非肝移植禁忌证，如存在其他有利的生物学因素，RAS基因突变也可考虑肝移植；
(4)微卫星高不稳定性或错配修复缺陷的患者采取免疫治疗的效果良好，同时考虑到移植物排斥反应发生的风险，这类患者无法在肝移植后接受免疫治疗，故不应考虑行肝移植。
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