修回日期: 2022-09-21
接受日期: 2022-10-19
在线出版日期: 2022-10-28
结直肠癌是临床常见的消化系统恶性肿瘤之一, 由于结直肠自身解剖特点, 结直肠癌极易发生肝转移, 15%-25%结直肠癌在确诊时合并肝转移, 15%-25%在结直肠肿瘤根治术后发生肝转移, 80%-90%肝转移肿瘤初始无法进行根治术, 5年生存率低于5%, 肝转移成为结直肠癌患者主要致死原因. 近年来随着高效化疗和分子靶向药物在临床应用, 以及外科技术的飞跃发展, 依据患者年龄、原发结直肠肿瘤部位和分化程度、Ras和Braf基因状态、肝转移肿瘤大小、数目和分布等因素, 制定个体化的安全、高效、快速转化治疗方案, 通过缩小肝转移肿瘤体积、增加剩余肝脏体积等转化治疗, 使初始不可手术切除的肝转移肿瘤获得手术切除或患者达到无证据疾病状态, 5年生存率可达30%-57%, 极大提高了结直肠癌肝转移患者生存期. 针对影响结直肠癌肝转移患者术后不利的预后因素, 制定个体化的预防措施, 降低不利因素的影响, 改善结直肠癌肝转移患者预后. 本文结合国内外相关文献较为系统地论述初始不可切除的结直肠癌肝转移转化治疗的临床策略与手术治疗, 为初始不可切除的结直肠癌肝转移患者临床治疗与方案的选择提供理论参考.
核心提要: 依据患者年龄、原发结直肠肿瘤部位和分化程度、Ras和Braf基因状态、肝转移肿瘤大小、数目和分布等因素, 制定个体化的安全、高效、快速转化治疗方案, 使初始不可手术切除的肝转移肿瘤获得手术切除, 提高结直肠癌肝转移患者生存期. 制定个体化的预防措施, 降低术后不利因素的影响, 改善结直肠癌肝转移患者预后.
引文著录: 张津玮, 黄孙桦, 秦建民. 结直肠癌肝转移转化治疗的临床策略与手术治疗. 世界华人消化杂志 2022; 30(20): 897-913
Revised: September 21, 2022
Accepted: October 19, 2022
Published online: October 28, 2022
Colorectal cancer is one of the common malignant tumors of the digestive system in clinical practice. Due to the anatomical characteristics of the colorectum itself, colorectal cancer is prone to liver metastasis. Approximately 15%-25% of colorectal cancer cases are complicated with liver metastasis at diagnosis, 15%-25% are complicated with liver metastasis after radical resection of colorectal cancer, and 80%-90% with liver metastasis cannot undergo radical resection initially. The 5-year survival rate is less than 5%, and liver metastasis is the main cause of death in patients with colorectal cancer. In recent years, with the clinical application of effective chemotherapy and molecular targeted drugs, as well as the rapid development of surgical techniques, an individualized safe, efficient, fast, treatment plan can be formulated according to patients' age, primary colorectal tumor location, degree of differentiation, Ras and B-Raf gene status, tumor size, number and distribution of metastases in the liver. By shrinking the tumor volume in the liver and increasing the residual liver volume, liver metastatic tumors can undergo surgical resection or disease-free status can be achieved in patients with liver metastasis. As a result, patients with colorectal liver metastases can achieve a 5-year survival rate of 30%-57%, which greatly improves the prognosis after operation. According to the postoperative adverse factors, individualized preventive measures are worked out to reduce the impact of adverse factors and improve the prognosis of patients with colorectal liver metastases. In this paper, we systematically discuss the clinical strategy of conversion therapy and surgical treatment for unresectable colorectal cancer liver metastases by reviewing the relevant domestic and foreign literature, so as to provide a theoretical reference for the selection of clinical treatment and program for patients with unresectable colorectal cancer liver metastases.
- Citation: Zhang JW, Huang SH, Qin JM. Clinical strategy of conversion therapy and surgical treatment for liver metastases from colorectal cancer. Shijie Huaren Xiaohua Zazhi 2022; 30(20): 897-913
- URL: https://www.wjgnet.com/1009-3079/full/v30/i20/897.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v30.i20.897
结直肠癌(colorectal cancer, CRC)全球发病率第3位、死亡率第2位[1], 由于结直肠自身解剖特点, CRC极易发生肝转移, 15%-25% CRC在确诊时合并肝转移, 15%-25%在CRC根治术后发生肝转移, 80%-90%肝转移肿瘤由于肝转移肿瘤数目多、体积大、累及多个肝段、广泛肝外转移初始无法进行根治术, 5年生存率低于5%, 60%-71%死于肝转移, 成为CRC患者的主要致死原因, 仅10%-20%结直肠癌肝转移(colorectal liver metas-tases, CRLM)患者确诊时接受肝转移灶根治性切除, 通过转化治疗可使10%-30%初始不可切除CRLM患者转化为可切除[2,3]. 经过全身化疗后22.5%-51.9% CRLM患者符合肝脏肿瘤局部治疗条件, 达到无疾病状态(no evidence of disease, NED)[4,5]. 与单纯全身化疗相比, 化疗联合肝肿瘤局部治疗5年生存率由9%提高到32%[6]. 因此对于初始不可切除的CRLM患者, 转化治疗后再进行肝脏肿瘤局部治疗显著改善患者预后, CRLM不同于原发性肝癌, 有其自身的临床特点, 且随着化疗、分子靶向药物发展和外科技术进步, 肝转移肿瘤数目、大小及切缘已不再是判定能否肝切除的绝对因素, 肝切除标准已扩大到肝容量或肝功能储备适当的CRLM患者, 本文结合相关文献探讨CRLM转化治疗的临床策略与手术治疗.
我国CRC男性多见,男性CRC发病率在全身恶性肿瘤中第五位, 女性第四位, 男性和女性CRC死亡率均位于第五位, 直肠癌较结肠癌多见, 右半结肠癌比例呈上升趋势[7,8]. 仅20% CRLM适合手术切除, 外科切除术后5年生存率为14%-40%[9-11]. 可切除CRLM患者中位总生存(overall survival, OS)为50 mo, 1、3和5年OS分别为91%、63%和45%, 不可切除CRLM患者中位OS为12 mo, 1、3和5年OS分别为51%、8%和3%[12]. 右侧结肠癌患者中低分化腺癌或粘液癌、远端淋巴结累及、组织学静脉侵犯的比例明显高于左侧结肠癌患者, 右侧结肠癌CRLM转化率低于左侧结肠癌, 与左侧结肠癌相比, 右侧结肠癌CRLM肝切除术后肝复发的倾向更强[13,14]. 左侧原发结肠癌CRLM转化R0/R1肝切除率显著高于右侧原发结肠癌 (75.0% vs 30.0%, P<0.05), 原发结肠肿瘤部位影响CRLM转化肝切除[15]. 低分化原发结直肠癌肝转移患者的死亡风险是高分化、中分化患者的2.86倍, 肝转移癌类型为H2、H3的CRLM患者死亡风险分别是肝转移癌类型为Hl者的1.86倍、2.14倍[16]. 未接受治疗的CRLM患者中位OS仅为6.9 mo, 不可切除的CRLM患者5年生存率<5%, 如果肝转移肿瘤完全切除或患者达到NED状态, 中位OS为35 mo, 5年生存率可达30%-57%[17,18]. 因此通过化疗、局部治疗等措施使初始不可切除CRLM转化为可切除治疗是提高CRLM患者长期生存的关键.
由于大多数CRLM发现时病期较晚, 存在[2]: (1)不可能对所有肝转移肿瘤完整切除; (2)切除后估计残肝体积<30%; (3)肿瘤浸润全部肝静脉、双侧肝动脉或双侧门静脉分支. 这些因素导致无法手术根治性切除, 需要通过化疗联合分子靶向药物、肝动脉灌注介入治疗、局部消融、门静脉栓塞/结扎、分期肝切除等措施进行转化治疗, 使初始不可切除但具有潜在可切除性的CRLM患者获得手术切除, 通过转化治疗可使10%-30%初始不可切除CRLM患者转化为可切除. CRLM转化治疗目的是通过转化治疗使CRLM患者获得最佳反应率, 提高可切除率和患者总生存率, 治疗方案的有效率与转移肿瘤的切除率呈正相关, 有效率越高, 切除率就越高[19]. 转化治疗应选择有效性强、达到可切除速度快、安全性高、不良反应可耐受和患者生存获益大的方案. 因此转化治疗方案应遵循个体化原则, 依据患者年龄、肿瘤分期、免疫状况、基因检测结果, 以及患者经济情况等综合考虑, 选择高效率和安全性高的治疗方案, 将初始不可切除的CRLM转化为可切除, 是转化治疗的终极目标.
肝脏脂肪变性(hepatic steatosis, HS)改变了肝脏微环境成分, 降低肝实质血管生成活性, 减少肿瘤相关的成纤维细胞数量, 为转移癌细胞的生存和增殖提供一个不适宜的环境[20,21]. 与非HS患者相比, 存在HS的CRLM患者接受转化治疗客观反应率 (36.3% vs 23.8%)和肝切除术率高(30.2% vs 18.5%), 中位无进展生存期(8.9 mo vs 5.9 mo)和3年OS(59% vs 41%)均优于非HS患者, HS可作为CRLM患者转化效率的有效预测因素[22]. 在初始不可切除的CRLM转化治疗中, 低肿瘤负荷评分(tumor burden score, TBS)的转化率是高TBS的3倍(57.3% vs 19.0%, P<0.001), 高TBS、一线治疗反应差(stable disease, SD、progressive disease, PD)、缺乏分子靶向药物治疗是转化治疗失败的3个独立危险因素[23]. 肝转移肿瘤≥10的CRLM患者转化率低于<10肿瘤(43.4% vs 57.3%, P<0.01), 临床N分期为1-2期、≥8个一线化疗疗程、RECIST评估为疾病稳定(SD)或疾病进展(PD)是预测转化治疗失败的独立因素[24]. 原发左侧结肠肿瘤、无肝外转移、H1或H2级、分子靶向药物治疗与转化肝切除率密切相关(P<0.01), 具有这些特征是初始不可切除CRLM患者转化治疗的候选者[25]. 肝转移肿瘤数量是影响转化疗效的主要危险因素, 肝转移肿瘤数量、最大直径、血清癌胚抗原(carcinoembryonic antigen, CEA)水平、K-Ras/N-Ras、BRAF V600E突变状态、靶向药物使用是决定转化治疗后患者能否获得NED状态的危险因素, 肝转移肿瘤最大直径<6 cm和肿瘤数目≤4个是转化治疗成功相关的独立因素[26]. 肝脏肿瘤双叶分布、基线CEA水平升高、肿瘤侵犯门静脉、转移瘤数目>8个、非FOLFOXIRI方案以及未使用靶向治疗是初始不可切除的CRLM患者转化治疗失败的高危因素. 转移瘤数目>8个、门静脉侵犯是转化失败的独立危险因素, 转移瘤数量和门静脉侵犯情况是影响转化治疗成败的关键性因素, 肿瘤负荷是决定转化治疗成败的决定性因素, 存在门静脉侵犯的患者转化失败的风险是没有门静脉侵犯者的2.727倍[27]. 因此, 对于初始不可切除的CRLM患者, 依据影响转化治疗的因素客观评估, 制定个体化的安全、高效、快速转化治疗方案, 通过缩小肿瘤或增大剩余肝脏体积, 提高肝转移肿瘤切除率.
CRLM初始不可切除的主要原因之一是转移肿瘤多发、分布于肝脏左右叶, 或肿瘤巨大侵及邻近大血管, 无法根治性切除, 利用化疗、联合分子靶向药物、免疫治疗等进行杀灭肿瘤细胞治疗, 短期内使肿瘤大小、数目减少, 达到缩小肿瘤体积目的, 提高肿瘤手术切除率.
2.2.1 化疗: 全身静脉化疗时, 抗癌药物主要随血流在全身静脉内大量分布, 而进入肝动脉的药物较少, 有效浓度较低, 疗效欠佳, 肿瘤组织中的化疗药物有效浓度越高, 其对癌细胞的活性抑制作用更强, 有利于其杀伤癌细胞, 疗效更显著[28]. 仅采用常规全身化疗, 不可切除CRLM患者中位生存期为30 mo(17 mo-24 mo), 转化为肝肿瘤切除率为13%-38%[29,30]. 细胞毒性抗癌药物(5-FU、奥沙利铂和伊立替康)应用于初始不可切除CRLM患者, 转化率为10%-60%[31]. FOLFOX和FOLFORI方案可使50%-60%患者肿瘤缩小, FOLFOX可使不可切除CRLM 患者获得7%-51%肝切除率, FOLFORI可获得9%-35%肝切除率. FOLFOXIRI使60%-70% 患者肿瘤缩小, 手术R0切除率提高至36%, 5年无病生存率可达30%-40%[32,33]. 单用化疗药物治疗初始不可切除CRLM, 转化为肝肿瘤切除效率较低, 目前多与分子靶向药物、肝动脉灌注、消融等局部治疗联合, 起到协同增效作用.
2.2.2 化疗联合分子靶向药物: 对于初始不可切除的CRLM患者, 依据患者身体状况、原发肿瘤部位、Ras和Braf基因状态, 选择合适的化疗联合分子靶向药物治疗方案, 标准化疗方案联合抗EGFR或抗VEGFR单抗显著提高潜在可切除CRLM患者的手术切除率. 抗EGFR单抗治疗仅在Ras野生型的CRLM患者中显示出更高的疗效, Ras基因状态是抗EGFR单抗治疗CRLM患者临床获益的潜在预测指标[34]. Karapetis等[35]应用mFOLFOX6或FOLFIRI化疗联合西妥昔单抗治疗初始不可切除的CRLM, 与单用化疗相比, 肝肿瘤R0切除率从7.4%提高到25.7%, 客观缓解率提高(57.1% vs 29.4%), 3年总生存明显改善(41% vs 18%)(P<0.05). 应用FOLFOX6或FOLFIRI联合西妥昔单抗治疗初始不可切除的CRLM患者, K-Ras野生型肿瘤患者的缓解率高于K-Ras突变型患者((70% vs 41%), 肝肿瘤切除率由治疗前的32%提高至化疗后的60%[11]. FOLFOX或FOLFIRI联合帕尼单抗治疗K-Ras野生型不可切除CRLM患者, 肝肿瘤转化切除率分别为45%、59%[36]. K-Ras野生型/突变型初始不可切除CRLM患者接受mFOLFOX6 联合西妥昔单抗/贝伐珠单抗治疗, K-Ras野生型CRLM肝肿瘤转化切除率为77.3%, K-Ras突变型为58.3%, K-Ras野生型/突变型初始不可切除CRLM患者R0肝切除率均为50%, 中位OS分别为74.3 mo、31.6 mo. 接受R0/R1肝切除术的K-Ras野生型和突变型CRLM患者的中位OS(78.7 mo vs 63 mo)、无复发生存(recurrence free survival, RFS)(11.3 mo vs 8.5 mo)均无显著性差异(P>0.05), 左侧原发结直肠癌CRLM转化为R0/R1肝切除率显著高于右侧原发结肠癌 (75% vs 30%, P<0.05), 原发结肠肿瘤部位是转化肝切除的预测因子[15]. RAS/BRAF/PIK3CA突变与CRLM较差的生物学特性和侵袭性转移有关, Shen等[37]应用mFOLFOXIRI联合贝伐珠单抗治疗初始不可切除的RAS/BRAF/PIK3CA突变CRLM, 36.3%转化为肝切除或联合局部消融, 达到根治性治疗; 与单用mFOLFOXIRI化疗相比, mFOLFOXIRI联合贝伐珠单抗治疗的客观反应率[(objective response rate, ORR), 77.4% vs 60.0%]较高, 中位肿瘤反应深度[(depth of tumor response, DpR), 45.6% vs 34.9%]好, 中位无进展生存期(progression free survival, PFS)延长(12.6 mo vs 9.1 mo), 中位OS延长(42.6 mo vs 35.3 mo), 获得较好的NED状态(40.7% vs 30.8%), 表明mFOLFOXIRI联合贝伐珠单抗为初始不可切除的RAS/BRAF/PIK3CA突变CRLM患者提供一种高效转化治疗方案. Hu等[38]应用mFOLFOXIRI联合西妥昔单抗治疗初始不可切除的RAS/BRAF野生型CRLM, 与单用mFOLFOXIRI化疗相比, 55.2%转化为肝切除, 优于单纯化疗(29.4%), ORR(95.5% vs 76.5%)和NED率高(70.1% vs 41.2%), R0切除率丛20.6%增加到35.8%, 通过转化治疗获得NED的CRLM患者具有较长OS, 表明mFOLFOXIRI联合西妥昔单抗是一种转化治疗初始不可切除的RAS/BRAF野生型CRLM选择方案. Zheng等[39]回顾性分析发现, 与单独化疗相比, K-Ras野生型左侧结肠癌CRLM患者化疗(mFOLFOX6或FOLFIRI)联合西妥昔单抗显著提高ORR(68.9% vs 30.6%)、PFS(12.1 mo vs 6.1 mo)和OS(不可评估 vs 23.1 mo), 肝切除转化率为(33.5% vs 10.8%, P<0.01). 与单独化疗相比, Ras野生型右侧结肠癌CRLM患者化疗(mFOLFOX6或FOLFIRI)联合西妥昔单抗治疗ORR(56.8% vs 29.3%)、PFS(9.3 mo vs 5.1 mo)和OS(25.3 mo vs 16.8 mo, P<0.05), 而肝切除转化率(20.5% vs 9.8%)无显著性差异(P>0.05). 表明肿瘤部位不同化疗联合西妥昔单抗对CRLM疗效存在差异, 左侧结肠癌CRLM肝切除转化率高于右侧结肠癌CRLM, 右侧结肠癌CRLM患者能从化疗联合西妥昔单抗治疗中获益, 但疗效不如左侧结肠癌CRLM患者. Morine等[40]分析发现, 与其他治疗方案(FOLFOX、XEROX、FOLFILI等)相比, FOLFOXIRI联合分子靶向药物(贝伐珠单抗或西妥昔单抗)治疗初始不可切除CRLM的转化率高(72.2% vs 37.5%), 显著缩短手术前的转化用药时间(中位疗程5.8 mo vs 14 mo), 肿瘤坏死率更高(84.4% vs 61.1%), FOLFOXIRI治疗3年生存率优于其他方案(83.1% vs 44.4%). FOLFOXIRI联合分子靶向药物治疗初始不可切除CRLM, 尤其肝转移肿瘤最大直径×数目(maximum diameter × number, MDN)之积小于70, 提供更高的转化手术切除率和预后获益. Ma等[41]分析发现初始不可切除的CRLM, 应用全身治疗(XELOX或FOLFIRI, 联合西妥昔单抗或贝伐珠单抗)4-6个周期, 肝转移肿瘤最大直径<6 cm和转移肿瘤数目≤4个成功转化手术切除率为50%, 而肿瘤最大直径≥6 cm, 转化率为18.2%, 移肿瘤数目>4个, 转化率为15%, 提示肝转移肿瘤最大直径<6 cm和转移肿瘤数目≤4个是转化治疗成功相关的独立因素. 术前化疗疗程越多、化疗线数越多, 肝切除术后并发症越多, 预后越差, 因此选择高效化疗联合分子靶向药物方案, 缩短疗程, 尽早获得手术机会, 是提高CRLM转化疗效的重要原则.
2.2.3 化疗、分子靶向药物联合免疫: 利用患者自身的免疫系统来对抗癌细胞, 通过调节特异性免疫反应抑制或杀死肿瘤细胞, 打破免疫耐受, 增强机体对肿瘤的免疫排斥反应, 延缓肿瘤进展. 免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)在肿瘤部位重新激活T细胞或抑制特异性T细胞的活化, 从而抑制肿瘤生长[42]. Shi等[43]研究发现程序性死亡分子配体1(programmed death ligand-1, PD-L1)在结肠癌组织中表达率为44.8%, 癌旁组织中为11.4%, PD-L1 表达与肿瘤分期相关, 下调结肠癌细胞HCT-116中PD-L1表达, 显著抑制结肠癌细胞增殖、迁移和侵袭, 提示PD-L1能够促使CRC发生远处转移. PD-L1在CRC原发灶肿瘤细胞中的阳性率为9.4%, 低于肝脏转移肿瘤细胞(15.6%), 表明PD-L1阳性率更高的结肠癌转移灶存在更强的免疫抑制效应, 其免疫微环境更适宜肿瘤细胞的生长与繁殖, 从而促进肿瘤细胞的肝转移; Ras基因突变与PD-L1阳性表达率正相关, Ras基因突变患者PD-L1阳性表达率明显高于Ras基因野生型患者, 预后较野生型差[44,45]. PD-L1表达与CRLM肝转移瘤中CD4、CD8细胞密度呈正相关, PD-L1在肝转移灶中的表达高于原发结直肠肿瘤, 提示原发结直肠肿瘤与肝转移肿瘤之间微环境有内在差异, PD-L1在原发结直肠肿瘤和肝转移肿瘤间表达差异与肿瘤分化密切相关[46]. 程序性死亡蛋白-1(programmed death-1, PD-1)抑制剂派姆单抗(pembrolizumab)在错配修复缺陷型(defect mismatch repair gene, dMMR)、微卫星不稳定性高(high microsatellite instability, MSI-H)表型的转移性CRC患者反应良好, 表达dMMR/MSI-H的CRC反应率为12%-15%, 而转移性CRC不存在表达dMMR/MSI-H反应率仅为４%[47,48]. 帕博利珠单抗或纳武利尤单抗(nivolumab)用于dMMR/MSI-H转移性CRC患者, ORR在30%-40%之间, DFS为50%[49]. Ⅱ期CheckMate 142临床试验评估了nivolumab联合或不联合伊匹木单抗(ipilimumab)治疗dMMR或MSI-H转移CRC, 结果显示单独应用时ORR、DFS分别为31%、69%, ipilimumab联合nivolumab时, ORR、DFS分别为41%和78%, 表明nivolumab联合ipilimumab治疗dMMR/MSI-H转移性CRC患者具有协同增效作用[50]. 因此MSI-H或dMMR的晚期CRC预后较差, 且对5-Fu化疗药物为基础的治疗耐药, 晚期结直肠癌患者PD-L1表达率与dMMR/MSI-H正相关, dMMR/MSI-H结直肠癌高度上调多种免疫检查点(PD-L1、PD-1等)表达, 下调机体对肿瘤的免疫攻击, 抑制免疫激活的肿瘤微环境, 降低以手术为主综合治疗对肝脏转移肿瘤中PD-L1阳性表达CRLM患者疗效, 影响患者生存 [51-53]. Stein等[54]应用mFOLFOX6、西妥昔单抗联合PD-L1抑制剂阿维拉单抗(avelumab)治疗RAS/BRAF野生型转移性CRC患者(93%为MSS), ORR为79.5, DFS为92.3%, 79.5%患者早期肿瘤收缩(early tumor shrinkage, ETS), 表明化疗、分子靶向药物联合免疫治疗在MSS的转移性CRC患者具有较好的疗效. PD-L1抑制剂阿特佐利珠单抗(atezolizumab)联合卡培他滨和贝伐珠单抗对于微卫星稳定型(microsatellite stability, MSS)和错配修复基因健全型(proficient mismatch repair, pMMR)的CRLM患者ORR为5.8%, 临床治疗获益较小[55]. PD-1抑制剂对MSI-H/dMMR的转移性结直肠癌有显著且持久的疗效, 但对MSS/pMMR的CRLM患者治疗作用有限, 目前关于化疗、分子靶向药物联合免疫治疗在初始不可切除CRLM转化治疗的临床研究较少, 尤其针对MSI/MMR不同状态的CRLM患者, 三者之间如何联合应用使转化治疗有效率最大化, 相信随着国内外多中心临床研究的深入开展, 化疗、分子靶向药物联合免疫在不可切除CRLM转化治疗中具有潜在巨大的临床应用前景.
2.2.4 化疗联合肝动脉灌注或栓塞化疗: 由于直径>3 mm肝转移肿瘤血供95%来自肝动脉, 优先由肝动脉网络灌注, 而非肿瘤肝实质血供75%来自门静脉, 主要由门静脉灌注, 局部动脉内给药绕过了肝脏第一关效应, 使肝脏转移瘤暴露于高浓度化疗药物中, 肿瘤组织化疗药物浓度是静脉给药的100-400倍, 提高肿瘤局部药物浓度和疗效, 减少全身药物副作用[56,57]. 肝动脉灌注化疗(hepatic artery infusion chemotherapy, HAIC)主要是增加肿瘤组织中药物浓度, 显著提高肿瘤对药物反应率, 与全身静脉药物灌注相比, 氟脲嘧啶脱氧核苷(FUDR)经肝动脉灌注第一次通过时被肝脏摄取超过95%, 导致肿瘤暴露增加100-300倍, 吡喃阿霉素为20倍, 5-FU为5-10倍, 顺铂为4-7倍, 丝裂霉素为6-8倍, 奥沙利铂为5倍, 阿霉素为2倍[58]. Ammori等[59]分析发现HAIC联合全身化疗治疗不可切除CRLM患者, 25%接受手术或局部消融治疗, 中位OS和5年OS分别为59 mo、47%, 显著优于未成功转化者(16 mo、6%, P<0.01 ), 提示HAIC联合全身化疗是治疗不可切除CRLM一种有效方法. Qiang等[60]应用HAIC联合全身化疗治疗单用化疗失败的不可切除CRLM, 与单用全身化疗相比, 15%转化后行治愈性肝肿瘤切除, 疾病控制率(disease control rate, DCR)高(70% vs 34.8%), 中位OS延长(19.8 mo±8.4 mo vs 9.0 mo±2.2 mo), 表明HAIC联合全身化疗克服化疗耐药性, 提高对肝脏局部肿瘤控制和肝转移肿瘤切除率. Lévi等[30]应用伊立替康、奥沙利铂和5-FU肝动脉灌注, 同时联合西妥昔单抗治疗不可切除CRLM, ORR为40.6%, DCR为84.4%, 29.7%转化为肝切除, 术后应用西妥昔单抗联合FOLFOXIRI治疗8个周期, 中位OS为35.2 mo, 中位PFS为15.7 mo, 4年生存率为37.4%. 对于静脉用药效果不佳时, 应用肝动脉灌注FUDR联合全身奥沙利铂/伊立替康静脉化疗, 或肝动脉灌注奥沙利铂联合全身静脉应用5-FU和西妥昔单抗治疗不可切除CRLM, 分别获得92%、90%反应率, 47%、42%患者转化为R0肝切除[61]. 不可切除的K-Ras野生型CRLM患者在接受1-3线化疗时进展, 三联药物HAIC(氟尿嘧啶、奥沙利铂和伊立替康)联合静脉应用西妥昔单抗治疗, 反应率为40.6%, DCR为84.4%, 33.3%患者转化为肝肿瘤切除; 二线应用此治疗方案肝切除转化率为46.4%, 三线及以上应用时转化率为16.7%. 能够完成二线治疗方案的不可切除CRLM患者中位OS明显长于接受三或四线治疗患者(31.8 mo vs 15.7 mo)[30]. 经动脉栓塞化疗(transarterial chemoembolization, TACE)将化疗药物和栓塞剂直接注入供瘤滋养动脉, 不仅有效提高化疗药物在肿瘤组织的局部浓度, 减少抗癌药物在血液中与血浆蛋白结合的机会, 显著降低其在外周血液中的药物浓度, 减少全身毒副作用, 而且经动脉注入的化疗药物能再次进入体循环, 对全身的临床或亚临床转移灶起到杀灭作用, 通过静脉回流再次流入肿瘤部位起到第2次化疗作用[62]. 碘油对微血管具有堵塞作用及肿瘤细胞特殊的吸收留滞作用, 使化疗药物在肿瘤组织内的浓度达到正常肝组织内的100倍, 提高药物的疗效[63]. Larsen等[64]应用FOLFOX静脉化疗, 奥沙利铂肝动脉灌注给药, 可降解淀粉微球作为栓塞剂栓塞滋养动脉, K-ras野生型给予西妥昔单抗治疗不可切除的CRLM, 有效率为82%, 58%转化为肝切除, 中位OS和PFS分别为38.7 mo和12.9 mo. Cao等[65]应用瑞戈非尼联合伊立替康DEB(100 μm-300 μm)-TACE治疗常规化疗治疗失败的不可切除CRLM, 与瑞戈非尼相比, 瑞戈非尼联合DEB-TACE治疗CRLM患者ORR(35.3% vs 7.1%)、DCR(76.5% vs 47.6%)、CEA转阴率(66.7% vs 28.6%)、PFS(7.6 mo vs 4.1 mo)和OS(15.7 mo vs 9.2 mo)均显著提高(P<0.001), 瑞戈非尼联合DEB-TACE具有持续栓塞和化疗的优势, 抑制肿瘤进展, 延长CRLM患者生存期, 可以作为不可切除的CRLM患者三线或以上治疗方法. Martin等[66]应用行伊立替康＋可降解淀粉微球＋丝裂霉素C的肝动脉化疗栓塞治疗不可切除的CRLM患者, 结果发现血液CEA、CA19-9分别降低至54.2%和45.1%, 33.3%患者病灶转化为可切除, 3年生存率为20%. Liu等[67]回顾性分析不可切除的CRLM治疗发现, 与单用全身化疗相比, 全身化疗加TACE中位PFS延长(6.7 mo vs 3.8 mo), DCR高(67% vs 51%)(P<0.05), 但不能延长中位OS(18.4 mo vs 14.8 mo), 总反应率(20% vs 22%)、肝切除术转化率(18% vs 16%)、术后患者PFS(11.8 mo vs 10.8 mo)均无显著差异(P>0.05), 表明对于不可切除的CRLM, 全身化疗联合TACE是一种安全的二线治疗选择, 但对患者肝切除转化率和OS无显著影响. 全身化疗联合HAIC/TACE治疗是肿瘤负荷较大不能切除CRLM一种有效的治疗方法, 尤其静脉化疗效果不佳时具有较高的反应率和肿瘤转化切除率, 提高患者长期生存和潜在治愈性.
2.2.5 化疗联合放疗: 对于化疗治疗低反应率的CRLM患者, 可以联合应用局部放射治疗, 控制肿瘤生长, 缩小肿瘤体积, 利用放射性核素钇-90(yttrium-90, 90Y)制备90Y玻璃或树脂微球微球, 经肝动脉注入肿瘤组织内进行选择性内放射治疗(selective internal radiationtherapy, SIRT), 微球因无法通过肿瘤的毛细血管床而聚集在肿瘤组织, 90Y发射纯β射线, 局部电离辐射剂量高达100-150 Gy, 使瘤细胞内DNA严重受损产生强大的杀瘤效应, 因射程短, 在肝组织中的射程仅2.5 mm, 半衰期短, 2 wk释放95%能量, 稳定性好, 无危害性衰变后产物, 生物相容性好, 肿瘤区与非肿瘤区放射剂量比值高, 对正常肝组织损伤小[68]. 90Y树脂微球选择性的由肝动脉注射入肿瘤内的局部放疗, 化疗联合放射粒子直接植入肿瘤内对不能手术切除的肝转移肿瘤具有一定的控制作用, 同时保证正常肝脏组织免受放射损伤, 实现10%-20%手术转化率[69,70]. Baltatzis等[71]应用90Y树脂微球的选择性内部放射治疗(selective internal radiation therapy, SIRT)联合全身化疗(FOLFOX/FOLFIRI)治疗初始不可切除CRLM患者, 利用转移肿瘤主要由新动脉微血管供血, 通过肝动脉向肝肿瘤区域提供靶向β射线杀灭肿瘤细胞, 13.6%转化为肝切除. 与FOLFOX相比, FOLFOX联合肝动脉90Y微球SIRT治疗显著提高CRLM患者肝转移肿瘤切除率(28.9% vs 38.1%), 提示化疗联合90Y微球SIRT能够协同增效, 提高CRLM肝肿瘤转化切除率[70,72]. Dabrowiecki等[73]研究发现90Y微球治疗CRLM患者, 无基因突变、MELD评分低、肿瘤负荷低、美国东部肿瘤协作组(Eastern Cooperative Oncology Group, ECOG)评分为0是延长一线化疗失败后接受90Y微球SIRT治疗患者OS的独立预测因素.
孜那提·努尔太等[74]分析初始不可切除的CRLM患者化疗(FOLFIRI或FOLFOX6方案)、化疗联合靶向治疗(西妥昔单抗或贝伐单抗)、局部治疗(肝动脉灌注、射频消融或无水酒精)转化治疗4-6个周期, 化疗联合靶向治疗转化切除率高于单纯化疗和化疗联合局部治疗(42.9% vs 19%、22.4%, P<0.05), 单纯化疗与化疗联合局部治疗转化切除率(19% vs 22.4%)无显著性差异, 转化后切除肝转移肿瘤的CRLM患者与不可切除肝转移肿瘤患者中位OS(42 mo vs 15 mo)、3年OS(45.6% vs 14.7%)具有显著性差异(P<0.05). 肝转移肿瘤切除显著提高初始不可切除CRLM患者生存时间, 肝转移肿瘤是否切除和转化治疗方式是影响CRLM患者OS的独立因素.
2.2.6 化疗联合中医药: CRLM中医辨证分型以湿热蕴结、脾肾亏虚、瘀毒内阻、肝肾两虚、气血两虚为主, 其中以湿热蕴结、脾肾亏虚为多, 治疗上当以补虚泻实, 补泻兼施, 脾肾同治为法. 中医药通过对肿瘤微环境的干预、改善CRC患者肝脏缺氧状态及肝纤维化环境来抑制结直肠癌肝转移的发生[75]. 脾虚不仅致痰、瘀、毒产生, 也使痰、瘀、毒等病理产物堆积,通过受损之络脉旁流, 造成结直肠癌转移, 脾虚与结直肠发生肝转移存在显著相关性, 因此对CRLM患者治疗以健脾扶正为主, 兼以化痰、化瘀、祛毒[76,77]. 异功散具有益气健脾, 理气和胃之功效, 改善患者脾虚症状, 在一定程度上增强患者自身免疫功能, 稳定或延缓肿瘤进展, 改善症状[78]. mF0LF0X6化疗联合异功散方案治疗初始不可切除CRLM, 使26.47%患者转化为肝转移肿瘤切除[79]. 通过化疗、分子靶向药物联合中医药辨证施治治疗CRLM, 中医药不仅提高患者自身免疫功能, 而且通过减少化疗和分子靶向药物副反应, 增加患者治疗耐受性, 提高转化治疗效率.
正常肝脏切除超过70%-75%而剩余肝体积不足为25%-30%, 病理性肝脏(病毒性肝炎、肝硬变等)肝切除超过60%-65%而剩余肝体积不足为35%-40%, 术后极易发生肝功能衰竭[80]. 剩余肝脏体积不足是影响CRLM根治性切除的主要原因之一, 通过门静脉栓塞或分期肝切除技术来增加或保留肝脏储备, 为手术切除、手术联合局部消融治疗提高CRLM长期生存创造条件.
2.3.1 门/和肝静脉栓塞术: 正常肝脏切除后剩余肝体积(future liver remnant, FLR)/标准肝体积(standard liver volume, SLV)>30%才能保证术后不发生肝功能衰竭, 而化疗相关肝损伤或代偿期肝硬化患者需要FLR/SLV>40%, 才能降低肝切除术后肝功能衰竭发生率[81]. 门静脉栓塞术(portal vein embolization, PVE)通过栓塞肿瘤侧门静脉能够诱导剩余肝脏组织增生20%-50%, Mueller等[82]利用PVE诱导肝脏组织增生60%-82%, 对CRLM患者进行肝肿瘤切除, 术后5年生存率可达25%-50%. Knoefel等[80]通过PVE或门静脉结扎使64%-73%剩余肝体积不足CRLM患者获得肝肿瘤切除. 肝静脉(hepatic vein embolization, HVE)栓塞术联合门静脉联合栓塞术(HVE+PVE)通过阻塞肝静脉流出道, 增加栓塞侧肝组织淤血损伤, 减少栓塞区动脉血流量及非栓塞区向栓塞区供血交通支的形成, 进一步刺激促进FLR增生[83]. Le Roy等[84]应用HVE+PVE治疗CRLM, FLR平均增长率51.2%, PVE为31.9%, HVE+PVE动态增长率为19%, PVE为8%, 表明HVE+PVE促进预留肝脏增生, 增生速度优于PVE, HVE+PVE切除率为80.6%, PVE为75.6%. 王晓颖等[85]应用HVE+PVE治疗初始不可切除CRLM, 肝脏平均增长率32.8%, FLR/SLV从平均33.5%增至43.8%, 使FLR快速增生, 联合静脉系统治疗可以增加初始不可切除CRLM的转化切除率.
2.3.2 二期肝切除: 对于肝脏转移肿瘤切除术后剩余肝脏体积不足, 需要采取增加剩余无瘤肝脏组织体积后行二期肝切除(two-stage hepatectomy, TSH), 对于CRLM患者TSH仅为57%, 除PVE和联合HVE增加剩余肝体积方法外, 联合肝脏分割和门静脉结扎的分阶段肝切除术(associating liver partition and portal vein ligation for staged hepatectomy, ALPPS)治疗初始不可切除的CRLM可行性为92%, 行ALPPS治疗的CRLM患者中位OS为46 mo, 具有较好的疗效[86,87]. HVE+PVE肝脏FLR增长绝对值、相对增长率分别为233 mL、63%, ALPPS分别为188 mL、56%二者无显著性差异(P>0.05). ALPPS肝脏动态绝对增长值、动态增长率为21 mL/d、7%/d, 优于HVE+PVE(8 mL/d、2%/d), 提示ALPPS后FLR增生速度优于HVE+PVE, HVE+PVE后肝肿瘤切除率为80.6%、ALPPS为100%, 初始不可切除的CRLM经ALPPS治疗术后2年OS、DFS分别为62%、18%, 平均总体生存期及无瘤生存期分别为29 mo、9 mo[88]. Olthof等[89]根据CRLM患者3个预后不良高危因素: (1)转移瘤数目≥6个; (2)残肝肿瘤≥2个; (3)侵犯肝段≥6个. 研究结果发现<2个高危因素和≥2个高危因素患者ALPPS术后2年总体生存率(72% vs 49%), 术后平均无瘤生存(12 mo vs 6 mo)具有显著性差异(P<0.05); 而≥2个高危因素行ALPPS治疗的患者和≥2个高危因素仅接受化疗患者总体生存无显著性差异(24.0 mo vs 17.6 mo, P>0.05). 提示与仅行化疗和分子靶向药物治疗的CRLM患者相比, 对于合并预后不良因素(≥2个高危因素)的CRLM患者行ALPPS治疗预后无明显改善, 因此对于合并≥2个高危因素的CRLM患者需谨慎选择ALPPS.
随着手术技术的进步和转化治疗理念的推广, 肝脏转移肿瘤的大小、数目、部位、分布等已不再是影响评估CRLM是否适宜手术的单一决定因素, 如果肝转移肿瘤能够R0切除, 且能保留足够的功能性肝组织[肝脏残留容积≥40%(同时性肝切除)或≥30%(异时性肝切除)]的CRLM患者均可考虑手术, 5年OS可达38%-71%[90,91]. 手术是CRLM首选治疗方式, 术后患者中位生存期为35 mo, 5年生存率为30%-50%, 10年生存率为25%[92].
CRLM患者转化治疗后3 mo需要接受多学科评估, 如果6 mo治疗后仍未能获得手术切除可能性, 则需要重新评估整体治疗策略, 因为患者接受8 mo转化治疗后, 极少有患者能够接受手术治疗[11]. 转化治疗期间应6 wk-8 wk评价一次疗效, 最佳术前治疗时间为3 mo-4 mo, 如果治疗3 mo-4 mo后评估治疗反应不明显,则应考虑更换治疗方案; 如3-4 mo后评估为有效但依然不能手术切除,可延长至6 mo-8 mo. 较为适宜的手术时机为停止化疗后4 wk, 如果使用贝伐单抗,需要至少停药5 wk, 如考虑停药时间过长, 可在等候手术期间采用不加贝伐单抗的方案化疗一个周期[93]. 经过一定周期的转化化疗后, 肝转移肿瘤一旦转化为可切除, 需要及时施行根治切除术, 转化后CRLM手术可切除判断[94]: (1)CRC原发灶能够或已经根治性切除; (2)肝转移灶可完全R0切除, 且保留足够的功能性肝组织(肝脏残留体积≥30%); (3)病人全身状况允许, 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的病人. 在转化治疗期间, 应密切监测治疗反应, 对疾病进展患者应及时更换治疗方案, 更换治疗方案后病情仍然进展的患者, 需要在多学科协作治疗(multidiscilinary team, MDT)小组专家判断和指导下, 改变治疗目的和总体策略. 切忌过度转化治疗, 导致存在转移肿瘤发生耐药继续生长, 再次成为不可切除肿瘤, 错过根治性切除术的最佳时机.
化疗或联合分子靶向药物治疗初始不可切除CRLM患者中31%出现肝转移肿瘤消失(disappearing liver metastasis, DLM), 发生DLM的CRLM患者随访6 mo、6 mo-12 mo、12 mo-24 mo肝转移肿瘤出现再复发率分别为3.4%、16.8%、34.8%, 24 mo以后无肿瘤复发. 与单独化疗相比, 化疗联合分子靶向药物治疗的CRLM患者发生DLM低(58.3% vs 37.1%), 肿瘤<5 mm DLM发生率高于肿瘤>10 mm(76.7% vs 30.4%), 肿瘤5 mm-10 mm DLM发生率高于肿瘤>10 mm(70.0% vs 30.4%)(P<0.01), 但肿瘤<5 mm与5 mm-10 mm肿瘤DLM发生率无显著性差异[95]. 由于DLM未能达到完全病理性缓解, 超过80%不可见的肝转移肿瘤内仍有存活的癌细胞, 随访过程中患者局部复发率为38%-74%[96]. 因此对于出现DLM的CRLM患者仍然需要手术切除肿瘤转移部位, 但DLM给手术切除带来很大难度, 与术前MRI检查相比, 术中超声能够新发现肝转移肿瘤为11%-19%[97]. 尤其术中超声造影检查, 不仅能够发现新的病灶, 直径<1 cm额外转移灶检出率为10-25%, 消失转移灶检出率为10%-15%, 2.7%-49%患者检查后改变手术策略, 而且能够定性定位, 协助引导肝切除手术, 实时评价疗效[98]. 术中腹腔镜超声(laparoscopic ultrasound, LUS)肿瘤检出率为78.82%, ICG荧光成像为74.71%, LUS联合ICG为100%, 55.32%改变手术方案[99]. 术前影像学提示肝脏转移肿瘤消失, 术中仍未能探及"消失"病灶, 可对照之前的影像检查结果, 切除可疑区域肝脏组织, 否则应不予处理, 待局部出现复发后再行治疗[93]. 术中LUS和ICG荧光影像技术的联合应用可避免遗漏肝转移病灶, 提高R0切除率, 降低术后转移瘤复发率, 改善CRLM患者预后.
保留肝实质手术方式(parenchymal sparing hepatectomy, PSH)的最大优势在于通过不规则楔形切除肿瘤, 能最大程度地保留肝体积, 使得肝内肿瘤复发后有更多的机会进行二次甚至多次肝切除, 显著延长复发CRLM患者的生存期. 与大范围肝切除(major hepatectomy, MH)相比, PSH手术时间短(177.5 min vs 220 min)、出血少(150 mL vs 300 mL), 术后并发症发生率低(47.4% vs 64.8%)(P<0.05), 而术后OS、肝内无复发生存时间无显著性差异[100]. 肝转移肿瘤手术保持1 mm-4 mm、5 mm-9 mm、l cm以上切缘对于CRLM患者预后无显著性差异[18]. 肝内>4个转移肿瘤的CRLM患者, PSH和MH中位手术切缘均是1 mm, 术后发现阳性切缘率分别为8.8%和9.4%, 肿瘤复发率分别为91.2%和87.5%, 仅有肝内肿瘤复发率分别为43.4%和50%, 均无显著性差异[101]. 肝转移肿瘤术中切缘阳性、切缘l mm-4 mm、5 mm-9 mm和切缘≥1 cm的CRLM患者术后5年OS分别为17.1%、62.3%、71.1%和63%, 复发率分别为51%、39%、41%和39%, 除切缘阳性外, 其余切缘复发率和OS无显著性差异[102]. 因此对于CRLM患者采用PSH治疗方式手术保持切缘阴性, 安全性更高, 对多发、双侧肝脏CRLM患者明显提高复发患者再次切除的比例, 是CRLM手术治疗的首选模式. 与非解剖性肝切除相比, 解剖性肝切除在K-Ras野生型CRLM患者中DFS无显著差异, 但K-Ras突变患者接受解剖性肝切除中位DFS(33.8 mo vs 10.5 mo)和5年DFS(46.4% vs 14.4%)显著延长, 提示侵袭性较强的CRLM患者解剖性肝切除具有优势[103,104]. 对于局限于左半或右半肝的较大肝转移肿瘤且无肝硬化者, 且剩余肝体积≥40%, 为了保证R0切除, 宜行规则的左或右半肝切除.
Kazaryan等[105]分析腹腔镜肝切除治疗CRLM, 结果发现单次肝肿瘤切除、多次保留肝实质肿瘤切除、肝切除联合射频消融治疗术后肝脏肿瘤复发率分别为50%、59%、52%, 5年OS分别为31%、42%、43%, 5年RFS分别为25%、16%、18%, 以及术后并发症均无显著性差异(P>0.05). 由于多次PSH使术后重复肝切除率高, 患者获得良好的总生存率, 对于肝内多发性转移肿瘤, 应选择PSH, 而不是单次大范围切除含有较多正常肝组织的肿瘤切除. 开腹与腹腔镜肝切除在治疗CRLM患者并发症、术后5年RFS(25.6% vs 21.4%)无显著性差异[106]. 达芬奇机器人手术系统能为术者提供三维高清立体术野图像, 操作时手眼协调性更佳, 相较于腹腔镜手术更适合在空间有限的部位进行精细解剖、切除和缝合等操作, 任昊桢等[107]回顾性分析腹腔镜与机器人肝切除治疗CRLM患者, 与腹腔镜肝切除相比, 机器人肝切除手术时间(155.4 min±40.2 min vs 184.5 min±56.8 min)、术中出血量(205.5 mL±124.8 mL vs 352.8 mL±206.6 mL)、术中输血(1单位 vs 8单位)和中转开腹(1例 vs 9例)、术后住院时间(4.5 d±1.3 d vs 6.3 d±2.2 d)、肛门排气时间(22.4 h±8.5 h vs 30.8 h±10.1 h)、术后进食时间(1.1 d±0.9 d vs 1.8 d±1.2 d)均显著少于腹腔镜肝切除(P<0.05), 术后24 h肝功能、并发症发生率无显著性差异(P>0.05), 表明机器人肝切除手术时间较短, 中转开腹率较低, 利于术后恢复. Wang等[108]研究发现右半结肠癌Ras突变率显著高于左半结肠癌, Ras突变对CRLM患者肝切除术后长期生存有不同的预后影响, 右半结肠癌的CRLM患者肝切除术后1、3、5年0S分别为91.9%、50.8%、46.5%, 1、3、5年DFS分别为58.1%、33.6%、29.1%, 左半结肠癌CRLM患者术后1、3、5年OS分别91.2%、53.7%、38.3%, 1、3、5年DFS分别为55.5%、29.1%、22.4%. 因此CRLM肝肿瘤切除手术应依据原发结直肠肿瘤部位、Ras基因状态、肝转移肿瘤(大小、数目、分布)、肝脏功能、转化治疗方案与次数等制定个体化的手术方式.
二十世纪以前由于术后免疫抑制剂和化疗药物疗效的原因, 对于无法手术切除的CRLM患者行肝移植(liver transplantation, LT)治疗, 术后1、3、5年OS分别为76%、32%和12%, 低的长期生存限制了LT治疗CRLM的临床应用[109]. 近年来随着高效抗免疫排斥、化疗药物, 尤其抗肿瘤复发免疫抑制剂的研制和治疗方案的改进, 不可切除CRLM行LT疗效有了极大提高, 术后1、3、5年OS分别为95%、68%和60%[110]. CRLM患者选择LT标准采用OSLO评分(0-4)[111]: (1)肿瘤最大直径>5.5 cm; (2)CEA>80 μg/L; (3)原发肿瘤切除与肝移植间隔时间少于2年; (4)根治术后化疗期间肿瘤进展. OSLO评分低于4分的患者行LT预后与在Milan标准范围内的肝细胞癌患者相似. Dueland等[111,112]对于不可切除CRLM患者行LT治疗术后5年OS为56%, 而仅接受化疗者为19%, 提示LT远期疗效优于化疗; OSLO评分低危险CRLM患者(<3分)LT术后5年生存率为75%, 而高危险CRLM患者(≥3分)5年生存率为0, 提示高危险CRLM患者应慎行LT. 肝转移肿瘤对化疗反应>10%, 且确诊至LT间隔>1年的CRLM患者LT术后1、3和5年总生存率分别为100%、100%和83%, 1、2和3年DFS分别为53%、44%和35%[113]. 通过严格筛选CRLM患者和规范的围手术期治疗, LT术后患者1、3和5年OS分别为94.5%、71.8%和65.8%, 1、3和5年DFS分别为46.8%、25.6% 和25.6%, LT术后患者多发转移率明显降低, 肝脏复发率仅为3%, 70%复发于肺(其中60%可以R0切除), 术后复发患者4年OS仍高达73%, 表明LT对于严格筛选的不可切除CRLM患者能够提供长期生存获益[113-115]. Hagness等[110]研究发现CRLM患者LT前接受6 wk以上化疗, LT术后1、3、5年生存率分别为95%、68%、60%, 表明LT前合适的治疗及围手术期严格管理、制定合理的治疗方案能够提高术后患者长期生存. 随着抗肿瘤复发与转移免疫抑制剂、高效低毒化疗药物、分子靶向药物研制和临床应用, LT有望成为不可切除CRLM治疗的主要方法之一, 但关于LT治疗CRLM患者指征、手术时机、术后免疫抑制剂、肿瘤复发与转移预防方案等问题仍需要进一步临床研究.
通过转化治疗后肝转移肿瘤大小、数目满足局部消融治疗条件时, 应及时进行肿瘤消融治疗, 局部消融治疗指征: 转移肿瘤数目≤5个, 且最大肿瘤直径<5 cm, 消融治疗效果与肿瘤大小、数目、位置、消融技术等因素密切相关, 结合我们临床实践, 应严格选择肿瘤最大直径<3 cm, 技术熟练人员操作, 影像能够清晰显示肿瘤轮廓进行消融治疗, 对于影像显示不清的肿瘤需要开腹或腹腔镜直视下引导, 减少肿瘤残留, 提高完全消融率[116]. 对于位于肝脏深处<2 cm转移肿瘤, 手术切除创伤大, 可以联合射频消融(radiofrequency ablation, RFA)治疗, 虽然RFA联合肝切除术不是R0切除术, 但单纯肝切除术和RFA联合肝切除术后CRLM患者OS相似[117]. 微波消融治疗(microwave ablation, MWA)CRLM术后肿瘤局部复发率为7.9%, 复发与肿瘤的大小、病变紧邻血管、被膜下病变、肿瘤性质、消融技术等因素相关, 当肿瘤直径分别为<1 cm, 1 cm-3 cm及>3 cm时, 消融术后复发率分别为1%、9.3%和33%[118]. 消融术中、术后进行超声造影实时监测, 简便易行, 依据超声造影病灶血供情况, 对超声造影显示肿瘤消融不全时, 进行精确定位再次消融, 判断准确性为95.2%, 显著优于B超CDFI检查(64.5%), 超声造影实时监测能够显著降低肿瘤残留率, 提高消融效率[119].
腹腔镜直视下行RFA与经皮穿刺RFA比较, 并发症更少且程度更轻, 肿瘤灭活更彻底, 相对于经皮RFA或MWA治疗, 腹腔镜或开腹直视下操作对于特殊位置(如靠近膈顶、膈肌以及第一、第二肝门等)肿瘤能够达到更小的损伤和更好的疗效[120]. MWA消融时间明显短于RFA(19 min vs 37 min), 局部复发率明显低于RFA(10% vs 20%)(P<0.05), 多因素分析提示MWA、肿瘤大小是影响局部肿瘤复发的独立因素[121]. Kennedy等[122]回顾性分析腹腔镜RFA治疗CRLM, 术后中位OS为40.4 mo, 1、3、5年OS分别为93.5%、50.1%、28.8%, 9.2%患者出现局部肿瘤复发(其中肿瘤直径<3 cm肿瘤复发率为3.6%). 尤孙武等[123]利用腹腔镜MWA治疗CRLM, 肿瘤完全消融率为98.6%, 肿瘤≤3 cm消融术后中位OS、DFS分别为33.1 mo、24.4 mo, 肿瘤>3 cm分别为29.7 mo、19.1 mo, 肝转移肿瘤单发分别为43.2 mo、31.5 mo, 多发分别为35.3 mo、15.2 mo, 1、3年OS分别为87.5%、41.6%, DFS分别为83.3%、20.8%, 肿瘤多发、肿瘤>3 cm是影响腹腔镜MWA总生存率的独立危险因素. CRLM肿瘤≤3个、肿瘤≤5 cm手术切除的DFS明显长于RFA(22 mo vs 14 mo), 而对于肿瘤≤3 cm者, 手术切除与RFA患者的DFS无显著性差异, 多因素分析显示较差的DFS与RFA、T4、淋巴结阳性及肝转移肿瘤>3 cm密切相关[124]. 手术联合MWA治疗CRLM肝转移灶数目明显高于单纯手术, 但两组患者肝内无肿瘤复发、术后DFS及OS均无显著性差异[125]. 对于多发肝转移肿瘤患者, 尤其位于特殊位置的肝转移肿瘤, 如行肝切除因残余肝体积不足, 术后有肝功能衰竭的风险, 可以考虑手术切除联合局部消融治疗手段, 切除表浅病灶, 而位置深在肿瘤可行RFA、MWA等局部治疗达到NED状态, 延长患者生存[126]. 与肝切除相比, 肝切除联合术中局部消融治疗术后5年生存率高(57% vs 61%), 通过联合术中消融治疗, 将不可切除CRLM患者转化成为"可局部治疗", 可以获得良好的预后[127], 肝切除联合术中局部消融治疗对于肝脏双叶、多发肝转移肿瘤CRLM患者是一种非常有效的治疗方法, 使一些无法通过单纯肝切除达到R0切除的患者从不可切除转换为可切除, 延长患者生存期.
CRLM肝切除术后5年OS为60%, 60%患者术后再次复发, 主要位于肝内, 重复肝切除是治疗复发CRLM有效措施[128,129]. Nordlinger等［130］报道复发再手术CRLM患者, 术后2、3、5年OS分别为73%、59%、22%, RFS为26%、19%、19%. 肝转移肿瘤复发后再次切除术后并发症发生率为20%, 死亡率为1.5%, 1、3、5年OS分别为91.2%、44.3%、29.4%, 再次手术切除是唯一可能治愈的治疗方式[131]. CRLM肝切除术后复发再次切除的患者中位生存期达56.5 mo, 仅接受化疗的患者中位生存期为28.7 mo, 5年OS具有显著性差异(51% vs 19%)[132,133]. 重复肝切除为CRLM患者术后再次肝内复发提供有效治疗手段, 依据患者具体情况, 积极采用不同的治疗方式增加肿瘤再切除的机会延长患者生存期.
CRLM术后患者临床危险评分(clinical risk score, CRS)>2的高危患者, 术后辅助化疗能够显著提高生存率, 而CRS≤2患者接受辅助化疗无明显受益[134]. CRLM患者肝转移肿瘤R0切除术后辅助治疗采用两种治疗模式: (1)术后辅助化疗: 选择FOLFOX方案化疗12个周期或XELOX方案8个周期(6 mo); (2)围手术期化疗: 术前FOLFOX方案或联合分子靶向药物治疗化疗6个周期(3 mo), 术后FOLFOX 方案辅助治疗6个周期(3 mo)[135,136]. 对于肝转移肿瘤切除术后高危患者应给予短程的辅助治疗, 应用与转化治疗相同的有效方案, 总疗程为6 mo, 以杀灭残留微小转移灶, 降低术后肝内再复发率.
经转化治疗手术切除的CRLM, PET-CT检查肿瘤标准摄取值(standard uptake value, SUV)变化率<0.293%的患者术后3、5年RFS分别为37.5%、18.8%, SUV变化率≥0.293%的3、5年RFS分别为0%、0%; SUV变化率<0.293%的3、5年OS分别为100%、100%, SUV变化率≥0.293%的3、5年OS分别为46.3%、13.9%, 高SUV变化率与较差的RFS独立相关. 肿瘤SUV变化率与肿瘤大小、病理反应有关, 肿瘤SUV变化率≥0.293%与术后较短的RFS相关[137]. 无论化疗反应、加入分子靶向药物治疗和K-Ras基因状态如何, 高TBS(>14.3)与转化治疗反应、OS差显著相关, 低TBS患者3年OS优于高TBS患者(43.1% vs 20%, P<0.05), TBS、肿瘤分化、T分期是影响初始不可切除CRLM患者OS的3个独立相关因素[23]. 原发肿瘤位于右半结肠、治疗反应(SD或PD)、缺乏分子靶向药物治疗是预测不良OS的独立因素, 而≥8个一线化疗疗程、应用分子靶向药物治疗有利于患者PFS[24]. 原发肿瘤位于左半结肠、肝转移肿瘤数目≤4个、肿瘤最大直径≤5 cm、无肝外转移、对化疗和分子靶向药物治疗有反应是转化后肝切除术后预后较好的重要预测因子[138]. 10%CRC患者存在BRAF V600E突变, CRLM患者BRAF突变率为9.62%, 肝切除术后DFS缩短, BRAF突变是肝切除术后CRLM患者预后不良的生物标志物, 与较差的OS密切相关[139,140]. Hayashi等[141]研究发现转化后切除的肝转移肿瘤中37%癌细胞存在膜CD44表达, CD44表达与Ki-67高增殖活性显著相关, 与肿瘤大小和数目无关, 提示CD44阳性的癌细胞即使在化疗后仍具有高度增殖能力, 与CD44阴性表达相比, 术后1年内肿瘤复发率高(76% vs 16%), CD44阳性表达与转化后肝切除术后较短的DFS和较差的OS显著相关, CD44可以作为转化治疗后肝切除CRLM患者术后早期肿瘤复发和死亡高风险的一个有用生物标志物. Ras基因突变是CRLM患者肝切除术后生存的危险因素, Ras基因突变率为30.6%, Ras基因野生型CRLM患者术后中位生存期(73 mo vs 30 mo)、无病生存期(13 mo vs 9 mo)、1、3、5年累积生存率(95.5%、66.9%、53.1% vs 89%、41.4%、36%)和无病生存率(53.3%、34.7%、29.4% vs 31.2%、20.9%、17.5%)均优于Ras基因突变型CRLM患者, 肝转移出现间隔≤12 mo、肝转移肿瘤>5 cm、Ras基因突变型是CRLM患者术后生存的独立危险因素, Ras基因突变型患者预后更差[142]. 术前接受一线化疗转化治疗CRLM患者术后5年生存率为42%, 接受二线化疗、三线化疗和三线以上化疗患者分别为36%、26%和15%(P<0.01), 表明术前化疗线数对肝转移肿瘤切除术后患者生存期有显著影响, 一线化疗转化成功预后最好. 术前接受1-6个疗程化疗患者术后5年生存率为44%, 7-12个疗程、13-18个疗程、19-24个疗程和>24个疗程化疗CRLM患者术后5年生存率分别为41%、37%、31%和22%(P<0.01), 表明术前化疗疗程长短影响肝转移肿瘤切除术后患者生存[143]. 原发肿瘤位于右半结肠、术前CA9-9≥50 u/mL、Ras基因突变型是单发CRLM患者肝转移肿瘤切除术后生存的独立危险因素, 1、3、5、10年累积生存率分别为92.5%、58.6%、51%、38.8%, RFS分别为53.5%、36.4%、31.6%、28.9%; 原发肿瘤为N1-2分期、肝转移肿瘤最大直径≥5 cm、Ras基因突变型是多发CRLM患者肝转移肿瘤切除术后生存的独立危险因素, 1、3、5、10年累及生存率分别为90.7%、53.2%、41.1%、29.9%, RFS分别为39.7%、22.4%、18.5%、15.4%, 单发肝转移CRLM患者预后优于多发肝转移CRLM患者(P<0.05)[144]. CEA水平、淋巴结转移、原发结肠肿瘤分化程度、原发结肠肿瘤部位(右半、左半)、术后化疗、K-Ras和Braf基因状态、肝转移肿瘤出现时间是影响CRLM患者术后OS的危险因素[145,146]. 肝转移肿瘤数量、大小、患者年龄、中性粒细胞-淋巴细胞比值、原发结直肠肿瘤的侵袭深度和淋巴转移是影响CRLM患者术后预后的因素[137]. 因此针对影响CRLM患者术后不利的预后因素, 应积极制定个体化的预防措施, 降低不利因素的影响, 提高CRLM患者术后生存期, 改善CRLM患者预后.
随着高效化疗药物、分子靶向药物、免疫抑制剂等的临床应用, 以及外科技术进步、手术器械的发展和临床实践的积累, 肝转移肿瘤的大小、数目、部位已经不是外科手术和肝移植治疗的绝对禁忌证, 但由于CRLM不同于原发性肝癌, 有其本身的临床特点, 受肿瘤大小、数目、部位、剩余功能肝体积等因素影响, 导致许多CRLM初始无法行手术切除或肝移植, 需要进行转化治疗. 依据CRLM患者身体情况、原发性结直肠肿瘤部位和分化程度、Ras和Braf基因状态、肝转移瘤大小、数目、分布和剩余肝体积情况, 通过MDT讨论制定个体化的安全、高效、快速转化治疗方案, 使初始不可手术切除的肝转移肿瘤获得手术切除或患者达到NED状态, 针对影响CRLM患者术后不利的预后因素, 制定个体化的预防措施, 才能提高CRLM患者长期生存期, 改善CRLM患者预后, 造福于广大CRLM患者.
学科分类: 胃肠病学和肝病学
手稿来源地: 上海市
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科学编辑:张砚梁 制作编辑:张砚梁
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