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1、结直肠癌肝转移治疗新进展,中山大学附属第六医院 邓艳红,1,结直肠癌肝转移,全球（CRC）发病： 120万例/年死亡: 60万例/年 我国发病率，17万例/年 北京、上海、广州等第二位50%CRC伴肝转移 15%25%诊断时已有同时性肝转移 另15%25%术后出现异时性肝转移,10%肝转移患者可手术.未治疗肝转移中位生存仅6.9个月,S, Camci C, et al. J Hepatobiliary Pancreat Surg. 2008;15:570-80. Elias D, et al. J Surg Oncol, 2004;86:49.,2018/9/16,结直肠癌肝转移切除与长期生存
2、,J Clin Oncol. 2009 Aug 1;27(22):3677-83,5,肝转移切除改善生存唯一治愈机会,Improved survival in mCRC is associated with adoption of hepatic resection and improved chemotherapy,Kopetz S, et al. J Clin Oncol 2009;27:36773683,Time (months),0,12,24,36,48,60,72,20,40,60,80,100,OS (%),Landmark,No liver resection,Liver re
3、section,0,Error bars represent 95% CIs,Resection of liver metastases has become a common approach at specialized centers，n=2470,OS, overall survival,国际多中心研究（-2012年12月） 包括来自67个国家415个医疗中心19120名患者,www.livermetsurvey.org,42%,26%,8%,切除 n=18115,未切除 n=1005,手术切除肝转移患者长期生存与III期患者相当,0,0.5,1,1.5,2,2.5,3,3.5,4,4
4、.5,5,1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0,生存率,时间（年）,所有期,所有患者,所有期,期中手术切除的肝转移患者n=3116,Morris EJ, et al. Br J Surg. 2010;97(7):1110-8.,1998-2004年间诊断为结直肠癌的患者：5年生存率（n=114,155）,英国国民健康服务中心,2018/9/16,10,化疗与不可切结直肠肝转移转化性切除,Paul Brousse Hospital: 2047 例患者 (Apr 1988Dec 2003),化疗: 1512例 (74%),14%,86%,28%,72%,切
5、除: 740例,Updated from: Adam R, et al. Ann Surg 2004;240:644658,Adam R. Ann Oncol. 2003;14(suppl 2):ii13-iii16.,转化后手术者生存获益相似,Initially nonresectable (n = 95),Resectable (n = 425),Survival Time (Years),100,80,60,40,20,0,Proportion Surviving,0,1,2,3,4,5,6,7,8,9,10,54%,34%,27%,19%,29%,34%,50%,肝转移切除后的患者5年
6、生存率可达30%，而10年生存率有17%-25%，对于这部分患者通常可认为疾病已经得到治愈。,2018/9/16,可切除性肝转移处理,13,TITLE,Nordlinger B et al Lancet Oncol 2013;14:1208-1215,Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, c
7、ontrolled, phase 3 trial,Nordlinger B et al Lancet Oncol 2013;14:1208-1215,Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial,2018/9/16,(Ann Surg 2012;2
8、55:534539),TITLE,TITLE,TITLE,TITLE,2018/9/16,2018/9/16,这个领域看似简单，实际上还有很多的问题没有解决可切除性的标准如何定义？（个数？大小？）先手术还是先化疗，如何选择？（预后好的直接切，预后不良的先化疗？）若行新辅助，化疗方案如何选择？（FOLFOX vs 其他？）合并局部晚期直肠癌如何处理？（Liver first vs CRT？）,2018/9/16,潜在可切除性肝转移处理,转化性化疗方案的切除率与有效率呈正相关,Folprecht G, et al. Ann Oncol 2005;16:13111319,初始不能手术切除的结直肠癌肝
9、转移灶，治疗后获得的有效率越高，切除率越高,纳入所有mCRC患者的研究（实线） （r=0.74; P0.001）,纳入经选择患者的研究（仅有肝转移，无肝外疾病）（r=0.96; P=0.002）,纳入所有mCRC患者的III期研究（虚线） （r=0.67; P=0.024）,有效率,0.9,0.8,0.7,0.6,0.5,0.4,0.3,切除率,0.6,0.5,0.4,0.3,0.2,0.1,0,P=0.05,初始不可切除肿瘤：一线治疗决定更大长期获益,术前化疗疗程越多、化疗线数越多，肝切除后预后越差,Response rates: Targeted therapies in 1st line
10、 mCRC,Response rate (%),0,10,20,30,40,50,60,70,*Significant vs CT control,p=0.004,45,BEV + CT (n=402),AVF2107g* (ITT),35,CT (n=411),p=0.99,38,BEV + CT (n=699),NO16966 (ITT),38,CT (n=701),p=0.018,57,Pani + CT (n=325),PRIME* (KRAS wt),48,CT (n=331),COIN* (KRAS wt),Cetuximab + CT (n=362),64,p=0.049,57,
11、CT (n=367),CRYSTAL* (KRAS wt),Cetuximab + CT (n=316),57,p0.001,40,CT (n=350),Cetuximab + CT (n=82),57,p=0.0027,OPUS* (KRAS wt),34,CT (n=97),Van Cutsem E, et al. J Clin Oncol 2011;29:20112019; Bokemeyer C, et al. Ann Oncol 2011;22:15351546; Maughan TS, et al. Lancet 2011;377:21032114; Douillard J-Y,
12、et al. ASCO 2011 (Abstract No. 3510); Hurwitz H, et al. N Engl J Med 2004;350:23352342; Saltz LB, et al. J Clin Oncol 2008;26:20132019,*P =.0034 for cetuximab + FOLFIRI vs FOLFIRI alone, all patients.,靶向药物的转化效能 西妥昔单抗,Van Cutsem E, et al. ASCO 2007. Abstract 4000. Bokemeyer C, et al. ASCO 2007. Abstr
13、act 4035. Cassidy J, et al. ASCO 2007. Abstract 4030. Hecht JR, et al. World GI Congress 2007.,CELIM: R0 Resection as a surgical maintenance therapy in the continuum of care,R0 resected: 15.4 95%CI: 11.3-19.5 Not R0 res.: 8.9 95%CI: 6.7-11.0 HR 2.10 1.37-3.20 p0.001,R0 resected: 53.9 95%CI: 35.9-71.
14、9 Not R0 res.: 27.3 95%CI: 21.1-33.4 HR 2.25 1.34-3.78, p=0.002,5y-OS: 45.8%,Overall survival,Progression free survival,Update CELIM 12/2012, ASCO 2013,Group 1Potentially resectable metastases,Chinese randomized trial in patients with non resectable k-ras wt CRC LLD Chemotherapy +/- Cetuximab,Ye et
15、al. JCO 2013,Group 1Potentially resectable metastases,中位生存期 30 . 9月 3年 OS 41%,MST 21 . 0月 3年 OS 18%,P=0.013,中位无进展生存期 A组 : 10 . 2月 B组 : 5 .8月 P 0.01,POCHER: Response and resection rates,Garufi C, et al. ECCOESMO 2009. Abstract No. P-6086,R0 resection rate,0,10,20,30,40,50,60,70,80,60,Patients (%),R0/R1 resection rate,46,0,10,20,30,40,50,60,70,80,Patients (%),65,Response rate KRAS WT,Patients (%),0,10,20,30,40,50,60,70,80,79,FOLFIRI vs. FOLFOXIRI,Falcone et al. JCO 2007/ASCO 2007,PFS,OS,TITLE,Presented By Alfredo Falcone, MD at 2013 ASCO Annual Meeting,
