结直肠癌新辅助治疗含肝转移 (2)

1、结直肠癌患者新辅助治疗1直肠癌术前放化疗2新辅助治疗的目的提高手术切除率提高保肛率降低局部复发延长患者无病生存期3推荐T3和/或N+的可切除直肠癌患者，推荐术前新辅助放化疗。直肠癌术前化疗推荐以氟尿嘧啶类药物为基础的化疗方案4567891011121314结肠癌肝转移术前化疗15推荐结直肠癌患者合并肝转移，可切除或者潜在可切除，推荐术前化疗或化疗联合靶向药物治疗：西妥昔单抗（推荐用于K-ras基因状态野生型患者），或联合贝伐珠单抗化疗方案推荐FOLFOX，或者FOLFIRI，或者CapeOx，16liver metastasesNot resectableresectablechemother

2、apy85%15%+ other locations of metastaseschemotherapy50%50%Patients with metastatic colorectal cancer5y Survival: 5%5 y survival: 5%Metastatic colorectal cancer5 y survival: 20-40%17Resection rate of metastases and tumor responseStudies incl. selected pats.(liver metastases only, no extrahepat. disea

3、se) r=.96, p=.002Studies incl. all patients with metastatic CRC (solid line) r=.74, p.001Phase III studies in metastatic CRC(dashed line) r=.67, p=.024, p=.024Folprecht Khne et al, Ann Oncol 200518新辅助化疗优势患者体内化疗药物的药敏试验清除微小转移灶观察甄别出快速进展病例提高R0切除率？并减少切除的正常肝组织延长生存期？19Adjuvant, neoadjuvant, conversion ther

4、apy for CRC liver metastasesResectableadjuvantneo-adjuvantUnresectableConversion chemotherapy20Colorectal Ca R0 Resection of MetastasesControversy: Adjuvant Therapy ?USA Yes (Kemeny NEJM 1999)EuropaNo(Lorenz NEJM 2000)21Kemeny et al NEJM 1999 and 2005Liver metastases: adjuvant HAI + i.v. CTXp=0.02Me

5、dian overall survivalFong 0-2Fong 3-5HAI+systemic83.3 mo60.0 mo(10y: 38.7%)systemic82.8 mo38.3 mo(10y: 16.3%)p=0.1322LV5FU vs. FOLFIRI as adjuvant therapy following resection of CLM - DFS1-year DFS: 63% vs. 77%2-year DFS: 46% vs. 51%Ychou et al. ASCO 200823Adjuvant Chemotherapy for CRC liver metasta

6、ses YES！ Which patients? 高复发风险 which regimen? 化疗？HAI？ 方案？FU、OXA？Target ？24EORTC phase III study 40983研究设计RandomizeSurgeryFOLFOX4FOLFOX4Surgery6 cycles (3months)6 cycles(3 months)364 例潜在可切除肝转移 (metachronous or synchronous) ，4个以上病灶，无肝外转移25EORTC Study 40983 CT S P3-y FPS % 42.4 33.2 0.025手术情况Peri-op CT

7、(N=182) Surgery(N=182)Operated159 (87.4) 170 (93.4) Resected 151 (83.0) 152 (83.5) Not resected8 ( 4.3)18 ( 9.9) 26乐沙定，伊立替康和持续滴注5-FULV(FOLFOXIRI)两周方案和Folfiri相比一线治疗转移性结直肠癌：III期临床结果（GONO）A. Falcone, et alASCO GI 2006, #227不能切除的结直肠癌肝转移新辅助化疗27伊立替康，乐沙定和持续滴注5-FULV(FOLFOXIRI)两周方案和Folfiri相比一线治疗转移性结直肠癌：III期临

8、床结果（GONO）* Douillard Lancet 2000* Masi Ann Oncol 2004临床设计FOLFIRI*RCPT-11180 mg/m2 1-h d.1L-LV100 mg/m2 2-h d.1,25FU400 mg/m2 bolus d.1,25FU600 mg/m2 22-h d.1,2q. 2 wks x 12个周期FOLFOXIRI*CPT-11165 mg/m2 1-h d.1LOHP85 mg/m2 2-h d.1L-LV200 mg/m2 2-h d.15FU3200 mg/m2 48-h CI d.1q. 2 wks x 12 个周期分层 中心 PS

9、0/1-2 辅助化疗FOLFIRI方案进展后，推荐含乐沙定的方案28A. Falcone, ASCO GI 2006, #227外部评估FOLFIRI(122 pts)FOLFOXIRI(122 pts)完全缓解6%7%部分缓解28%53%完全 + 部分95% 可信区间34%0.25-0.4360%*0.51-0.68稳定34%21%进展24%11%不可评估8%8%*p0.001有效率(ITT 分析)化疗后手术切除率(所有病人)*p0.033疗效结果主要目标：RR次要目标：PFS, OS, post surgical resectionsn, safety QOL29Rescue Surger

10、y for Unresectable Colorectal Liver Metastases Downstaged by ChemotherapyA Model to Predict Long-term SurvivalRetrospective study1104 cases with unresectable liver metastases Chemotherapy regimens：5-FU/LV/OXA or IRI or both138(12.5%) achieved secondary curative hepatic resection Survival rate: 5-yea

11、r 33% 10-year 23%Adam R et al,Ann surg.2004;240:644-65730Resection of liver metastases: non-selected patients treated with targeted/cytotoxic agentsFirst authorN Regimen RR Resection rate Folprecht21Cetuximab/irinotecan67%19% /AIO (24%)*Diaz Rubio43Cetuximab/FOLFOX479%19%Rougier42Cetuximab/FOLFIRI45

12、%21%Fisher27Gefitinib/FOLFOX4 78%22%Hurwitz411IFL35% （2%412IFL/bevacizumab 45% resection)Hoff21FOLFIRI/bevacizumab70%19% *One patient declined offered resectionUpdated information based on Folprecht et al. Ann Oncol, 200531Liver-limited disease PFS and RR in KRAS wild-typeaCochran-Mantel-Haenszel (C

13、MH) testVan Cutsem, Khne in press32Randomized multicenter study of cetuximab plus FOLFOX or cetuximab plus FOLFIRI in neoadjuvant treatment of non-resectable colorectal liver metastases (CELIM study) G. Folprecht,1 T. Gruenberger,2 J.T. et alPatients with non-resectable colorectal liver metastasesNo

14、 extrahepatic disease33Efficacy: Confirmed Response Responses confirmed by 2nd CT scan according to RECIST or by resectionChi square test for comparison between FOLFOX6+Cet vs FOLFIRI+Cet would be 0.23 34ResectionsComparison of R0 resections between strata technically non-resectable and 5 liver mets: p=0.1435手术前化疗时限化疗时间最佳选