结直肠癌新辅助治疗（含肝转移）.ppt

1、结直肠癌患者新辅助治疗,北京大学肿瘤医院 消化肿瘤内科,直肠癌术前放化疗,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,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,结肠癌肝转移术前化疗,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，,liver metastases,Not resectable,resectable

2、,chemotherapy,85%,15%+,other locations of metastases,chemotherapy,50%,50%,Patients with metastatic colorectal cancer,5y Survival: 5%,5 y survival: 5%,Metastatic colorectal cancer,5 y survival: 20-40%,Resection rate of metastases and tumor response,Studies incl. selected pats. (liver metastases only,

3、 no extrahepat. disease) r=.96, p=.002,Studies incl. all patients with metastatic CRC (solid line) r=.74, p.001 Phase III studies in metastatic CRC (dashed line) r=.67, p=.024, p=.024,Folprecht Khne et al, Ann Oncol 2005,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？,Adjuvant,

4、neoadjuvant, conversion therapy for CRC liver metastases,Resectable adjuvant neo-adjuvant Unresectable Conversion chemotherapy,Colorectal Ca R0 Resection of Metastases,Controversy: Adjuvant Therapy ?,USA Yes (Kemeny NEJM 1999),Europa No(Lorenz NEJM 2000),Kemeny et al NEJM 1999 and 2005,Liver metasta

5、ses: adjuvant HAI + i.v. CTX,p=0.02,LV5FU vs. FOLFIRI as adjuvant therapy following resection of CLM - DFS,1-year DFS: 63% vs. 77% 2-year DFS: 46% vs. 51%,Ychou et al. ASCO 2008,Adjuvant Chemotherapy for CRC liver metastases,YES！ Which patients? 高复发风险 which regimen? 化疗？HAI？ 方案？FU、OXA？Target ？,EORTC

6、phase III study 40983研究设计,Randomize,Surgery,FOLFOX4,FOLFOX4,Surgery,6 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,EORTC Study 40983,CT S P 3-y FPS % 42.4 33.2 0.025,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,

7、et alASCO GI 2006, #227,不能切除的结直肠癌肝转移新辅助化疗,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期临床结果（GONO）,* Douillard Lancet 2000 * Masi Ann Oncol 2004,临床设计,FOLFIRI*,R,CPT-11180 mg/m2 1-h d.1 L-LV100 mg/m2 2-h d.1,2 5FU400 mg/m2 bolus d.1,2 5FU600 mg/m2 22-h d.1,2 q. 2 wks x 12个周期,FOLFOXIRI*,

8、CPT-11165 mg/m2 1-h d.1 LOHP85 mg/m2 2-h d.1 L-LV200 mg/m2 2-h d.1 5FU3200 mg/m2 48-h CI d.1 q. 2 wks x 12 个周期,分层 中心 PS 0/1-2 辅助化疗,FOLFIRI方案进展后，推荐含乐沙定的方案,A. Falcone, ASCO GI 2006, #227,*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 QOL,Rescue

9、Surgery for Unresectable Colorectal Liver Metastases Downstaged by ChemotherapyA Model to Predict Long-term Survival,Retrospective study 1104 cases with unresectable liver metastases Chemotherapy regimens：5-FU/LV/OXA or IRI or both 138(12.5%) achieved secondary curative hepatic resection Survival ra

10、te: 5-year 33% 10-year 23%,Adam R et al,Ann surg.2004;240:644-657,Resection of liver metastases: non-selected patients treated with targeted/cytotoxic agents,First authorN Regimen RR Resection rate Folprecht21Cetuximab/irinotecan67%19% /AIO (24%)* Diaz Rubio43Cetuximab/FOLFOX479%19% Rougier42Cetuxim

11、ab/FOLFIRI45%21% Fisher27Gefitinib/FOLFOX4 78%22% Hurwitz411IFL35% （2% 412IFL/bevacizumab 45% resection) Hoff21FOLFIRI/bevacizumab70%19% *One patient declined offered resection,Updated information based on Folprecht et al. Ann Oncol, 2005,Liver-limited disease PFS and RR in KRAS wild-type,aCochran-M

12、antel-Haenszel (CMH) test,Van Cutsem, Khne in press,Randomized 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 al,Patients with non-resectable colorectal

13、liver metastases No extrahepatic disease,Efficacy: Confirmed Response,Responses confirmed by 2nd CT scan according to RECIST or by resection,Chi square test for comparison between FOLFOX6+Cet vs FOLFIRI+Cet would be 0.23,Resections,Comparison of R0 resections between strata technically non-resectable and 5 liver mets: p=0.14,手术前化疗时限,化疗时间,最佳选择时间？,More than 6 cycles of neoadjuvant systemic chemotherapy i