结直肠癌新辅助治疗(含肝转移).ppt

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,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, 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, 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 metastases: 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 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, et al ASCO 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-11 180 mg/m2 1-h d.1 L-LV 100 mg/m2 2-h d.1,2 5FU 400 mg/m2 bolus d.1,2 5FU 600 mg/m2 22-h d.1,2 q. 2 wks x 12个周期,FOLFOXIRI*,CPT-11 165 mg/m2 1-h d.1 LOHP 85 mg/m2 2-h d.1 L-LV 200 mg/m2 2-h d.1 5FU 3200 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 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 rate: 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 author N Regimen RR Resection rate Folprecht 21 Cetuximab/irinotecan 67% 19% /AIO (24%)* Diaz Rubio 43 Cetuximab/FOLFOX4 79% 19% Rougier 42 Cetuximab/FOLFIRI 45% 21% Fisher 27 Gefitinib/FOLFOX4 78% 22% Hurwitz 411 IFL 35% （2% 412 IFL/bevacizumab 45% resection) Hoff 21 FOLFIRI/bevacizumab 70% 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-Mantel-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 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