1、2015ASCO直肠癌新辅助治疗进展,医学百事通转载,SACN.OXA.15.07.1410,刘志华医师-直肠癌治疗,主要内容,教育专场：局部进展期直肠癌（LARC）是时候改变了吗口头报告：FOWARC研究壁报讨论：JFMC35-C1: ACTS-RC，veliparib combined with capecitabine，S0713普通壁报,局部进展期直肠癌（LARC）：是时候改变了吗？,化疗、放疗和手术，是每一个病例都必须的吗？,2015NCCN指南仍然保留术前放化疗,NCCN2015指南依然要求没有禁忌症的情况下，T3以上，或者N+的患者应该行术前的放化疗,放疗地位的确立单纯手术VS围
2、手术期放疗,80-90年代初，TME手术尚未普及，美国通过GITSG、NCCTG、NSABP R01，瑞典的SRCT研究确立围手术期放疗，既降低局部复发，又提高OS,Swedish Rectal Cancer Trial1168 patients randomised to 25 Gy (5x5) PRT or no RTSurgery alonePreop. RTRate of local recurrence27% 11% 0.0015-year overall survival48% 58% p=0.004,Swedish Rectal Cancer Trial. NEJM 1997;3
3、36:980,美国,瑞典,TME时代放疗的作用荷兰结直肠癌协作组结果1748例,Lancet Oncol. 2011 Jun;12(6):575-82.,N Engl J Med. 2001 Aug 30;345(9):638-46.,Dutch研究12年随访结果仍与10年前结果相似，即与单纯TME手术相比，术前放疗降低了局部复发（8.2% VS 2.4%）率，但是OS没有提高,经典德国AIO-94研究设计,German Rectal Trial Pre-op Superior to Post-op ChemoRT,Presented By Martin Weiser at 2015 ASCO
4、 Annual Meeting,Local versus Distant Recurrence,Presented By Martin Weiser at 2015 ASCO Annual Meeting,TME年代的局部复发,Heald, Lancet. 1993 Feb 20;341(8843):457-60.,Individualize Treatment,Presented By Martin Weiser at 2015 ASCO Annual Meeting,Substitute “Modern” Chemotherapy for Chemoradiation,Presented
5、By Martin Weiser at 2015 ASCO Annual Meeting,Rationale for the Selective use of Radiation in Rectal Cancer,Presented By Martin Weiser at 2015 ASCO Annual Meeting,Swedish Rectal Cancer Trial,J Clin Oncol 2005; 23(25): 61996206.,瑞典研究的患者中大便失禁、肛门排粘液、肛门出血、使用护垫的比例明显高于单纯手术的患者,医学百事通，医生在线咨询,Late Morbidity of
6、 Pelvic RadiationDutch Rectal Cancer Trial,Presented By Martin Weiser at 2015 ASCO Annual Meeting,Late Morbidity of Pelvic RadiationNorwegian Rectal Cancer Registry,Presented By Martin Weiser at 2015 ASCO Annual Meeting,Late Morbidity of Pelvic RadiationDutch Rectal Cancer Trial,Presented By Martin
7、Weiser at 2015 ASCO Annual Meeting,降低局部复发率的代价很大,有报道显示，15.5%做了保留括约肌手术的患者出现缝线裂开Int J Colorectal Dis 2008; 23(3): 257264.17.8%的患者发生了大的并发症，26.6%的患者出现小并发症，34.5%的患者出现感染相关并发症，其中主要是吻合口瘘以及会阴伤口感染。J Gastrointest Surg 2009; 13(4): 657667. 21.8%患者在放疗期间出现3度以上毒性，10.2%腹泻，11.6%放射性皮炎，33%的患者出现吻合口漏或会阴伤口愈合不良，21.7%患者需要重新
8、手术干预，19.6%的患者需要30天内重新入院 Br J Surg 2011; 98(3): 418426. 20-25%的患者无法开始术后治疗,医学百事通,MSKCC 07-021: Phase II Trial of Selective Radiation for Rectal Cancer,Presented By Martin Weiser at 2015 ASCO Annual Meeting,单纯新辅助化疗的探索,FOWARC N=495N1048（PROSPECT) N=1060,PROSPECT: N1048 is ongoingSelective Use of Pelvic
9、XRT,Presented By Deborah Schrag at 2015 ASCO Annual Meeting,Selective use of Surgery,Presented By Martin Weiser at 2015 ASCO Annual Meeting,Complete Response to Neoadjuvant Therapy,Presented By Martin Weiser at 2015 ASCO Annual Meeting,Selective Use of Surgery: “Watch and Wait”,Presented By Martin W
10、eiser at 2015 ASCO Annual Meeting,Selective use of Surgery: “Watch and Wait”,Presented By Martin Weiser at 2015 ASCO Annual Meeting,MSKCC Experience (2006-2014)Non-Operative Management,Presented By Martin Weiser at 2015 ASCO Annual Meeting,4 Year Outcome,Presented By Martin Weiser at 2015 ASCO Annua
11、l Meeting,是时候改变了,三种治疗模式向两种治疗模式转变手术VS放疗,主要内容,教育专场：局部进展期直肠癌（LARC）是时候改变了吗口头报告：FOWARC研究壁报讨论：JFMC35-C1: ACTS-RC，veliparib combined with capecitabine，S0713普通壁报,A Multi-center Randomized Controlled Trial of mFOLFOX6 with or without Radiation in Neoadjuvant Treatment of Locally Advanced Rectal Cancer (FOWAR
12、C Study) - Preliminary Results,Yanhong Deng, Pan Chi, Ping Lan, Lei Wang, Long Cui, Daoda Chen, Jie Cao, Hongbo Wei, Xiang Peng, Zonghai Huang, Guangfu Cai, Ren Zhao, Zhongcheng Huang, Yiding Luo, Yuxin Zhang, Chuyuan Hong, Hao Zhang, Yue Cai, Liang Kang, Meijing Huang, Jian Zheng, Jianping Wang*Chi
13、nese Society of Colorectal Surgery (CSCS),*Corresponding author and principal investigator,依据（1）,以5-FU为基础的术前放化疗是局部进展期直肠癌患者的标准治疗5-FU的作用是放疗增敏剂，对远处转移无效足量新辅助mFOLFOX6加同期放疗是否可以改善治疗效果及生存率尚不明确,Sauer R，et al. J Clin Oncol. 2012; 30:1926-33,医学百事通，在线问医生,放疗带来肛门和性功能的一系列问题，但并不带来太多的生存获益由于直肠癌在中国发病率高，很多医院都可为这类患者开展手术
14、；但放疗的设备并未广泛普及为避免不必要的放疗，值得探讨单用mFOLFOX6的新辅助治疗策略,Peeters KC，et al. J Clin Oncol. 2005 Sep 1;23（25）:6199-206.Quirke P，et al. Lancet. 2009 Mar 7;373（9666）:821-8. Schrag D，et al. J Clin Oncol. 2014 Feb 20;32（6）:513-8.,依据（2）,随机化,放疗46-50.4Gy,TME,随访,De Gramont5,De Gramont7,放疗46-50.4Gy,TME,随访,mFOLFOX65,mFOLFO
15、X67,TME,随访,mFOLFOX64-6,mFOLFOX66-8,放疗开始于第二次化疗的第一天。根据NCCN指南，放疗采用23-25段分割的长程模式。De Gramont方案包含第一天的醛氢叶酸0.4/m2，然后静脉推注5-FU 0.4/m2，然后连续静脉灌注48小时5-FU 2.4/m2；FOLFOX方案包含奥沙利铂85mg/m2静脉关注2小时后应用醛氢叶酸。C组可根据临床医师的判断加入放疗。,Study Design,15 centers NCT01211210,A组,B组,C组,三年无病生存率（DFS）样本量计算 三年无病生存率: 60%上升至75% = 5%（双侧），= 80% 预
16、计13%的失访 每组165例,主要终点,病理完全缓解率（pCR）R0切除率保肛率 局部复发 总生存率 生存质量 毒性疗效预测性标记物,次要终点,直肠腺癌18-75岁肿瘤距肛缘小于12cmT3/4 和/或 N+MRI分期（如无条件，可以直肠腔内超声+盆腔CT代替）预计可切除（R0/1）ECOG 0-1,主要入选标准,2010.06-2015.02随机入组495例,CONSORT图,5-FU-RT N=165,入选N=1587例撤回知情同意,手术N=14210例拒绝1例严重不良反应2例疾病进展,mFOLFOX6-RT N=165,入选N=1623例撤回知情同意,术前放化疗 N=1581例直接手术3
17、例转其他组治疗（C）,术前放化疗 N=1553例转其他组治疗（1B，2C）,Surgery N=1499例拒绝,mFOLFOX6 N=165,入选N=1632例撤回知情同意,术前化疗 N=163,Surgery N=152*11例拒绝,* C组8例接受放疗,A组,B组,C组,患者临床特征（intent-to-treat）,术前放化疗/放疗：安全性和依从性,手术,*现有数据,* 现有数据 Cochran-Mantel-Haenszel 检验比较组间差异 pCR由两名病理学家用盲法进行评估TRG，tumor regression grading,术后病理,手术并发症,* 现有数据 Cochran-
18、Mantel-Haenszel 检验比较组间差异,低位直肠癌患者的亚组分析（肿瘤距肛缘5cm以内）,mFOLFOX6结合同期放疗的新辅助方案与5-FU单药结合放疗相比，为局部进展期直肠癌患者带来：更高的pCR率更高的降期率略微增加的毒性无明显改变的依从性,结论（1）,单用mFOLFOX6的新辅助方案与5-FU单药结合放疗相比，为局部进展期直肠癌患者带来相似的R0切除率相似的降期率更少的手术并发症低位直肠癌亚组中也有类似疗效对复发和生存率的随访正在进行,结论（2）,对新辅助治疗的启示,由于mFOLFOX6加同期放疗的方案可行，并带来更高的pCR率和降期率（ypT0-2N0），mFOLFOX6 加
19、放疗或可取代5-FU加放疗，可成为这部分患者的标准新辅助方案大约35%（C组ypT0-2N0的比例）的患者可能不需要放疗建立良好的手术切除平面,主要内容,教育专场：局部进展期直肠癌（LARC）是时候改变了吗口头报告：FOWARC研究壁报讨论：JFMC35-C1: ACTS-RC，veliparib combined with capecitabine，S0713普通壁报,3515：A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cance
20、r (JFMC35-C1: ACTS-RC),增强的全身化疗，对局部控制也是增加的,N=958S1 VS UFT 1年辅助治疗直肠癌3-DFS 66.7% vs 61.5%局部复发 8% vs 13%,3517: Safety and tolerability of veliparib combined with capecitabine plus radiotherapy in patients with locally advanced rectal cancer (LARC): Final results of a phase Ib study.,veliparib,PARP-1/2抑制
21、剂N=3275%的患者降期28%pCR,主要内容,教育专场：局部进展期直肠癌（LARC）是时候改变了吗口头报告：FOWARC研究壁报讨论：JFMC35-C1: ACTS-RC，veliparib combined with capecitabine，S0713普通壁报,3609: A phase II single arm feasibility trial of neoadjuvant chemotherapy (NAC) with oxaliplatin/fluorouracil (OxMdG) then short-course preoperative radiotherapy (SC
22、PRT) then immediate surgery in operable rectal cancer (ORC): COPERNICUS (NCT01263171).,Results:60 UK pts ypT0ypN0 in 7/57 pts (12%),3607: A phase II study of 5-fluorouracil (5-FU), ziv-aflibercept, and radiation for the preoperative and adjuvant treatment of patients (pts) with stage II/III rectal c
23、ancer.,Results:N=39 8 pts (25%) achieved pCR,3592: Phase II trial of preoperative radiation with concurrent capecitabine, oxaliplatin, and bevacizumab followed by surgery and postoperative 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX), and bevacizumab in patients with locally advanced rectal canc
24、er: 5-year clinical outcomes of a trial of the ECOG-ACRIN Cancer Research Group (E3204).,研究方案,57例可切除的T3/T4直肠腺癌术前放化疗：卡培他滨825奥沙利铂50贝伐单抗5，D1、15、29RT 50.4Gy手术：新辅助8周后术后8-12周：FOLFOX联合贝伐单抗12周期,结果,5年OS：80%5年PFS：81%2例复发,3569: Phase I study of preoperative chemoradiation with temozolomide and capecitabine in
25、patients with locally advanced rectal cancer.,研究设计,放疗剂量：45Gy/25fr QD，再推量5.4Gy/3fr卡培他滨：825mg/m2 BID替莫唑胺：1级-45、2级-60、3级-75mg/m2 QDMGMT甲基化检测：甲基特异性PCR,62,结果,2013年5月-2014年4月：22例患者总pCR：31.8%（7/22）MGMT甲基化：72.7%（16/22）亚组pCR：MGMT甲基化组：37.5%（6/16） MGMT非甲基化组：16.7%（1/6） p=0.62,结论,替莫唑胺推荐剂量：75mg/m2 QD耐受性良好MGMT甲基化组
26、pCR率稍高需进一步研究证实,ganetespib+capecitabineHSP 90抑制剂N=12pCR25%,TPS3626: Induction mFOLFOX6 with or without aflibercept followed by chemoradiation (CRT) and surgery in high risk rectal cancer: Phase II randomized, multicenter, openlabel trialThe GEMCAD RIA study.,Enrollment began in January 2015. ClinicalTrials.gov Identifier: NCT02340949 Clinical trial information: 02340949.,总结,如何减少远处转移是局部进展期直肠癌的研究重点单纯化疗是趋势，值得进一步探索和加强更多的药物将整合进入直肠癌的新辅助治疗,67,Thanks,
