1、直肠癌新辅助治疗进展,广西医科大学附属肿瘤医院 覃宇周,II-III期直肠癌术前放疗和放化疗,术前放疗和单纯手术比较，降低了局部区域复发率，提高了无病生存率和总生存率(I类)术前放化疗和术前放疗比较，进一步降低了局部区域复发率，但两组生存率相同(I类)术前放化疗和术后放化疗比较，毒副作用低，显著降低了局部区域复发率，生存率相似(I类)术前放化疗之新辅助化疗，未提高近期疗效，生存率有待长期随诊(III类),辅助化疗-NCCN指南,EORTC 22921,Long-term results：术后辅助化疗不改善无病生存和总生存,无病生存时间,Bosset, Jean-Franois, et al.
2、Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study.The lancet oncology15.2 (2014): 184-190.,EORTC 22921,Long-term results：术后辅助化疗不改善无病生存和总生存,总生存时间,Bosset, Jean-Franois, et al. Fluorouracil-based adjuvan
3、t chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study.The lancet oncology15.2 (2014): 184-190.,EORTC 22921,Long-term results：术后辅助化疗不改善无病生存和总生存,1、化疗依从性非常差： 术前依从率为82% 术后依从率为42.9%,2、化疗方案中不包括奥沙利铂,Bosset, Jean-Franois, et al. Chemother
4、apy with preoperative radiotherapy in rectal cancer.New England Journal of Medicine355.11 (2006): 1114-1123.,CAO/ARO/AIO-94 Trial,术后放化疗增加短期和长期的毒副作用,Sauer, Rolf, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer.New England Journal of Medicine351.17 (2004): 1731-1740.,CAO/A
5、RO/AIO-94 Trial,术后的辅助放疗和化疗多数无法按疗程完成,Sauer, Rolf, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer.New England Journal of Medicine351.17 (2004): 1731-1740.,SEER Data,超过1/3的患者因为各种原因未能接受辅助化疗,Cancer.2014 Apr 15;120(8):1162-70. doi: 10.1002/cncr.28545. Epub 2014 Jan 28.Postope
6、rative chemotherapy use after neoadjuvant chemoradiotherapy for rectal cancer: Analysis of Surveillance, Epidemiology, and End Results-Medicare data, 1998-2007.Haynes AB1,You YN,Hu CY,Eng C,Kopetz ES,Rodriguez-Bigas MA,Skibber JM,Cantor SB,Chang GJ.,手术并发症的影响,手术并发症导致化疗推迟及预后不良,Tevis, Sarah E., et al.
7、Postoperative Complications in Patients With Rectal Cancer Are Associated With Delays in Chemotherapy That Lead to Worse Disease-free and Overall Survival.Diseases of the Colon & Rectum56.12 (2013): 1339-1348.,手术并发症的影响,手术并发症导致化疗推迟及预后不良,Tevis, Sarah E., et al. Postoperative Complications in Patients
8、With Rectal Cancer Are Associated With Delays in Chemotherapy That Lead to Worse Disease-free and Overall Survival.Diseases of the Colon & Rectum56.12 (2013): 1339-1348.,局部晚期直肠癌术前治疗模式的发展,主要内容,1.单纯术前化疗2.诱导化疗+放化疗3.新辅助放化疗+化疗,新辅助放化疗（6 weeks) + （6-8weeks of recovery）+ 手术 +（4 weeks of recovery）+ 辅助化疗辅助化疗的
9、时间推迟至少4个月尽快的开始化疗在理论上可以杀灭微转移灶从而减少远处转移,单独应用新辅助化疗,高危直肠癌患者：59.4%为T491%的患者按时完成化疗，且90%的患者达到R0切除pCR率为13%，且37%的患者肿瘤消退明显,Uehara, Keisuke, et al. Neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy for poor-risk rectal cancer: N-SOG 03 Phase II Trial.Japanese journal of clinical onco
10、logy43.10 (2013): 964-971.,单独应用新辅助化疗,Hasegawa, Junichi, et al. Neoadjuvant capecitabine and oxaliplatin (XELOX) combined with bevacizumab for high-risk localized rectal cancer.Cancer Chemotherapy and Pharmacology73.5(2014):1079-1087.,高危直肠癌患者：T4/淋巴结阳性；化疗方案为CAPOX+贝伐单抗92%的患者接受手术治疗，且均为R0切除pCR率为4%，大多数的患者
11、肿瘤消退明显26%的患者出现术后并发症，且在中位随访期达31个月时，已经出现5例远处转移，且1例伴有局部复发,单独应用新辅助化疗,Schrag, Deborah, et al. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial.Journal of Clinical Oncology32.6 (2014): 513-518.,中危直肠癌患者：N=32，（cT3N+/-，淋巴结2cm）,单
12、独应用新辅助化疗,Schrag, Deborah, et al. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial.Journal of Clinical Oncology32.6 (2014): 513-518.,单独应用新辅助化疗,对高危直肠癌患者而言，新辅助化疗或许能带来治疗获益，但是由于样本例数少，患者的预后较差，因此难以分析得到的结果。因此在局部复发高危患者中，应该谨慎地减少局
13、部治疗。对于中危直肠癌患者而言，研究结果令人振奋，但是样本量太小，这显著阻碍了我们评估上述方案给患者带来的真正获益情况。,单独应用新辅助化疗,单独应用新辅助化疗,PROSPECT Trial (NCT01515787),期/期临床研究术前化疗组 versus 术前放化疗组,单纯术前化疗,BACCHUS Trial (NCT 01650428) 期临床研究 FOLFOX versus FOLFOXIRI 主要观察指标：pCR率NCT01211210 (中山大学) 期临床研究 FOLFOX versus FOLFOX+Chemoradiation versus Chemoradiation 主要观
14、察指标：3年无病生存期,单纯术前化疗,主要内容,1.单纯术前化疗2.诱导化疗+放化疗3.新辅助放化疗+化疗,最常被研究的治疗策略，诱导化疗继之以放化疗是一种极具吸引力的治疗方案远处转移是最主要的危险因素，因此需要维持早期系统治疗诱导化疗能早期治疗微转移性病变，降低原发肿瘤的分期在化疗后立即进行放化疗，或许能达到最佳的局部控制，有望增加完全缓解率在诸如肛门癌、肺癌或头颈部肿瘤中，并没有数据支持上述治疗获益的存在从理论上来说，在放疗前进行化疗的话有可能会增高对放疗不敏感的肿瘤克隆的出现风险,诱导化疗+放化疗,高危患者：N=77；治疗方式：CAPOX*12 weeks chemoRT with ca
15、pecitabine adjuvant capecitabine*12 weekspCR率：24%；R0切除率：99%；1年DFS：87%；1年总生存率：93%,EXPERT Trial,Chau, Ian, et al. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imagingdefined poor-risk rectal cancer.Journal of Clinic
16、al Oncology24.4 (2006): 668-674.,诱导化疗+放化疗,Spanish GCR-3 Trial,诱导化疗+放化疗,两组pCR率及R0切除率相差不大,Spanish GCR-3 Trial,Fernndez-Martos, Carlos, et al. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX
17、 followed by concomitant chemoradiotherapy and surgery in magnetic resonance imagingdefined, locally advanced rectal cancer: grupo cncer de recto 3 study.Journal of Clinical Oncology28.5 (2010): 859-865.,诱导化疗+放化疗,诱导化疗组的毒性反应更加少（19% vs 54%）诱导化疗组的依从性更加好（94% vs 57%）,Spanish GCR-3 Trial,诱导化疗+放化疗,两组5年远处转移
18、率基本相同（21.1% versus 23.2%；P=0.80）两组5年总生存率基本相同（77.9% versus 74.7%；P=0.64）,Spanish GCR-3 Trial,Fernandez-Martos, Carlos, et al. Chemoradiation (CRT) followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant CRT and surgery for locally a
19、dvanced rectal cancer: Results of the Spanish GCR-3 randomized phase II trial after a median follow-up of 5 years.JOURNAL OF CLINICAL ONCOLOGY. Vol. 32. No. 3. 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA: AMER SOC CLINICAL ONCOLOGY, 2014.,诱导化疗+放化疗,现有的数据主要来自于小型的II期研究，这些研究具有较大的异质性，如T4患者所占的比例、放疗的
20、剂量和手术的时机。所有的这些因素都可能对pCR率造成影响。,诱导化疗+放化疗,诱导化疗+放化疗,PRODIGE (NCT 01804790) 期临床研究 FOLFIRINOX+chemoradiation versus standard chemoradiation 主要观察指标： 3年无病生存期COPERNICUS (NCT01263171) 期临床研究 FOLFOX+短程放疗+手术 主要观察指标：评价该方案的可行性,诱导化疗+放化疗,主要内容,1.单纯术前化疗2.诱导化疗+放化疗3.新辅助放化疗+化疗,最少被研究的治疗策略随着放化疗完成至手术评估之间的间歇期的延长，对治疗反应或许会改善放疗
21、和手术治疗之间的时间过长，那么有可能会出现纤维化增加以及增加手术干预的难度盆腔放疗或许会影响后续全剂量化疗的进行，从而影响化疗的疗效,新辅助放化疗+化疗,T3-T4/淋巴结阳性（N=51）chemoradiation 3 weeks of capecitabine 手术pCR率：18%5年无病生存率：85.4%；T4N+的病人只占3%，且无其它高危因素,Zampino, Maria Giulia, et al. Capecitabine initially concomitant to radiotherapy then perioperatively administered in loca
22、lly advanced rectal cancer.International Journal of Radiation Oncology* Biology* Physics75.2 (2009): 421-427.,新辅助放化疗+化疗,和期：N=144；SG1：放化疗+手术SG2：放化疗+化疗+手术,新辅助放化疗+化疗,提高pCR率虽然由于手术推迟导致盆腔纤维化增多，但是并没有增加手术难度及术后并发症,Garcia-Aguilar, Julio, et al. Optimal timing of surgery after chemoradiation for advanced recta
23、l cancer: preliminary results of a multi-center, non-randomized phase II prospective trial.Annals of surgery254.1 (2011): 97.,新辅助放化疗+化疗,pCR率增加至31%，并发症率未增加,Garcia-Aguilar, Julio, et al. “Impact of neoadjuvant chemotherapy following chemoradiation on tumor response, adverse events, and surgical compli
24、cations in patients with advanced rectal cancer treated with TME.”Journal of Clinical Oncology 2011；29：abstr 3514.,新辅助放化疗+化疗,新辅助放化疗+化疗,The Polish Colorectal Cancer Study Group (NCT00833131)RAPIDO Study (NCT01558921),pCR率：21% versus 9%,Bujko, Krzysztof, et al. Neoadjuvant treatment for unresectable rectal cancer: an interim analysis of a multicentre randomized study.Radiotherapy and Oncology107.2 (2013): 171-177.,新辅助放化疗+化疗,总 结,对于新的新辅助治疗策略仍缺少可靠的证据新辅助治疗策略是目前最有可能帮助改善现有的治疗方式改善预后相关临床研究亟待进一步开展,Thank You !,
