直腸癌新輔助治療進(jìn)展

1、直腸癌新輔助治療進(jìn)展,廣西醫(yī)科大學(xué)附屬腫瘤醫(yī)院 覃宇周,II-III期直腸癌術(shù)前放療和放化療,術(shù)前放療和單純手術(shù)比較，降低了局部區(qū)域復(fù)發(fā)率，提高了無(wú)病生存率和總生存率(I類)術(shù)前放化療和術(shù)前放療比較，進(jìn)一步降低了局部區(qū)域復(fù)發(fā)率，但兩組生存率相同(I類)術(shù)前放化療和術(shù)后放化療比較，毒副作用低，顯著降低了局部區(qū)域復(fù)發(fā)率，生存率相似(I類)術(shù)前放化療之新輔助化療，未提高近期療效，生存率有待長(zhǎng)期隨診(III類),輔助化療-NCCN指南,

2、,,EORTC 22921,Long-term results：術(shù)后輔助化療不改善無(wú)病生存和總生存,無(wú)病生存時(shí)間,Bosset, Jean-François, et al. "Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the E

3、ORTC 22921 randomised study." The lancet oncology 15.2 (2014): 184-190.,EORTC 22921,Long-term results：術(shù)后輔助化療不改善無(wú)病生存和總生存,總生存時(shí)間,Bosset, Jean-François, et al. "Fluorouracil-based adjuvant chemothera

4、py after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study." The lancet oncology 15.2 (2014): 184-190.,EORTC 22921,Long-term results：術(shù)后輔助化療不改善無(wú)病生存和總生存,1

5、、化療依從性非常差： 術(shù)前依從率為82% 術(shù)后依從率為42.9%,2、化療方案中不包括奧沙利鉑,Bosset, Jean-François, et al. "Chemotherapy with preoperative radiotherapy in rectal cancer." New England Journal of Medicine 355.11

6、(2006): 1114-1123.,CAO/ARO/AIO-94 Trial,術(shù)后放化療增加短期和長(zhǎng)期的毒副作用,Sauer, Rolf, et al. "Preoperative versus postoperative chemoradiotherapy for rectal cancer." New England Journal of Medicine 351.17 (2004): 17

7、31-1740.,CAO/ARO/AIO-94 Trial,術(shù)后的輔助放療和化療多數(shù)無(wú)法按療程完成,,Sauer, Rolf, et al. "Preoperative versus postoperative chemoradiotherapy for rectal cancer." New England Journal of Medicine 351.17 (2004): 1731-1740

8、.,SEER Data,超過(guò)1/3的患者因?yàn)楦鞣N原因未能接受輔助化療,Cancer. 2014 Apr 15;120(8):1162-70. doi: 10.1002/cncr.28545. Epub 2014 Jan 28.Postoperative chemotherapy use after neoadjuvant chemoradiotherapy for rectal cancer: Analysis of Sur

9、veillance, 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.,,手術(shù)并發(fā)癥的影響,手術(shù)并發(fā)癥

10、導(dǎo)致化療推遲及預(yù)后不良,Tevis, Sarah E., et al. "Postoperative Complications in Patients With Rectal Cancer Are Associated With Delays in Chemotherapy That Lead to Worse Disease-free and Overall Survival." Diseases of

11、 the Colon & Rectum 56.12 (2013): 1339-1348.,手術(shù)并發(fā)癥的影響,手術(shù)并發(fā)癥導(dǎo)致化療推遲及預(yù)后不良,Tevis, Sarah E., et al. "Postoperative Complications in Patients With Rectal Cancer Are Associated With Delays in Chemotherapy That Lea

12、d to Worse Disease-free and Overall Survival." Diseases of the Colon & Rectum 56.12 (2013): 1339-1348.,局部晚期直腸癌術(shù)前治療模式的發(fā)展,,,,主要內(nèi)容,,1.單純術(shù)前化療2.誘導(dǎo)化療+放化療3.新輔助放化療+化療,新輔助放化療（6 weeks) + （6-8weeks of recovery）

13、+ 手術(shù) +（4 weeks of recovery）+ 輔助化療輔助化療的時(shí)間推遲至少4個(gè)月盡快的開始化療在理論上可以殺滅微轉(zhuǎn)移灶從而減少遠(yuǎn)處轉(zhuǎn)移,單獨(dú)應(yīng)用新輔助化療,高危直腸癌患者：59.4%為T491%的患者按時(shí)完成化療，且90%的患者達(dá)到R0切除pCR率為13%，且37%的患者腫瘤消退明顯,Uehara, Keisuke, et al. "Neoadjuvant oxaliplatin and capecita

14、bine and bevacizumab without radiotherapy for poor-risk rectal cancer: N-SOG 03 Phase II Trial." Japanese journal of clinical oncology 43.10 (2013): 964-971.,單獨(dú)應(yīng)用新輔助化療,Hasegawa, Junichi, et al. "Neoad

15、juvant capecitabine and oxaliplatin (XELOX) combined with bevacizumab for high-risk localized rectal cancer." Cancer Chemotherapy and Pharmacology 73.5(2014):1079-1087.,高危直腸癌患者：T4/淋巴結(jié)陽(yáng)性；化療方案為CAPOX+貝伐單抗92%

16、的患者接受手術(shù)治療，且均為R0切除pCR率為4%，大多數(shù)的患者腫瘤消退明顯26%的患者出現(xiàn)術(shù)后并發(fā)癥，且在中位隨訪期達(dá)31個(gè)月時(shí)，已經(jīng)出現(xiàn)5例遠(yuǎn)處轉(zhuǎn)移，且1例伴有局部復(fù)發(fā),單獨(dú)應(yīng)用新輔助化療,Schrag, Deborah, et al. "Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally

17、advanced rectal cancer: a pilot trial."Journal of Clinical Oncology 32.6 (2014): 513-518.,中危直腸癌患者：N=32，（cT3N+/-，淋巴結(jié)2＜cm）,單獨(dú)應(yīng)用新輔助化療,Schrag, Deborah, et al. "Neoadjuvant chemotherapy without routine use of r

18、adiation therapy for patients with locally advanced rectal cancer: a pilot trial."Journal of Clinical Oncology 32.6 (2014): 513-518.,單獨(dú)應(yīng)用新輔助化療,對(duì)高危直腸癌患者而言，新輔助化療或許能帶來(lái)治療獲益，但是由于樣本例數(shù)少，患者的預(yù)后較差，因此難以分析得到的結(jié)果。因此在局部復(fù)發(fā)高?；颊?/p>

19、中，應(yīng)該謹(jǐn)慎地減少局部治療。對(duì)于中危直腸癌患者而言，研究結(jié)果令人振奮，但是樣本量太小，這顯著阻礙了我們?cè)u(píng)估上述方案給患者帶來(lái)的真正獲益情況。,單獨(dú)應(yīng)用新輔助化療,單獨(dú)應(yīng)用新輔助化療,PROSPECT Trial (NCT01515787),Ⅱ期/Ⅲ期臨床研究術(shù)前化療組 versus 術(shù)前放化療組,單純術(shù)前化療,BACCHUS Trial (NCT 01650428) Ⅱ期臨床研究 FOLFOX versus FO

20、LFOXIRI 主要觀察指標(biāo)：pCR率NCT01211210 (中山大學(xué)) Ⅱ期臨床研究 FOLFOX versus FOLFOX+Chemoradiation versus Chemoradiation 主要觀察指標(biāo)：3年無(wú)病生存期,單純術(shù)前化療,主要內(nèi)容,,1.單純術(shù)前化療2.誘導(dǎo)化療+放化療3.新輔助放化療+化療,最常被研究的治療策略，誘導(dǎo)化療繼之以放化療是一

21、種極具吸引力的治療方案遠(yuǎn)處轉(zhuǎn)移是最主要的危險(xiǎn)因素，因此需要維持早期系統(tǒng)治療誘導(dǎo)化療能早期治療微轉(zhuǎn)移性病變，降低原發(fā)腫瘤的分期在化療后立即進(jìn)行放化療，或許能達(dá)到最佳的局部控制，有望增加完全緩解率在諸如肛門癌、肺癌或頭頸部腫瘤中，并沒有數(shù)據(jù)支持上述治療獲益的存在從理論上來(lái)說(shuō)，在放療前進(jìn)行化療的話有可能會(huì)增高對(duì)放療不敏感的腫瘤克隆的出現(xiàn)風(fēng)險(xiǎn),誘導(dǎo)化療+放化療,高危患者：N=77；治療方式：CAPOX*12 weeks chemoR

22、T with capecitabine adjuvant capecitabine*12 weekspCR率：24%；R0切除率：99%；1年DFS：87%；1年總生存率：93%,EXPERT Trial,Chau, Ian, et al. "Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total me

23、sorectal excision in magnetic resonance imaging–defined poor-risk rectal cancer." Journal of Clinical Oncology 24.4 (2006): 668-674.,誘導(dǎo)化療+放化療,Spanish GCR-3 Trial,誘導(dǎo)化療+放化療,兩組pCR率及R0切除率相差不大,Spanish GCR-3 Tri

24、al,Fernández-Martos, Carlos, et al. "Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by

25、concomitant chemoradiotherapy and surgery in magnetic resonance imaging–defined, locally advanced rectal cancer: grupo cáncer de recto 3 study." Journal of Clinical Oncology 28.5 (2010): 859-865.,誘導(dǎo)化療

26、+放化療,誘導(dǎo)化療組的毒性反應(yīng)更加少（19% vs 54%）誘導(dǎo)化療組的依從性更加好（94% vs 57%）,Spanish GCR-3 Trial,誘導(dǎo)化療+放化療,兩組5年遠(yuǎn)處轉(zhuǎn)移率基本相同（21.1% versus 23.2%；P=0.80）兩組5年總生存率基本相同（77.9% versus 74.7%； P=0.64）,Spanish GCR-3 Trial,Fernandez-Martos, Carlos, et

27、 al. "Chemoradiation (CRT) followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant CRT and surgery for locally advanced rectal cancer: Results of

28、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, 201

29、4.,誘導(dǎo)化療+放化療,現(xiàn)有的數(shù)據(jù)主要來(lái)自于小型的II期研究，這些研究具有較大的異質(zhì)性，如T4患者所占的比例、放療的劑量和手術(shù)的時(shí)機(jī)。所有的這些因素都可能對(duì)pCR率造成影響。,誘導(dǎo)化療+放化療,誘導(dǎo)化療+放化療,PRODIGE (NCT 01804790) Ⅲ期臨床研究 FOLFIRINOX+chemoradiation versus standard chemoradiation 主要觀察指

30、標(biāo)： 3年無(wú)病生存期COPERNICUS (NCT01263171) Ⅲ期臨床研究 FOLFOX+短程放療+手術(shù) 主要觀察指標(biāo)：評(píng)價(jià)該方案的可行性,誘導(dǎo)化療+放化療,主要內(nèi)容,,1.單純術(shù)前化療2.誘導(dǎo)化療+放化療3.新輔助放化療+化療,最少被研究的治療策略隨著放化療完成至手術(shù)評(píng)估之間的間歇期的延長(zhǎng)，對(duì)治療反應(yīng)或許會(huì)改善放療和手術(shù)治療之間的時(shí)間過(guò)長(zhǎng)，那么有可能會(huì)出現(xiàn)纖維化增加以及增加手術(shù)干預(yù)的難度

31、盆腔放療或許會(huì)影響后續(xù)全劑量化療的進(jìn)行，從而影響化療的療效,新輔助放化療+化療,T3-T4/淋巴結(jié)陽(yáng)性（N=51）→chemoradiation →3 weeks of capecitabine →手術(shù)pCR率：18%5年無(wú)病生存率：85.4%；T4N+的病人只占3%，且無(wú)其它高危因素,Zampino, Maria Giulia, et al. "Capecitabine initially concomitant to

32、 radiotherapy then perioperatively administered in locally advanced rectal cancer." International Journal of Radiation Oncology* Biology* Physics 75.2 (2009): 421-427.,新輔助放化療+化療,Ⅱ和Ⅲ期：N=144；SG1：放化療+手術(shù)SG2：

33、放化療+化療+手術(shù),新輔助放化療+化療,提高pCR率雖然由于手術(shù)推遲導(dǎo)致盆腔纖維化增多，但是并沒有增加手術(shù)難度及術(shù)后并發(fā)癥,Garcia-Aguilar, Julio, et al. "Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multi-center, non-ran

34、domized phase II prospective trial." Annals of surgery 254.1 (2011): 97.,,,,新輔助放化療+化療,,pCR率增加至31%，并發(fā)癥率未增加,Garcia-Aguilar, Julio, et al. “Impact of neoadjuvant chemotherapy following chemoradiation on tumor

35、 response, adverse events, and surgical complications in patients with advanced rectal cancer treated with TME.”Journal of Clinical Oncology 2011；29：abstr 3514.,新輔助放化療+化療,新輔助放化療+化療,The Polish Colorectal Cancer Study Grou

36、p (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." Rad