晚期結(jié)直腸癌的規(guī)范化治療-課件

1、晚期結(jié)直腸癌的規(guī)范化治療Tianshu liu, M.D., Ph.D.Zhongshan Hospital, Fudan UniversityDept of Medical OncologyCenter of Evidence-based medicine晚期結(jié)直腸癌的規(guī)范化治療Tianshu liu, M.D.,mCRC分組全程管理治愈初始可切快速縮小腫瘤/疾病控制疾病惡化伴有癥狀組 2疾病控制/低毒無癥狀組 3患者目標(biāo)最大程度縮小腫瘤潛在可切組 1治療強(qiáng)度組0手術(shù)mCRC分組全程管理治愈初始可切快速縮小腫瘤/疾病惡化伴有癥整體治療策略的應(yīng)用顯著延長(zhǎng)了mCRC患者的OS貝伐珠單抗4中位OS

2、時(shí)間 (月)BSC5-FU3020100伊立替康1卡培他濱2奧沙利鉑3西妥昔單抗5,61980s 1990 2000s 2010帕尼單抗7阿柏西普8瑞戈非尼9*1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 2004; 3. Rothenberg, et al. JCO 20034. Hurwitz, et al. NEJM 2004; 5. Cunningham, et al. NEJM 2004; 6. Van Cutsem, et al. NEJM 20097. Van Cutsem, et al. JCO 200

3、7; 8. Van Cutsem, et al, JCO 2012; 9. Grothey, Van Cutsem, et al. Lancet 2012整體治療策略的應(yīng)用顯著延長(zhǎng)了mCRC患者的OS貝伐珠單抗4中晚期結(jié)直腸癌的規(guī)范化治療-課件晚期結(jié)直腸癌的規(guī)范化治療-課件一線治療決策制定的驅(qū)動(dòng)因素腫瘤特征患者特征治療特征臨床表現(xiàn)腫瘤負(fù)擔(dān)腫瘤部位年齡毒性腫瘤生物學(xué)體力狀態(tài)靈活性RAS 突變狀態(tài)器官功能社會(huì)經(jīng)濟(jì)因素BRAF 突變狀態(tài)合并癥生活質(zhì)量患者預(yù)期和偏好一線治療決策制定的驅(qū)動(dòng)因素腫瘤特征患者特征治療特征臨床表現(xiàn)年mCRC患者的一線治療決策需充分考慮三大特征化療 +/- 貝伐珠單抗化療 +/

4、-靶向藥物再評(píng)估/每2-3個(gè)月評(píng)估腫瘤緩解情況RAS WTRAS MTBRAF MT疾病控制治療特征腫瘤特征右半左半化療 +/- 貝伐珠單抗化療 +/- 貝伐珠單抗化療 +/- 西妥昔單抗FitUnfitUnfit(但可能獲益）患者的臨床分類疾病進(jìn)展高強(qiáng)度治療繼續(xù)治療暫停治療維持治療患者特征化療 +/- 西妥昔單抗mCRC患者的一線治療決策需充分考慮三大特征化療 +/-再評(píng)OXACPT-11靶向藥物BEV、CETFOLFOXXELOXFLOXFOLFIRIIFLXELIRI5-FUCAPE中國(guó)可獲取的藥物OXACPT-11靶向藥物FOLFOXFOLFIRI5-FU氟尿嘧啶的作用機(jī)制1. Lon

5、gley DB, et al. Nat Rev Cancer 2003;3:330338;2. Peters GJ. Ther Adv Med Oncol 2015;7:340356;3. Wilson PM, et al. Nat Rev Clin Oncol 2014;11:282298;4. Van Cutsem E, et al. Ann Oncol 2014;25(Suppl 3):iii1iii9; 5. Lonsurf US PI, September 2015;6. Taiho Pharmaceuticals Co. Ltd. Available at: www.taiho.c

6、o.jp.; 7.http:/www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_Initial_authorisation/human/003897/WC500202369.pdf.卡培他濱5dFCR5dFURCDHPTFTFURFUMPFUDPFUTPFUdRFdUDPFdUTP5-hydroxytegafurCarboxylesteraseCytidinedeaminase80% of systemic 5-FU is subject to hepatic DPD-mediated degradationTAS

7、-102Thymidine kinaseThymidine phosphorylaseThymidine kinaseDNA damageRNA damageUMP-CMPKNDKNDKUMP-CMPKOPRTThymidine phosphorylase/uridine phosporylaseUridine phosporylaseTFT-MPTegafurS-1TFT-TPdTTP depletion due to inhibition of thymidylate synthaseThymidylate synthase5-FU5dFURUridine-cytidinekinaseFd

8、UMP5-FU雷替曲賽氟尿嘧啶的作用機(jī)制1. Longley DB, et al.奧沙利鉑1,2奧沙利鉑和伊立替康的作用機(jī)制1. Adapted from Boulikas T, et al. Cancer Ther 2007;5:537583; 2. Oxaliplatin SmPC, September/2008; 3. Adapted from Frese S, Diamond B. Nat Rev Rheumatol 2011;7:733738; 4. Van Cutsem E, et al. Ann Oncol 2014;25(Suppl 3):iii1iii9.DNA synthe

9、sisCell deathInter- and intra-strand DNA cross-links伊立替康Induction of apoptosis奧沙利鉑1,2奧沙利鉑和伊立替康的作用機(jī)制1. Adapte晚期結(jié)直腸癌盡量暴露于所有有效藥物的理念11個(gè)III期臨床研究（n=5768）結(jié)果分析：晚期結(jié)直腸癌整個(gè)治療過程中用過所有3個(gè)有效細(xì)胞毒藥物（5-FU/LV、伊立替康和奧沙利鉑）的患者生存期最長(zhǎng)Adapted from Grothey & Sargent. JCO 20050 10 20 30 40 50 60 70 80靜滴5-FU/LV + 伊立替康靜滴5-FU/LV + 奧沙

10、利鉑靜注5-FU/LV + 伊立替康伊立替康,+ 奧沙利鉑靜注5-FU/LV LV5FU2FOLFOXIRICAIRO三藥治療患者比例(%)一線治療方案2221201918171615141312中位生存(月)p=0.00012007晚期結(jié)直腸癌盡量暴露于所有有效藥物的理念11個(gè)III期臨床Douillard JY, et al. Lancet 2000;355:10411047.*Primary endpoint.TTPOSp0.001p=0.031PFS probability MonthsOS probabilityMonthsRandomized Phase III trial of

11、FOLFIRI vs 5-FU/LV in 1st line treatment of (K)RAS-unselected mCRCFOLFIRI(n=198)5-FU/LV(n=187)p-valueORR, %*35220.0054.46.714.117.4FOLFIRI (n=198)5-FU/LV (n=187)FOLFIRI (n=198)5-FU/LV (n=187)FOLFIRI vs 5FU：顯著的生存獲益Douillard JY, et al. Lancet 20*Primary endpoint.FOLFOX vs 5FU：顯著的生存獲益Randomized Phase I

12、II trial of FOLFOX4 vs 5-FU/LV in 1st line treatment of (K)RAS-unselected mCRCFOLFOX4(n=210)5-FU/LV(n=210)Odds ratiop-valueORR, %50291.840.0001de Gramont A, et al. J Clin Oncol 2000;18:29382947.*Primary endpoint.FOLFOX vs 5F化療藥物的次序分布mCRC交叉研究設(shè)計(jì)化療藥物的次序分布mCRC交叉研究設(shè)計(jì)V308 療效結(jié)果Tournigand et al. J Clin Onco

13、l. 2004;22:229-237.A組FOLFIRI-FOLFOXn = 109 n=81 B組FOLFOX-FOLFIRIn = 111 n=69中位一線無進(jìn)展生存 8.5月8.0月中位二線無進(jìn)展生存 4.2月* P=0.003 2.5月一線緩解率二線緩解率56 % 15 %* P=0.0554 %4 %接受二線化療的比例7462中位總生存21.5月20.6月V308 療效結(jié)果Tournigand et al. J CFOLFOXIRIvsFOLFIRI：結(jié)果不一致1. Falcone A, et al. J Clin Oncol 2007;25:16701676; 2. Souglak

14、os J, et al. Br J Cancer 2006;94:798805.*Primary endpoint; NR, not reported.GONO, Gruppo Oncologico Nord Ovest; HORG, Hellenic Oncology Research Group.FOLFOXIRI (n=122)FOLFIRI (n=122)HR (95% CI)p-valueMedian PFS, months3 (0.470.81)0.0006ORR, %*6641NR0.0002FOLFOXIRI (n=137)FOLFIRI (n=146)HR

15、(95% CI)p-valueMedian TTP, months3 (0.641.08)0.17ORR, %4334NR0.168Italian GONO study1Greek HORG study2FOLFOXIRIvsFOLFIRI：結(jié)果不一致1. F分子靶向治療 EGFRCOX-2VEGFNew targetHER-2腫瘤細(xì)胞表達(dá)水平正常細(xì)胞靶點(diǎn)細(xì)胞受體信號(hào)轉(zhuǎn)導(dǎo)細(xì)胞周期血管生成分子靶向治療 EGFRCOX-2VEGFNew taVEGF及受體家族PlGFVEGF-R1VEGF-R3VEGF-R2(most prominent)VEGF-AVEGF-DVEGF-CEn

16、dothelial progenitor recruitmentMigration/invasionProliferationLymphangiogenesisPermeabilitySurvivalLigands: VEGF-A VEGF-CVEGF-D VEGF-ELigands: VEGF-C VEGF-DLigands: VEGF-A VEGF-B PlGFVEGF-BPlGFVEGF-AVEGF-BVEGF-DVEGF-CVEGF-EVEGF-A1. Adapted from Wang T-F and Lockhart AC. Clin Med Insights Oncol 2012

17、;6:1930; 2. Avastin SmPC, October/2015; 3. Zaltrap SmPC, September/2014; 4. Stivarga SmPC, October/2015; 5. Cyramza PI, April/2015.VEGF及受體家族PlGFVEGF-R1VEGF-R3VEGPlGFVEGF-R1VEGF-R3VEGF-R2(most prominent)VEGF-AVEGF-DVEGF-CLigands: VEGF-A VEGF-CVEGF-D VEGF-ELigands: VEGF-C VEGF-DLigands: VEGF-A VEGF-B

18、PlGFVEGF-BPlGFVEGF-AVEGF-BVEGF-DVEGF-CVEGF-EVEGF-AAflibercept3Bevacizumab2Regorafenib4Ramucirumab51. Adapted from Wang T-F and Lockhart AC. Clin Med Insights Oncol 2012;6:1930; 2. Lambrechts D, et al. J Clin Oncol 2013;31:121930; 3. Zaltrap SmPC, September/2014; 4. Stivarga SmPC, October/2015; 5. Cy

19、ramza PI, April/2015.Endothelial progenitor recruitmentMigration/invasionProliferationLymphangiogenesisPermeabilitySurvival抗血管生成藥物的作用機(jī)制apatinibPlGFVEGF-R1VEGF-R3VEGF-R2VEGF-貝伐珠單抗一線治療AVF2107藥物注冊(cè)研究Hurwitz, et al. NEJM 2004貝伐珠單抗一線治療AVF2107藥物注冊(cè)研究Hurwit貝伐珠單抗一線治療: NO16966研究貝伐珠單抗一線治療: NO16966研究貝伐珠單抗一線治療的II

20、I期研究貝伐珠單抗一線治療的III期研究ARTIST（中國(guó)本土數(shù)據(jù)）1.00.20.006121824時(shí)間 (月)13.4m18.7mOS貝伐珠單抗+mIFL (n=142)mIFL (n=72)HR=0.62 P=0.0141.00.20.061218240mlFL (n=72)貝伐珠單抗+mlFL (n=142)時(shí)間 (月)PFSHR=0.44; 95%CI=0.31-0.63P0.0014.2m8.3mARTIST（中國(guó)本土數(shù)據(jù)）1.00.20EGFR單抗1. Martinelli E, et al. Clin Exp Immunol 2009;158

21、:19; 2. Brand TM, Wheeler DL. Small GTPases 2012;3:3439.EGF, epidermal growth factor. TGF, transforming growth factor-.VEGF, vascular endothelial growth factor.RASCetuximabPanitumumabxEGFR單抗1. Martinelli E, et al. 西妥昔單抗的一線治療CRYSTAL trialVan Cutsem E, et al. J Clin Oncol西妥昔單抗的一線治療CRYSTAL trialVan Cut

22、26HR=0.69 (0.540.88)p=0.0024 = 8.2 monthsHR=0.796 (0.670.95)p=0.0093HR=0.878 (0.771.00)p=0.0419 = 3.5 months = 1.3 months1. Van Cutsem E, et al. J Clin Oncol 2011;29:20112019;2. Van Cutsem E, et al. J Clin Oncol 2015;33:692700;3. Douillard J-Y, et al. N Engl J Med 2013;369:10231034; 4. Erbitux SmPC

23、June 2014; 5. Vectibix SmPC February 2015. Figure adapted from data from Van Cutsem E, et al.2Cetuximab and panitumumab are approved in patients with RAS wt mCRC.4,5 Cetuximab and panitumumab are not indicated for the treatment of patients with mCRC whose tumors have RAS mutations or for whom RAS tu

24、mor status is unknown.4,5Cetuximab + FOLFIRI (n=178)FOLFIRI (n=189)0.00.81.0Months5442481861224303628.420.20Months54424823.520.00.00.81.0180612243036Months5442480.00.81.0180612243036OS estimate19.918.6Cetuximab + FOLFIRI (n=599)FOLFIRI (n=599)Cetuximab + FOLFIRI (n=316)FOL

25、FIRI (n=350)RAS wt2KRAS exon 2 wt1ITT (unselected)1西妥昔單抗的療效與RAS狀態(tài)有關(guān)26HR=0.69 (0.540.88) = 8.2 HR, hazard ratio; IRC, independent review committee; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.*In the case of non-PD treatment discontinuation, tumor assessment is co

26、ntinued.EndpointsPrimary: PFS (by IRC according to RECIST 1.0), target HR = 0.70Key secondary: OS, ORR, safety/tolerabilityStatistical assumption for the primary endpoint247 events required, 80% power, = 0.05 (2-sided)TAILOR Study Design1:1 RFirst-line, RAS wt mCRCRTreatment until progressive diseas

27、e or unacceptable toxicity*Arm A:Cetuximab + FOLFOX-4Arm B:FOLFOX-4 aloneSurvival follow-upHR, hazard ratio; IRC, indepenEfficacy: Primary Endpoint of PFS by IRCAdding cetuximab to FOLFOX-4 significantly improved the primary endpoint of PFS by IRCEfficacy: Primary Endpoint of RASWT一線治療的選擇頭對(duì)頭研究結(jié)果1. H

28、einemann V, et al. ASCO 2013 (Abstract No. LBA3506); 2. Naughton MJ, et al. ASCO 2013 (Abstract No. 3611); 3. NCT00265850; 4. Schwartzberg LS, et al. ASCO GI 2013 (Abstract No. 446) FIRE-31 (IST)CALGB 804052,3PEAK4Patients with untreated KRAS (exon 2) wt mCRCN=592RCetuximab + FOLFIRIBevacizumab + FO

29、LFIRIPatients with untreated KRAS (exon 2) wt mCRCN1200 (after trial modification)Cetuximab + FOLFOX/FOLFIRIBevacizumab + FOLFOX/FOLFIRIBevacizumab + cetuximab + FOLFOX/FOLFIRI*Arm closed to accrual as of 09/10/2009RPanitumumab + mFOLFOX6Bevacizumab + mFOLFOX6REfficacy data expected Q2 2014Phase IIP

30、hase IIIPatients with untreated KRAS (exon 2) wt mCRCN=285ORROSPFSPrimary endpointIST, investigator-sponsored trialRASWT一線治療的選擇頭對(duì)頭研究結(jié)果1. Heine1. Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506) 2. Stintzing S, et al. ECC 2013 (Abstract No. LBA17)33.1months25.6 months Cetuximab + FOLFIRI (n=171)

31、Bevacizumab + FOLFIRI (n=171)0.01224364860720.751.00.500.250.0OS estimateOS estimate28.7months25.0 months0.7551.00.500.2550.0122436486072Months since start of treatmentKRAS wt (exon 2)1RAS* wt(KRAS and NRAS wt)2 Cetuximab+ FOLFIRI (n=297) Bevacizumab + FOLFIRI (n=295) = 3.7 months = 7.5 monthsMonths

32、 since start of treatment*Including KRAS exon 2, 3, 4 and NRAS exon 2, 3, 4HR 0.77 (95% CI 0.620.96)p=0.017HR 0.70 (95% CI 0.530.92)p=0.011FIRE-3: KRAS以外RAS的意義OS的獲益001. Heinemann V, et al. ASCO 20主要研究終點(diǎn)2013年6月2014年6月CALGB80405n = 1,137PEAKn = 285FIRE-3n = 5922013年1月PFS（）ORR（）OS（）貝伐珠單抗 VS 西妥昔單抗29 VS

33、29.9P=0.34貝伐珠單抗 VS 帕尼單抗10.1 VS 10.9P=0.353貝伐珠單抗 VS 西妥昔單抗58 VS 62P=0.1832016年之前的觀點(diǎn)，一線治療中兩類靶向藥物總體療效相當(dāng)主要研究終點(diǎn)2013年6月2014年6月CALGBPEAKF 右半結(jié)腸癌 30-40%左半結(jié)直腸癌60-70%胚胎起源中原腸后原腸血供腸系膜上動(dòng)脈腸系膜下動(dòng)脈組織學(xué)類型低分化較多見低分化較少見血管受侵較常見較少見生物學(xué)特性BRAF突變較多見MSI（微衛(wèi)星不穩(wěn)定）鋸齒狀通路信號(hào)傳導(dǎo)通路突變頻率BRAF突變較少見染色體不穩(wěn)定EGFR或HER2擴(kuò)增、EREG信號(hào)傳導(dǎo)通路突變頻率2016：左右半結(jié)直腸癌具有

34、不同的特點(diǎn)1. Lee GH, et al. Eur J Surg Oncol. 2015;41(3):300-308.2. Price TJ ,et al. Cancer. 2015;121(6):830-8353. Snaebjornsson P, et al. Int J Cancer. 2010;127(11):2645-2653.4. Missiaglia E, et al. Ann Oncol. 2014;25(10):1995-2001. EREG：表皮調(diào)節(jié)素，EGFR配體 右半結(jié)腸癌 左半結(jié)直腸癌60-7CALGB/SWOG 80405的左右半數(shù)據(jù)結(jié)果KRAS WT預(yù)測(cè)作用預(yù)后

35、作用 KRAS wt N = 1025Right 1mOSLeft 1mOSHR 95% CI(adjusted*)P (adjusted*)All pts19.433.31.55 (1.32,1.82)P 0.0001Cet 16.736.01.87 (1.48, 2.32)P 0.0001Bev2 (1.05, 1.65)P = 0.01“19.3 MONTHS IS A BIG DIFFERENCE !”BIOLOGICSIDE OF PRIMARYHR95% CIP (adjusted*)Any biologicOS and PFS Cet v Bev; left

36、 Cet Bev; right1.53(1.13, 2.08) Pint = 0.005Cet v BevOS Left 0.82(0.69, 0.96)p = 0.01PFS 0.84(0.72, 0.98)Cet v BevOS Right 1.26(0.98, 1.63) p = 0.08PFS1.26(1.00, 1.62)*Adjusted for biologic, protocol chemotherapy, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary, liv

37、er metastases 結(jié)論：野生型患者無論何種治療方式，左半比右半有更好的OS結(jié)論：西妥昔單抗和貝伐珠單抗一線治療在左右半中有不同的療效Venook AP, et al. 2016 ASCO Abstract 3504CALGB/SWOG 80405的左右半數(shù)據(jù)結(jié)果KRAS80405研究及FIRE-3*研究：不同腫瘤部位的中位OS (RAS全野生型患者)*Stintzing MD，個(gè)人口頭交流*Stintzing et al, Lancet Oncology, 2016Venook A, et al. Presented at 2016 ESMO.右1中位OS (月)左1中位OS (月)

38、P (校正后)RAS全野生型N=474N=149N=325CET13.639.30.001BEV0FIRE-3研究RAS全野生型N=394N=88N=306CET18.338.30.00001BEV23.028.00.03880405研究及FIRE-3*研究：不同腫瘤部位的中位OS預(yù)后分析：OS左側(cè)腫瘤的預(yù)后顯著優(yōu)于右側(cè)腫瘤Arnold D. Presented at 2016 ESMO. FOLFIRICETFOLFIRI：+CET vs. +BEVFOLFOX：+PMAB vs. +BEVFOLFOXPMABFOLFIRIPMAB化療：+CET vs. +BEV一線治

39、療二線治療預(yù)后分析：OS左側(cè)腫瘤的預(yù)后顯著優(yōu)于右側(cè)腫瘤Arnold D預(yù)測(cè)分析：OSOS - 左側(cè)腫瘤：化療+抗EGFR藥物更好；右側(cè)腫瘤：化療及貝伐珠單抗更好Arnold D. Presented at 2016 ESMO. 交互檢驗(yàn)的異質(zhì)性：P=0.53交互檢驗(yàn)的HR=1.53; 95%CI:1.21-1.93;P0.001預(yù)測(cè)分析：OSOS - 左側(cè)腫瘤：化療+抗EGFR藥物更好；改善mCRC生存的關(guān)鍵提高一線治療的療效- 個(gè)體化選擇最佳治療創(chuàng)造“治愈的機(jī)會(huì)”- 轉(zhuǎn)移灶的手術(shù)切除（和其他局部毀損性治療）采用“治療的延續(xù)”- 在不同線數(shù)的治療中采用最佳療法改善mCRC生存的關(guān)鍵提高一線治療

40、的療效- 個(gè)體化選擇最佳治結(jié)直腸癌肝轉(zhuǎn)移外科切除價(jià)值 延長(zhǎng)生存，獲得治愈R. Adam, et al Oncologist. 2012;17(10):1225-39.0123456789100102030405060708090100P0.0001切除(n=90)手術(shù)但未切除(n=68)年生存率0123456789100102030405060708090100P0.001起始切除是(n=91)否(n=87)年生存率1年2年3年4年5年6年7年8年9年10年切除90746049423632292725未切除68412411864生存率(%)生存率(%)起始切除1年2年3年4年5年6年7年8年9

41、年10年是91766352463936322928否87695341332925212020結(jié)直腸癌肝轉(zhuǎn)移外科切除價(jià)值 R. Adam, et al O不可手術(shù)切除結(jié)直腸癌肝轉(zhuǎn)移可手術(shù)切除可局部治療不可局部治療轉(zhuǎn)化治療的目標(biāo):轉(zhuǎn)移灶的R0切除或毀損轉(zhuǎn)化目標(biāo)1轉(zhuǎn)化目標(biāo)2MDT討論不可手術(shù)切除結(jié)直腸癌肝轉(zhuǎn)移可手術(shù)切除可局部治療不可局部治療初始可切除mCRC：圍手術(shù)期治療策略治愈初始可切快速縮小腫瘤/疾病控制疾病惡化伴有癥狀組 2疾病控制/低毒無癥狀組 3患者目標(biāo)最大程度縮小腫瘤潛在可切組 1治療強(qiáng)度組0手術(shù)圍術(shù)期初始可切除mCRC：圍手術(shù)期治療策略治愈初始可切快速縮小腫瘤以轉(zhuǎn)化為治療目標(biāo)的群體治愈

42、初始可切快速縮小腫瘤/疾病控制疾病惡化伴有癥狀組 2疾病控制/低毒無癥狀組 3患者目標(biāo)最大程度縮小腫瘤潛在可切組 1治療強(qiáng)度組0手術(shù)轉(zhuǎn)化優(yōu)先以轉(zhuǎn)化為治療目標(biāo)的群體治愈初始可切快速縮小腫瘤/疾病惡化伴有2016觀點(diǎn)：應(yīng)根據(jù)原發(fā)腫瘤部位選擇合適的轉(zhuǎn)化治療方案初始不可切CRLM化療+/-靶向E+化療ORR首要療效標(biāo)準(zhǔn)首選治療方案左半結(jié)腸右半結(jié)腸2016觀點(diǎn)：應(yīng)根據(jù)原發(fā)腫瘤部位選擇合適的轉(zhuǎn)化治療方案初始不改善mCRC生存的關(guān)鍵提高一線治療的療效- 個(gè)體化選擇最佳治療創(chuàng)造“治愈的機(jī)會(huì)”- 轉(zhuǎn)移灶的手術(shù)切除（和其他局部毀損性治療）采用“治療的延續(xù)”- 在不同線數(shù)的治療中采用最佳療法改善mCRC生存的關(guān)鍵提

43、高一線治療的療效- 個(gè)體化選擇最佳治多線治療的最佳策略總結(jié)維持治療 在強(qiáng)烈治療疾病控制后減弱治療強(qiáng)度，使用靶向藥物或者單藥維持可以減輕毒副反應(yīng)而不影響生存的獲益二線治療選擇根據(jù)一線治療方案更換全新二線治療方案 保持一線治療中靶向藥物更換化療藥物（跨線治療） 多線治療的最佳策略總結(jié)維持治療PFSFOLFOXFOLFOX5-FUFOLFOX觀察FOLFOX/XELOX+貝伐 NO 16966 持續(xù)治療組12個(gè)月10.4個(gè)月OPTIMOX1OPTIMOX1/2OPTIMOX2 9個(gè)月8.7 / 8.6 個(gè)月6.6個(gè)月XELOX卡培他濱8.1個(gè)月XelQuali研究XELOX+貝伐 化療+貝伐 貝伐卡

44、培他濱+貝伐XELOX+貝伐 MACROSTOP & GO/MACRO8.3 / 10.4 個(gè)月9.7個(gè)月13 / 11個(gè)月維持治療的方案8個(gè)月觀察XELOX+貝伐 CARIO-3CARIO-3/STOP&GO8.6個(gè)月PFSFOLFOXFOLFOX5-FUFOLFOX觀察FOL貝伐珠單抗二線治療mCRCn治療方案OS(月)PFS(月)ORR (%)Bendell, et al. ASCO GI 201151Avastin + FOLFIRI15.76.921.6 35Avastin + FOLFOX14.16.420.0Moriwaki, et al. ESMO 2010*104Avasti

45、n + FOLFIRI23.17.527.035Avastin + FOLFOX18.57.413.1Odabas, et al. ESMO 201035 Avastin + FOLFIRI12717.1Kwon, World J Gastroenterol 200714Avastin + FOLFIRI 10.93.928.5Giantonio,et al. JCO 2007 （E3200）271Avastin + FOLFOX12.97.322.7271FOLFOX貝伐珠單抗二線治療mCRCn治療方案OS(月)PFS(月BOND-1 (ITT)1EPIC (KRAS W

46、T)2三線(KRAS WT)3西妥昔單抗 伊立替康伊立替康 西妥昔單抗西妥昔單抗/BSCn218 vs 11897 vs 95125 vs100OS (月)8.6 vs 6.910.9 vs 11.6 9.5 vs 4.8 HRNR1.280.55 p 值0.48NR0.001PFS (月)4.1 vs 1.54.0 vs 2.8 3.7 vs 1.9 HRNR0.770.4 p 值0.001NR0.001ORR (%)23 vs 1010 vs 713 vs 0 p 值0.007NR3,000位隨機(jī)臨床研究中的患者1KRAS WTKRAS MT13.7%有其他RAS突變(KRAS 外顯子 3

47、 和 4, 和 NRAS 突變)無數(shù)已知存在于mCRC的額外基因突變擁有預(yù)測(cè)和/或預(yù)后的功能PIK3CAPTENFGFR3ERBB2 轉(zhuǎn)移性結(jié)直腸癌中生物靶標(biāo)的意義1. Sorich. 2015CRC中的突變狀態(tài)有預(yù)后作用: 野生型 RAS MT BRAF MTSinicrope. 2015.以5-Fu為基礎(chǔ)的輔助化療的III期結(jié)直腸癌 (n = 737)0102030405060708090100012347311265236215197270233187163148140 28 22 18 15 13 13 33 27 26 23 19 19 59 5146 44 40 39243648605-yr DFS 率(95% CI)P-值無BRAFV600E & KRAS, pMMR突變65.3%(65.3-70.6)REFKRAS, pMMR突變57.7%(60.3-73-9).0265BRAFV600E, pMMR突變49.2%(33.6-72.1).1770偶發(fā) dMMR71.