1、晚期结直肠癌的规范化治疗晚期结直肠癌的规范化治疗Tianshu liu, M.D., Ph.D.Zhongshan Hospital, Fudan UniversityDept of Medical OncologyCenter of Evidence-based medicinemCRCmCRC分组全程管理分组全程管理治愈初始可切快速缩小肿瘤快速缩小肿瘤/疾病控制疾病控制疾病恶化伴有症状疾病恶化伴有症状组组 2疾病控制疾病控制/低毒低毒无症状无症状组组 3患者目标最大程度缩小肿瘤最大程度缩小肿瘤潜在可切潜在可切组组 1治疗强度组组 0手术整体治疗策略的应用显著延长了mCRC患者的OS贝伐珠单
2、抗4中位OS时间 (月)BSC5-FU3020100伊立替康1卡培他滨2奥沙利铂3西妥昔单抗5,61980s 1990 2000s 2010帕尼单抗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. J
3、CO 2007; 8. Van Cutsem, et al, JCO 2012; 9. Grothey, Van Cutsem, et al. Lancet 2012改善mCRC生存的关键n 提高一线治疗的疗效- 个体化选择最佳治疗n 创造“治愈的机会”- 转移灶的手术切除（和其他局部毁损性治疗）n 采用“治疗的延续”- 在不同线数的治疗中采用最佳疗法改善mCRC生存的关键n 提高一线治疗的疗效- 个体化选择最佳治疗n 创造“治愈的机会”- 转移灶的手术切除（和其他局部毁损性治疗）n 采用“治疗的延续”- 在不同线数的治疗中采用最佳疗法一线治疗决策制定的驱动因素肿瘤特征患者特征治疗特征临床表现
4、肿瘤负担肿瘤部位年龄毒性肿瘤生物学体力状态灵活性RAS 突变状态器官功能社会经济因素BRAF 突变状态合并症生活质量患者预期和偏好mCRC患者的一线治疗决策需充分考虑三大特征化疗 +/- 贝伐珠单抗化疗 +/-靶向药物再评估/每2-3个月评估肿瘤缓解情况RAS WTRAS MTBRAF MT疾病控制治疗特征肿瘤特征右半左半化疗 +/- 贝伐珠单抗化疗 +/- 贝伐珠单抗化疗 +/- 西妥昔单抗FitUnfitUnfit(但可能获益）患者的临床分类疾病进展高强度治疗继续治疗暂停治疗维持治疗患者特征化疗 +/- 西妥昔单抗OXACPT-11靶向药物靶向药物BEV、CETFOLFOXXELOXFLO
5、XFOLFIRIIFLXELIRI5-FUCAPE中国可获取的药物中国可获取的药物氟尿嘧啶的作用机制氟尿嘧啶的作用机制1. Longley 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
6、 2015;6. Taiho Pharmaceuticals Co. Ltd. Available at: www.taiho.co.jp.; 7.http:/www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_Initial_authorisation/human/003897/WC500202369.pdf.卡培他滨卡培他滨5dFCR5dFURCDHPTFTFURFUMPFUDPFUTPFUdRFdUDPFdUTP5-hydroxytegafurCarboxylesteraseCytidinedeaminase8
7、0% of systemic 5-FU is subject to hepatic DPD-mediated degradationTAS-102Thymidine kinaseThymidine phosphorylaseThymidine kinaseDNA damageRNA damageUMP-CMPKNDKNDKUMP-CMPKOPRTThymidine phosphorylase/uridine phosporylaseUridine phosporylaseTFT-MPTegafurS-1TFT-TPdTTP depletion due to inhibition of thym
8、idylate synthaseThymidylate synthase5-FU5dFURUridine-cytidinekinaseFdUMP5-FU雷替曲赛奥沙利铂奥沙利铂1,2奥沙利铂和伊立替康的作用机制奥沙利铂和伊立替康的作用机制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
9、 E, et al. Ann Oncol 2014;25(Suppl 3):iii1iii9.Cancer Therapy Vol 5, page 545 545 by a different mechanism of action to the classical cisplatin or carboplatin. The alkaline hydrolysis of oxaliplatin produces the oxalato monodentate intermediate complex (pKa 7.23) and the dihydrated oxaliplatin compl
10、ex in 2 consecutive steps. The monodentate intermediate is assumed to rapidly react with endogenous compounds (Jerremalm et al, 2003). The crystal structures of oxaliplatin bound to a DNA dodecamer duplex with the sequence 5-d (CCTCTGGTCTCC) has been reported (Spingler et al, 2001). The platinum ato
11、m forms a 1,2-intrastrand cross-link between two adjacent guanosine residues bending the double helix by approximately 30 degrees toward the major groove. Crystallography has provided structural evidence for the importance of chirality in mediating the interaction between oxaliplatin and duplex DNA
12、(Spingler et al, 2001). With oxaliplatin, like cisplatin, adduct lesions are repaired by the nucleotide excision repair system. Oxaliplatin, like cisplatin, is detoxified by glutathione (GSH)-related enzymes. Oxaliplatin produces the same type of inter- and 1,2-GG intrastrand cross-links as cisplati
13、n but has a spectrum of activity and mechanisms of action and resistance different from those of cisplatin and carboplatin. The cellular and molecular aspects of the mechanism of action of oxaliplatin have not yet been fully elucidated. However, the intrinsic chemical and steric characteristics of t
14、he non-hydrolyzable diaminocyclohexane (DACH)-platinum adducts on DNA appear to contribute to the lack of cross-resistance with cisplatin and carboplatin (reviewed by Di Francesco et al, 2002). Platinum-DNA adducts result in DNA-strand breaks. The pyrimidine analog trifluorothymidine (TFT) forms tog
15、ether with a thymidine phosphorylase inhibitor (TPI) the anticancer drug formulation TAS-102, in which TPI enhances the bioavailability of TFT in vivo. The combined cytotoxic effects of oxaliplatin and TFT resulted in synergistic apoptosis for all human colorectal cancer cells examined (Temmink et a
16、l, 2007). ERCC1 and XPA expressions were predictive of oxaliplatin sensitivity in 6 colon cell lines in vitro (Arnould et al, 2003). Oxaliplatin combined with 5Fluorouracil and folinic acid improved the response rate and progression-free and overall survival of patients with advanced colorectal canc
17、er (De Vita et al, 2005). The dose-limiting adverse reaction of oxaliplatin is neurotoxicity (sodium channel inactivation) and the kinetics are altered after exposure of animals to oxaliplatin. The results from preliminary clinical studies indicate that the sodium channel blockers carbamazepine and
18、gabapentin may be effective in preventing neurotoxicity (Lersch et al, 2002). Fludarabine increases oxaliplatin cytotoxicity; inhibition by fludarabine of the activity of the DNA excision repair pathways activated by oxaliplatin adducts appears to be the mechanism of synergy of the two drugs studied
19、 in lymphocytes from patients with chronic lymphocytic leukemia (Moufarij et al, 2006). Figure 3. DNA adducts formed by oxaliplatin. DNA synthesisCell deathInter- and intra-strand DNA cross-links伊立替康伊立替康Induction of apoptosis晚期结直肠癌尽量暴露于晚期结直肠癌尽量暴露于所有有效药物的理念所有有效药物的理念 11个III期临床研究（n=5768）结果分析：晚期结直肠癌整个治疗
20、过程中用过所有3个有效细胞毒药物（5-FU/LV、伊立替康和奥沙利铂）的患者生存期最长Adapted from Grothey & Sargent. JCO 20050 10 20 30 40 50 60 70 80静滴静滴5-FU/LV + 伊立替康伊立替康静滴静滴5-FU/LV + 奥沙利铂奥沙利铂静注静注5-FU/LV + 伊立替康伊立替康伊立替康伊立替康,+ 奥沙利铂奥沙利铂静注静注5-FU/LV LV5FU2FOLFOXIRICAIRO三药治疗患者比例三药治疗患者比例(%)一线治疗方案一线治疗方案2221201918171615141312中位生存中位生存(月月)p=0.000120
21、07Douillard JY, et al. Lancet 2000;355:10411047.*Primary endpoint.TTPOSp0.001p=0.031PFS probability MonthsOS probabilityMonthsRandomized Phase III trial of 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=19
22、8)5-FU/LV (n=187)FOLFIRI (n=198)5-FU/LV (n=187)FOLFIRI FOLFIRI vsvs 5FU5FU：显著的生存获益：显著的生存获益*Primary endpoint.FOLFOX FOLFOX vs vs 5FU 5FU：显著的生存获益：显著的生存获益Randomized Phase III 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, %50
23、291.840.0001de Gramont A, et al. J Clin Oncol 2000;18:29382947.PFS*PFS probabilityMonthsFOLFOX (n=210)5-FU / LV (n=210)1008060402000510152025p=0.00016.29.0OSOS probabilityMonthsFOLFOX (n=210)5-FU / LV (n=210)1008060402000510153040p=0.1214.716.2202535化疗药物的次序分布化疗药物的次序分布mCRC交叉研究设计交叉研究设计V308 V308 疗效结果疗效
24、结果Tournigand et al. J Clin Oncol. 2004;22:229-237.A A组组FOLFIRI-FOLFOXn = 109 n=81n = 109 n=81 B B组组FOLFOX-FOLFIRIn = 111 n=69n = 111 n=69中位一线无进展生存中位一线无进展生存 8.58.5月月8.08.0月月中位二线无进展生存中位二线无进展生存 2.5月一线缓解率一线缓解率二线缓解率二线缓解率56 % 54 %4 %接受二线化疗的比例接受二线化疗的比例7462中位总生存中位总生存21.5月20.6月FOLFOXIRIFOLFOXIRIvs vsFOLFIRIF
25、OLFIRI：结果不一致：结果不一致1. Falcone A, et al. J Clin Oncol 2007;25:16701676; 2. Souglakos 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, months9
26、.86.90.63 (0.470.81)0.0006ORR, %*6641NR0.0002FOLFOXIRI (n=137)FOLFIRI (n=146)HR (95% CI)p-valueMedian TTP, months8.46.90.83 (0.641.08)0.17ORR, %4334NR0.168Italian GONO study1Greek HORG study2OSPFS probabilityMonths100806040200061218243016.722.8OSOS probabilityMonths1.00.80.60.40.20010506019.521.5304
27、0 FOLFOXIRI (n=122) FOLFIRI (n=122)HR=0.70 (95% CI: 0.390.84)p=0.005 FOLFOXIRI (n=137) FOLFIRI (n=146)20分子靶向治疗分子靶向治疗 EGFRCOX-2VEGFNew targetHER-2肿瘤细胞表表达达水水平平正常细胞靶点靶点 细胞受体细胞受体 信号转导信号转导 细胞周期细胞周期 血管生成血管生成VEGFVEGF及受体家族及受体家族PlGFVEGF-R1VEGF-R3VEGF-R2(most prominent)VEGF-AVEGF-DVEGF-CEndothelial progenitor
28、 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;6:1930; 2. Avastin
29、SmPC, October/2015; 3. Zaltrap SmPC, September/2014; 4. Stivarga SmPC, October/2015; 5. Cyramza PI, April/2015.PlGFVEGF-R1VEGF-R3VEGF-R2(most prominent)VEGF-AVEGF-DVEGF-CLigands: VEGF-A VEGF-CVEGF-D VEGF-ELigands: VEGF-C VEGF-DLigands: VEGF-A VEGF-B PlGFVEGF-BPlGFVEGF-AVEGF-BVEGF-DVEGF-CVEGF-EVEGF-A
30、Aflibercept3Bevacizumab2Regorafenib4Ramucirumab51. 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. Cyramza PI, April/2015.Endothelial progenitor recrui
31、tmentMigration/invasionProliferationLymphangiogenesisPermeabilitySurvival抗血管生成药物的作用机制抗血管生成药物的作用机制apatinib贝伐珠单抗一线治疗贝伐珠单抗一线治疗AVF2107AVF2107药物注册研究药物注册研究Hurwitz, et al. NEJM 2004贝伐珠单抗一线治疗贝伐珠单抗一线治疗: : NO16966NO16966研究研究贝伐珠单抗一线治疗的贝伐珠单抗一线治疗的III III期研究期研究ARTISTARTIST（中国本土数据）（中国本土数据）1.00.80.60.40.20.00612182
32、4时间 (月)13.4m18.7mOS贝伐珠单抗+mIFL (n=142)mIFL (n=72)HR=0.62 P=0.0141.00.80.60.40.20.061218240mlFL (n=72)贝伐珠单抗贝伐珠单抗+mlFL (n=142)时间时间 (月月)PFSHR=0.44; 95%CI=0.31-0.63P0.0014.2m8.3mEGFR单抗1. Martinelli E, et al. Clin Exp Immunol 2009;158:19; 2. Brand TM, Wheeler DL. Small GTPases 2012;3:3439.EGF, epidermal g
33、rowth factor. TGF, transforming growth factor-.VEGF, vascular endothelial growth factor.RASCetuximabPanitumumabx西妥昔单抗的一线治疗西妥昔单抗的一线治疗CRYSTAL trialVan Cutsem E, et al. J Clin Oncol26HR=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
34、. 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 June 2014; 5. Vectibix SmPC February 2015. Figure adapted from data from Van Cutsem E, et al.2Cetuximab and panitumumab ar
35、e 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 tumor status is unknown.4,5Cetuximab + FOLFIRI (n=178)FOLFIRI (n=189)0.00.20.40.60.81.0Months5442 481861224 30 3628.420.20Mo
36、nths5442 4823.520.00.00.20.40.60.81.018061224 30 36Months5442 480.00.20.40.60.81.018061224 30 36OS estimate19.918.6Cetuximab + FOLFIRI (n=599)FOLFIRI (n=599)Cetuximab + FOLFIRI (n=316)FOLFIRI (n=350)RAS wt2KRAS exon 2 wt1ITT (unselected)1西妥昔单抗的疗效与西妥昔单抗的疗效与RAS状态有关状态有关HR, hazard ratio; IRC, independen
37、t review committee; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.*In the case of non-PD treatment discontinuation, tumor assessment is continued. Endpoints Primary: PFS (by IRC according to RECIST 1.0), target HR = 0.70 Key secondary: OS, ORR, safety/tolerability
38、Statistical assumption for the primary endpoint 247 events required, 80% power, = 0.05 (2-sided)TAILOR Study Design1:1 RFirst-line, RAS wt mCRCTreatment until progressive disease or unacceptable toxicity*Arm A:Cetuximab + FOLFOX-4Arm B:FOLFOX-4 aloneSurvival follow-upEfficacy: Primary Endpoint of PF
39、S by IRC Adding cetuximab to FOLFOX-4 significantly improved the primary endpoint of PFS by IRCRASWTRASWT一线治疗的选择一线治疗的选择头对头研究结果头对头研究结果1. Heinemann 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
40、(Abstract No. 446) FIRE-31 (IST)CALGB 804052,3PEAK4Patients with untreated KRAS (exon 2) wt mCRCN=592R RCetuximab + FOLFIRIBevacizumab + FOLFIRIPatients with untreated KRAS (exon 2) wt mCRCN1200 (after trial modification)Cetuximab + FOLFOX/FOLFIRIBevacizumab + FOLFOX/FOLFIRIBevacizumab + cetuximab +
41、 FOLFOX/FOLFIRI*Arm closed to accrual as of 09/10/2009R RPanitumumab + mFOLFOX6Bevacizumab + mFOLFOX6R REfficacy data expected Q2 2014Phase IIPhase IIIPatients with untreated KRAS (exon 2) wt mCRCN=285ORROSPFSPrimary endpointIST, investigator-sponsored trial1. Heinemann V, et al. ASCO 2013 (Abstract
42、 No. LBA3506) 2. Stintzing S, et al. ECC 2013 (Abstract No. LBA17)33.1months25.6 months Cetuximab + FOLFIRI (n=171) 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)
43、1RAS* wt(KRAS and NRAS wt)2 Cetuximab+ FOLFIRI (n=297) Bevacizumab + FOLFIRI (n=295) = 3.7 months = 7.5 monthsMonths 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: KRASFIRE-3: KRAS以外以外RASRAS的意义的意义OSOS的
44、获益的获益00主要研究终点2013年6月2014年6月CALGB80405n = 1,137PEAKn = 285FIRE-3n = 5922013年1月PFS（）ORR（）OS（）贝伐珠单抗 VS 西妥昔单抗29 VS 29.9P=0.34贝伐珠单抗 VS 帕尼单抗10.1 VS 10.9P=0.353贝伐珠单抗 VS 西妥昔单抗58 VS 62P=0.18320162016年之前的观点，一线治疗中两类靶向药物总体疗效年之前的观点，一线治疗中两类靶向药物总体疗效相当相当 右半结肠癌 30-40%左半结直肠癌60-70%胚胎起源中原肠后原肠血供肠系膜上动脉肠系膜下动脉组织学类型低分化较多见低分
45、化较少见血管受侵较常见较少见生物学特性BRAF突变较多见MSI（微卫星不稳定）锯齿状通路信号传导通路突变频率BRAF突变较少见染色体不稳定EGFR或HER2扩增、EREG信号传导通路突变频率2016：左右半结直肠癌具有不同的特点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
46、al. Ann Oncol. 2014;25(10):1995-2001. EREG：表皮调节素，EGFR配体CALGB/SWOG 80405CALGB/SWOG 80405的左右半数据结果的左右半数据结果KRAS WTKRAS WT预测作用预后作用 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 0.0001Bev24.231.41.32 (1.05, 1.65)P
47、= 0.01“19.3 MONTHS IS A BIG DIFFERENCE !”BIOLOGICSIDE OF PRIMARYHR95% CIP (adjusted*)Any biologicOS and PFS Cet v Bev; left 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
48、for biologic, protocol chemotherapy, prior adjuvant therapy, prior RT, age, sex, synchronous disease, in place primary, liver metastases 结论：野生型患者无论何种治疗方式，左半比右半有更好的OS结论：西妥昔单抗和贝伐珠单抗一线治疗在左右半中有不同的疗效Venook AP, et al. Venook AP, et al. 2016 ASCO Abstract 3504 ASCO Abstract 35048040580405研究及研究及FIRE-3FIRE-3
49、* *研究：研究：不同肿瘤部位的中位不同肿瘤部位的中位OS (RASOS (RAS全野生型患全野生型患者者) )*Stintzing MD，个人口头交流*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)P (校正后)RAS全野生型N=474N=149N=325CET13.639.30.001BEV29.232.60.50FIRE-3研究RAS全野生型N=394N=88N=306CET18.338.30.00001BEV23.028.00.038预后
50、分析：OS左侧肿瘤的预后显著优于右侧肿瘤Arnold D. Presented at 2016 ESMO. FOLFIRICETFOLFIRI：+CET vs. +BEVFOLFOX：+PMAB vs. +BEVFOLFOXPMABFOLFIRIPMAB化疗：+CET vs. +BEV一线治疗二线治疗预测分析：OSOS - 左侧肿瘤：化疗+抗EGFR药物更好；右侧肿瘤：化疗及贝伐珠单抗更好Arnold D. Presented at 2016 ESMO. 交互检验的异质性：P=0.53交互检验的HR=1.53; 95%CI:1.21-1.93;P0.001改善mCRC生存的关键n 提高一线治疗
