转移性结直肠癌治疗的新进展Mar

转移性结直肠癌化疗的新进展,中山大学肿瘤医院 内科何友兼 教授,结 直 肠 癌,西方国家中，结 直肠癌占癌症死亡第二位（10%-12%）。发病率每年递增4.2%。外科手术五年生存率：期90%、期70%-75%、期35%-50%、期 推注FOLFOX 的疗效大致与 FOLFIRI相当, 但毒性各异三药方案(FOLFOXIRI)疗效和生存比二药略佳合用靶向药可提高疗效, 改善生存用足三药(5FU.L-OHP.IRI)者中位生存可超过2年维持治疗或间歇休息(treatment holiday)应个体化处理,效力和毒性: FOLFIRI vs FOLFOX,Efficacy/Toxicity5FU/LVIrinotecan OxaliplatinRR(first line) 56% 54%OS(mo) 21.5 20.4G3/4 neutropenia 24% 44%G3/4 febrile neutr. 7% 0%G3/4 mucositis 10% 1%G2/3 neurological 0% 71%G3/4 diarrhea 14% 11%,Tournigand et al. JCO 2004. 22:229-237,III 期试验: FOLFOXIRI vs FOLFIRI,Souglakos J, et al. Br J Cancer. 2006;94:798-805. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.,*Statistically significant difference.,用足三药.改善生存: Update 200511 Phase III Trials, 5768 Patients,OS (mos) = 13.2 + (%3drugs x 0.1), R2 = 0.85,Grothey & Sargent, JCO 2005,0 10 20 30 40 50 60 70 80,Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV LV5FU2,First-Line Therapy,mCRC: 一线治疗的中位生存,BSC,0,6,12,18,24,Median OS (Mos), 4-6 mos,12-14 mos, 15-16 mos,20.3 mos,19-20 mos,5-FU/LV,FOLFOX4 or CAPEOX,IFL + Bevacizumab,IFL or FOLFIRI,21.5 mos,FOLFOX6,FOLFIRI + Bevacizumab,24 mos,Gallagher DJ, et al. Oncology. 2010;78:237-248.,mCRC: 主要的一线化疗效果,1. Goldberg RM, et al. J Clin Oncol. 2004;22:23-30. 2. Colucci G, et al. J Clin Oncol. 2005;23:4866-4875. 3. Cassidy J, et al. J Clin Oncol. 2008;26:2006-2012. 4. Cassidy J, et al. Br J Cancer. 2011;105:58-64. 5. Fuchs CS, et al. J Clin Oncol. 2007;25:4779-4786.,mCRC : 分子靶点药,分子靶药物 (in CRC): 以往临床研究结果,Cet(Pan), Bev与化疗联合均可增效.延长生存,可用于各线(一.二.三)的治疗Cet(Pan)单药有效, Bev必须与化疗联合使用,两个单抗合用不增效Bev.在一线进展后用仍可获生存效益Cet(Pan)只能用于K-RAS野生型或G13d突变的病人, Bev.的使用不须测靶首次皮疹程度反映Cet(Pan)的疗效,与K-RAS无关Cet(Pan),Bev 用于术后辅助治疗均未证实有效,VEGF 和 VEGF-受体家族,VEGF regulates angiogenesis via interaction with receptor tyrosine kinases VEGFR-2/KDR and VEGFR-1/Flt-1,VEGFR-1,(Flt-1),VEGF-A,Receptor,isoforms,Ligand,isoforms,VEGFR-2,(KDR),VEGF-B,VEGFR-1s,Angiogenesis,VEGF-E,VEGF-C,VEGF-D,VEGFR-3,(Flt-4),Lymph angiogenesis,tumor metastases,Extracellular,Intracellular,VEGF-A 165,NRP-1,PlGF,Shinkaruk S, et al. Curr Med Chem Anti-Canc Agents. 2003;3:95-117. Luttun A, et al. Ann N Y Acad Sci. 2002;979:80-93.,mCRC: 一线化疗/贝伐单抗,1. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342. 2. Saltz LB, et al. J Clin Oncol. 2008;26:2013-2019. 3. Bendell JC, et al. Oncologist. 2012;17:1486-1495.,1. Bevacizumab package insert. South San Francisco, CA: Genentech; 2011. 2. Nalluri SR, et al. JAMA. 2008;300;2277-2285. 3. Hurwitz H, et al. J Clin Oncol. 2011;29:1757-1764.,Potential for increased VTE risk controversial; increased risk noted in 1 study but not in others.2,3,*Predominantly grade 3.May apply more to NSCLC.When surgery conducted during bev therapy.,贝伐单抗 : 相关毒性,KRAS WT mCRC: 一线EGFR-靶向药,Worse PFS outcome with panitumumab + FOLFOX4 in mutant KRAS disease3,1. Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019. 2. Bokemeyer C, et al. Ann Oncol. 2010;22:1535-1546. 3. Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705. 4. Douillard JY, et al. ASCO 2013. Abstract 3620. 5. Douillard JY, et al. N Engl J Med. 2013;369:1023-1034. 6. Maughan TS, et al. Lancet. 2011;377:2103-2114.,mCRC: 个体化治疗应考虑,病变范围治疗目的 (姑息 vs 可能根治)活动能力年龄合并疾病 以往一年内的辅助治疗分子标记,器官(肝肾,造血)功能毒性风险: 活动性出血,蛋白尿,伤口不愈,神经病变,过敏,是否方便花费/资源病人意愿,mCRC : 化疗有关的选择,mCRC：化疗选择临床依据,无病间歇（DFI) , 缓解期 PS（01，2） 年龄（70，70） 肿瘤分子生物学标记 ( TS.DDP.UGT.KRAS.NRAS.BRAF) 化疗目的(新辅助, 辅助) 患者取舍,mCRC: 临床处理程序,确定治疗目的,选择治疗策略,决定治疗强度,病人是否需要(渇望)积极治疗,Yes85%,No15%,KRAS,无法检测,野生型,突变型,5FU/CAPECITABINE,+/-Bevacizumab,二联化疗,+Bevacizumab,二联+Cet,二联+Bev,二联化疗,+Bevacizumab,KRAS WT mCRC: 一线EGFR vs VEGF单抗,The primary endpoint of ORR was not significantly different between treatment arms in the FIRE-3 study (62% vs 58%; P = .183)2,1. Schwartzberg LS, et al. ASCO GI 2013. Abstract 446. 2. Heinemann V, et al. ASCO 2013. Abstract LBA3506.,*Statistically significant difference.,mCRC: 其它的生物标志物,KRAS G13D1综合有关预测和预后的资料大型随机研究抗EGFR治疗无价值BRAF2,3预后结局很差未见综合 一线治疗有关预测资料Expanded RAS analysis4,5 10% of KRAS 12/13 野生型肿瘤有其它 RAS 突变KRAS exons 3, 4NRAS exons 2,3,4抗-EGFR 单抗无效,1. Peeters M, et al. J Clin Oncol. 2013; 31:759-765. 2. Richman SD, et al. J Clin Oncol. 2009;27:5931-5937. 3. Van Custem E, et al. J Clin Oncol. 2011;29:2011-2019 4. Peeters M, et al. Clin Cancer Res. 2013;19:1902-1912. 5. Douillard JY, et al. N Engl J Med. 2013;369:1023-1034.,III期 80405 试验 : 一线化疗 Either Cetux or Bev in KRAS-WT mCRC,Primary endpoint: OSSecondary endpoints: ORR, PFS, TTF, duration of response,Patients with mCRC and KRAS WT, ECOG PS 0/1(N = 2900),FOLFOX or FOLFIRI + Bevacizumab q2w,ClinicalT. NCT00265850.,FOLFOX or FOLFIRI + Cetuximab q1w,A third arm with CT + bevacizumab + cetuximab was closed to accrual in September 2009,延续治疗策略上的考虑,增加病变得到长时间良好控制病人的数目大多数新治疗研究到病人病变进展或毒性受限而终止对病变得到良好控制病人的策略:继续治疗到病变进展或毒性而终止维持治疗治疗停息(Treatment holidays),OPTIMOX : 维持 or 间歇休息,OPTIMOX11 Maintenance therapy(n = 620),FOLFOX 4 until progression,FOLFOX 7,FOLFOX 7,sLV5FU2,OPTIMOX22 Chemotherapy-free interval(n = 202),mFOLFOX 7,mFOLFOX 7,sLV5FU2,mFOLFOX 7,mFOLFOX 7,Chemotherapy-Free Interval,1. Tournigand C, et al. J Clin Oncol. 2006;24:394-400. 2. Chibaudel B, et al. J Clin Oncol. 2009;27:5727-5733.,OPTIMOX : 研究结果,OPTIMOX1 (维持 vs 继续治疗)疾控期, PFS, or OS 无明显差异OPTIMOX2 (治疗休息 vs 维持治疗)维持治疗的疾控期, PFS 明显为好但 OS 无差异,Tournigand C, et al. J Clin Oncol. 2006;24:394-400. Chibaudel B, et al. J Clin Oncol. 2009;27:5727-5733.,维持贝伐单抗 : MACRO Trial,Capecitabine +Oxaliplatin +Bevacizumabx 6 cycles q3w(n = 241),Bevacizumabuntil progression,Capecitabine +Oxaliplatin +Bevacizumabx 6 cycles q3w(n = 239),Capecitabine +Oxaliplatin +Bevacizumabuntil progression,Patients with newly diagnosedmCRC and ECOG PS 2,Diaz-Rubio E, et al. Oncologist. 2012;17:15-25.,MACRO : OS (ITT),Mos,XELOX-Bev,Bev,Patients at Risk, n,241,239,Survival Probability,0,0.25,0.50,0.75,1.00,0,0,2,39,19,13,33,26,23,30,39,40,27,54,60,24,77,85,21,101,120,18,132,146,15,159,170,12,193,191,9,210,208,6,226,227,3,8,6,36,Bev,XELOX-Bev,Diaz-Rubio E, et al. Oncologist. 2012;17:15-25.,HR: 1.05 (95% CI: 0.851-1.295),间歇休息 : GISCAD Trial,CR, PR, SD,Previously untreated mCRC,RANDOM I ZAT I ON,FOLFIRI x 2 mos,2:1,FOLFIRI x 2 mos,EVALUATE,Progression: Off Trial,Break x 2 mos then FOLFIRI x 2 mos,FOLFIRI x 4 mos,Labianca R, et al. Ann Oncol. 2011;22:1236-1242.,146,147,75,70,25,27,10,9,146,147,95,101,39,43,10,13,Pts at Risk, n,Continuous,Intermittent,Mos,0,Patients (%),0,6,12,18,Mos,100,80,60,40,20,0,Patients (%),6,12,18,24,30,36,130,124,60,68,19,29,Labianca R, et al. Ann Oncol. 2011;22:1236-1242.,OS,PFS,100,80,60,40,20,0,间歇休息 : GISCAD Trial,Continuous armIntermittent arm,Events145143,Totals146147,Continuous armIntermittent arm,Events145143,Totals146147,Arm CBevacizumab (n = 243),Arm AFOLFOX4 + Bevacizumab(n = 286),Arm BFOLFOX4(n = 291),Patients with previously treated mCRC; no previous bevacizumab(N = 820),FOLFOX4Oxaliplatin 85 mg/m2 on Day 1 q2w5-FU 400 bolus/600 mg/m2 IV on Days 1 and 2 q2wLV 200 mg/m2 on Days 1 and 2 q2wBevacizumab10 mg/kg on Day 1 q2w,Giantonio BJ, et al. J Clin Oncol. 2007;25:1539-1544.,Stratified by ECOG performance score 0 vs 1 or 2; previous XRT,E3200: 二线用贝伐单抗 for mCRC,Alive, n,Dead, n,Median, Mos,Total, n,A: FOLFOX4 + bevacizumab,286,254,32,12.9,B: FOLFOX4,291,264,27,10.8,C: Bevacizumab,243,219,24,10.2,Giantonio BJ, et al. J Clin Oncol. 2007;25:1539-1544.,E3200: 在以前治疗过的 mCRC FOLFOX + Bev 改善 OS,OS (Mos),Probability,0,0.2,0,0.4,0.6,0.8,1.0,6,12,18,24,30,36,HR: 0.76A vs B: P = .0018B vs C: P =.95,ML18147 (TML): 进展后继续用贝伐单抗,A randomized, open-label phase III intergroup study,Standard second-line CT (oxaliplatin or irinotecan based) until PD(n = 411),BEV 2.5 mg/kg/wk + standard second-line CT (oxaliplatin or irinotecan-based) until PD(n = 409),Progressive mCRC after BEV + standard first-line CT (either oxaliplatin oririnotecan based)(n = 820),Bennouna J, et al. Lancet Oncol. 2013;14:29-37.,Stratified by first-line CT (oxaliplatin or irinotecan based), first-line PFS ( 9 or 9 mos), time from last BEV dose ( 42 or 42 days),ECOG PS at baseline (0/1 or 2),Primary endpoint: OS,ML18147 (TML): 改善 OS (ITT),OS (%),Mos,CT (n = 410)BEV + CT (n = 409),100,80,60,40,20,0,0 6 12 18 24 30 36 42 48,9.8 mos,11.2 mos,Unstratified* HR: 0.81 (95% CI: 0.69-0.94; log-rank P = .0062),Stratified HR: 0.83 (95% CI: 0.71-0.97; log-rank P = .0211),*Primary analysis method. Stratified by first-line CT (oxaliplatin based, irinotecan based), first-line PFS ( 9 mos, 9 mos), time from last dose of BEV ( 42 days, 42 days), ECOG PS at baseline (0, 1).,Bennouna J, et al. Lancet Oncol. 2013;14:29-37.,100,80,60,40,20,0,PFS (%),0 6 12 18 24 30 36 42,Mos,Unstratified* HR: 0.68 (95% CI: 0.59-0.78; log-rank P .0001),Stratified HR: 0.67 (95% CI: 0.58-0.78; log-rank P .0001),4.1 mo,5.7 mo,一线治疗后继续用血管生成抑制剂 ?,Bevacizumabziv-aflibercept (阿帕西普),(阿帕西普),III期 VELOUR 研究: FOLFIRI ziv-Aflibercept 二线治疗 mCRC,Primary endpoint: OSSecondary endpoints: PFS, ORR, safety, immunogenicityNo correlatives,Patients with mCRC progressing on first-line oxaliplatin-based chemotherapy*(planned N = 1226),FOLFIRI + ziv-Aflibercept 4 mg/kg q2w(n = 612),FOLFIRI + Placebo q2w(n = 614),*30% had previous bevacizumab.,Stratified by previous bevacizumab (yes vs no),ECOG PS (0 vs 1 vs 2),Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506. ClinicalT. NCT00561470.,(阿帕西普),VELOUR 研究 : 生存结果,Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.,OS (%),100,80,60,40,20,0,Mos,0,3,6,9,12,15,18,21,24,27,30,33,36,39,Stratified HR: 0.817 (95.34% CI: 0.713-0.937; log-rank P = .0032),Placebo/FOLFIRIMedian: 12.06 mos,Aflibercept/FOLFIRIMedian: 13.50 mos,PFS (%),100,80,60,40,20,0,Mos,0,3,6,9,12,15,18,21,24,27,30,Stratified HR: 0.758 (95% CI: 0.661-0.869; log-rank P .0001),Placebo/FOLFIRIMedian: 4.67 mos,Aflibercept/FOLFIRIMedian: 6.90 mos,(阿帕西普),(阿帕西普),VELOUR 研究 : 按贝伐单抗分层OS,Tabernero J, et al. Eur J Cancer. 2013;Epub ahead of print.,OS (%),100,80,60,40,20,0,Mos,0,3,6,9,12,15,18,21,24,27,30,33,36,39,HR: 0.862 (95.34% CI: 0.673-1.104),Placebo/FOLFIRIMedian: 11.7 mos,Aflibercept/FOLFIRIMedian: 12.5 mos,Pts at Risk, n PlaceboAFL,187186,170178,138150,115121,8189,5459,3736,2222,1313,Previous Bevacizumab,OS (%),100,80,60,40,20,0,Mos,0,3,6,9,12,15,18,21,24,27,30,33,36,39,HR: 0.788 (95.34% CI: 0.699-0.927),Placebo/FOLFIRIMedian: 12.4 mos,Aflibercept/FOLFIRIMedian: 13.9 mos,Pts at Risk, n PlaceboAFL,427426,403388,347348,286295,205222,139157,94112,6582,3862,No Previous Bevacizumab,(阿帕西普),(阿帕西普),ziv-Aflibercept (阿帕西普): 毒性,Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.,(阿帕西普),mCRC : 二线EGFR 单抗治疗,1. Sobrero AF, et al. J Clin Oncol. 2008;26:2311-2319. 2. Peeters M, et al. J Clin Oncol. 2010;28:4706-4713. 3. Hecht JR, et al. ASCO 2013. Abstract 335.,*Statistically significant difference.,(瑞格非尼),CORRECT: 所有治疗肠癌方案失效后用Regorafenib(瑞格非尼),Primary endpoint: OSApproximately 50% of patients with 4