课件：转移性结直肠癌治疗的新进展_.ppt

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5%。 大约30%-40%发现时已属局部晚期或转移。 50%病人最终死于本病。,结直肠癌 : 诊断时的分期,National Cancer Database.,转移性结直肠癌化疗,化疗药物, 化疗方案; 首次治疗; 个体化用药策略 根据生物标记物选择; 较新靶向药物; 进展后的延续治疗 小结,MCRC : 有效药物,*雷替曲塞(Raltitrexate)也是有效的嘧啶类药物,常用结直肠癌化疗药物作用机制,TS（胸苷酸合成酶）,嘧啶结合部位,叶酸结合部位,雷替曲塞与5-Fu区别,雷替曲塞的临床应用,雷替曲塞单药一线治疗转移性结直肠癌的期临床试验,雷替曲塞单药与5-FU/LV等效，毒副反应低,ap=0.48,bp=0.896,cp=0.896,dp=0.42,ep=0.158,fp=0.197 Therapy=化疗方案，CR+PR=客观有效率，Median Survival=中位生存期(月)；Raltitrexed=雷替曲塞，LDLV=低剂量亚叶酸钙，HDLV=高剂量亚叶酸钙。,2、D. Cunningham. British Joumal of Cancer (1998) 77(Supplement 2), 15-21,雷替曲塞联合方案:期试验,研究方案,复发转移的大肠癌 n=216,R,雷替曲塞 3mg/m2, iv gtt., 15min , 21d重复 奥沙利铂 130mg/m2, iv gtt., 2h ,21d重复,亚叶酸钙 200mg/m2,iv gtt.d1-5，21d重复 5-Fu 375mg/m2,iv gtt.4h,d1-5,21d重复 奥沙利铂 130mg/m2,iv gtt.d1，21d重复,主要疗效指标：肿瘤客观有效率 次要疗效指标：疾病控制率、疾病进展时间、总生存期,王佳蕾、李进、秦叔逵等。临床肿瘤学杂志，2012,17（1）：6-11,雷替曲塞联合奥沙利铂治疗复发转移结直肠癌,客观有效率,p=0.0400,p=0.3368,p=0.0448,初治病例中与5Fu/CF等效 复治病例中与5Fu相比为优效结果。（不完全耐药）,P= 0.0427,至疾病进展时间(TTP),试验组：雷替曲塞+奥沙利铂 mTTP=260(108 587),对照组：5Fu/CF+奥沙利铂 mTTP=216(70 407),总生存时间,试验组：雷替曲塞+奥沙利铂 mOS=306(206 401),对照组： 5Fu/CF +奥沙利铂 mOS=328(183 689),不良事件,雷替曲赛临床应用特点 (1),作用强 雷替曲赛对其他叶酸盐依赖性靶酶如甘氨酰胺核甘酸转化酶或二氢叶酸还原酶无抑制作用，对胸苷酸合成酶（TS）的抑制作用为二氢叶酸还原酶的100倍。,雷替曲赛临床应用特点 (2),耐受性好 5-fu最严重的副作用是粘膜炎，雷替曲赛发生3-4度粘膜炎的发生率2-3%，显著低于5-fu/亚叶酸钙的发生率（为10%）。 雷替曲赛发生3-4度白细胞减少的发生率6-18%，为5-fu/亚叶酸钙的一半（为13-41%）。,雷替曲赛临床应用特点 (3),患者依从性好 雷替曲赛推荐剂量为3mg/M2,15分钟静脉滴注，每三周一个疗程。故雷替曲赛的用药方案明显由于5-FU/亚叶酸钙的每4周连续5天的用药方案。给患者带来更大便利。,雷替曲赛临床应用特点 (4),抗肿瘤谱广 雷替曲赛除对结直肠癌有效外，临床试验中单药或与其他抗肿瘤药及化疗联用，对其他多种肿瘤（如乳腺癌，胰腺癌，非小细胞肺癌，难治性卵巢癌）有效。,结 论,综上所述：雷替曲赛作为近几十年来第一个新的一线细胞毒治疗药，可成为5-FU为主的化疗方案的较好替代药。他的问世可为医生和患者提供更多选择。为患者带来方便，治疗效益显著。,mCRC化疗 : 二药联合,mCRC : 化疗50年,5FU静脉持续灌注 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/Toxicity 5FU/LV Irinotecan Oxaliplatin RR(first line) 56% 54% OS(mo) 21.5 20.4 G3/4 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 2005 11 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 + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 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, 4 NRAS 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: OS Secondary 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 + Bevacizumab x 6 cycles q3w (n = 241),Bevacizumab until progression,Capecitabine + Oxaliplatin + Bevacizumab x 6 cycles q3w (n = 239),Capecitabine + Oxaliplatin + Bevacizumab until progression,Patients with newly diagnosed mCRC 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 arm Intermittent arm,Events 145 143,Totals 146 147,Continuous arm Intermittent arm,Events 145 143,Totals 146 147,Arm C Bevacizumab (n = 243),Arm A FOLFOX4 + Bevacizumab (n = 286),Arm B FOLFOX4 (n = 291),Patients with previously treated mCRC; no previous bevacizumab (N = 820),FOLFOX4 Oxaliplatin 85 mg/m2 on Day 1 q2w 5-FU 400 bolus/600 mg/m2 IV on Days 1 and 2 q2w LV 200 mg/m2 on Days 1 and 2 q2w Bevacizumab 10 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: 0.76 A vs B: P = .0018 B 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 or irinotecan 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 ?,Bevacizumab ziv-aflibercept (阿帕西普),(阿帕西普),III期 VELOUR 研究: FOLFIRI ziv-Aflibercept 二线治疗 mCRC,Primary endpoint: OS Secondary endpoints: PFS, ORR, safety, immunogenicity No 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/FOLFIRI Median: 12.06 mos,Aflibercept/FOLFIRI Median: 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/FOLFIRI Median: 4.67 mos,Aflibercept/FOLFIRI Median: 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/FOLFIRI Median: 11.7 mos,Aflibercept/FOLFIRI Median: 12.5 mos,Pts at Risk, n Placebo AFL,187 186,170 178,138 150,115 121,81 89,54 59,37 36,22 22,13 13,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/FOLFIRI Median: 12.4 mos,Aflibercept/FOLFIRI Median: 13.9 mos,Pts at Risk, n Placebo AFL,427 426,403 388,347 348,286 295,205 222,139 157,94 112,65 82,38 62,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