轉(zhuǎn)移性結(jié)直腸癌治療的新進(jìn)展_Mar_2014_

1、轉(zhuǎn)移性結(jié)直腸癌化療的新進(jìn)展轉(zhuǎn)移性結(jié)直腸癌化療的新進(jìn)展中山大學(xué)腫瘤醫(yī)院中山大學(xué)腫瘤醫(yī)院 內(nèi)科內(nèi)科何友兼何友兼 教授教授n西方國(guó)家中，結(jié)西方國(guó)家中，結(jié) 直腸癌占癌癥死亡第二位直腸癌占癌癥死亡第二位（10%-12%）。）。n發(fā)病率每年遞增發(fā)病率每年遞增4.2%。n外科手術(shù)五年生存率：外科手術(shù)五年生存率：期期90%、期期70%-75%、期期35%-50%、期期 推注nFOLFOX 的療效大致與 FOLFIRI相當(dāng), 但毒性各異n三藥方案(FOLFOXIRI)療效和生存比二藥略佳n合用靶向藥可提高療效, 改善生存n用足三藥(5FU.L-OHP.IRI)者中位生存可超過(guò)2年n維持治療或間歇休息(treat

2、ment holiday)應(yīng)個(gè)體化處理效力和毒性效力和毒性: FOLFIRI vs FOLFOXTournigand et al. JCO 2004. 22:229-237III 期試驗(yàn)期試驗(yàn): FOLFOXIRI vs FOLFIRIMosMosSouglakos(n = 283)43.0 vs 33.68.4 vs 6.921.5 vs 19.5 Souglakos J, et al. Br J Cancer. 2006;94:798-805. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.*Statistically signific

3、ant difference.用足三藥用足三藥 改善生存改善生存: OS (mos) = 13.2 + (%3drugs x 0.1), R2 = 0.85Grothey & Sargent, JCO 20050 10 20 30 40 50 60 70 80Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV LV5FU22221201918171615141312Median OS (

4、mo)Patients with 3 drugs (%)P =.0001First-Line TherapyMultivariate analysis:Effect on OSPFirst-line doublet0.69All 3 drugs0.005 mCRC: 一線治療的中位生存一線治療的中位生存06121824Median OS (Mos) 4-6 mos12-14 mos 15-16 mos20.3 mos19-20 mos5-FU/LVFOLFOX4 or CAPEOXIFL + BevacizumabIFL or FOLFIRI21.5 mosFOLFOX6FOLFIRI + B

5、evacizumab24 mos Gallagher DJ, et al. Oncology. 2010;78:237-248.mCRC: 主要的一線化療效果主要的一線化療效果比較方案比較方案中位中位 PFS, Mos中位中位 OS, MosIFL vs FOLFOX vs IROX16.9 vs 8.7 vs 6.515.0 vs 19.5 vs 17.4XELOX (CapeOx) vs FOLFOX43,47.3 vs 7.719.0 vs 18.91. Goldberg RM, et al. J Clin Oncol. 2004;22:23-30. 2. Colucci G, et a

6、l. 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.分子靶藥物分子靶藥物 (in CRC): 以往臨床研究結(jié)果以往臨床研究結(jié)果nCet(Pan), Bev與化療聯(lián)合均可增效與化療聯(lián)合均可增效.延長(zhǎng)生存延長(zhǎng)生存,可用可用于各線于各線(一一.二二.三三)的治療的治療nCe

7、t(Pan)單藥有效單藥有效, Bev必須與化療聯(lián)合使用必須與化療聯(lián)合使用,兩個(gè)兩個(gè)單抗合用不增效單抗合用不增效nBev.在一線進(jìn)展后用仍可獲生存效益在一線進(jìn)展后用仍可獲生存效益nCet(Pan)只能用于只能用于K-RAS野生型或野生型或G13d突變的病突變的病人人, Bev.的使用不須測(cè)靶的使用不須測(cè)靶n首次皮疹程度反映首次皮疹程度反映Cet(Pan)的療效的療效,與與K-RAS無(wú)關(guān)無(wú)關(guān)nCet(Pan),Bev 用于術(shù)后輔助治療均未證實(shí)有效用于術(shù)后輔助治療均未證實(shí)有效VEGF 和和 VEGF-受體家族受體家族VEGF regulates angiogenesis via interacti

8、on with receptor tyrosine kinases VEGFR-2/KDR and VEGFR-1/Flt-1VEGFR-1(Flt-1)VEGF-AReceptorisoformsLigandisoformsVEGFR-2(KDR)VEGF-BVEGFR-1sAngiogenesisVEGF-E VEGF-CVEGF-DVEGFR-3(Flt-4)Lymph angiogenesistumor metastasesExtracellularIntracellularVEGF-A 165NRP-1PlGFShinkaruk S, et al. Curr Med Chem Ant

9、i-Canc Agents. 2003;3:95-117. Luttun A, et al. Ann N Y Acad Sci. 2002;979:80-93.mCRC: 一線化療一線化療/貝伐單抗貝伐單抗IFL/Bev vs IFL110.6 vs 6.220.3 vs 15.6FOLFOX/Bev vs FOLFIRI/Bev310.3 vs 10.223.7 vs 25.51. 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

10、. 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.Adverse EventIncidence With Bev Across Indications,1 %CommentsGrade 3 ATE2.

11、6nRisk of ATE increased in pts 65 yrs of age or older or with ATE historyGI perforations0.3-2.4Wound complications15nDiscontinue 4-8 wks before surgery; resume 6-8 wks postsurgeryPotential for increased VTE risk controversial; increased risk noted in 1 study but not in others.2,3*Predominantly grade

12、 3.May apply more to NSCLC.When surgery conducted during bev therapy.貝伐單抗貝伐單抗 : 相關(guān)毒性相關(guān)毒性CRYSTAL1FOLFIRI/Cetux vs FOLFIRI9.9 vs 8.423.5 vs 20.0PRIME3-5FOLFOX4/Pmab vs FOLFOX49.6 vs 8.023.8 vs 19.4FOLFOX4/Pmab vs FOLFOX4 (KRAS/NRAS WT)10.1 vs 7.926.0 vs 20.2KRAS WT mCRC: 一線一線EGFR-靶向藥靶向藥nWorse PFS outc

13、ome with panitumumab + FOLFOX4 in mutant KRAS disease31. 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 Eng

14、l J Med. 2013;369:1023-1034. 6. Maughan TS, et al. Lancet. 2011;377:2103-2114. mCRC: 個(gè)體化治療應(yīng)考慮個(gè)體化治療應(yīng)考慮n病變范圍病變范圍n治療目的治療目的 (姑息姑息 vs 可能可能根治根治)n活動(dòng)能力活動(dòng)能力n年齡年齡n合并疾病合并疾病 n以往一年內(nèi)的輔助治療以往一年內(nèi)的輔助治療n分子標(biāo)記分子標(biāo)記n器官器官(肝腎肝腎,造血造血)功能功能n毒性風(fēng)險(xiǎn)毒性風(fēng)險(xiǎn): 活動(dòng)性出血活動(dòng)性出血,蛋蛋白尿白尿,傷口不愈傷口不愈,神經(jīng)病變神經(jīng)病變,過(guò)敏過(guò)敏,n是否方便是否方便n花費(fèi)花費(fèi)/資源資源n病人意愿病人意愿NRA .mCR

15、C: 臨床處理程序臨床處理程序確定治療目的確定治療目的選擇治療策略選擇治療策略決定治療強(qiáng)度決定治療強(qiáng)度病人是否需要病人是否需要(渇望渇望)積極治療積極治療Yes85%No15%KRAS無(wú)法檢測(cè)無(wú)法檢測(cè)野生型野生型突變型突變型5FU/CAPECITABINE+/-Bevacizumab二聯(lián)化療二聯(lián)化療+Bevacizumab二聯(lián)二聯(lián)+Cet二聯(lián)二聯(lián)+Bev二聯(lián)化療二聯(lián)化療+BevacizumabKRAS WT mCRC: 一線一線EGFR vs VEGF單抗單抗nThe primary endpoint of ORR was not significantly different between

16、 treatment arms in the FIRE-3 study (62% vs 58%; P = .183)21. Schwartzberg LS, et al. ASCO GI 2013. Abstract 446. 2. Heinemann V, et al. ASCO 2013. Abstract LBA3506. *Statistically significant difference.PEAK1(N = 285)mFOLFOX6/Pmab vs mFOLFOX6/Bev10.9 vs 10.1NR vs 25.4FIRE-32(N = 592)FOLFIRI/Cetux v

17、s FOLFIRI/Bev10.0 vs 10.328.7 vs 25.0*mCRC: 其它的生物標(biāo)志物其它的生物標(biāo)志物nKRAS G13D1 綜合有關(guān)預(yù)測(cè)和預(yù)后的資料綜合有關(guān)預(yù)測(cè)和預(yù)后的資料 大型隨機(jī)研究抗大型隨機(jī)研究抗EGFR治療無(wú)價(jià)值治療無(wú)價(jià)值nBRAF2,3 預(yù)后結(jié)局很差預(yù)后結(jié)局很差 未見(jiàn)綜合未見(jiàn)綜合 一線治療有關(guān)預(yù)測(cè)資料一線治療有關(guān)預(yù)測(cè)資料nExpanded RAS analysis4,5 10% of KRAS 12/13 野生型腫瘤有其它野生型腫瘤有其它 RAS 突變突變nKRAS exons 3, 4nNRAS exons 2,3,4 抗抗-EGFR 單抗無(wú)效單抗無(wú)效1. Pe

18、eters 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期期 80405 試驗(yàn)試驗(yàn) : 一線化療一線化療

19、 Either Cetux or Bev in KRAS-WT mCRCnPrimary endpoint: OSnSecondary endpoints: ORR, PFS, TTF, duration of responsePatients with mCRC and KRAS WT, ECOG PS 0/1(N = 2900)FOLFOX or FOLFIRI + Bevacizumab q2w ClinicalT. NCT00265850.FOLFOX or FOLFIRI + Cetuximab q1wA third arm with CT + bevacizuma

20、b + cetuximab was closed to accrual in September 2009延續(xù)治療策略上的考慮延續(xù)治療策略上的考慮n增加病變得到長(zhǎng)時(shí)間良好控制病人的數(shù)目n大多數(shù)新治療研究到病人病變進(jìn)展或毒性受限而終止n對(duì)病變得到良好控制病人的策略: 繼續(xù)治療到病變進(jìn)展或毒性而終止 維持治療 治療停息(Treatment holidays)OPTIMOX : 維持維持 or 間歇休息間歇休息OPTIMOX11 Maintenance therapy(n = 620)FOLFOX 4 until progressionFOLFOX 7FOLFOX 7sLV5FU2OPTIMOX22

21、 Chemotherapy-free interval(n = 202)mFOLFOX 7mFOLFOX 7sLV5FU2mFOLFOX 7mFOLFOX 7Chemotherapy-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 : 研究結(jié)果研究結(jié)果n疾控期疾控期, PFS, or OS 無(wú)明顯差異無(wú)明顯差異治療休息治療休息 n維持治療的疾控期維持治療的疾控期, PFS 明顯為

22、好明顯為好n但但 OS 無(wú)差異無(wú)差異 Tournigand C, et al. J Clin Oncol. 2006;24:394-400. Chibaudel B, et al. J Clin Oncol. 2009;27:5727-5733.維持貝伐單抗維持貝伐單抗 : MACRO TrialCapecitabine +Oxaliplatin +Bevacizumabx 6 cycles q3w(n = 241)Bevacizumabuntil progression Capecitabine +Oxaliplatin +Bevacizumabx 6 cycles q3w(n = 239)

23、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)MosXELOX-BevBevPatients at Risk, n 241 239Survival Probability00.250.500.751.00002391913332623303940275460247785211011201813214615159

24、170121931919210208622622738636BevXELOX-Bev Diaz-Rubio E, et al. Oncologist. 2012;17:15-25.HR: 1.05 (95% CI: 0.851-1.295)間歇休息間歇休息 : GISCAD TrialCR, PR, SDPreviously untreated mCRCRANDOM I ZAT I ONFOLFIRI x 2 mos2:1FOLFIRI x 2 mosEVALUATEProgression: Off TrialBreak x 2 mos then FOLFIRI x 2 mosFOLFIRI

25、x 4 mos Labianca R, et al. Ann Oncol. 2011;22:1236-1242.146147757025271091461479510139431013Pts at Risk, nContinuousIntermittentMos0Patients (%)061218Mos100806040200Patients (%)6121824303613012460681929 Labianca R, et al. Ann Oncol. 2011;22:1236-1242.OSPFS100806040200間歇休息間歇休息 : GISCAD TrialContinuou

26、s armIntermittent armEvents145143Totals146147Continuous armIntermittent armEvents145143Totals146147Arm 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

27、 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 q2wGiantonio BJ, et al. J Clin Oncol. 2007;25:1539-1544.Stratified by ECOG performance score 0 vs 1 or 2; previous XRTE3200: 二二線用貝伐單抗線用貝伐單抗 for mCRCAlive, nDead, nMedian, MosTotal, nA: FOLFOX4 + bevac

28、izumab2862543212.9B: FOLFOX42912642710.8C: Bevacizumab2432192410.2Giantonio BJ, et al. J Clin Oncol. 2007;25:1539-1544.E3200: 在以前治療過(guò)的在以前治療過(guò)的 mCRC FOLFOX + Bev 改善改善 OSOS (Mos)Probability00.81.061218243036HR: 0.76A vs B: P = .0018B vs C: P =.95ML18147 (TML): 進(jìn)展后繼續(xù)用貝伐單抗進(jìn)展后繼續(xù)用貝伐單抗nA randomized

29、, open-label phase III intergroup studyStandard 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)(

30、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: OSML18147 (TML): 改善改善 OS (ITT)OS (%)MosCT (n = 410)BEV + CT (n

31、= 409)1008060402000 6 12 18 24 30 36 42 48Unstratified* 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 la

32、st dose of BEV ( 42 days, 42 days), ECOG PS at baseline (0, 1).Bennouna J, et al. Lancet Oncol. 2013;14:29-37.100806040200PFS (%)0 6 12 18 24 30 36 42MosUnstratified* 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)一線治療后繼續(xù)用血管生成抑制劑一線治療后繼續(xù)用血管生成抑制劑

33、 ?(阿帕西普阿帕西普)(阿帕西普阿帕西普)III期期 VELOUR 研究研究: FOLFIRI ziv-Aflibercept 二線治療二線治療 mCRCnPrimary endpoint: OSnSecondary endpoints: PFS, ORR, safety, immunogenicitynNo correlativesPatients with mCRC progressing on first-line oxaliplatin-based chemotherapy*(planned N = 1226)FOLFIRI + ziv-Aflibercept 4 mg/kg q2w

34、(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.(阿帕西普阿帕西普)VELOUR 研究研究 : 生存結(jié)果生存結(jié)果 Van Cutsem E, et al. J Clin Oncol. 2012;30:

35、3499-3506.OS (%)100806040200Mos0369 12 15 18 21 24 27 30 33 36 39Stratified HR: 0.817 (95.34% CI: 0.713-0.937; log-rank P = .0032)Placebo/FOLFIRIMedian: 12.06 mosAflibercept/FOLFIRIMedian: 13.50 mosPFS (%)100806040200Mos036912151821 2427 30Stratified HR: 0.758 (95% CI: 0.661-0.869; log-rank P .0001)

36、Placebo/FOLFIRIMedian: 4.67 mosAflibercept/FOLFIRIMedian: 6.90 mos(阿帕西普阿帕西普)(阿帕西普阿帕西普)VELOUR 研究研究 : 按貝伐單抗分層按貝伐單抗分層OS Tabernero J, et al. Eur J Cancer. 2013;Epub ahead of print.OS (%)100806040200Mos0369 12 15 18 21 24 27 30 33 36 39HR: 0.862 (95.34% CI: 0.673-1.104)Placebo/FOLFIRIMedian: 11.7 mosAfli

37、bercept/FOLFIRIMedian: 12.5 mosPts at Risk, n PlaceboAFL18718617017813815011512181895459373622221313Previous BevacizumabOS (%)100806040200Mos0369 12 15 18 21 24 27 30 33 36 39HR: 0.788 (95.34% CI: 0.699-0.927)Placebo/FOLFIRIMedian: 12.4 mosAflibercept/FOLFIRIMedian: 13.9 mosPts at Risk, n PlaceboAFL

38、4274264033883473482862952052221391579411265823862No Previous Bevacizumab(阿帕西普阿帕西普)(阿帕西普阿帕西普)ziv-Aflibercept (阿帕西普阿帕西普): 毒性毒性Increased Grade 3/4 AEs in Aflibercept Arm, % FOLFIRI + Aflibercept(n = 611)FOLFIRI + Placebo(n = 605)Any83.562.5Diarrhea19.37.8Asthenia16.910.6Stomatitis/ulceration13.75.0Infe

39、ction12.36.9Palmar-plantar erythrodysesthesia2.80.5Neutropenia36.729.5Thrombocytopenia3.31.7 Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.(阿帕西普阿帕西普) mCRC : 二線二線EGFR 單抗治療單抗治療EPIC1Irinotecan/Cetux vs Irinotecan4.0 vs 2.6*10.7 vs 10.0SPIRITT3FOLFIRI/Pmab vs FOLFIRI/Bev7.7 vs 9.218.0 vs 21.41. S

40、obrero 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.(瑞格非尼瑞格非尼)CORRECT: 所有治療腸癌方案失效后用所有治療腸癌方案失效后用Regorafenib(瑞格非尼瑞格非尼)nPrimary endpoint: OSnApproximately 50% of patients with 4 systemic therapies All patients had received bevacizumab