NCCN非小细胞肺癌指南解读.

1、2008年NCCN非小细胞癌指南扁决上海市胸科医院NCCN*NgQL r“hl oi Cor j、上海市肺部肿瘤临床医学中心陆舜打記兽鳥色豐先08o nSm a 11 Cell Lung Cancer Summary of tho GuidoliiwUPatosThe 2.20M vrKn of tht HotvsmaN Co Cancvr GukMiiws rvpreswnte tlw Mdkicn of the updated luscriptSunitruvy ol Ute cltdiiyes i tlie U008 veraion of (be Mon-snidll Ceil Lung

2、 Cncw gukMhwt from the 1 JOO? v*r%kMi Includ# ThelMth tuMe wa recnovocl from MLung Cancer Prevention and Screening*. The guidtones were clarified that the NCCN panel does not rwconwnevwi the routine use* of 9 screenlig CT Yh emiK wm addtfd lht If crOThg CT itratvyy hb UMd. Clwr l-CLCAP tcreining pro

3、tocol should be followed (PREY-U、Thegory of medically inoprbUM was Added whh referral tc pagv NSCL-B for tratmnl rcammtndaton OiSCL 2) Ad)MVAnt TrMtmtnt (NSCL-31;a Fotnot IT is new to the w Stage IA mrg ns negative - the recommendation forcl vrvKlhvf|y lor hl# rink ptivnt* chmiued to CMlvyory 3 Stdg

4、e IA margins positive the reccnirTitaidtlon fotc卜mothefjpy Alterwas charod to a cfl9ocy 3 Cliwnotherapy was added as an option after chemoriidUtlon RT alone was added a a trtatmnt opticn Stag* HUk.vnurglM negtl the recommendation for cbemradiation fallowd by ciimothtrapy urae rmovd MdlM(inal RT was

5、added to chemotherapy. Adjuvant Treatment (N,CJL footnoto F trw doso was changed from 44-46 Gy to 45-50 Gy. Tli* rcommend*tloi for my wn chand Io pathQlonic rMdiastmal lymph node evaluation with fotnott cfescnbing the typ of evaluation (NSCL-6) Footnote r h nw Io png N3CL*Z und a cfgory 3 dMignahon

6、was addad to *Conidar surgical rMoctlonM If tho paltoni Ims an excellent response stiar definitive chemoradiation. ForBIB (resel4ible ottwr than stelHte) thereccmrmridation forchmothrapy following chemoeadtation was addd for R1, R2 diBMM oftor Inlttal treatment with surgery tHSCL-er P solitary br ji

7、n metactcoc. 金ehangod to for RT nd dfined at whole brain or eterootnetle radiosurgery |HfiL 11) The Surveillance recommendations ar for vcry 44 m* for 2 y and a category 2B doaignation was ddd (NSCL 12) Therapy for RecurrtMtce wild Metdstdis 1NSCL-13L The criteria was daflHed for trMtnwnt with bevac

8、lxumab The Pdormance status 2 pxtlwtB were mowd from the grouping with PS 0 and 1 patterns and tholr recommended treatment is chemo Foonoo*W 9 clwiflcatteMi w” ddd ttiat bvaclniniat) should not bo ucod at a inglo agent, unlocs as main to no neo 11 initially usod with charnetborapy*. Principles of Su

9、rggvd to*bould rvcvlvvpottnoally curative RT as their local approach.* Prlnciplos Gf Rad iatlon The rap/ INSCL-Ck this section was r W and updated. Chomothonpy Roglmnc for /td|uvant Therapy (NSCj 4 1 cf ): Two Ubls were acid with drug and dosing rwgimont for wOtber acceptable Cloplalin-baMd Regimens

10、M and Clietnothwapy Revlnieii* foe patients whli comofbldltles of not dble io tokrrjte cisplMin*. Chemothenpy RpmaM UMd with Radiatton (NGVlD J_fif J： The cHphtlnietopotlde and eliplattnMnblatfine regimen w I4m1 proUrrxi npi3tln regimen Concurrent chemoWierapyJRI 心lowed by ehemotherapy - cetegory 3

11、designation wa added to dsplotlnelopoiid* end category 2B designation wns added co paclita carbo pl Mln Systernlc Therapy for Advanced or Metastatic Disease (NSCL E = of 2J： A hullet acktod *lf patient with a known dcfivt EGFR rmitationor ne amplification and a never smoker, consider u&o of car loti

12、n ib chemotherapy.* GuidalinftA for the mannomM)t of ThymicwareMclctecl (IHIlfcU.2008 NSCLC指引更新要点:辅助治疗 2008版：推荐IA期、切端阴性，具有高危因素的患者术后化 疗3级共识 2007版：2B级共识 2008版:推荐IA期、切端阳性,具有高危因素的患者，再次 手术后术后化疗-3级共识。化疗可以作为化放疗后的选择 2007版：2B级共识高危凶索：分化羞,肿瘤侵犯血管.帥叶契形切除,病灶与切端近 2008版：IIIA期、切端阴性患者一化疗（1类）+纵隔放疗 2007版：IIL入期、切端阴性患者化疗

13、（1类）或化疗+纵 隔放疗（2B类共识） 2008版:IIIB期患者（可手术切除但不是有卫星结节）， 切端R1：化放疗+化疗；切端R2,同步化放疗+化疗 2007版:切端R1；化放疗;切端R2,同步化放疗切端R1：显微镜卜肿瘤钱存：切端R2肉眼见肿痫残存NCCNePractice Guidelines in Oncology - v.2.2008Non-Small Cell Lung CancerMniAl TRFATMFNT FINDINGS AT SURGFRVStage IB12. NOSUqe IAMargins poilttw (R1 R2)FM virgin s ncyuUve (

14、ROjfposit iw (R1 R2)fMargin,/ ”9耐匕(RO)1Margns posittw(R1 R2)Mo advorso factorsAernorMlia6ci * (cUrcry 28) chrmthfd*y Re resect ion chemotherspyJ orClwinorjKliBticvtM Mt diwnotlivfiip/ Chemotherapy ( CtawrnorMliAtjceiM *i* chMnotfivftfp/SurveiiiaieNSCl 12*RU- ppmOuq lur-wr.Ri - mtosc-Gpic TCiaa tumor

15、. R2 - mocrejcwc tuF*or.CAdvcw (c8旳 cctuOo.wo fndistdl iynp edo Swctv叫mjcapMjA screed.posH/e hikf nogs dos nwpgvi patarlB dWhoO br pxirly dftermbvd iurw, vaKdur hvaUan. w ozo psecilg ninimai mjrgifw.2008 NSCLC指引更新要点：辅助化疗的方案 2007版：顺锂+心存瑞滨；顺I0+VP16；顺钳+VDS 2008版:原來的基础上增加了2个方案-健择+顺钳、多西他赛+顺釦对于有合并症、不能耐受顺钳

16、的患者采用:健择+卡钳、紫 杉醇+氏钳、多西他赛+1二钳、多西他赛+健择NCCNPractico Guidclinos in Oncology 一 v22008Non -Small Cell Lung CancerCHFMOTMFRARY REGIMRtna dy 1： VinoolbifMi 25-30mQim7days 1 CiBpiatin q00mans uy 1CkSfHMin 80 rngn?on i、y 1.22, 43. 6* based RegimensSclwdukCwpiatin BO mg m2 on dy 1Gemcitabine 1000on days 1v 8Ev

17、ery 21 days11Cicpiattn IS mgm2 OOMtaxei 75笆 wy 21 dayc Every days for 4 cyclweEvary 28 days For 4 eyelebcfevery 21 day* for 4 eyclM*Every 28 days for 4 eyclMbCheniotlvwpy RwgiitBMiB for pjilivut* with coinotbklitieB or pMme not able to totorM# chiplstlnSchedul.OvcvkAhMiw 1000 mnon dyt 1. B. 15CMtC0l

18、dtin AUC 5 on day 1Evitrx ?8 cUy for 4 cychfJPiicliUx*! 200 rn/m2 on day 1Carbcplatln AUC 6 oti ddy 1Evvry 21 daydDocetaxel 75JCMbcphtinAUCGEvry 21 days9GcndKaMne 1000 mm2ctys 1.8 Docgi BO mfnZciay Every 21for 8 c/dSee 如粉“ on DM。NSCLP (2 5 31亡 Chf? :io?y lji,Qr HSCL-D fl of H1N9CLD 、of ?1990 2000NSC

19、LC的术后辅助化疗历史、现状许多III期随机临丿木研究的结果都足阴性 1995: NSCLC合作组织的Meta-分析2000后许多III期随机临床研究获得阳性的结果 2006:顺钳用于帅強辅助化疗评佔研究(LACE)的Meta分析 2006: LACE研究中口春瑞滨的Meta分析KHI908()70605040302010观察组在NSCLC中含钳术后辅助化疗95荟萃分析(BMJ1995)HR= 0.87| P= 0.08f5%获益含钳化疗方案组含钳术后辅助化疗和术后观察在IAJIIA期N=1867 I期川期完全手术切除v60天New Engl J Med 2004; 350:351-60NSC

20、LC中的随机对照研究(IALT)含钳术后辅助化疗和术后观察在IA-IIIA期NSCLC中的对照研究(IALT)02年45(x)80604020n(金)曹頑辅助化疗中位75年的随访结果012345678 yearsAt risk 935 9326556865175654374803764233213542482671811901091238 years 935 775 619 520 447 372 282 208 125932 780 650 550 487 399 300 208 133At risk-935 695 553-932 704 591464 400 343501 446 367

21、267277194 118196 127第二原发肿瘤201193121123764772425474935932604639358383272282496539At risk非肺癌死亡率(oouopo匚一a)4B-nEnoHR: 1.34NSCLC手术后标本中ERCC1 （免疫组化） IAI.T （国际肺癌辅助化疗研究）研究中可用于术标 本为761例 1867例I-III期完整丁术切除的NSCLC患者，随机接受观 察或EP方案化疗或长春瑞滨用ERCC1的单克隆抗体进行免疫染色，通过2个双盲的病 理医生检查根据中位值，将ERCC1分为高表达与低表达2组Ohussen, Dunontet al.：

22、 N Engl J Med, 2006 JA All PUwnUP = 0.09No. at l&skChemocheopy 3S9 Ml U1 206 bO1CothqI)7?)1?247I&Years黄)3 =S6-soNo. at RKkChe noth? rapr 224194161121SIControl2021631209159Years4/J5C Pabeots with EKCCl-Ncf atwe TumorsUS14?121tsu14Ct RiskChrTKJthrfapy 224”81411047542Coatvol2021421M734826No M 2Bwith ER

23、CCbNtive TumorsOlatissen, Dtmant et al. N Engi I Med. 2006ERCC1 表达(IHC)2008761名病人，交叉试验P二0.02CT vs ControlERCC1阴性HR 0.76 0.59-0.98ERCC1 阳性HR 1.200.91-1.59小结随访结果肯定了辅助化疗在术后5年的疗效-5年之后的疗效差异的减少提示可能由于化疗引起的 相关死亡的发生 ERCC1仍然可以被认为是化疗获益的一个预测因子有待进一步的辅助化疗临床的长期随访机化IB期和II期NSCLC长春瑞滨联合顺钳术后辅助化疗对照术后观察的临床研究(BR.10)(完整切除)

24、T2N0 (IB) T1-2N1(II) NSCLCWinton N Engl J Med 2005; 352:2589-97IB期和II期NSCLC长春瑞滨联合顺钳术后辅助化疗对照术后观察的临床研究(BR.10)长春瑞滨/DDP组获得了更长的总体生存期(94 vs 73 月)长春瑞滨/DDP组获得了更高的5生存率(69% vs 54%)死亡风险降低30% (p=0.012) 59%的恵者接受了 3个以上的化疗周期可以接受的毒副反应和感觉神经障碍Winton N Engl J Med 2005; 352:2589-97泰素联合卡钳进行IB期NSCLC术后辅助化疗的随机对照研究(CALG9633

25、)卡钳(AUC=6) 泰素(200mg/m2) 4疗程/12周观察T2N0M0 (IB) NSCLC(完整切除)Strauss Proc ASCO 2006; 24:365泰素联合卡钳进行IB期NSCLC术后辅助化疗的随机对照研究(CALGB 9633)ASCO 2006 更新中位随访期54个月 5年生存率-泰素/卡钳：60%-观察：57%(p=0.32) 3-年生存率一泰素/卡钳：79%一 观察：70%(p二0.045)无疾病进展期：HR 0.74 (p=0.02)Strauss Proc ASCO 2006; 24:365长春瑞滨联合顺钳在IB期IIIA期N SCLC中进行术后辅助化疗的随

26、机对照研究(ANITA) 840例接受了完整手术切除的IB期IIIA期NSCLC患者 随机化：长春瑞滨(30mg/m2/周)+ DDP (100mg/m2每4周)x 4个 周期vs观察中位生存期66 vs 44月5年 生存率IBNIII 东体化疗组62%52%42%51%观察组63%39%26%43%Douillard Lancet Oncology 2006;7:719-27顺釦用于肺癌辅助化疗评估(LACE)5项随机研究人4,584例患者的资料进行分析入选标准完整手术切除的NSCLC患者以顺钳为基础的化疗vs.未化疗或以顺钉I为基础的化疗+术后放疗(PORT)vs 术后放疗主要研究目的以顺

27、tn为基础化疗后的生存期2006年关于以顺钳为基础辅助化疗的meta 分析LACE:生存情况研究死亡人数 /入组人数Hazard ratio(化疗组/对照组)HR 95% ClALPI569/1088F0.95 0.81 ;1.12ANITA458 / 8400.82 0.68;0.98BLT152/3071.00 0.72;1.38IALT980/18671 T0.91 0.80J.03JBR10197/482:r0.71 0.54;0.94Total2356 /45840.89 0.82;0.960.00.51.01.52?0Chemotherapy better | Control be

28、tterTest for heterogeneity: p = 0.34化疗对生存期有明显影响p=0.004LACE:生存曲线Chemotherapy No chemotherapyAbsolute differenceat 5 years:5.3% 1.6%()要己弓604020ooat 3 years:3.9%土 1.5%61.057.148.81234Time from randomization (Years)5年绝对生存获益：5.3%NSCLC辅助化疗Meta分析:MRC收集辅助化疔进行Meta-分析（Stewart#P7552） 30项随机临床研究（共37项研究）包括8147例患者

29、所有随机患者的95% （37项研究） 22项研究以顺钳为畢础（1888例患者接受NP方案）+ K：存尼生物碱/鬼臼乙义试（11项研究）+ tegafur / UFT （7 项研究）+ Jt他方案（4项研究）8项研究为不含顺钳的抗代谢药物Tegafur / UFT （7项研究）Tegafur / UFT与其他与药物（1项研究）中位随访时间超过5.3年ASCO07 NSCLC Neo/Adj - PHO MANSCLC辅助化疗Meta分析:MRC绝对获益绝对改变VS基线2 YEARS2%80%82%5 YEARS4% (2%-4%)60%-64%8 YEARS5% (2 %7%)50%55%5年生

30、存率提高4%相当于死门率降低13%ASCO()7 NSCLC Neo/Adj 一 PFO MANSCLC辅助化疗Meta分析:MRC结呆HR (95% CI)P 值研究数目生存期0.86 (0.81-0.93)ica/2U03;14：116; Dpierte et a1./CO20020:247;PhT ei 心 P.SCO 2005,LBA7012Ch.E.S.T研究设计化疗后3 6周内匸术ScdgLotta GV et 1 Cim Oaeo】20. 26 Stpl Abs 7508Ch.E.S.T研究结论新辅助化疗耐受性良好 85%?rt人接受了 3周期化疗 92%病人接受了至少2周期化疗

31、新辅助化疗缓解率为35% S9900研究：41% LU22研究：49%结果由于早期截至所以有所限制新辅助化疗绍较单纯于术红|3年PFS增加5%（3年OS増加7%）新辅助化疗的显苦:性优势只期亚组得到体现ScaUoth GV t 4.1 Clin Oncol 20：8. 26 Sippl Ab： 7508不可手术的局限晚期N SCLC 80年代:化疔一放疗优r放疗MST捉高3 4月CALGB8633 与 RTOG/ECOG8808/458890年代：同步化放疗优于化疗一放疗MST捉陆3 4丿WJLCG 与RTOG9410本世纪：人部分思者预后牧怎MST 15-17 月大部分患者死于转移2008

32、NSCLC指引更新要点：联合放疗时的化疗方案 2008版：同步放化疗后的巩固化疗：顺钳+VP16 联合放疗后加多西他赛巩固化疗-3类共识，紫 杉醇+ R钳联合放疗后加紫杉醇巩固化疗-2B类 共识 2007版：为2八类共识 2008版：同步化放疗时采用的化疗方案：顺钳+VP16、顺钳+VDS作为“推荐(preferred) ” 紫杉醇+卡钳方案作为2B类共识 2007版：未标明Concurrent Chemotherapy/RT Regimens*Cuphtln 50 mg In%2 on day 1. 8, 29. ond 36FiftpoiW 50 mfl*n2d*yopMli)AUC =

33、2ovr 30 mln weeMlyConcurrent thoracic RT 63 Gy/7 w1(s34 Fractons0 (category 2B)Sequential C hemotherapy J RT Roglnpladn AUC 6. 2 cyclMfoilowed by thoracic RT Q Gye beginning on day 42NCCNBPractice Guidelines in Oncology - V.2.200S,亠r. -l 川.?Non-Small Cell Lung Cancer込CHEMOTHERAPY REGIMENS USED WITH

34、RADIATION THERAPY (3OF 3)*R*rMorTijd dau11 doeen overcait(ik629O3Coneurmnf t hot a etc RT (toUI dOM. G1 Gy)4PacKaxel 4S-W mgim2 woXlyCsrtooplatln AUG 2. eoMurrent thoracic RT 63 Gyfollowed by 2 cycles of pack tax* 1200 gmandcaropUtin AUCE (category 2B)Altaen KS. Cnmfeiy Jl Tirr*iAT II. tal Cururreit

35、 dscuil* eMxmiiB. mdcties? ft otferwjr n palhcAjgc IB ncrTuiB.r sr-allla rancor aoaptiaM httwrapy in rag* IIB non.na luftg enecr prata n Sup Slud x S96O4 J Cin Oncol 208 i(10X200A-2Cr 0.Ict. Aiar c csgc|r 2A !(*% otndci HBCL-DClin&lMCO4 baiivBthatOi bast rwfMr ent el May c w X Hr4cal Id乙.la citfcal

36、iala $Uy rwearMl.不可手术的NSCLC序贯放化疗生存期病中位3 年CALGB #84-53化疗+放疗组7814 mo24%单独放疗组7710 mo10%Sause (RTOG)化疗+放疗组15114 mo13%单独放疗组14911 mo9%超分割放疗组15212 mo14%Le Chevalier化疗+放疗组17612 mo12%单独放疗组17710 mo4%SWOG在病理分期111b NSCLC中的临床试验研究病例数中位生存期（月）2年生存率3年生存率S9019501534%17%（PE化疗/放疗9(10-22)*(21- 4刀*(7-27)*PE化疗）S9504832654%37%（PE化疗/放疗9 泰素帝化疗）(18-35)*(43-65)*(22-52)*95 1分烁 PS 0-1 vs. 2 Cis 50 iiig/m2 lv day 1, 8, 29, 36 Etp 50 rr/m2 iv day 15 & 29-33 Concurrent RTE 59.4 Gy (18 Gy/ )Doc 75 mg/m2 q 3 wk X 3观察目标:检测总生存期从19个 月提高至25个月主要终点：总生存期次要终点：无进展生存期，毒性反应 in A vs. IHB CR vs. iiojv-CR组ASC02007-