晚期非小細(xì)胞肺癌一線化療后的治療策略

晚期非小細(xì)胞肺癌一線化療后的治療策略安徽醫(yī)科大學(xué)第一附屬醫(yī)院腫瘤內(nèi)科陳振東chenzhendong@什么叫晚期肺癌？一線化療后可能有幾種情況？一線化療后的治療有哪些選擇？ASCO：thetreatmentofstage

4NCSLC什么叫晚期肺癌？不可手術(shù)的Ⅲ期Ⅳ期一線化療后可能有幾種情況？進(jìn)展穩(wěn)定、稍有縮小或難以精確測(cè)量部分或完全緩解發(fā)現(xiàn)了新病灶，但不能肯定為進(jìn)展目標(biāo)病灶與非目標(biāo)病灶的反應(yīng)不同化療有效但因?yàn)獒t(yī)療或非醫(yī)療的原因改變治療一線化療后的治療：不同的情況維持治療是指在完成標(biāo)準(zhǔn)的幾個(gè)周期化療且疾病得到控制后再接受的化療。理論基礎(chǔ)：GoldieandColdman假設(shè)，早期使用非交叉耐藥的藥物可以在耐藥性產(chǎn)生前增加殺傷腫瘤細(xì)胞的效能。使治療效果最優(yōu)化，殺死更多的腫瘤細(xì)胞。完全緩解、部分緩解或者疾病穩(wěn)定的患者最有可能從維持治療中獲益。但同時(shí)也延長(zhǎng)了治療時(shí)間，且化療的毒性反應(yīng)可在體內(nèi)蓄積，導(dǎo)致過(guò)度治療。一線化療失敗后的治療嚴(yán)格意義上屬于挽救治療，但兩者并沒(méi)有本質(zhì)區(qū)別。一線化療后的治療有哪些選擇？放療中醫(yī)藥治療及最佳支持治療化療分子靶向治療聯(lián)合治療放療

有下列情況者一般不做根治性放療：兩肺或全身廣泛轉(zhuǎn)移胸膜廣泛轉(zhuǎn)移有癌性胸腔積液癌性空洞或腫瘤巨大嚴(yán)重肺氣腫心包或心肌有癌瘤侵犯者伴有感染，抗炎治療不能控制肝、腎功能嚴(yán)重受損，KPS<60分者。姑息放療可能有價(jià)值（心理支持、老年人）藥物維持治療二線細(xì)胞毒藥物，并非都是單抗類靶向治療藥物表皮生長(zhǎng)因子受體酪氨酸蛋白激酶抑制劑聯(lián)合治療

PemetrexedJuly6,2009—FDAhasapprovedpemetrexedforthemaintenancetherapyofadvancedormetastaticNSCLC.Pemetrexedisthefirstdrugindicatedasamaintenancetherapyinthissetting.JMEN研究，patientsreceivedeitherpemetrexed(n

=441)orplacebo(n

=222),alongwiththebestsupportivecare.Patientshadadvancedormetastatic(stage

3Bor4)NSCLC(bothsquamousandnonsquamoussubtypes)thathadnotprogressedafter4cyclesofinitialplatinum-basedchemotherapy.Forallpatientsinthestudy,thepemetrexedtreatmentgrouphadanoverallsurvivalof13.4months,comparedwith10.6monthsfortheplacebogroup.Forthenonsquamoussubgroup,overallsurvivalwas15.5monthsforpatientstakingpemetrexedand10.3monthsforpatientstakingplacebo(P

=.002).thetrialwasnotdesignedtoindicatewhethermaintenancetherapywassuperiortousingpemetrexedattimeofdiseaseprogression.don'tthinkwehavetheanswerastowhenitisbesttostartpemetrexed.Shouldwestartimmediatelyafterstandardchemotherapyorlateron?多西紫杉醇第一個(gè)被認(rèn)可的二線治療藥物。Fidias等，進(jìn)展期NSCLC，4周期卡鉑聯(lián)合吉西他濱的誘導(dǎo)化療后，對(duì)治療有反應(yīng)或者穩(wěn)定的患者隨機(jī)分成2組，一組立即接受多西他賽，另外一組于疾病進(jìn)展時(shí)接受多西他賽作為挽救治療(延遲組)。結(jié)果：立即組的總有效率高于延遲組(42．5VS9．9)；中位生存時(shí)間，立即組為11．9個(gè)月，延遲組9．1個(gè)月，但無(wú)統(tǒng)計(jì)學(xué)意義；中位PFS，立即組為6．5個(gè)月顯著高于延遲組2．8個(gè)月(P<0．0001)，生活質(zhì)量評(píng)估兩組無(wú)顯著性差異。分子靶向藥物：厄洛替尼SATURN，889例一線化療后疾病未進(jìn)展的晚期NSCLC患者，隨機(jī)分組后給予150mg/d維持治療或安慰劑，直至疾病進(jìn)展。維持治療顯著改善了患者的PFS，疾病進(jìn)展風(fēng)險(xiǎn)顯著降低了29%，其中EGFR免疫組化（IHC）陽(yáng)性患者疾病進(jìn)展風(fēng)險(xiǎn)降低31%。無(wú)論年齡、種族、病理類型和吸煙史如何，均可從維持治療中顯著獲益。EGFR突變者疾病進(jìn)展風(fēng)險(xiǎn)大幅度降低90%，野生型患者降低22%。分子靶向藥物：厄洛替尼SATURN，維持治療顯著延遲了疼痛癥狀的出現(xiàn)，對(duì)其他各生活質(zhì)量指標(biāo)也無(wú)不利影響。在維持治療組中發(fā)生率超過(guò)10%的不良反應(yīng)僅有皮疹和腹瀉，但達(dá)到3～4級(jí)的比例很低?；颊呓?jīng)一線化療后仍有癥狀（如咯血、胸痛和胸悶等），維持治療的價(jià)值最大。分子靶向藥物：吉非替尼日本，WJTOG0203研究，一線化療后疾病未進(jìn)展的晚期NSCLC患者給予吉非替尼維持治療或安慰劑，結(jié)果維持治療組PFS有顯著延長(zhǎng)，但OS未見(jiàn)顯著獲益。但在亞組分析中，有腺癌和吸煙患者可從吉非替尼維持治療中顯著獲得生存益處。分子靶向藥物與化療效果比較韓國(guó)李（Lee）：313例從不吸煙、PS0－2分、具有足夠器官功能的初治ⅢB/Ⅳ期肺腺癌患者，隨機(jī)給予吉非替尼（250mg，口服，每日1次）或GP方案化療（吉西他濱1250mg/m2，d1、d8；順鉑80mg/m2，d1，每3周為1個(gè)周期，共3個(gè)周期）。主要終點(diǎn)為OS；次要終點(diǎn)為ORR、PFS期和毒性。初次疾病進(jìn)展后，依照臨床醫(yī)師的推薦接受二線治療。309例，其中女性占88.7%，Ⅳ期患者占90.0%，PS2分者占9.1%。結(jié)果：吉非替尼組ORR優(yōu)于GP組（53.5%對(duì)42.0%），但無(wú)顯著差異，而中位PFS（5.9個(gè)月）顯著優(yōu)于GP組（5.8個(gè)月，HR=0.737，P=0.0063）。分子靶向藥物與化療合用有待研究：EGFR突變患者應(yīng)用時(shí)機(jī)化療與TKI的使用順序單藥維持治療EGFR-TKI耐藥的后續(xù)治療對(duì)野生型患者的作用貝伐單抗、西妥昔單抗JMEN研究中安慰劑組在進(jìn)展后僅有19％的患者使用了培美曲塞作為二線治療。SATURN中安慰劑組只有16％的患者在進(jìn)展后使用了厄洛替尼。ASCO：

thetreatmentofstage

4NCSLCNovember24,2009—GuidelinesforusingchemotherapyinhavebeenupdatedbytheASCO.JClinOncol.PublishedonlineNovember16,2009.cytotoxicsinfirst-linetreatmentTherecommendationsforusingcytotoxicsinfirst-linetreatmenthavenotchanged,butthereareseveraladditionalrecommendationsabouttheuseoftargetedagents.cytotoxicsinfirst-linetreatmentForpatientswithaperformancestatusof0or1,aplatinum-based2-drugcombinationofcytotoxicdrugsisrecommended.Forpatientswithaperformancestatusof2,single-agentchemotherapyisrecommended.Nonplatinumcytotoxicdoubletsareacceptableforpatientswithcontraindicationstoplatinumtherapy.First-linechemotherapyshouldbestoppedatdiseaseprogression,orafter4cyclesinpatientsnotrespondingtotreatment.Two-drugcytotoxiccombinationsshouldbeadministeredfornomorethan6cycles.cytotoxicsinfirst-linetreatmentPlatinumcompoundsarepreferredovernonplatinumcompoundsbecausetheyaresuperiorinresponserateandmarginallysuperiorinoverallsurvival,theauthorsexplain.Thechoiceofeithercisplatin(Platinol)orcarboplatin(Paraplatin)isacceptablebecauseneitherisconsistentlysuperior,theynote;cisplatinmighthavebetterefficacybutcarboplatinmighthavelesstoxicity.targetedagentsinfirst-linetreatmentNewintheupdatearerecommendationsontheuseoftargetedagentsinfirst-linetreatment,asfollows:targetedagentsinfirst-linetreatmentTheadditionofbevacizumab(Avastin)tocarboplatin/paclitaxelisrecommended,exceptinpatientswithcertaincharacteristics(i.e.,thosewithsquamouscellcarcinomahistology,brainmetastases,clinicallysignificanthemoptysis,inadequateorganfunction,aperformancestatusgreaterthan

1,therapeuticanticoagulation,clinicallysignificantcardiovasculardisease,ormedicallyuncontrolledhypertension).targetedagentsinfirst-linetreatmentTheadditionofcetuximab(Erbitux)tocisplatin/vinorelbinecanbeconsideredinpatientswithtumorstestingpositiveforepidermalgrowth-factorreceptor(EGFR),asmeasuredbyimmunohistochemistry.targetedagentsinfirst-linetreatmentFirst-linegefitinib(Iressa)usecanberecommendedforpatientswithactivatingEGFRmutations.However,ifEGFRmutationstatusisnegativeorunknown,cytotoxicchemotherapyispreferred.Erlotinib(Tarceva)orgefitinibshouldnotbeusedinfirst-linetherapyincombinationwithcytotoxicsinunselectedstage

4NSCLCpatients.Second-andThird-LineTreatment

Therehasbeenachangeinthedrugsrecommendedforuseinsecond-linetherapy.Previously,onlydocetaxel(Taxotere)wasrecommendedforuseafterprogressiononplatinum-basedfirst-linetherapy,andgefitinibwasrecommendedafterafailureofbothplatinum-basedtherapiesanddocetaxel.Nowtheguidelinesstatethatdocetaxel,gefitinib,erlotinib,andpemetrexedareacceptableassecond-linetherapies.Second-andThird-LineTreatmentTheguidelinecommitteenotesthatpemetrexedwasrecentlyapprovedbytheUSFoodandDrugAdministrationformaintenancetherapyinNSCLC,butthisisbasedonrecentlypresenteddatathatwere"outsidethescope"ofthecomprehensivedatareviewundertaken.Second-andThird-LineTreatmentThird-linetherapywitherlotinibcanberecommendedforpatientswithaperformancestatusof0to3whohaveprogressedonoraftersecond-linetherapyandwhohavenotpreviouslyreceivederlotiniborgefitinib.Thereisnotenoughevidencetomakearecommendationfororagainstusingacytotoxicdrugasathird-linetherapySecond-andThird-LineTreatmentThereisinsufficientevidencetorecommendtheroutineuseofmolecularmarkerstoselectsystemictreatmentinpatientswithmetastaticNSCLC.DrugEstimatedCostfor2CyclesofTherapy

($)

Bevacizumab14,040Carboplatin146Cetuximab18,981Cisplatin68Docetaxel5,060Erlotinib9,114Gefitinib4,255Gemcitabine6,914Irinotecan527Paclitaxel201Pemetrexed9,682Vinorelbine257

DrugEstimatedCostforTherapyMostofthecanceragents(>90%)approvedbytheFDA)inthepast4yearscostmorethan$20,000fora12-weekcourseoftherapy,1.2-monthsurvivalbenefitwithcetuximabplusaplatinum-basedchemotherapycomparedwithchemotherapyalonewashailedasthe"newstandard"forNSCLC.cetuximabforNSCLC,whichcosts$80,000foran18-weekcourse.DrugEstimatedCostforTherapybevacizumabformetastaticbreastcancer