实体癌化疗基础知识

实体癌化疗基本知识梅蔚德1.合理化疗的基本原理和要点1.1化学治疗的基本原理

1.1.1化疗作用点

1.1.2细胞周期与化疗药物

1.1.2.11.1.2.21.1.2.31.1.3癌的增殖1.1.4肿瘤的生长比例和化疗

1.1.4.11.1.4.21.1.5细胞毒药物对肿瘤的杀灭

1.1.5.1对数杀灭

1.1.5.2剂量密度

1.1.5.3生长比例改变

1.2化学治疗无效或复发的有关问题1.2.1“个体化问题”1.2.1.1ERCC-1(核苷酸切除修复交叉互补组-1),主要在核内，低表达则伴随基因不稳定，产生恶性表型。51例NSCLC手术标本﹤50（低）35.594.6﹥50（高）生存期（周）ERCC1表达P=0.01

ERCC1高水平，铂相对耐药，低水平者铂相对敏感。这对新辅助治疗可能较为重要，33例铂类新辅助治疗结果

ERCC1水平RRMST阳性31.3%36月阴性58.8%54月

上述对宫颈癌，卵巢癌亦适用1.2.1.2RRM1为核糖核苷酸还原酶亚单位M1，主要在核内，功能为将核苷酸还原为脱氧核苷酸，在NSCLC治疗中，高水平对健择及铂耐药。1.2.1.3TS为胸甘酸合酶，核及胞浆内均有，高水平时对5-FU及培美曲塞耐药1.2.1.4BRCA1（乳癌-1基因），为乳癌，卵巢癌易感基因，涉及DNA损伤修复，低水平者（﹤0.61）生存期长于高水平者（﹥2.45）p=0.01,对铂敏感。突变的BRCA1（编码第1815个氨基酸的密码子中G突变为A）对紫杉醇敏感。1.2.2耐药及其解决方法

1.2.2.1细胞动力学因素（生长比例小）可采取手术/放疗降低肿瘤体积应用可杀休止期细胞的药物用药安排中应防止对某时相的忽略促成时相同步化1.2.2.2生物化学因素包括影响药物吸收，药物激活障碍，药物进靶细胞少而排除多，损伤DNA的快速复原，诱导癌凋亡受阻，MDR蛋白出现等，其中，相当一部分与基因突变有关，（如p53，HER-2，K-ras等）对策：联合化疗，G-CSF支持下或造血干细胞移植条件下大剂量化疗，钙通道阻滞剂，抗心律失常药，环孢菌素D,在某种情况下化疗与靶向治疗同用，如Cetuximab可逆转CPT-11对大肠癌的耐药性。1.2.2.3癌干细胞1.2.2.3.1致癌干细胞在癌瘤中的重要性

tosharecharacteristswithhealthystemcells(selfrenew,multilineagedifferentiation,andmaintainedproliferation—activationofsurvivalresponses,promotionofvesselformation,enhancedmotility)

RecapitulatetumorigenesiswhenxenotransptantedTocontributeto

therapeuticresistance,soeradicationofthestem-cellcompartmentofatumormaybeessentialtoachievestable,long-lastingremission,andevencureofcancer

FromCraigT.Jordanetal1.2.2.3.2近代研究证实致癌干细胞(肿瘤起始细胞)的存在Theidentificationoftumor—initiatingcellsHemotopoieticsystem血液系统：CD34-CD38+LapiodotTetal:(GenesDev.2003Dec15;17C243029-35)˙Toidentify

anhumanAML-initiatingcell(AIC)

bytransplatationintoSCIDmice,thesecellshomedtoBM,resultingapatternofdissemination,andleukaemiccellmorphologysimilartothatseeninoriginalpatient˙AICinthebloodofAMLpatientswas

one

engraftmentunitin250,000cells1.2.2.3.3乳癌“干细胞”(FromMuhammadAI-Hajj,ProcNatlAca5c;USA2003:100:3983-88)

CD44+CD24-

/lowLineage-

1.2.2.3.4脑肿瘤“干细胞”CD133+(prominin1)

1.2.2.3.5结肠癌“干细胞”CD133+1.2.2.3.6胰腺癌“干细胞”CD44,CD24,andepithelial-specificantigen(ESA)均阳性。1.2.2.3.7进一步的明确干细胞可以由此研究出针对其特性的杀灭药2化疗指征及方案2.1由循证医学决定(NCCN)，目的在于尽可能保证“量体裁衣”,既不治疗过度又不治疗不足，其依据主要为：2.1.1关于NCCN(国立综合癌症网)（1）anot-for-profitallianceof21oftheworld’sleadingcancercenters为21个世界首要癌症中心的非盈利性联盟组织（2）TheleadershipandexpertiseofclinicalprofessionalsatNCCNMemberInstitutions临床专家组成的委员会（3）TheprimarygoalofallNCCNinitiativesis:improvingthequality,effectiveness,andefficiencyofoncologypracticesopatientscanlivebetterlives主要任务：不断改进患者生活质量，治疗效果及效率-----改善生存（4）ThedevelopmentofNCCNinformationisbasedupontheindependentevaluationofavailablescientificevidenceintegratedwiththeexpertjudgmentofleadingclinicians.由首要的临床专家们对提供的科学证据进行独立评估并结合专业判断，据此每年改进NCCN“指南”

2.1.2ClinicalTrials指南内容根据----临床试验结果（1）TheNCCNbelievesthatthebestmanagementforanycancer.Patientisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.（2）AllrecommendationsareCategory2Aunlessotherwisespecified（3）NCCNCategoriesofEvidenceandConsensus:NCCN临床证据及评判意见一致性的分类如下表CategoryofEvidenceandConsensus临床证据及小组评判分类QualityofEvidence证据的可靠性LevelofConsensus评价的一致性1High:high-poweredrandomizedclinicaltrialsormeta-analyses

Uniform:nearunanimouspositivesupportwithsomepossibleneutralpositions2ALower:Lowerlevelevidenceisinterpretedbroadly,andrunsthegamutfromphaseⅡorlargecohortstudiestoindividualpractitionerexperience.Inmanyinstances,theretrospectivestudiesarederivedfromclinicalexperienceoftreatinglargenumbersofpatientsatamemberinstitution,sopanelmembershavefirst-handknowledgeofthedataUniform2BLowerNon-uniform3AnyMajordisagreement2.1.3SafeguardsforEliminatingBiases消除指南偏差2.1.3.1Twosafeguardslistedasfollow:panelsreflectingallschoolsofthoughtforaparticulartumor,andtheprocessofiterationandfeedback广泛性及反复讨论2.1.3.2ToaddressbiasisthepresentationofnewNCCNGuidelinesattheannualmeeting,wheremeetingattendeesareinvitedtoprovidebothoralandwrittencommentsontheguidelines.每年年会根据临床试验的结果，讨论对指南的不同意见形成新指南2.1.4指南形成过程

NCCNGuidelinesDevelopmentProcess“指南”指导委员会挑选主要内容

GuidelinesSteeringCommitteeSelectsTopic某指南专门小组GuidelinePanelSelected形成某指南一稿PreliminaryPathwayDerivation多中心复核小组材料讨论按NCCN方法当归纳InstitutionalReviewCollection采集补充GuidelineRevision指南修正FinalGuideline指南定稿

ContinuousReview继续复核2.1.5NCCN开本格式TreatmentPathways治疗步骤

诊断Diagnosis

检查分期Work-up&Staging首要初治PrimaryTreatment

辅助治疗AdjuvantTherapy复发治疗、补救治疗Salvage/RecurrenceTherapy

对症、支持处理步骤SymptomManagement/SupportiveCarePathways筛查Screening危险性评估RiskAssessment分级Triage特异性评估SpecializedEvaluation特异性干预SpecificIntervention再次评估Reevaluation随访Follow-up2.1.2病理诊断是关键，除组织形态学外，还常需分子病理学（分子遗传病理，免疫组化病理）严格重视病理诊断应与临床诊断一致。存在下列两种情况，可在无病理诊断下行治疗（约1%）。a建立诊断的措施或不迅速治疗将导致较严重后果或死亡b良性病变可能性小2.1.3在TNM分类的基础上分期（以胃癌为例2009）2.1.3.12.1.3.22.1.3.32.1.3.42.1.4体能状态分级

2.2应用化疗的四种目的2.2.1Adjuvantchemotherapy辅助性化疗（根治性手术/放疗后）2.2.1Primary/Neuadjuvantchemotherapy:起始/新辅助化疗（局部根治性手术/放疗前，少数疾病作为主要治疗）2.2.3局部治疗（如介入，腔内应用等）2.2.4晚期疾病的姑息治疗2.3化疗毒副反应及其处理2.3.1推荐WHO或美国NCI的不良反应分类，分1，2，3，4度，1，2度为可允许反应，3度应避免，发生后应停药，日后需再行化疗要改善调整剂量，4度则需立即停药，急救及时，慎重处理。2.3.2通过用药方式削弱蒽环类的毒性并提高疗效。

2.3.3抗恶心呕吐处理原则抗5HT3受体拮抗剂（如枢复宁类）最可靠，无禁忌下应与地塞米松合用，以化疗前0.5-1小时开始用最佳，化疗结束后再用1-3日，主要针对急性呕吐。Aprepitant(抗敏吐/阿瑞匹坦)，为神经激肽-1受体拮抗剂，对急性，特别是延迟性呕吐均有效，可与上方案联合应用。未用化疗前的“预期性呕吐”，常有心理因素，可予心理治疗及治疗前一日用Lorazepan(罗拉)0.5mg-2mg每4-6小时一次。（可有遗忘，精神错乱等副作用）。或安定10mg化疗前2小时肌注或静注2.4时辰化疗以下摘自Michcelperry:Thechemotherapysorcebook(2ndEdition）2.4.1时辰影响水平：生理和病理，系统和器官，细胞和分子2.4.2时辰化疗的需要：不少非时辰化疗方案对平衡宿主—肿瘤损害，毒性和治疗指数有欠缺。2.4.3抗癌治疗时辰依赖性的基础2.4.3.1时辰性药理动力学：吸收，分布，代谢，排泄2.4.3.1.12.4.3.1.22.4.3.2机体组织细胞动力学：S时相特异性药物对胃肠道及骨髓损害以夜间给药为轻。2.4.3.3内分泌及免疫：肾上腺皮质激素，T，B，NK细胞及各种免疫反应。2.4.3.4癌瘤时辰特点2.4.3.4.1

2.4.3.4.2癌瘤血流时辰性，实验表明皮下癌瘤活跃时相与非活跃时相供血相差一倍，但不伴瘤体积变化，此时给药化疗疗效增强。2.4.3.4.3时辰治疗对疗效与毒性的影响2.4.3.4.3.12.4.3.4.3.22.4.3.4.3.32.5如何预防继发癌2.5.1Definetheriskofrecurrenceandtailortheintensityofcancertherapy:Loweringthedoseoftreatmentforlowriskgroupsisprobablytheimportantwaytopreventsecondarycancer2.5.2Avoidradiationtherapy2.5.2.1ThishasbeensuccessfulinchildhoodALLwhereintrathecalchemotherapyhasbeensubstitutedforradiation2.5.2.2Hodgkin`sdiseaseandnon-Hodgkin`slymphoma:wherecertaingroupsofpatientshavebeenfoundtosurvivejustaswellwithchemotherapyaloneaswithchemotherapyplusradiationtherapy2.5.3Avoiddrugswithhighcarcinogenicpotential2.5.3.1Thisisdifficulttodosinceallchemotherapydrugsarecarcinogenic

2.5.3.2Etoposideisassociatedwitharelativelyhighincidenceofmyelodysplasiaandacutemyeloidleukemiaandinsomeinstancesotherdrugscouldbeusedinstead2.6化/放疗心血管并发症2.6.1EdwardT.H.etc;CardiovascularcomplicationsofCancerTherapyDiagonsis,Pathogenesis,andManagement(Circulation.2004;109:3112-3131.)2.6.1.1

CardiotoxicSyndromesAssociatedWithChemotherapeuticAgents（1）AgentsassociatedwithmyocardialdepressionAnthracyclinesMitoxantrone(Novantrone)Cyclophosphamide(Cytoxan)—highdoseTrastuzumab(Herceptin)Ifosfamide(Ifex)All-transretinoicacid(Tretinoin)（2）Agentsassociatedwithischemia5-FU(adrucil)Cisplatin(platinol)Capecitabine(Xeloda)IL-2（3）AgentsassociatedwithhypotensionEtoposide(Vepesid)Paclitaxel(Taxol)Alemtuzumab(Campath)阿仑单抗抗CD52Cetuximab(Erbitux)爱必妥抗表皮生长因子受体（HER1)Rituximab(Rituxan)美罗华抗CD20IL-2Denileukin(Ontak)IL-2/白喉毒素融合蛋白Interferon-α

All-transretinoicacid(tretinoin)Homoharringtonine高三尖杉酯碱

（4）AgentsassociatedwithhypertensionBevacizumab(Avastin)抗VEGFCisplatinin(Platinol)（5）AgentsassociatedwithothertoxiceffectsCardiactamponadeorendomyocardialfibrosis:busulfan(Myleran)Hemorrhagicmyocarditil:cyclophosphamide(Cytoxan)Bradyarrhythmias:paclitaxel(Taxol),thalidomide(Thalomid)Raynaudphenomenon:vinblastine(Velban)Autonomicneuropathy:vincristine(Oncovin)QTprolongationortorsadesdePointes:arsenictrioxide(Trisenox)Pulmonaryfibrosis:bleomycin(Blenoxane)2.6.2RiskFactorforDevelopingCardiovascularComplications2.6.2.1

Somechemotheraperapeuticagentsevokecardiotoxicityonlywhenthedrugisadministeredathighdose:examplesincludeCHFandpericarditiswithplatinumdrugs.Systolicdysfunctionandpericarditiswithcyclophosphamide.LVdysfunctionwithanthracyclines2.6.2.2Administeringanthracyclinesbycontinuousinfusionover24to92hoursratherthanbyrapidintravenousinfusioncouldreducethecardiotoxicityofthesedrugs.Busulfancausestachyarrythmias,hypertensionorhypotension,andLVdysfunctionwheninjectedbutnotwhentakenorally.ThecombinationofIL-2andinterferonsignificantlyincreaseshypotension,butdeliveringinterferonaloneforthefirst2weeksfollowedbyIL-2hasmuchlesscardiovasculartoxicity.(interval)ThecombinationofpaclitaxelanddoxorubicincausedCHFin20%ofcasesiftheintervalbetweendoxorubicinandpaclitaxelwas15to30minutes,butincreasingtheintervalto4to16hoursreducedthecardiotoxicityofthiscombination.2.6.2.3AdvancedageisaknownriskfactorforanthracyclinecardiotoxicityCardiovascularsideeffectsfromaparticulardrugoccurinaspecificsubset

ofcancerpatients①Cardiovascularcomplicationfromcisplatinonlyinpatientswithmetastatictesticularcancer②Episodesofcardiotoxicityfromlow-dose

ifosfmidebeingmorecommominpatientswithlymphoma.③AlemtuzumabbeingassociatedwithLVdysfunctioninpatientswithmycosisfungoides.2.6.3cardiotoxicityAssociatedWithRadiationTherapy2.6.3.1Radiation-inducedheartdiseaseishigherinpatientsgivenhighdosesofradiationtherapyconcurrentwithdoxorubicin.2.6.3.2Vascularinjuryfromradiationtherapycanbesilent;approximately50%ofasymptomaticpatientsdevelopnewmyocardialperfusiondefects.2.6.3.3Suddendeathinpatientsisthoughttoresultfromdiffuseintimalhyperplasisofallcornaryarteriesorfromsignificantleftmainstenosis.ThemeanintervalfordevelopingCAD(coronaryarterydisease)afterradiationtherapyisapproximately82months.2.6.3.4Radiationtherapyalsocausesfibrousthickeningofthepericardium,rangingfrom2to145months.Pericardialeffusionistypicallyanearlypresentation.Whereaspericardialconstrictionisalatemanifestation.Usuallyappearingaftermonths.2.6.3.5Myocardialfibrosisisalsoasideeffectofradiationtherapy.radiationalsocausesfibrousthickeningofcardiacvalveslefi-sidevalvesaremoreofteninvolvedthanrightvalves.2.7预防与处理2.7.1MonitoringCardiovascularToxiciity2.7.1.1

B-typenatriureticpeptide(BNP)

(B型利钠肽脑钠素）hasbeenshowntobeelevatedbeforethedevelopmentofLVdysfunction.2.7.1.2ProvocativetestingwithexerciseordobutamineechocardiographymaybesensitivefortheearlydetectionofsubclincialcardiomvonpathyandmayprovideanopportunityfortherapeuticinterventionbeforethedevelopmentofovertLVdysfunction.2.7.1.3

Diastolicdysfunctionisanearlysign.2.7.1.4

FractionalshorteningandLVejectionfractionarenotsensitivefortheearlydetectionofpreclinicalcardiacdiaease.2.7.2StrategiestoReduceCardiovascularToxicityandManageComplications2.7.2.1Anthracyclinetoxicitycanbeminimizedbyreducingthetotaldoseto<400mg/m²andchangingtheadministrationfromarapidinfusiontoacontinuousinfusion.2.7.2.2Newerliposomalformulationsalsomayreducecardiotoxicity.2.7.2.3

①DexrazoxaneaderivativeofEDTAcanreducetheamountoffreeironinmyocytesbyproducingfreeradicalsthatdecreaseoxidizedironlevelsduringanthracyclineinfusion.②RecommendedforpatientswithmetastaticbreastCa

havereceivedcumulativeanthracyclinedosesof﹤300mg/m².③However,thatdexrazoxancecanworsenthrombocyto-peniaandgranulocytopenia2.7.2.4①Combinationoftrastuzumab,anthracyclines.andcyclophosphamideledtosevereheartfailureinupto16%ofpatientswithbreastcancerundergoingthistreatment.②Toavoidgivingtheseddrugssimultaneously,considerablyreducedtoxicityrates.③Trastuzumab-relatedcardiomyopathyseemstobelargelyreversiblewithappropriatetherapy

④ACEIandβ-blockersarethecornerstonesoftherapyforLVdysfunction.

⑤rechallengewithtrastuzumabdosenotnecessarilyleadtoredevelopmentofLVdysfunctionorCHF.3常见实体癌化疗应用指征（推荐NCCN2009）3.1胃癌3.1.1T≥2术前：新辅助：（C1）

R1术后R2术后同上B同上A或BM1：KPS≥60EPS≤2姑息化疗T2N0T3/T4或N+A：术前新辅助化疗术后ECF（C1）

B：高危者术后放疗以5-Fu同步曾敏（C1）同上R0术后3.1.2方案推荐新辅助：ECF（C1）术后：ECF（C1）术后放化疗：5Fu或希罗达（C1）M1或局部晚期DCF/ECF/(C1)3.2食道癌化疗指征3.2.1术前：3.2.1.1新辅助化疗：T1bN0远端腺癌

3.2.1.2术前同步放化疗：T1b,N1或T3T4N0-1，Nx或ⅣA期3.2.2术后R0切除

腺癌

T2N0T3N0

R1切除

R2切除

氟脲嘧啶类基础上的同步放化疗同上同上或姑息治疗

3.2.3不适于手术者如上同步放化疗，不适于放疗者化疗3.2.4远