实体癌化疗基础知识.ppt

单击此处编辑母版标题样式,*,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,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,1.1.2.1,1.1.2.2,1.1.2.3,1.1.3,癌的增殖,1.1.4,肿瘤的生长比例和化疗,1.1.4.1,1.1.4.2,1.1.5,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”,1.2.1.1,ERCC-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）,35.5,94.6,50,（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,RR,MST,阳性,31.3%,36,月,阴性,58.8%,54,月,上述对宫颈癌，卵巢癌亦适用,1.2.1.2 RRM1,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。,1.2.1.3 T S,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,1.2.1.4 BRCA1,（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,to share,characterists,with healthy stem cells,(self renew,multilineage,differentiation,and maintained proliferationactivation of survival responses,promotion of vessel formation,enhanced motility),Recapitulate tumorigenesis,when xenotransptanted,To contribute to,therapeutic resistance,so eradication of the stem-cell compartment of a tumor may be essential to achieve stable,long-lasting remission,and even cure of cancer,From CraigT.Jordan et al,1.2.2.3.2,近代研究证实致癌干细胞,(,肿瘤起始细胞,),的存在,The identification of tumorinitiating cells,Hemotopoietic system,血液系统：,CD34,-,CD38,+,Lapiodot T et al:(Genes Dev.2003 Dec 15;,17C24 3029-35),To identify,an human AML-initiating cell(AIC),by transplatation into SCID mice,these cells homed to BM,resulting a pattern of dissemination,and leukaemic cell morphology similar to that seen in original patient,AIC in the blood of AML patients was,one,engraftment unit in,250,000 cells,1.2.2.3.3,乳癌“干细胞”,(From Muhammad AI-Hajj,Proc Natl Aca 5c;USA,2003,:100:3983-88),CD44,+,CD24,-,/low,Lineage,-,1.2.2.3.4,脑肿瘤“干细胞,”CD133+(prominin 1),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,and epithelial-specific antigen(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,）,a not-for-profit alliance of 21 of the worlds leading cancer centers,为,21,个世界首要癌症中心的非盈利性联盟组织,（,2,）,The leadership and expertise of clinical professionals at NCCN Member Institutions,临床专家组成的委员会,（,3,）,The primary goal of all NCCN initiatives is:improving the quality,effectiveness,and efficiency of oncology practice so patients can live better lives,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,）,The development of NCCN information is based upon the independent evaluation of available scientific evidence integrated with the expert judgment of leading clinicians.,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”,2.1.2 Clinical Trials,指南内容根据,-,临床试验结果,（,1,）,The NCCN believes that the best management for any cancer.Patient is in a clinical trial.Participation in clinical trials is especially encouraged.,（,2,）,All recommendations are Category 2A unless otherwise specified,（,3,）,NCCN Categories of,Evidence,and,Consensus,:NCCN,临床证据及评判意见一致性的分类,如下表,Category of Evidence and Consensus,临床证据及小组评判分类,Quality of Evidence,证据的可靠性,Level of Consensus,评价的一致性,1,High:high-powered randomized clinical trials or meta-analyses,Uniform:near unanimous positive support with some possible neutral positions,2A,Lower:Lower level evidence is interpreted broadly,and runs the gamut from phase or large cohort studies to individual practitioner experience.In many instances,the retrospective studies are derived from clinical experience of treating large numbers of patients at a member institution,so panel members have first-hand knowledge of the data,Uniform,2B,Lower,Non-uniform,3,Any,Major disagreement,2.1.3 Safeguards for Eliminating Biases,消除指南偏差,2.1.3.1 Two safeguards listed as follow:panels reflecting all schools of thought for a particular tumor,and the process of iteration and feedback,广泛性及反复讨论,2.1.3.2 To address bias is the presentation of new NCCN Guidelines at the annual meeting,where meeting attendees are invited to provide both oral and written comments on the guidelines.,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,NCCN Guidelines Development Process,“,指南”指导委员会挑选主要内容,Guidelines Steering Committee Selects Topic,某指南专门小组,Guideline Panel Selected,形成某指南一稿,Preliminary Pathway Derivation,多中心复核 小组材料讨论按,NCCN,方法当归纳,Institutional Review,Collection,采集补充,Guideline Revision,指南修正,Final Guideline,指南定稿,Continuous Review,继续复核,2.1.5 NCCN,开本格式,Treatment Pathways,治疗步骤,诊断,Diagnosis,检查分期,Work-,up&Staging,首要初治,Primary Treatment,辅助治疗,Adjuvant Therapy,复发治疗、补救治疗,Salvage/Recurrence Therapy,对症、支持处理步骤,Symptom Management/Supportive Care Pathways,筛查,Screening,危险性评估,Risk,Assessment,分级,Triage,特异性评估,Specialized,Evaluation,特异性干预,Specific,Intervention,再次评估,Reevaluation,随访,Follow,-up,2.1.2,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,）,2.1.3.1,2.1.3.2,2.1.3.3,2.1.3.4,2.1.4,体能状态分级,2.2,应用化疗的四种目的,2.2.1 Adjuvant chemotherapy,辅助性化疗（根治性手术,/,放疗后）,2.2.1 Primary/,Neuadjuvant,chemotherapy:,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,Michcel,perry,:The chemotherapy,sorce,book(2nd Edition,）,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,2.4.3.1.1,2.4.3.1.2,2.4.3.2,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,2.4.3.4.3.1,2.4.3.4.3.2,2.4.3.4.3.3,2.5,如何预防继发癌,2.5.1,Define the risk of recurrence and tailor the intensity of cancer therapy:Lowering the dose of treatment for low risk groups is probably the important way to prevent secondary cancer,2.5.2 Avoid radiation therapy,2.5.2.1,This has been successful in childhood ALL where,intrathecal,chemotherapy has been substituted for radiation,2.5.2.2,Hodgkins,disease and non-,Hodgkins,lymphoma:where,certain groups of patients have been found to survive just as well with chemotherapy alone as with chemotherapy plus radiation therapy,2.5.3 Avoid drugs with high carcinogenic potential,2.5.3.1,This is difficult to do since all chemotherapy drugs are carcinogenic,2.5.3.2,Etoposide,is associated with a relatively high incidence of,myelodysplasia,and acute myeloid leukemia and in some instances other drugs could be used instead,2.6,化,/,放疗心血管并发症,2.6.1,Edward T.H.etc;Cardiovascular complications of Cancer Therapy,Diagonsis,Pathogenesis,and Management(Circulation.2004;109:3112-3131.),2.6.1.1,Cardiotoxic,Syndromes Associated With Chemotherapeutic Agents,（,1,）,Agents associated with myocardial depression,Anthracyclines,Mitoxantrone(Novantrone,),Cyclophosphamide(Cytoxan,)high dose,Trastuzumab(Herceptin,),Ifosfamide(Ifex,),All-trans retinoic,acid(Tretinoin,),（,2,）,Agents associated with ischemia,5-FU(adrucil),Cisplatin,(,platinol,),Capecitabine,(,Xeloda,),IL-2,（,3,）,Agents associated with hypotension,Etoposide(Vepesid,),Paclitaxel(Taxol,),Alemtuzumab,(,Campath,),阿仑单抗 抗,CD52,Cetuximab,(,Erbitux,),爱必妥抗表皮生长因子受体（,HER1),Rituximab,(,Rituxan,),美罗华 抗,CD20,IL-2,Denileukin(Ontak,)IL-2/,白喉毒素融合蛋白,Interferon-,All-trans,retinoic,acid(tretinoin,),Homoharringtonine,高三尖杉酯碱,（,4,）,Agents associated with hypertension,Bevacizumab(Avastin,),抗,VEGF,Cisplatinin(Platinol,),（,5,）,Agents associated with other toxic effects,Cardiac,tamponade,or,endomyocardial,fibrosis:,busulfan(Myleran,),Hemorrhagic,myocarditil,:,cyclophosphamide(Cytoxan,),Bradyarrhythmias,:,paclitaxel(Taxol),thalidomide(Thalomid,),Raynaud,phenomenon:,vinblastine(Velban,),Autonomic neuropathy:,vincristine(Oncovin,),QT prolongation or,torsades,de Pointes:,arsenic,trioxide(Trisenox,),Pulmonary fibrosis:,bleomycin(Blenoxane,),2.6.2 Risk Factor for Developing Cardiovascular Complications,2.6.2.1,Some,chemotheraperapeutic,agents evoke,cardiotoxicity,only when the drug is administered at,high dose,:examples include CHF and,pericarditis,with,platinum drugs,.,Systolic dysfunction and,pericarditis,with,cyclophosphamide,.,LV dysfunction with,anthracyclines,2.6.2.2,Administering,anthracyclines,by continuous infusion over 24 to 92 hours rather than by,rapid intravenous infusion,could reduce the,cardiotoxicity,of these drugs.,Busulfan,causes,tachyarrythmias,hypertension or hypotension,and LV dysfunction when,injected,but not when taken orally.,The combination of IL-2 and interferon significantly increases hypotension,but delivering,interferon,alone for the first 2 weeks followed by,IL-2,has much less cardiovascular toxicity.(,interval,),The combination of,paclitaxel,and doxorubicin caused CHF in 20%of cases if the,interval between doxorubicin and,paclitaxel,was 15 to 30 minutes,but increasing the interval to 4 to 16 hours reduced the,cardiotoxicity,of this combination.,2.6.2.3,Advanced,age,is a known risk factor for,anthracycline,cardiotoxicity,Cardiovascular side effects from a,particular drug,occur in a,specific subset,of cancer patients,Cardiovascular complication from,cisplatin,only in patients with,metastatic testicular cancer,Episodes of,cardiotoxicity,from,low-dose,ifosfmide,being more,commom,in patients with,lymphoma,.,Alemtuzumab,being associated with LV dysfunction in patients with,mycosis,fungoides,.,2.6.3,cardiotoxicity,Associated With Radiation Therapy,2.6.3.1,Radiation-induced heart disease is higher in patients given,high doses,of radiation therapy,concurrent with doxorubicin.,2.6.3.2,Vascular injury from radiation therapy can be,silent,;approximately 50%of asymptomatic patients develop new myocardial perfusion defects.,2.6.3.3,Sudden death,in patients is thought to result from diffuse,intimal,hyperplasis,of all,cornary,arteries or from significant left main,stenosis,.The mean interval for developing,CAD,(coronary artery disease)after radiation therapy is approximately 82 months.,2.6.3.4,Radiation therapy also causes fibrous thickening of the,pericardium,ranging from 2 to 145 months.Pericardial,effusion,is typically an early presentation.Whereas pericardial,constriction,is a late manifestation.Usually appearing after months.,2.6.3.5,Myocardial fibrosis,is also a side effect of radiation therapy.radiation also causes fibrous thickening of,cardiac valves,lefi,-side valves are more often involved than right valves.,2.7,预防与处理,2.7.1 Monitoring Cardiovascular,Toxiciity,2.7.1.1,B-type,natriuretic,peptide,(BNP),(B,型利钠肽 脑钠素）,has been shown to be elevated before the development of LV dysfunction.,2.7.1.2,Provocative testing with,exercise or,dobutamine,echocardiography,may be sensitive for the early detection of,subclincial,cardiomvonpathy,and may provide an opportunity for therapeutic intervention before the development of overt LV dysfunction.,2.7.1.3,Diastolic dysfunction,is an early sign.,2.7.1.4,Fractional shortening and LV ejection fraction,are,not,sensitive for the early detection of preclinical cardiac,diaease,.,2.7.2 Strategies to Reduce Cardiovascular Toxicity and Manage Complications,2.7.2.1,Anthracycline toxicity can be minimized by,reducing the total dose,to A,期均行辅助化疗，,R1R2,者同样是再切除,/,放化疗后化疗。,3.5.2,新辅助化疗,3.5.2.1,胸壁，近端气道或纵隔,T3T4,N0-1,肺上沟瘤：可能切除者，行术前同步放化疗，（不能切除行常规同步放化疗）。,3.5.2.2 B(T3N0),A,B(T3-4,N1),可切除者术前同步放化疗，（不能切除者常规同步放化疗）,3.5.2.3,推荐化疗方案（,NCCN 2009,）,3.6,乳癌,3.6.1,可行新辅助化疗者为：（一般,3-4,周期，无效换方案）,3.6.1.1,要求保乳并且符合保乳手术条件者,A(T2N0M0),B T2N1M0 T3N0M0,A(T3N1M0),3.6.1.2 A T,0-3,N,2,M,0,B T,4,N0-1,M0,C Tany,N3,M0,3.6.1.3,炎性乳癌,3.6.2,辅助治疗：只要有下列条件之一，均可考虑,T 0.6-1cm(,有不佳因素,),，,C1,T1cm,N+,3.6.3,对妊娠患者，乳房切除后有化疗指征者或需保乳者，新辅助化疗应在中,1/3,妊娠期开始。,3.6.4,推荐化疗方案,3.6.4.1,3.6.4.2,3.7,卵巢上皮癌和输卵管癌,除,A B,高分化可观察外，,A B,中非高分化和,C,建议做,3-6,周期，紫杉醇类,卡铂治疗（,C1,）,.,期需做,6-8,周期上述治疗，对,期及,期减瘤手术较成功，直径,1cm,者考虑腹腔化疗（,C1,）,对上述治疗二周期无效者，或,CR,停药后,6,个月内复发者，或,，,，,期部分缓解者可考虑进入“临床试验组”或“复发治疗”中的非铂类单药治疗（,C2B,）,.,CR,停药,6-12,月复发者除采取上述选择外尚可用铂为基础的联合方案。,无病生存,6,个月后小灶性复发可再次减瘤手术后化疗。,“复发治疗”见下表,3.8,鼻咽癌,3.8.1 T1N0M0 T2aN0M0,不化疗,3.8.2 T1-2a N1-3,T2b-T4,N,any,：,CDDP 100mg/m,2,D1,22,43+RT,RT,结束后,CDDP 80mg/m,2,D1+5Fu 1000mg/m,2,CI4days,如此每,4,周,一疗程，若颈部仍有肿块考虑切除。,3.8.3 M1,：铂为基础的化疗常规放疗,3.8.4,全身治疗常用方案（见下表）,3.9,宫颈癌,3.9.1,化疗指征,3.9.2,化疗方案,4,肿瘤治疗的评价,4.1,客观反应率,4.1.1 WHO,标准,SD,4.1.2,R,esponse,E,valuation,C,riteria,I,n,S,olid,T,umor,4.1.2.1,肿瘤缓解的评价,(1),肿瘤病灶基线的评价,要确立基线的全部肿瘤负荷，对此在其后的测量中进行比较，可测量的目标病灶至少有一个，如是有限的弧立的病灶需组织病理学证实。,(a),可测量的目标病灶：应代表所有累及的器官，每个脏器最多,5,个病灶，全部病灶总数最多,10,个作为目标病灶，并在基线时测量并记录。目标病灶应根据病灶长径大小和可准确重复测量性来选择。所有目标病灶的长度总和，作为有效缓解记录的参考基线。,(b),非目标病灶：所有其它病灶应作为非目标病灶并在基线上记录，不需测量的病灶在随诊期间要注意其存在或消失。,(2),缓解的标准,目标病灶的评价,CR,：所有目标病灶消失。,PR,：基线病灶长径总和缩小,30%,。,SD,：基线病灶长径总和有缩小但未达,PR,或有增加但未达,PD,。,PD,：基线病灶长径总和增加,20%,或出现新病灶。,非目标病灶的评价,CR,：所有非目标病灶消失和肿瘤标志物水平正常。,PD,：出现一个或多个新病灶或,/,和存在非目标病灶进展。,SD,：一个或多个非目标病灶和,/,或肿瘤标志物高于正常持续存在。,(3),总的疗效评价,(,见表,1),目标病灶 非目标病灶 新病灶 总疗效,CR CR,无,CR,CR,未达,CR/SD,无,PR,PR,无,PD,无,PR,PD,任何 有,/,无,PD,任何,PD,有,/,无,PD,任何 任何有,PD,SD,无,PD,无,SD,4.2,生存时间指标,4.2.1 DFS/RFS:,从另一个意义讲代表了,CR,的 质量。,4.2.2 TTP,：代表了开始一种新治疗疾病控制的质量。,4.2.3 PFS,：,4.2.4 MST,：,4.2.5 OS,：,4.3,生活质量,4.4,疾病得益,4.5 ITT,和独立调查,谢谢大家！,