医学精品课件实体癌化疗基础知识

1、实体癌化疗基本知识梅蔚德2021/7/15 星期四1 1.合理化疗的基本原理和要点2021/7/15 星期四21.1 化学治疗的基本原理1.1.1 化疗作用点 2021/7/15 星期四31.1.2 细胞周期与化疗药物1.1.2.12021/7/15 星期四41.1.2.22021/7/15 星期四51.1.2.32021/7/15 星期四61.1.3癌的增殖2021/7/15 星期四71.1.4肿瘤的生长比例和化疗1.1.4.12021/7/15 星期四81.1.4.22021/7/15 星期四91.1.5细胞毒药物对肿瘤的杀灭1.1.5.1对数杀灭 2021/7/15 星期四101.1.5

2、.2 剂量密度 2021/7/15 星期四111.1.5.3 生长比例改变 2021/7/15 星期四121.2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。2021/7/15 星期四1351例NSCLC手术标本 50 （低）35.594.6 50 （高）生存期（周）ERCC1表达P=0.012021/7/15 星期四14ERCC1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

3、58.8%54月 上述对宫颈癌，卵巢癌亦适用2021/7/15 星期四151.2.1.2 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2021/7/15 星期四161.2.1.4 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。2021/7/15 星期四17

4、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2021/7/15 星期四181.2.2.2 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

5、癌的耐药性。2021/7/15 星期四191.2.2.3 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)2021/7/15 星期四20 Recapitulate tumorigenesis

6、 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 2021/7/15 星期四21From CraigT.Jordan et al2021/7/15 星期四221.2.2.3.2 近代研究证实致癌干细胞(肿瘤起始细胞)的存在 The identi

7、fication 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

8、similar to that seen in original patient AIC in the blood of AML patients was one engraftment unit in 250,000 cells2021/7/15 星期四231.2.2.3.3 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” CD1

9、33+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2021/7/15 星期四242 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：2021/7/15 星期四252.1.1 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

10、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

11、2021/7/15 星期四26（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

12、 best management for any cancer. Patient is in a clinical trial. Participation in clinical trials is especially encouraged.2021/7/15 星期四27（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2021/7/15 星期四28Category o

13、f 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1High: high-powered randomized clinical trials or meta-analyses Uniform: near unanimous positive support with some possible neutral positions 2ALower: Lower level evidence is interpreted broadly, and runs the gamut

14、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 2BLowerNon-uniform

15、3AnyMajor disagreement2021/7/15 星期四292.1.3 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 Gui

16、delines 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 2021/7/15 星期四302.1.4 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 Pa

17、nel 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2021/7/15 星期四312.1.5 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 T

18、herapy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RiskAssessment分级Triage特异性评估SpecializedEvaluation特异性干预SpecificIntervention再次评估Reevaluation随访Follow-up2021/7/15 星期四322.1.2 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

19、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2021/7/15 星期四332.1.3 在TNM分类的基础上分期（以胃癌为例2009）2.1.3.1 2021/7/15 星期四342.1.3.22021/7/15 星期四352.1.3.32021/7/15 星期四362.1.3.42021/7/15 星期四372.1.4 体能状态分级 2021/7/15 星期四382.2 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 chemo

20、therapy: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2021/7/15 星期四392.3 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。2021/7/15 星期四402.3.2 通过用药方式削弱蒽环类的毒性并提高疗效。 2021/7/15 星期四412.3.3 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

21、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 2021/7/15 星期四422.4 时辰化疗 以下摘自Michcel perry: The chemotherapy sorce book (2nd Edition）2.4.1 时辰影响

22、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2021/7/15 星期四432.4.3.1 时辰性药理动力学：吸收，分布，代谢，排泄2021/7/15 星期四442.4.3.1.12021/7/15 星期四452.4.3.1.22021/7/15 星期四462.4.3.2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2021/7/15 星期四472.

23、4.3.4.1 2021/7/15 星期四482.4.3.4.2 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2021/7/15 星期四492.4.3.4.3.12021/7/15 星期四502.4.3.4.3.2 2021/7/15 星期四512.4.3.4.3.32021/7/15 星期四522.5 如何预防继发癌2.5.1 Define the risk of recurrence and tailor the intensity of cancer therapy: Loweri

24、ng the dose of treatment for low risk groups is probably the important way to prevent secondary cancer 2021/7/15 星期四532.5.2 Avoid radiation therapy2.5.2.1 This has been successful in childhood ALL where intrathecal chemotherapy has been substituted for radiation2.5.2.2 Hodgkins disease and non-Hodgk

25、ins lymphoma:where certain groups of patients have been found to survive just as well with chemotherapy alone as with chemotherapy plus radiation therapy2021/7/15 星期四542.5.3 Avoid drugs with high carcinogenic potential2.5.3.1 This is difficult to do since all chemotherapy drugs are carcinogenic 2.5.

26、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 instead2021/7/15 星期四552.6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 (

27、Circulation. 2004; 109 : 3112- 3131.)2021/7/15 星期四562.6.1.1 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 retin

28、oic acid(Tretinoin)2021/7/15 星期四57（2） Agents associated with ischemia 5-FU (adrucil) Cisplatin (platinol) Capecitabine (Xeloda ) IL-22021/7/15 星期四58（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) Ritu

29、ximab (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)2021/7/15 星期四59（5）Agents associated with other toxic effects Cardiac tamponade

30、 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(T

31、risenox) Pulmonary fibrosis : bleomycin(Blenoxane)2021/7/15 星期四602.6.2 Risk Factor for Developing Cardiovascular Complications2.6.2.1 Some chemotheraperapeutic agents evoke cardiotoxicity only when the drug is administered at high dose :examples include CHF and pericarditis with platinum drugs.Systo

32、lic dysfunction and pericarditis with cyclophosphamide.LV dysfunction with anthracyclines2021/7/15 星期四612.6.2.2Administering anthracyclines by continuous infusion over 24 to 92 hours rather than by rapid intravenous infusion could reduce the cardiotoxicity of these drugs.Busulfan causes tachyarrythm

33、ias, hypertension or hypotension, and LV dysfunction when injected but not when taken orally .2021/7/15 星期四62The 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 .(inte

34、rval )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.2021/7/15 星期四632.6.2.3Advanced age is a known risk facto

35、r 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 pa

36、tients with lymphoma. Alemtuzumab being associated with LV dysfunction in patients with mycosis fungoides.2021/7/15 星期四642.6.3 cardiotoxicity Associated With Radiation Therapy2.6.3.1 Radiation-induced heart disease is higher in patients given high doses of radiation therapy concurrent with doxorubic

37、in.2.6.3.2 Vascular injury from radiation therapy can be silent; approximately 50% of asymptomatic patients develop new myocardial perfusion defects.2021/7/15 星期四652.6.3.3 Sudden death in patients is thought to result from diffuse intimal hyperplasis of all cornary arteries or from significant left

38、main stenosis. The mean interval for developing CAD (coronary artery disease ) after radiation therapy is approximately 82 months.2021/7/15 星期四662.6.3.4 Radiation therapy also causes fibrous thickening of the pericardium, ranging from 2 to 145 months. Pericardial effusion is typically an early prese

39、ntation. 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.2021/7/15 星

40、期四672.7预防与处理2.7.1 Monitoring Cardiovascular Toxiciity2.7.1.1 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.2021/7/15 星期四682.7.1.2 Provocative testing with exercise or dobutamine echocardiography may be sensitive for the early dete

41、ction of subclincial cardiomvonpathy and may provide an opportunity for therapeutic intervention before the development of overt LV dysfunction.2021/7/15 星期四692.7.1.3 Diastolic dysfunction is an early sign.2.7.1.4 Fractional shortening and LV ejection fraction are not sensitive for the early detecti

42、on of preclinical cardiac diaease.2021/7/15 星期四702.7.2 Strategies to Reduce Cardiovascular Toxicity and Manage Complications2.7.2.1Anthracycline 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。2021/7/15 星期四873.5.2 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

43、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）2021/7/15 星期四882021/7/15 星期四892021/7/15 星期四903.6 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 T0-3,N2,M0 B T4,N0-1,M0 C Tany,N3,M02021/7/15 星期四913.6.1.3 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+2021/7/15 星期四923.6.3 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 2021/7/15 星期四933.6.4.12021/7/15 星期四943.6.4.22021/7/15 星期四953.7卵巢上皮癌和输卵管癌除A B高分化可观察外，A