肺癌肺癌李峻岭20082008年进修医生讲座年进修医生讲座进修医生讲座肺癌肺癌流行病学肺癌流行病学进修医生讲座肺癌JCO 2008 JANUARY 10JCO 2008 JANUARY 10进修医生讲座肺癌JCO 2008 JANUARY 10JCO 2008 JANUARY 10进修医生讲座肺癌JCO 2008 JANUARY 10JCO 2008 JANUARY 10进修医生讲座肺癌男性恶性肿瘤死亡率男性恶性肿瘤死亡率JCO 2008 JANUARY 10JCO 2008 JANUARY 10肺癌进修医生讲座肺癌女性恶性肿瘤死亡率女性恶性肿瘤死亡率JCO 2008 JANUARY 10JCO 2008 JANUARY 10进修医生讲座肺癌中国肺癌流行病学回顾中国肺癌流行病学回顾26.9%38.4%30.5%2000-2005年肺癌患者数Yang et al, 2005患者数进修医生讲座肺癌中国肺癌流行病学回顾中国肺癌流行病学回顾2000-2005年肺癌发病率14.0%19.9%Per 100,000Yang et al, 2005*ASR: Age-standardized incidence rate (per 100,000) using world standard population进修医生讲座肺癌中国肺癌流行病学回顾中国肺癌流行病学回顾2000-2005年癌症发病率排名RankMale (ASR*)2000RankMale (ASR*)20051Lung43.01Lung49.02Stomach41.92Liver40.03Liver38.93Stomach37.14Esophagus27.64Esophagus24.05Colon/rectum14.05Colon/rectum15.0Yang et al, 2005RankFemale (ASR*)2000RankFemale (ASR*)20051Breast19.91Breast24.82Stomach19.52Lung22.93Lung19.23Stomach17.44Liver14.54Liver15.35Esophagus12.15Esophagus9.7* ASR: Age-standardized incidence rate (per 100,000) using world standard population进修医生讲座肺癌中国肺癌流行病学回顾中国肺癌流行病学回顾Cumulative Risk: (up to 74 years of age) were calculated to give the net risk (as a percentage) which an individual would have of developing the cancer in question before the age of 75 in the absence of other causes of death肺癌成为累积危险性最高的癌症MaleCumulative Risk2000MaleCumulative Risk20051Lung5.11Lung5.72Stomach4.92Liver4.33Liver4.22Stomach4.34Esophagus3.34Esophagus2.95Colon/rectum1.65Colon/rectum1.7FemaleCumulative Risk2000FemaleCumulative Risk20051Stomach2.31Lung2.62Lung2.22Breast2.33Breast1.93Stomach2.04Liver1.64Liver1.75Esophagus1.45Esophagus1.2Yang et al, 2005进修医生讲座肺癌北京市卫生局公布的北京市卫生局公布的20072007年北京市居民死因年北京市居民死因恶性肿瘤首次排第一恶性肿瘤首次排第一 2007年前十位死因顺位与2006年相比，恶性肿瘤由第三位升至第一位，以“肺癌、肝癌、肠癌”为主，共占恶性肿瘤死亡的52.01%。 男性死亡率高于女性男性死亡率高于女性本市男性总死亡率为6.09，女性总死亡率为4.93；在恶性肿瘤死亡中，男性、女性排在第一位的都是肺癌。郊县死亡率高于城区郊县死亡率高于城区城区的首位死因是恶性肿瘤，郊县的首位死因是脑血管病。恶性肿瘤死亡中，城区、郊县居民排在首位的也都是肺癌。 癌症死亡率上升速度加快癌症死亡率上升速度加快恶性肿瘤死亡率首次排在本市居民死因的第一位，说明本市近年来恶性肿瘤死亡率上升速度不断加快 北京市卫生局邓小虹进修医生讲座肺癌病病 因因吸烟（吸烟（8585）氡气：镭氡气：镭226226的衰变产物的衰变产物石棉（石棉（3 34 4）其他：肺部感染，肺结核，家族史，双乙其他：肺部感染，肺结核，家族史，双乙醚，多环芳香烴，铬，镍，有机砷等醚，多环芳香烴，铬，镍，有机砷等进修医生讲座肺癌20252025年中国归因于烟草的年中国归因于烟草的疾病和死亡将达到疾病和死亡将达到3333 中国卫生部2007中国控制吸烟报告：中国烟民3.5亿、“被动”烟民5.4亿。目前我国15岁以上男性人群的吸烟率达到66%。现阶段我国归因于烟草的死亡为12%到2025年，我国归因于烟草的疾病和死亡将达33%。每年因为吸烟带来人力资源的消耗以及由此带来的医疗费用，事实上完全稀释了烟草的经济效益。烟草对国民健康和社会发展的危害越来越严重 来源：工人日报2007年9月29日进修医生讲座肺癌预后因素预后因素诊断时分期：早诊断时分期：早体力状态：体力状态：ECOG 0ECOG 0、1 1、2 2体重变化：下降体重变化：下降 5 2 cm 2 cmORORORORN0: No lymph node involvementN0: No lymph node involvementNo lobarNo lobarbronchusbronchusinvolvementinvolvementT T 3 cm3 cmT1T1N0N0M0M0T2T2N0N0M0M0T T 3 cm3 cmT + visceral pleuraT + visceral pleurainvolvedinvolvedT + atelectasisT + atelectasis进修医生讲座肺癌LUNG CANCERLUNG CANCERStage II Stage II （A B A B ）diseasedisease 2 cm 2 cmOROROROR N1: Intrapulmonary and/or hilar nodes involvedN1: Intrapulmonary and/or hilar nodes involvedNo lobarNo lobarbronchusbronchusinvolvementinvolvementT T 3 cm 3 cmT1T1N1N1M0M0T2T2N1N1M0M0T3 T3 N0N0M0M0T T 3 cm3 cmT + visceral pleuraT + visceral pleurainvolvedinvolvedT + atelectasisT + atelectasis进修医生讲座肺癌LUNG CANCER LUNG CANCER Stage IIIA diseaseStage IIIA disease 2 cm 2 cm 2 cmT2T2ORORORORORORORORT1T1N1: peribronchial or ipsilateral hilarN1: peribronchial or ipsilateral hilarT T 3 cm 3 cmNo lobarNo lobarbronchus involvementbronchus involvementT T mediastinal mediastinal pleura pleura (or pericardium) (or pericardium)T T chest wall chest wall (or diaphragm) (or diaphragm)T3T3N1N1M0M0T3T3N2N2M0M0T1 T1 N2N2M0M0T2T2N2N2M0M0T T 3 cm3 cmT + visceral pleuraT + visceral pleurainvolvedinvolvedT + atelectasisT + atelectasisN2: ipsilateral mediastinal and subcarinalN2: ipsilateral mediastinal and subcarinal进修医生讲座肺癌LUNG CANCERLUNG CANCERStage IIIB diseaseStage IIIB diseaseAny T, N3, M0Any T, N3, M0Any N, T4, M0Any N, T4, M0ScaleneScaleneSupraclavicularSupraclavicularN3: lymph nodes involvedN3: lymph nodes involvedT4: mediastinal involvementT4: mediastinal involvementAny TAny TAny NAny NT4T4进修医生讲座肺癌LUNG CANCERLUNG CANCERSpread to lymph nodesSpread to lymph nodesNode involvement sequence:Node involvement sequence:FirstFirstSubsequentSubsequentFrom upper lobeFrom upper lobeFrom middle lobeFrom middle lobeFrom lower lobeFrom lower lobeRoute of spread:Route of spread:进修医生讲座肺癌LUNG CANCERLUNG CANCERLocal and distal spreadLocal and distal spreadBrainBrainDraining lymph nodesDraining lymph nodesLiverLiverAdrenalsAdrenalsBoneBone进修医生讲座肺癌将于将于20092009年开始采用年开始采用新的肺癌分期新的肺癌分期进修医生讲座肺癌进修医生讲座肺癌进修医生讲座肺癌外科手术是早期肺癌外科手术是早期肺癌根治的主要手段根治的主要手段进修医生讲座肺癌肺癌术前分期手段肺癌术前分期手段T分期：胸片，CT, 气管镜N分期：CT; CT-PET; 纵膈镜；胸腔镜 TBNA（经气管镜纵隔LN穿刺)M分期：头MRI; 腹部B超；骨扫描；CT-PETpTNM: 穿刺细胞学，痰细胞学，气管镜刷片细胞学，气管镜活检病理，手术切除标本病理学检查进修医生讲座肺癌肺癌术前分期标准肺癌术前分期标准常规分期检查应至少包括：胸片正侧位、痰细胞学检查、胸部加强CT、头部MRI、骨扫描、气管镜等鼓励行PETCT检查尽量争取用纵隔镜、胸腔镜或经气管镜穿刺以获取病理或细胞学证据进行术前正确分期，如确有困难，应做好以影像诊断为基础的临床分期严格按1997年国际UICC肺癌分期标准进行TNM分期胸部CT显示淋巴结短径1.5cm临床上可视为有淋巴结转移进修医生讲座肺癌肺肺癌癌引引流流淋淋巴巴结结分分布布示示意意图图进修医生讲座肺癌肺肺癌癌引引流流淋淋巴巴结结分分布布示示意意图图进修医生讲座肺癌肺癌完全切除标准定义肺癌完全切除标准定义以标准肺癌切除术式完整切除肿瘤组织和所侵及器官与组织及相关引流区肺门和纵隔淋巴结进修医生讲座肺癌不同期别不同期别NSCLCNSCLC完全切除手术标准完全切除手术标准(1)(1)-术式术式(1). 术前分期：Ia、Ib、IIa、IIb、T3N1病变(2). IIIa N2病变必须是两站以内的（含两站）纵隔 淋巴结转移，无明显侵犯纵隔结构或引起上腔静 脉压迫综合症者(3). 标准切除术式：肺叶切除 或 全肺切除 + 系统淋 巴结清扫（含复合肺叶切除；气管支气管成形肺 叶或全肺切除)进修医生讲座肺癌不同期别不同期别NSCLCNSCLC完全切除手术标准完全切除手术标准(1)(1)-切缘切缘(1).支气管断端须经病理证实为阴性。(2).肺癌跨叶，受侵叶行部分切除的，切缘须经病 理证实为阴性。(3).肺癌侵犯胸壁（包括壁层胸膜,肋骨，肋间肌等），须行胸壁部分切除，切缘须经病理证实为阴性。进修医生讲座肺癌系统淋巴结清扫系统淋巴结清扫肺门淋巴结清扫：包括主支气管旁、叶间支气管旁淋巴结、切除叶支气管旁的及以远的淋巴结。纵隔淋巴结清扫：（）右侧至少包括：2R区、4R区、隆凸下、下肺静脉旁、下肺韧带旁和食管旁6站。（）左侧至少包括：主肺动脉窗、隆凸下、下肺静脉旁、下肺韧带旁、食管旁5站 进修医生讲座肺癌左左肺肺癌癌引引流流淋淋巴巴结结分分布布示示意意图图进修医生讲座肺癌右右右右侧侧侧侧肺肺肺肺癌癌癌癌引引引引流流流流淋淋淋淋巴巴巴巴结结结结分分分分布布布布示示示示意意意意图图图图进修医生讲座肺癌进修医生讲座肺癌进修医生讲座肺癌我国非小细胞肺癌手术治疗效果我国非小细胞肺癌手术治疗效果报告人（年份）报告人（年份）手术例数手术例数5 5年生存率年生存率黄孝迈等（黄孝迈等（19871987）76576533.6%33.6%廖美琳等（廖美琳等（19881988）2636263640.6%40.6%丁嘉安等（丁嘉安等（19881988）2048204831.8%31.8%裴广廷等（裴广廷等（19911991）1336133633.4%33.4%李世业等（李世业等（19921992）3568356834.6%34.6%张汝安等（张汝安等（19931993）2025202540.8%40.8%吴一龙等（吴一龙等（19991999）1757175739.8%39.8%方德康等（方德康等（19991999）1471147142.4%42.4% 手术切除后手术切除后NSCLCNSCLC病人生存率病人生存率孙燕等：内科肿瘤学，人民卫生出版社孙燕等：内科肿瘤学，人民卫生出版社2001，P658 进修医生讲座肺癌术后辅助化疗术后辅助化疗以铂类为基础的两药联合肺癌辅助的趋向：靶向治疗的参与进修医生讲座肺癌不能耐受顺铂的患者可选非顺铂方案及非铂类方案不能耐受顺铂的患者可选非顺铂方案及非铂类方案辅助化疗首选含顺铂两药联合方案辅助化疗首选含顺铂两药联合方案进修医生讲座肺癌ObservationMonths100908070605040302010006121824303642485460Survival ProportionCisplatin-Based ChemotherapyHazard ratio= 0.87P= 0.08顺铂为基础的化疗对比观察辅助治疗顺铂为基础的化疗对比观察辅助治疗NSCLCNSCLC的的metameta分析分析 (BMJ 1995) (BMJ 1995) 5% Benefit5% Benefit进修医生讲座肺癌辅助顺铂化疗方案对比观察治疗辅助顺铂化疗方案对比观察治疗IA IIIAIA IIIA期期 NSCLC (IALT) NSCLC (IALT)N=1867N=1867 Stage I-IIIStage I-III Complete surgical Complete surgical resection within 60 resection within 60 daysdaysR RA AN ND DO OMMI IZ ZE ECisplatin 80 mg/mCisplatin 80 mg/m2 2 q 3 wk q 3 wk 4 4 ORORCisplatin 100 mg/mCisplatin 100 mg/m2 2 q 4 wk q 4 wk 3-4 3-4 ORORCisplatin 120 mg/mCisplatin 120 mg/m2 2 q 4 wk q 4 wk 3 3PLUSPLUSEtoposide 100 mg/mEtoposide 100 mg/m2 2 3 days OR 3 days ORVinorelbine 30 mg/mVinorelbine 30 mg/m2 2 weekly OR weekly ORVinblastine 4 mg/mVinblastine 4 mg/m2 2 weekly OR weekly OR Vindesine 3 mg/mVindesine 3 mg/m2 2 weekly weeklyNo chemotherapyNo chemotherapyNew Engl J Med 2004; 350:351-60进修医生讲座肺癌0 01 12 2 3 3 4 4 5 5ObservationObservationCisplatin-basedCisplatin-basedChemotherapyChemotherapyp0.03p 661.048.857.143.5Survival (%)020406080100Time from randomization (Years)012345 661.048.857.143.5Absolute DifferenceChemotherapyNo chemotherapyChemotherapyNo chemotherapyat 5 years5.3 % 1.6%进修医生讲座肺癌Resected Stage IB-IIIA NSCLCCisplatin 75mg/m2 d1Docetaxel 75mg/m2 d1 4 cyclesCisplatin 75mg/m2 d1Vinorelbine 25mg/m2 d1,8 4 cyclesEnd points5y OS5y DFSToxicityQOL正在进行的肺癌术后辅助治疗研究：正在进行的肺癌术后辅助治疗研究：TAX 622TAX 622 Target N = 1700RANDOMIZE主要研究者：储大同 王子平进修医生讲座肺癌ECOG1505 ECOG1505 研究研究（辅助化疗（辅助化疗 贝伐单抗的贝伐单抗的IIIIII期临床研期临床研究）究） Chemotherapy q 3 wk x 4Vinorelbine-cisplatinTaxotere-cisplatinGemcitabine-cisplatinTarget enrollment = 1,500 patientsPrimary endpoint = Overall survivalSecondary endpoints: Disease-free survival, safetyRANDOMIZATIONChemotherapy q 3 wk x 4 +Bevacizumab q 3 wk x 1 yearEligibilityResected IB( 4cm )IIIA lobectomyNo previous chemoNo planned XRTNo CVA/TIANo ATE in 12 months进修医生讲座肺癌长春瑞滨顺铂重组人血管内皮抑素长春瑞滨顺铂重组人血管内皮抑素长春瑞滨 25mg/m2 IV d1.8顺 铂 75 mg/m2 IV d1重组人血管内皮抑素7.5mg/m2 IV d1-14 21天为一周期，用4周期非小细胞肺癌非小细胞肺癌NSCLC IB-IIIAIB-IIIA术后术后 随随机机长春瑞滨顺铂长春瑞滨顺铂长春瑞滨 25mg/m2 IV d1.8顺 铂 75 mg/m2 IV d1 21天为一周期，用4周期IB-IIIAIB-IIIA期期NSCLCNSCLC术后辅助长春瑞滨顺铂术后辅助长春瑞滨顺铂（NPNP）联合恩度方案对比单纯）联合恩度方案对比单纯NPNP方案的临方案的临床研究（床研究（IIIIII期、随机、开放、多中心）期、随机、开放、多中心）张湘茹 李峻岭 王子平N=1100进修医生讲座肺癌局部晚期非小细胞局部晚期非小细胞肺癌的治疗肺癌的治疗多模式多手段的结合提高5年生存率的潜在群体进修医生讲座肺癌局部晚期局部晚期NSCLCNSCLC诱导化疗的优势诱导化疗的优势在早期阶段杀伤微小转移病灶在早期阶段杀伤微小转移病灶实施性及耐受性好实施性及耐受性好评估药物敏感性评估药物敏感性局部治疗前甄别已有转移的患者局部治疗前甄别已有转移的患者局部治疗前发现未被认识的合并症局部治疗前发现未被认识的合并症大量可用的治疗后的病理资料大量可用的治疗后的病理资料进修医生讲座肺癌同期化放疗化疗方案同期化放疗化疗方案序贯化放疗化疗方案序贯化放疗化疗方案同期化放疗后巩固化疗同期化放疗后巩固化疗进修医生讲座肺癌不可手术不可手术NSCLCNSCLC序贯化放疗序贯化放疗SurvivalCALGB #84-53Chemo + RTRT AloneN7877Median14 mo10 mo3-Year24%10%Sause (RTOG)Chemo + RTRT AloneHFX RT15114915214 mo11 mo12 mo13%9%14%Le ChevalierChemo + RTRT alone17617712 mo10 mo12%4%进修医生讲座肺癌同步对比序贯化放疗同步对比序贯化放疗 (RTOG 9410) (RTOG 9410)序贯序贯: Cisplatin/Vinblastine x 2 60 Gy RT D50 同步每天同步每天1次次RT: Cisplstin/Vinb x 2/60 Gy RT D1同步每天同步每天2次次 RT: Cis/Oral Etoposide/69.6 Gy BID RT D1Median4 Year P-value Gr 3/4SurvivalSurvivalvs SEQEsophagitisSequential15 mo12% 4%Con Daily RT17 mo21%0.04625%Con Twice-15 mo17%0.29647% Daily RTCurran Proc ASCO 2003进修医生讲座肺癌诱导诱导Carboplatin/PaclitaxelCarboplatin/Paclitaxel后后CT/RTCT/RT对比单纯对比单纯CT XRTCT XRT治疗不可切除的治疗不可切除的NSCLC (CALGB 39801)NSCLC (CALGB 39801) 366 stage III pts entered between OCT 1998 and MAY 2002 Goal: To show a 40% in median survival: 13 to 18 monthsCT/XRTCT CT/XRTNumber of Patients182184Gr 3/4 Neutopenia (%)15%27%Gr 3 anemia (%)5 %11%Gr 3/4 esophagitis (%)31%35%Median Survival (months)1114p = 0.1541 Year Survival (%)48%54% Vokes Proc ASCO 2004进修医生讲座肺癌有关有关IIIIII期不可手术期不可手术NSCLCNSCLC的问题的问题1.1.化疗和放疗的顺序?改变分割改变分割? ?2.2.标准标准 RT vs. RT vs.3-D RT?3-D RT?3.3.化疗药物化疗药物? ?进修医生讲座肺癌INT 0139: Definitive Concomitant INT 0139: Definitive Concomitant ChemoRT vs Induction ChemoRT then ChemoRT vs Induction ChemoRT then Surgery for Stage IIIA NSCLCSurgery for Stage IIIA NSCLCStage IIIA (T1-3, pN2, M0)NSCLCRANDOMIZECis/Etop x 2 cyclesw/concurrent XRT 45GyCis/Etop x 2 cyclesw/concurrent XRT 45GySurgeryCis/Etop x 2 cyclesCis/Etop x 2 cyclesAlbain Proc ASCO 2005Continue RT to 61GY进修医生讲座肺癌SurgeryRT/SCT/RTMedian24 mo22 mo5-yr OS27%20%Logrank P = .24; HR 0.87 (CI, 0.7, 1.10)60INT 0139 : Overall SurvivalINT 0139 : Overall SurvivalAlbain Proc ASCO 2005Proportion Alivexxxx进修医生讲座肺癌Toxic Deaths on 0139Toxic Deaths on 0139DeathSurgery (n=202)RT (n=194)Total8%2% (during or after consolidation)During induction0030 d post-op5%-Surgery ArmType of surgeryTotal #DeathsWedge30Lobectomy981 (1%)Pneumonectomy5414 (26%)Albain Proc ASCO 2005进修医生讲座肺癌INT 0139: Results In INT 0139: Results In “Lobectomy” and “Lobectomy” and “Pneumonectomy” Patients“Pneumonectomy” PatientsPneumonectomy “Matched”SurgeryRTMedian Overall Survival19 mo29 mo3-yr survival36%45%5-yr survival22%24%# Dead 3842Lobectomy “Matched”SurgeryRTMedian Overall Survival34 mo22 mo5-yr survival36%18%# Dead 5774Albain Proc ASCO 2005进修医生讲座肺癌晚期非小细胞肺癌的晚期非小细胞肺癌的一线治疗一线治疗铂类两药三代联合方案铂类两药三代联合方案化疗与血管靶向药物的联合化疗与血管靶向药物的联合进修医生讲座肺癌ECOG 1594: ECOG 1594: 研究设计研究设计分层分层:uStage: IIIB vs IVuPS: 01 vs 2uWt Loss: 5% vs 5%uCNS Mets: no vs yesArmA:Cisplatin+PaclitaxelPaclitaxel:135mg/m2/24hDay1Cisplatin:75mg/m2day2q3wkArmD:Carboplatin+PaclitaxelPaclitaxel:225mg/m2/3hDay1Carboplatin:AUC6Day1ArmC:Cisplatin+DocetaxelDocetaxel:75mg/m2Day1Cisplatin:75mg/m2Day1ArmB:Cisplatin+GemcitabineGemcitabine:1000mg/m2Days1,8,15Cisplatin:100mg/m2Day1q4wkq3wkq3wkSchiller JH, et al. Proc ASCO 36th Annual Meeting. 2000;19:abstr 2.Schiller JH, et al. N Engl J Med. 2002;346:92-98.RANDOMIZE进修医生讲座肺癌E1594 E1594 进修医生讲座肺癌 TAX326 TAX326 研究研究RANDOMIZE分层因素: Stage of DiseaseIIIB vs. IVand RegionUS/Canada South AmericaEurope/LebanonIsraelSouthAfrica/AustraliaNew ZealandResponse assessment every 2 cyclesDocetaxel 75mg/m2 IV Carboplatin AUC 6 IV Q 3 wksVinorelbine 25mg/m2 IV D 1, 8, 15 & 22Cisplatin 100mg/m2 IV D 1Q 4 wksDocetaxel 75mg/m2 IVCisplatin 75mg/m2 IV Q 3 wksvs.or进修医生讲座肺癌TAX 326 TAX 326 ：总生存：总生存Fossella et al. J Clin.Oncol. 2003;21:3016-3024.100806040200Survival (%)0369 12 15 18 21 24 27 30 33Time (months)TCVC100806040200Survival (%)036912 15 18 21 24 27 30 33Time (months)P = .657, adjustedlog-rank testTCbVC1-y survival 46% vs 41% with VC2-y survival 21% vs 14% with VCMedian survival: 11.3 vs 10.1 moP = .044, adjusted log-rank test1-y survival 38% vs 40% with VC2-y survival 18% vs 14% with VC进修医生讲座肺癌Bevacizumab Bevacizumab 与化疗联合能延长患者生存与化疗联合能延长患者生存NSCLC: 与单纯化疗相比，bevacizumab联合化疗可使患者中位生存时间从10.3月延长至 12.3 月Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.Sandler A, et al. ASCO 2005. Abstract LBA4.Median Median Survival, mosSurvival, mosChemotherapyChemotherapyBevacizumabBevacizumabHRHRP P Value ValueLung cancerLung cancerOverall10.312.30.79.003PFS4.56.20.66 .001Colon cancerColon cancerOverall15.620.30.66.00004PFS6.210.60.54 .00001进修医生讲座肺癌ECOG 4599: Bevacizumab ECOG 4599: Bevacizumab 治疗非治疗非鳞癌鳞癌NSCLCNSCLC的的IIIIII期临床研究期临床研究Sandler A, et al. N Engl J Med. 2006;355:2542-2550.Stratified by RT vs no RT, stage IIIB or IV vs recurrent, weight loss 5% vs 5%, measurable vs nonmeasurableTreatment-naive patients with confirmed stage IIIB or IV cancer; adequate hematologic, hepatic, and renal function(N = 878)PCPaclitaxel 200 mg/m2Carboplatin AUC = 6 mg/mL/min(once every 3 weeks) x 6 cycles(n = 433*)PCBPC (once every 3 weeks) x 6 cycles +Bevacizumab 15 mg/kg (once every 3 weeks) until disease progression(n = 417*)*Eligible patients included in analysis.进修医生讲座肺癌ECOG 4599: ECOG 4599: 有效率有效率Sandler A, et al. N Engl J Med. 2006;355:2542-2550.PCPCBP Value15% 35% .001N = 773 患者(可测量疾病)进修医生讲座肺癌ECOG 4599: PCB ECOG 4599: PCB 组患者生存时间延长组患者生存时间延长PCB 组中位生存时间显著延长 (12.3 个月对比PC 组10.3 个月) 12-月生存率PCB: 51%PC: 44%24-月生存率PCB: 22%PC: 15%PCB 组PFS也显著延长(6.2 月对比PC组4.5 月)Sandler A, et al. N Engl J Med. 2006;355:2542-2550.进修医生讲座肺癌ECOG 4599: PCB ECOG 4599: PCB 相关不良反应相关不良反应PCB组III-V度不良反应增加 Sandler A, et al. N Engl J Med. 2006;355:2542-2550.Grade 3-5 Adverse Event,* %PC (n = 440)PCB (n = 427)P ValueHemorrhage (all)0.74.4 .001Hypertension0.77.0 .001Proteinuria0.03.1 .001Headache0.53.0.003Rash0.52.3.020Neutropenia16.825.5.002Thrombocytopenia0.21.6.040*Grade 4 and Grade 5 events reported for hematologic adverse events.进修医生讲座肺癌ECOG 4599: ECOG 4599: 肿瘤及治疗相关死亡肿瘤及治疗相关死亡Decrease in lung cancerrelated deaths and increase in treatment-related deaths associated with PCB useSandler A, et al. N Engl J Med. 2006;355:2542-2550.Cause of Death, nPC(n = 440)PCB (n = 427)Total344305Lung cancer309260HemorrhageHemoptysis05GI bleed12Neutropenic fever15Cerebrovascular02Pulmonary Embolus01进修医生讲座肺癌Manegold C et alAbstract LBA7514Abstract LBA7514Oral PresentationOral PresentationBO17704 (AVAIL)BO17704 (AVAIL)BO17704 (AVAIL)BO17704 (AVAIL)：bevacizumab bevacizumab bevacizumab bevacizumab 联合健择顺铂一线联合健择顺铂一线联合健择顺铂一线联合健择顺铂一线治疗晚期非鳞癌非小细胞肺癌的治疗晚期非鳞癌非小细胞肺癌的治疗晚期非鳞癌非小细胞肺癌的治疗晚期非鳞癌非小细胞肺癌的随机双盲多中心三期临床研究随机双盲多中心三期临床研究随机双盲多中心三期临床研究随机双盲多中心三期临床研究进修医生讲座肺癌BO17704 (AVAIL): 研究设计RCisplatin/gemcitabine + Bevacizumab 15 mg/kgN = 1,044一线晚期或复发的非鳞癌一线晚期或复发的非鳞癌NSCLCNSCLCCisplatin/gemcitabine + Bevacizumab 7.5 mg/kgCisplatin/gemcitabine + Placebo主要终点主要终点: : PFSPFS次要终点次要终点: :OS, TTF, SafetyOS, TTF, SafetyManegold et al. ASCO 2007: Abstract LBA7514.进修医生讲座肺癌G/C(n=324)G/C/7.5(n=323)G/C/15(n=332)Median PFS, mo6.16.76.5HR: 0.75 p=0.026HR: 0.82 p=0.030ORR, %203430p0.0001p0.0017Duration of response, mo4.76.16.1BO17704 (AVAIL): BO17704 (AVAIL): BO17704 (AVAIL): BO17704 (AVAIL): 疗效疗效疗效疗效Manegold et al. ASCO 2007: Abstract LBA7514.进修医生讲座肺癌BO17704 (AVAIL): BO17704 (AVAIL): 毒性毒性Grade 3/4 toxicity, %G/C(n=347)G/C/7.5(n=345)G/C/15(n=351)白细胞减少白细胞减少324036血小板减少血小板减少232723出血出血244高血压高血压269Manegold et al. ASCO 2007: Abstract LBA7514.Grade 3/4/5 toxicity, %G/C(n=347)G/C/7.5(n=345)G/C/15(n=351)咯血咯血 Hemoptysis 0.61.50.9进修医生讲座肺癌AVAIL: AVAIL: 作者的结论作者的结论AVAIL是第二个有bevacizumab参与治疗晚期非小细胞肺癌在PFS和ORR均获益的III期临床研究两种剂量的bevacizumab组的疗效相似CG 联合bevacizumab (7.5 和 15 mg/kg) 耐受性良好，伴有低的严重咯血和肺出血正在期待OS 的数据Manegold et al. ASCO 2007: Abstract LBA7514.进修医生讲座肺癌BevacizumabBevacizumab用于用于NSCLCNSCLC Safety with all chemotherapy? Duration of use - Maintenance? Use second-line and beyond? Safety in patients excluded from trials (brain metastases, squamous histology, warfarin)? Can we identify patients at high risk for hemorrhage? Management of hypertension? 进修医生讲座肺癌二线治疗二线治疗进修医生讲座肺癌试验设计试验设计 - TAX 317 - TAX 317NSCLC 分层分层: ECOG PS (0,1 vs. 2) 和和既往对含铂方案的既往对含铂方案的最佳疗效最佳疗效 (PD vs. non-PD) RANDOMIZE317 ATaxotere 100 mg/m2, one-hour IV infusion on Day 1, every 21 days Premedication: Dexamethasone 8 mg x 10 doses, beginning 12 hours before TaxotereBy Protocol Amendment 6:Taxotere 75 mg/m2, one-hour IV infusion on Day 1, every 21 days Premedication: Dexamethasone 8 mg x 5 doses, beginning 12 hours before Taxotere317 B最佳的支持治疗最佳的支持治疗没有化疗没有化疗进修医生讲座肺癌p=0.004p=0.004p=0.037p=0.037Log-rank TestLog-rank Test7.07.012.312.35.95.99.19.1中位中位TTPTTP( (周周) )317A317A317B317BBSC75 BSC75 (n=49)(n=49)T75 T75 (n=55)(n=55)BSC100 BSC100 (n=51)(n=51)T100 T100 (n=49)(n=49)到疾病进展时间到疾病进展时间(TTP) - TAX (TTP) - TAX 317317进修医生讲座肺癌生存分析生存分析TAX 317 BTAX 317 B生存时间生存时间 ( (月月) )中位生存时间中位生存时间 7.5 vs. 4.6 7.5 vs. 4.6 月月月月Log-rank p = 0.010Log-rank p = 0.0101-1-年生存率年生存率 37% vs. 12%37% vs. 12%Chi-square p = 0.003Chi-square p = 0.003T 75T 751.01.00.90.90.80.80.70.70.50.50.30.30.20.20.10.10.00.00 03 36 6 9 91212 15 1518182121累计概率累计概率BSC75 BSC75 0.40.40.60.6进修医生讲座肺癌NSCLCNSCLC：二线治疗：二线治疗Pemetrexed Pemetrexed 500 mg/m500 mg/m2 2 i.v. q3wks i.v. q3wks (n=283)(n=283)(folic acid 350-1,000 g daily + (folic acid 350-1,000 g daily + vitamin Bvitamin B1212 1,000 g q 9wks; 1,000 g q 9wks; dexamethasone 4mg bid on dexamethasone 4mg bid on d-1,d0,d+1)d-1,d0,d+1)Docetaxel Docetaxel 75 mg/m75 mg/m2 2 i.v. q3wks (n=288) i.v. q3wks (n=288)(dexamethasone 8 mg bid on (dexamethasone 8 mg bid on d-1,d0,d+1)d-1,d0,d+1)R RA AN ND DO OM MI IZ ZE ED D进修医生讲座肺癌总生存PemetrexedDocetaxelSurvival distribution functionMonths1.000.750.500.25002.55.07.510.012.515.017.520.022.5Hanna N, et al. J Clin Oncol 2004;22:158997进修医生讲座肺癌血液学毒性血液学毒性 (Grade 3/4) (Grade 3/4) Pemetrexed Docetaxel(n=265) (n=276)Neutropenia5.340.2 .001Febrile Neutropenia1.912.7 .001Infection w/ gr 3/4 Neutropenia0 3.3 .004Anemia4.24.31.00Thrombocytopenia2 1 .116 进修医生讲座肺癌 有效性评价 De Marinis (Poster # 7133)力比泰力比泰 NSCLCNSCLC二线治疗二线治疗进修医生讲座肺癌ISEL: Gefitinib ISEL: Gefitinib Gefitinib：小分子EGFR抑制剂1692 例患者随机接受Gefitinib (n = 1129) 或 placebo (n = 563) 1-年生存: gefitinib 27% 对比 placebo 21%Thatcher N, et al. Lancet. 2005;366:1527-1537.Patient Median OS, mosGefitinib PlaceboHRP ValueAll patients5.65.10.89.087Never smoked8.96.10.67.012Asian9.55.50.66.010Adenocarcinoma6.35.40.84.089进修医生讲座肺癌易瑞沙在中国的注册临床研究易瑞沙在中国的注册临床研究 总体结总体结果果易瑞沙易瑞沙 (250mg/d)N=159 (%)客观有效率客观有效率43 (27.1%)CR2 (1.3%)PR41 (25.8)SD 43 (27.0%)疾病控制率疾病控制率86 (54.1%)中位生存期中位生存期 (月月)10中位无疾病进展时间中位无疾病进展时间 (天天)971年生存率年生存率 (%)44Guan et al, Chinese Journal of Cancer, 2005, 24(8): 980-984进修医生讲座肺癌易瑞沙二线单药与病人选择小结易瑞沙二线单药与病人选择小结种族是EGFR-TKI最重要的临床预测因素之一易瑞沙是目前中国NSCLC二线标准方案之一女性或腺癌或不吸烟者对EGFR-TKI疗效较好在中国的男性或非腺癌或吸烟者的疗效为：非腺癌有效率8.3%-16.2%吸烟有效率15.4%-23.0%男性有效率17.5%-25.9%易瑞沙可以降低各种类型亚洲患者死亡风险进修医生讲座肺癌BR.21: Erlotinib BR.21: Erlotinib 单变量分析与延长生存有关的因素Erlotinib treatment (P = .002)Asian origin (P = .01)Adenocarcinoma (P = .004)Never smoked (P = .048)Shepherd FA, et al. N Engl J Med. 2005;353:123-132.Patient OutcomePatient OutcomeErlotinibErlotinibPlaceboPlaceboHR (95% CI)HR (95% CI)P P ValueValue1 year survival, %3121-Median OS, mos6.74.70.70 (0.58 -0.85).001进修医生讲座肺癌亚洲群体的疗效亚洲群体的疗效特罗凯在东亚化疗经治的患者中的疗效： 有效率: 25%, 中位TTP: 24周 中位OS: 9个月特罗凯的耐受性因治疗相关不良事件导致5%严重的不良事件和5%的出组 17%的患者需要剂量调整 进修医生讲座肺癌A Randomized, Open-Label, Parallel Group, International, A Randomized, Open-Label, Parallel Group, International, A Randomized, Open-Label, Parallel Group, International, A Randomized, Open-Label, Parallel Group, International, Multicenter Phase III Study of Oral ZD1839 (IRESSAMulticenter Phase III Study of Oral ZD1839 (IRESSAMulticenter Phase III Study of Oral ZD1839 (IRESSAMulticenter Phase III Study of Oral ZD1839 (IRESSA ) ) ) ) Versus Intravenous Docetaxel (TAXOTEREVersus Intravenous Docetaxel (TAXOTEREVersus Intravenous Docetaxel (TAXOTEREVersus Intravenous Docetaxel (TAXOTERE ) in Patients With ) in Patients With ) in Patients With ) in Patients With Locally Advanced or Metastatic Recurrent Non-Small Cell Locally Advanced or Metastatic Recurrent Non-Small Cell Locally Advanced or Metastatic Recurrent Non-Small Cell Locally Advanced or Metastatic Recurrent Non-Small Cell Lung Cancer who have Previously Received Platinum-Based Lung Cancer who have Previously Received Platinum-Based Lung Cancer who have Previously Received Platinum-Based Lung Cancer who have Previously Received Platinum-Based ChemotherapyChemotherapyChemotherapyChemotherapy(INTEREST)(INTEREST)评估易瑞沙对照多西他赛治疗评估易瑞沙对照多西他赛治疗评估易瑞沙对照多西他赛治疗评估易瑞沙对照多西他赛治疗NSCLCNSCLCNSCLCNSCLC疗效和生存的研究疗效和生存的研究疗效和生存的研究疗效和生存的研究进修医生讲座肺癌INTEREST：研究设计*modified Hochberg procedure applied to control for multiple testing; CT, chemotherapy; PS, performance status吉非替尼250 mg/day多西他赛75 mg/m2 每三周方案1:1 随机分组入组病例年龄 18 岁生存预期8周既往化疗进展或复发可继续接受多西他赛治疗既往1或2次化疗(至少1次含铂方案)体力评分PS 0-2主要终点总生存期协同分析(1)所有人群非劣效(2)EGFR 基因复制高表达(FISH阳性)人群优效性次要终点无疾病进展生存期客观有效率生活质量改善率疾病相关症状安全性和耐受性探索性终点生物标记物研究终点Doulliard et al; Data presented at WCLC 2007 in Seoul, Korea进修医生讲座肺癌INTERESTINTEREST：主要终点主要终点 总生存期总生存期 ( (FISH+)FISH+)Doulliard et al; Data presented at WCLC 2007 in Seoul, KoreaProbabilityof survival8572 (84.7%)8971 (79.8%)NEventsCox analysis without covariatesHR (95% CI) = 1.09 (0.78, 1.51), p=0.6199Median OS (months)1-year survival8.432%7.535%Conclude no statistical superiorityin EGFR FISH+ patientsGefitinibDocetaxel854426131064300894231221474100666304812162024283236400.00.20.40.60.81.0MonthsAt risk :GefitinibDocetaxel375 例患者可以进行FISH评价EGFR FISH阳性患者总共174例 (47%)易瑞沙组和多西他赛组的总生存期相似，并未达优效性终点进修医生讲座肺癌INTERESTINTEREST：次要终点：次要终点 QOL QOLP=0.0026P 18 years of age Confirmed SCLC-ED Adequate renal, hepatic, hematologic function Main exclusion criteriaMain exclusion criteria Previous systemic chemotherapy Active cancer other than SCLC Chronic inflammatory bowel disease Pregnant or lactating Impaired mental status Inadequate contraception进修医生讲座肺癌Baseline characteristics well Baseline characteristics well balanced between armsbalanced between armsCharacteristicCharacteristicIrinotecan/CarboplatiIrinotecan/Carboplatin n (n = 105)(n = 105)Etoposide/CarboplatiEtoposide/Carboplatin n (n = 104) (n = 104)Male, %Male, %Median age, yrs (range)Median age, yrs (range)WHO performance status 0-2, WHO performance status 0-2, % %Site of metastases, %Site of metastases, %LiverLiverOtherOtherAdrenalAdrenalBoneBoneCNSCNS636367 (46-81)67 (46-81)838344443838191918181616696968 (42-82)68 (42-82)828245455050151519191212CNS, central nervous system; WHO, World Health Organization.进修医生讲座肺癌Main Main FindingsFindings93% of planned doses delivered in both arms Higher response and slight but significant survival improvement in irinotecan-containing armResponse, nIrinotecan/Carboplatin (n = 105)Etoposide/Carboplatin (n = 104)PValueMedian OS, mos1-yr survival, %CR, %8.534187.1247.02NA.02NA, not available.进修医生讲座肺癌Toxicity profile: Toxicity profile: differencesdifferencesThrombocytopenia more common in etoposide-containing arm: 26% vs 11% for irinotecan/carboplatin (P = .05) Diarrhea more common in irinotecan-containing arm: 11% vs 1% for etoposide/carboplatin (P = .003)进修医生讲座肺癌Significant number of patients Significant number of patients in both arms received additional in both arms received additional therapytherapyAdditional Treatment, nIrinotecan/Carboplatin (n = 105)Etoposide/Carboplatin (n = 104)Second-line therapyRadiotherapy, palliativePrimary regimen as second-line treatment492813482217进修医生讲座肺癌Summary of Key ConclusionsSummary of Key ConclusionsCombination therapy with irinotecan/carboplatin superior to etoposide/carboplatin in patients with SCLC-EDMedian (OS) prolonged by 1.4 months with irinotecan CR rate more than doubled in irinotecan- containing arm Toxicity profiles comparable between arms Investigators recommend irinotecan/carboplatin as new standard of care for SCLC-ED进修医生讲座肺癌预防性脑照射预防性脑照射PCIPCIPROPHYLACTIC CRANIAL IRRADIATION PROPHYLACTIC CRANIAL IRRADIATION FOR PATIENTS WITH SMALL-FOR PATIENTS WITH SMALL-CELLLUNG CANCER IN COMPLETE CELLLUNG CANCER IN COMPLETE REMISSIONREMISSION进修医生讲座肺癌BackgroundBackgroundProphylactic cranial irradiation reduces the incidence of brain metastasis in patients with small-cell lung cancer. Whether this treatment, when given to patients in complete remission, improves survival is not known. The author performed a meta analysis to determine whether prophylactic cranial irradiation prolongs survival.进修医生讲座肺癌MethodsMethodsThe author analyzed individual data on 987 patients with small-cell lung cancer in complete remission who took part in seven trials that compared prophylactic cranial irradiation with no prophylactic cranial irradiation. The main end point was survival.进修医生讲座肺癌ResultsResultsPCI increased 5.4 percent rate of survival PCI increased 5.4 percent rate of survival at three yearsat three years .PCI increased the rate of disease-free survival ( P0.001)PCI decreased the cumulative incidence of brain metastasis (relative risk 0.46; P0.001).The effect on survival did not differ significantly according to the dose.The author also identified a trend (P=0.01) toward a decrease in the risk of brain metastasis with earlier administration of PCI after the initiation of induction chemotherapy.进修医生讲座肺癌ConclusionsConclusionsPCI improves both overall survival and disease-free survival among patients with SCLC in complete remission.Cranial Irradiation Overview Collaborative Group was therefore created to undertake a meta analysis进修医生讲座肺癌Prophylactic Cranial Irradiation Prophylactic Cranial Irradiation Decreases Risk for Brain Decreases Risk for Brain Metastases and Death in Patients Metastases and Death in Patients With Extensive-Disease Small-With Extensive-Disease Small-Cell Lung CancerCell Lung CancerRandomized, controlled phase III trial: European Organisation for Research and Treatment of Cancer 08993-22993进修医生讲座肺癌BackgroundBackgroundIncidence of brain metastases in patients with SCLC-ED 2 years postdiagnosis: 80% Affects physical and psychological capabilities Suboptimal therapeutic response to brain radiotherapy and systemic agents PCI decreases risk of brain metastases in limited-disease SCLC patients without significant increases in neuropathy Associated with survival improvements in patients with complete remissionCurrent study evaluated safety and efficacy of PCI following chemotherapy in patients with SCLC-ED进修医生讲座肺癌Schematic of Study Schematic of Study DesignDesign进修医生讲座肺癌EligibilityEligibilityMain inclusion criteria 18-75 years of age World Health Organization (WHO) performance status 0-2 Confirmed SCLC-ED Responsive to 4-6 cycles chemotherapy Main exclusion criteria Brain or leptomeningeal metastases Corticosteroid use Previous radiotherapy to head or neck Previous or current cancer other than SCLC-ED进修医生讲座肺癌Baseline Baseline CharacteristicsCharacteristicsPatients accrued February 2001 - March 2006 (N = 286) No statistically significant differences in baseline characteristics between armsCharacteristicPCI (n = 143)No PCI (n = 143)Male, %Median age, yrs (range)WHO performance status 0-1, %Persistent primary disease, %Presence of metastases, %Lymph nodesBoneLung67.862 (37-75)92.375.569.250.022.024.057.363 (39-75)89.576.972.747.026.025.0进修医生讲座肺癌Main FindingsMain Findings94% of patients randomized to PCI received treatment Rates of brain metastases, FFS, PS improved with PCI Rate of extracranial progression comparable between arms (P = .27)Response, %PCI (n = 143)No PCI (n = 143)HR (95% CI)PValueBrain metastases at 1 yr1-yr FFS1-yr OS14.623.427.140.415.513.30.27 (0.16-0.44)0.76 (0.59-0.96).68 (0.52-0.88) .001.02.003进修医生讲座肺癌89% of patients followed 89% of patients followed until disease progression or until disease progression or deathdeathParameter, %PCI (n = 143)No PCI (n = 143)Symptomatic brain metastasesExtracranial disease progressionDeaths Death due to SCLC16.885.376.268.541.393.087.480.4Median follow-up PCI arm: 170 days Control arm: 156 days进修医生讲座肺癌Other OutcomesGlobal quality-of-life scores comparable between arms (P = .10) More fatigue in PCI-treated patients at 6-week and 3-month follow-ups Levels converged by 6-month follow-up Grade 3 radiation-related toxicity rare Headache: 5% (grade 3): 2.2%进修医生讲座肺癌Most common radiation-Most common radiation-related grade 1/2 toxicityrelated grade 1/2 toxicityHeadache: 40%Nausea/vomiting: 37% Fatigue/lethargy: 10% Skin reactions: 5%Late radiation reactions primarily grade 1/2Late radiation reactions primarily grade 1/2 Mild headache, slight lethargy (grade 1): 21.6% Moderate headache, great lethargy (grade 2): 11.2% Severe headache, severe central nervous system dysfunction (grade 3): 2.2%进修医生讲座肺癌Generalized treatment outline for patients with SCLCGeneralized treatment outline for patients with SCLC进修医生讲座肺癌Results after Results after treatmenttreatmentLimited-stage: EP+RTLimited-stage: EP+RT Response rate 70%-90% Median survival 14-20 months 2-year survival rate 40%Extensive-stage: combination Extensive-stage: combination chemotherapychemotherapy Response rate 60%-70% Median survival 9-11months 2-year survival rate less than 5%进修医生讲座肺癌Second-line Second-line chemotherapychemotherapy Clinical trial preferred. Relapse 2-3 mo up to 6 mo: topotecan, irinotecan, cyclophosphamide/doxorubicin/vincristine (CAV), gemcitabine, taxane, oral etoposide, vinorelbine. Relapse 6 mo: original regimen.Consider dose reductions versus growth factors in the poor performance status patient进修医生讲座肺癌Expected results of Expected results of salvage therapysalvage therapyrelapse or progress after initial treatment, median survival only 4 to 5 monthsSecond-line chemotherapy can provides significant palliationRelapse timeExpected response rate to other regimensWithin 3monthsLess than 10% Great than 3 monthsApproximately 25%进修医生讲座肺癌谢谢！谢谢！进修医生讲座肺癌