呼吸病区：王呼吸病区：王 洁洁 肺癌内科治疗进展肺癌内科治疗进展非小细胞肺癌非小细胞肺癌内科治疗研究进展内科治疗研究进展 NSCLCNSCLC: : NSCLC NSCLC NSCLC NSCLC的流行病学及诊断分期的流行病学及诊断分期的流行病学及诊断分期的流行病学及诊断分期 早期可手术切除早期可手术切除早期可手术切除早期可手术切除NSCLCNSCLCNSCLCNSCLC的辅助化疗的辅助化疗的辅助化疗的辅助化疗 局部晚期不可手术切除局部晚期不可手术切除局部晚期不可手术切除局部晚期不可手术切除NSCLCNSCLCNSCLCNSCLC同步化放疗同步化放疗同步化放疗同步化放疗 IIIb(IIIb(IIIb(IIIb(胸水胸水胸水胸水)/IV)/IV)/IV)/IV期期期期NSCLCNSCLCNSCLCNSCLC姑息化疗姑息化疗姑息化疗姑息化疗 分子靶向治疗分子靶向治疗分子靶向治疗分子靶向治疗SCLCSCLCSCLCSCLC的全身治疗的全身治疗的全身治疗的全身治疗肺癌的分子异常肺癌的分子异常常见的基因改变常见的基因改变烟草烟草对细胞外信号异常应答对细胞外信号异常应答细胞周期失控细胞周期失控凋亡机制失控凋亡机制失控接触抑制丧失接触抑制丧失获得转移能力获得转移能力血管生成血管生成永生化永生化自分泌生长自分泌生长肺泡不典型增生肺泡不典型增生癌前腺瘤癌前腺瘤肺癌肺癌原位癌原位癌异型性变异型性变支气管化生支气管化生正常上皮正常上皮2005 Estimated US Cancer Deaths*ONS=Other nervous system.Source: American Cancer Society, 2005.Men295,280Women275,000n n27%27% Lung and bronchusLung and bronchusn n15%15% BreastBreastn n10%10% Colon and rectumColon and rectumn n 6% 6% OvaryOvaryn n 6% 6%PancreasPancreasn n 4% 4% LeukemiaLeukemian n 3% 3%Non-HodgkinNon-Hodgkin lymphoma lymphoman n 3% 3% Uterine corpusUterine corpusn n 2% 2%Multiple myelomaMultiple myeloman n 2% 2%Brain/ONSBrain/ONSn n22% All other sites22% All other sitesLung and bronchus 31%Prostate10%Colon and rectum10%Pancreas5%Leukemia4%Esophagus4%Liver and intrahepatic 3%bile ductNon-Hodgkin 3% Lymphoma Urinary bladder3%Kidney3%All other sites 24%高龄肺癌发病概况高龄肺癌发病概况肺癌患者肺癌患者年龄年龄 7070岁占岁占40%40%加拿大加拿大20022002年统计年统计 男男:75-79:75-79岁肺癌发病达高峰岁肺癌发病达高峰 女女:70-74:70-74岁肺癌发病达高峰岁肺癌发病达高峰意大利：意大利：6565岁以上肺癌患者大约占岁以上肺癌患者大约占60%60%我国肺癌发病率我国肺癌发病率4040岁以后上升，岁以后上升，7070岁达岁达高峰高峰鳞癌鳞癌 (30%)(30%)男性最常见男性最常见主要与吸烟相关（剂量相关）主要与吸烟相关（剂量相关）局部播散倾向局部播散倾向痰中较易检出痰中较易检出高表达具有解毒和抗氧化特性的高表达具有解毒和抗氧化特性的基因编码蛋白基因编码蛋白非小细胞肺癌非小细胞肺癌(NSCLC)病理类型病理类型腺癌腺癌 (30-50%)在女性和不吸烟者中最常见的在女性和不吸烟者中最常见的肺癌类型肺癌类型病变常发于外周病变常发于外周全世界发病率上升全世界发病率上升高表达与小气道与免疫相关的高表达与小气道与免疫相关的基因编码蛋白基因编码蛋白K-ras 突变常见突变常见支气管肺泡癌是其一个亚型支气管肺泡癌是其一个亚型大细胞肺癌大细胞肺癌 (10-25%)原始的、未分化细胞原始的、未分化细胞病变常发于外周病变常发于外周l 高度转移倾向高度转移倾向NSCLC 分期分期淋巴结淋巴结主支气管主支气管对侧淋巴结对侧淋巴结远处器官转移远处器官转移胸壁侵犯胸壁侵犯 IV 期期 0 期期 IA 期期 IIB 期期 IIIB 期期 NSCLC: NSCLC: 分期及生存分期及生存Mountain. Chest. 1997;1710-1717.Stage IStage IStage IIStage IIStage IIIStage IIIStage IVStage IV002020404060608080100100Percent survivorsPercent survivorsStage at DiagnosisSt ISt IISt IIIASt IIIBSt IV肺癌肺癌内科治疗研究进展内科治疗研究进展 NSCLCNSCLC: : NSCLCNSCLCNSCLCNSCLC的流行病学及诊断分期的流行病学及诊断分期的流行病学及诊断分期的流行病学及诊断分期早期可手术切除早期可手术切除早期可手术切除早期可手术切除NSCLCNSCLCNSCLCNSCLC的辅助化疗的辅助化疗的辅助化疗的辅助化疗局部晚期不可手术切除局部晚期不可手术切除局部晚期不可手术切除局部晚期不可手术切除NSCLCNSCLCNSCLCNSCLC同步化放疗同步化放疗同步化放疗同步化放疗IIIb(IIIb(IIIb(IIIb(胸水胸水胸水胸水)/IV)/IV)/IV)/IV期期期期NSCLCNSCLCNSCLCNSCLC姑息化疗姑息化疗姑息化疗姑息化疗 分子靶向治疗分子靶向治疗分子靶向治疗分子靶向治疗SCLCSCLCSCLCSCLC的全身治疗的全身治疗的全身治疗的全身治疗NSCLC：复发形式复发形式期别期别期别期别胸部胸部胸部胸部(%)(%)(%)(%)远道转移远道转移远道转移远道转移(%)(%)(%)(%)I I I I期期期期T1N0T1N0T1N0T1N01010101015151515T2N0T2N0T2N0T2N01010101030303030IIIIIIII期期期期T1-2N1T1-2N1T1-2N1T1-2N11212121240404040IIIAIIIAIIIAIIIA期期期期N2N2N2N21515151560606060背景背景过去二十年来，非小细胞肺癌采用辅助化疗，特别过去二十年来，非小细胞肺癌采用辅助化疗，特别是早期的非小细胞肺癌，由于缺乏有力的证据，治是早期的非小细胞肺癌，由于缺乏有力的证据，治疗效果仍然不明确。疗效果仍然不明确。第一代的临床试验设计得不完善，使用的药物有效第一代的临床试验设计得不完善，使用的药物有效率不高。率不高。第二代的临床研究以老的化疗药物与铂类联用，但第二代的临床研究以老的化疗药物与铂类联用，但样本量太小，不足以检测疗效。样本量太小，不足以检测疗效。IALTIALT临床研究设计临床研究设计RChemotherapyControl Thoracic Radiotherapy 60 Gy*optional, but predefined by N stage at each center 完全切除完全切除 NSCLCNSCLC ASCO, Chicago, June 2, 2003 化疗方案化疗方案 顺铂顺铂顺铂顺铂 80 mg/m q 3 weeks x 80 mg/m q 3 weeks x 4 4 or 100 mg/m q 4 weeks x 3 or or 100 mg/m q 4 weeks x 3 or 4 4 or 120 mg/m q 4 weeks x 3 or 120 mg/m q 4 weeks x 3 + + Vp-16 100 mg/m x 3 days per Vp-16 100 mg/m x 3 days per cyclecycleor NVB 30 mg/m weeklyor NVB 30 mg/m weeklyor or 长春新碱长春新碱长春新碱长春新碱 4 mg/m4 mg/m4 mg/m4 mg/m weekly weekly weekly weeklyor or or or 长春地辛长春地辛长春地辛长春地辛 3 mg/m weekly 3 mg/m weekly 结结 果果化疗化疗对照对照 N 932935 中位生存期中位生存期50.8 months44.4 months 中位无病生存期中位无病生存期40.2 months30.5 months 5-年生存率年生存率44.5 %40.4 % 5-年年无病生存率无病生存率39.4 %34.3 %总生存期总生存期ControlChemotherapy Years164286432602774935181308450624775932At risk 无病生存无病生存ControlChemotherapy Years141244365505655935158272397544684932At risk 总总 结结 5年总生存率提高年总生存率提高4.1% （ 40.4% Vs 44.5%） p0.03 5年无病生存提高年无病生存提高5.1 % ( 34.3% VS 39.4%，p2cm2cm低分化低分化 分子标记物指标分子标记物指标Dr.Strass Dr.Strass 的个人观点的个人观点禁忌症：禁忌症：1.IA1.IA期期 2.2.全肺切除术全肺切除术？3.3.年龄年龄7575岁岁？ 4.4.细支气管肺泡癌细支气管肺泡癌5.5.有合并症有合并症 6.6.术后恢复慢术后恢复慢化疗的时机？化疗的时机？一般术后一般术后4-64-6周开始化疗周开始化疗。化疗周期？化疗周期？推荐推荐4 4个化疗周期个化疗周期 新辅助治疗新辅助治疗增加肿瘤的手术控制率增加肿瘤的手术控制率减少肿瘤的微转移减少肿瘤的微转移 新辅助化疗新辅助化疗新辅助治疗新辅助治疗：SWOG 9900 泰素泰素 225 mg/m2卡铂卡铂 AUC = 6X 3 cycles 手术手术RANDOMIZE手术手术Stage IB, II and IIIA (T3N1) N= 374/600Primary Endpoint: 33% improvement in the expected 2.7 medians survival for surgery alonePisters K, et alASCO Abstract # 7012:无疾病进展生存期无疾病进展生存期HR=0.80 0.59-1.07, p=0.140%20%40%60%80%100%01224364860Months After Registrationmedian F/U 31 mo SWOG 9900总生存总生存 HR=0.84 0.60-1.18, p=0.320%20%40%60%80%100%01224364860Months After Registration SWOG 9900Median 1 yr 2 yrPreop47 mo 82%69% Control40 mo 79%63%Median FU 31 months 可切除的可切除的 N2 NSCLC: INT 0139 TrialCisplatin, 50 mg/m2 IVPB d1, 8, 29, 36Etoposide, 50 mg/m2 IVPB d1-5, 29-33Thoracic RT, 45 Gy (1.8 Gy/d), begin d1疾病无进展者疾病无进展者 手术手术继续放疗至继续放疗至 61 Gy61 Gy 巩固化疗巩固化疗cisplatin plus etoposideX 2 cycles诱导治疗诱导治疗Albain KS et alASCO Abstract ASCO Abstract #7014#7014CT/RT/S 145/202CT/RT 155/194Logrank p = 0.24Hazard ratio = 0.87 (0.70, 1.10)% Alive0255075100Months from Randomization01224364860Dead/Total INT 0139 UpdateOverall SurvivalMedian FU 81 months Overall Survival by Pathologic Nodal StatusNo surgery (n=38)Pathologic N0 (n=76)Pathologic N1-3, unknown (n=88)p 0.0001% Alive0255075100Months from Randomization020406080100120 INT 0139 Update 肺叶切除的总生存肺叶切除的总生存Subset VS Matched CT/RT Subset % Alive0255075100Months from Randomization01224364860/ / / / / / / / /logrank p = 0.002CT/RT/S 57/90CT/RT 74/90Dead/TotalMS 34 mos. 22 mos.5 yr OS 36% 18%CT/RT/S CT/RT INT 0139Months from Randomization全肺切除的总生存全肺切除的总生存Subset VS Matched CT/RT Subset MS3 yr OS5 yr OS19 mos. 36% 22%CT/RT/SCT/RT% Alive025507510001224364860/29 mos. 45% 24%Dead/TotalCT/RT/S38/51CT/RT42/51logrank p = NS INT 0139 Update 部分N2病人可能为外科手术受益者： 外科因素: 能行肺叶切除的N2病人 肿瘤因素：能淋巴结完全清扫者有更长的生存期 Role for post treatment PET? Restagingmediastinoscopy/VATS/EUS? N2 病人是否外科治疗需肺癌多学科讨论决定病人是否外科治疗需肺癌多学科讨论决定 局部晚期局部晚期 （N2 ）NSCLCMessage: Surgical resection does not offer a survival advantageover radiotherapy in patients with clinically operable (INT 0319) or inoperable (EORTC 8941) stage III N2 disease.Concurrent chemoradiotherapy is the standard of care.Pneumonectomies should be avoided. Locally Advanced N2 Lung Cancer2005 NCCN2005 NCCN临床肿瘤指南临床肿瘤指南多学科治疗：辅助化疗多学科治疗：辅助化疗 基于基于IALTIALT研究，对术后辅助化疗进行修订研究，对术后辅助化疗进行修订 IAIA期期: T1N0 : T1N0 不进行辅助治疗不进行辅助治疗 IBIB期期: T2N0 : T2N0 推荐术后进行辅助化疗推荐术后进行辅助化疗 IIII期期:T1-2N1 :T1-2N1 推荐术后辅助化疗或放疗推荐术后辅助化疗或放疗(2B)+(2B)+化疗化疗 期期 术后可选择单用化疗或放疗术后可选择单用化疗或放疗(2B)+(2B)+化疗化疗2005 NCCN2005 NCCN临床肿瘤指南临床肿瘤指南多学科治疗：辅助化疗多学科治疗：辅助化疗 对对于于临临床床分分期期N2N2阴阴性性而而术术后后病病理理分分期期N2N2阳阳性性者者, , 术后可以选择化疗或观察术后可以选择化疗或观察(2B)(2B)或联合放化疗或联合放化疗(2B)(2B) T4N0-1 T4N0-1同叶内卫星结节者同叶内卫星结节者, ,术后需辅助化疗术后需辅助化疗 辅助化疗应选择含铂的二药联合方案辅助化疗应选择含铂的二药联合方案术后辅助化疗术后辅助化疗n n 基于基于基于基于CALGB9633CALGB9633和和和和BR10BR10研究研究研究研究n n对于术后辅助化疗的推荐级别：对于术后辅助化疗的推荐级别：对于术后辅助化疗的推荐级别：对于术后辅助化疗的推荐级别：2004 2A2004 2An n 2005 12005 1级级级级 n n对对对对IA(T1N0)(T1N0)者完全切除术后：者完全切除术后：者完全切除术后：者完全切除术后：n n 2004 2004 观察观察观察观察n n 2005 2005 高危者：化疗高危者：化疗高危者：化疗高危者：化疗(2B)(2B)n n化疗方案化疗方案化疗方案化疗方案 含铂二药联合方案含铂二药联合方案含铂二药联合方案含铂二药联合方案肺癌肺癌内科治疗研究进展内科治疗研究进展 NSCLCNSCLC: : NSCLCNSCLCNSCLCNSCLC的流行病学及诊断分期的流行病学及诊断分期的流行病学及诊断分期的流行病学及诊断分期早期可手术切除早期可手术切除早期可手术切除早期可手术切除NSCLCNSCLCNSCLCNSCLC的辅助化疗的辅助化疗的辅助化疗的辅助化疗局部晚期不可手术切除局部晚期不可手术切除局部晚期不可手术切除局部晚期不可手术切除NSCLCNSCLCNSCLCNSCLC同步化放疗同步化放疗同步化放疗同步化放疗IIIb(IIIb(IIIb(IIIb(胸水胸水胸水胸水)/IV)/IV)/IV)/IV期期期期NSCLCNSCLCNSCLCNSCLC姑息化疗姑息化疗姑息化疗姑息化疗 分子靶向治疗分子靶向治疗分子靶向治疗分子靶向治疗SCLCSCLCSCLCSCLC的全身治疗的全身治疗的全身治疗的全身治疗 不能手术局部晚期不能手术局部晚期NSCLCNSCLC化化放疗结合的方式放疗结合的方式 Sequential: CT RT Concurrent: CT/RT Combinations: CT CT/RT CT/RT CT LAMP: Randomized Phase II Study of 3 Chemoradiation Schedules for Stage III NSCLC Arm 1: Sequential Chemo/XRT: Carbo AUC 6 + Pac 200 mg/m2 Q3 wks x 2 XRT 63 Gy/7 wksArm 2: Induction Chemo Concurrent ChemoXRT: Carbo AUC 6 + Pac 200 mg/m2 Q3 wks x 2 XRT 63 Gy/7 wks + weekly Carbo AUC 2 + Pac 45 mg/m2 Arm 3:Concurrent ChemoXRT Consolidation Chemo: XRT 63 Gy/7 wks + weekly Carbo AUC 2 + Pac 45 mg/m2 Carbo AUC 6 + Pac 200 mg/m2 Q3 wks x 2 LAMP: Pre-Treatment CharacteristicsCT CT RTRTCT CT CT+RTCT+RTCT+RT CT+RT CTCT (N=92) (N=92) (N=74) (N=74) (N=92) (N=92)Age:Age: 70 7074(80%)74(80%) 53(72%) 53(72%) 69(75%) 69(75%) 70+70+18(20%)18(20%) 21(28%)21(28%) 23(25%)23(25%)Gender:Gender: MaleMale63(68%)63(68%) 54(73%)54(73%) 62(67%)62(67%) FemaleFemale29(32%)29(32%) 20(27%) 20(27%) 30(33%) 30(33%)KPS:KPS: 70-8070-80 25(27%)25(27%) 23(31%)23(31%) 22(24%)22(24%) 90-10090-10067(73%)67(73%) 51(69%) 51(69%) 70(76%) 70(76%)% Weight Loss% Weight Loss 5% RTCT - RT141455%55%30%30%25%25%CT/RTCT/RT171765%65%35%35%50%50%CT - CT/RTCT - CT/RT151560%60%40%40%35%35%CT/RT - CT *CT/RT - CT *262678%78%54%54% 20% 20% Adapted from Pisters: ASCO, 2000 * S95042005 NCCN临床肿瘤指南多学科治疗：辅助化疗对对于于临临床床分分期期N2阴阴性性而而术术后后病病理理分分期期N2阳阳性性者者,术后可以选择化疗或观察术后可以选择化疗或观察(2B)或联合放化疗或联合放化疗(2B) T4N0-1同叶内卫星结节者同叶内卫星结节者,术后需辅助化疗术后需辅助化疗 辅助化疗应选择含铂的二药联合方案辅助化疗应选择含铂的二药联合方案肺癌肺癌内科治疗研究进展内科治疗研究进展 NSCLCNSCLC: : NSCLCNSCLCNSCLCNSCLC的流行病学及诊断分期的流行病学及诊断分期的流行病学及诊断分期的流行病学及诊断分期早期可手术切除早期可手术切除早期可手术切除早期可手术切除NSCLCNSCLCNSCLCNSCLC的辅助化疗的辅助化疗的辅助化疗的辅助化疗局部晚期不可手术切除局部晚期不可手术切除局部晚期不可手术切除局部晚期不可手术切除NSCLCNSCLCNSCLCNSCLC同步化放疗同步化放疗同步化放疗同步化放疗IIIb(IIIb(IIIb(IIIb(胸水胸水胸水胸水)/IV)/IV)/IV)/IV期期期期NSCLCNSCLCNSCLCNSCLC姑息化疗姑息化疗姑息化疗姑息化疗 分子靶向治疗分子靶向治疗分子靶向治疗分子靶向治疗SCLCSCLCSCLCSCLC的全身治疗的全身治疗的全身治疗的全身治疗 治疗原则治疗原则控制症状提高生活质量延长生存期联合化疗作为联合化疗作为NSCLCNSCLC的一线治疗的一线治疗Good PS Patients1990s: Platinum-based CT standardNSCLC Collaborative Group BMJ. 1995;311:899-909Current ASCO Guidelines:Platinum doublets or non-platinum doublets are standard for advanced NSCLC pts with good PSPfister et al. J Clin Oncol. 2004;22:330-353Advanced NSCLCUS FDA Approved Therapies1994 vinorelbine/cisplatin and vinorelbine1998 gemcitabine/cisplatin1998 paclitaxel/cisplatin1999 docetaxel (after platinum)2003 docetaxel/cisplatin2003 gefitnib (after platinum and docetaxel)2004 pemetrexed (after platinum)2004 erlotinib (after 1 prior chemotherapy) NSCLC: 一线化疗一线化疗化疗化疗 VsVs BSC BSC？有无最好的铂类联合方案？有无最好的铂类联合方案？含铂方案含铂方案VsVs非铂方案？非铂方案？卡铂卡铂 VsVs 顺铂？顺铂？化疗靶向治疗化疗靶向治疗VsVs化疗化疗 治治 疗疗长春瑞滨长春瑞滨 30 mg/m30 mg/m2 2，第第1 1、8 8天天 每每3 3周周 + + 最佳支持治疗最佳支持治疗最佳支持最佳支持治疗治疗 (BSC)紫杉醇紫杉醇 200 mg/m200 mg/m2 2 第第1 1天天 每每3 3周周 + BSC + BSC最佳支持治疗最佳支持治疗泰索帝泰索帝 100 mg/m100 mg/m2 2 第第1 1天天 每每3 3周周 + BSC + BSC最佳支持治疗最佳支持治疗吉西他滨吉西他滨 1000 mg/m 1000 mg/m2 2 第第1 1、8 8和和1515天天 每每4 4周周 + BSC + BSC最佳支持治疗最佳支持治疗1.00.80.60.40.2003691215182124长春瑞滨长春瑞滨最佳支持治疗最佳支持治疗月月概率概率Log-rank Log-rank p p = 0.03= 0.031 .00 .80 .60 .40 .2003691 21 51 82 12 4紫杉醇紫杉醇最佳支持治疗最佳支持治疗月月概率概率Log-rank Log-rank p p = 0.04= 0.041 .00 .80 .60 .40 .2003691 21 51 82 12 4泰索帝泰索帝最佳支持治疗最佳支持治疗月月概率概率Log-rank Log-rank p p = 0.03= 0.03吉西他滨吉西他滨最佳支持治疗最佳支持治疗月月概率概率Log-rank Log-rank p p = 0.84= 0.84ECOG 1594: Study DesignStratification:uStage: IIIB vs IVuPS: 01 vs 2uWt Loss: 5% vs 5%uCNS Mets: no vs yesArm AArm A: Cisplatin + Paclitaxel: Cisplatin + PaclitaxelPaclitaxel: 135 mg/mPaclitaxel: 135 mg/m2 2/24 h Day 1/24 h Day 1 Cisplatin: 75 mg/m Cisplatin: 75 mg/m2 2 day 2 day 2q3wkq3wkArm DArm D: Carboplatin + Paclitaxel: Carboplatin + PaclitaxelPaclitaxel: 225 mg/mPaclitaxel: 225 mg/m2 2/3 h Day 1/3 h Day 1Carboplatin: AUC 6 Day 1Carboplatin: AUC 6 Day 1Arm CArm C: Cisplatin + Docetaxel: Cisplatin + DocetaxelDocetaxel: 75 mg/mDocetaxel: 75 mg/m2 2 Day 1 Day 1Cisplatin: 75 mg/mCisplatin: 75 mg/m2 2 Day 1 Day 1Arm BArm B: Cisplatin + Gemcitabine: Cisplatin + GemcitabineGemcitabine: 1000 mg/mGemcitabine: 1000 mg/m2 2 Days 1, 8, 15 Days 1, 8, 15Cisplatin: 100 mg/mCisplatin: 100 mg/m2 2 Day 1 Day 1q4wkq4wkq3wkq3wkq3wkq3wkSchiller JH, et al. Proc ASCO 36th Annual Meeting. 2000;19:abstr 2.Schiller JH, et al. N Engl J Med. 2002;346:92-98.R RA AN ND DO OM MI IZ ZE EE1594 ECOG 1594:Analysis of ECOG 1594:Analysis of ToxicityToxicity222266667 7626211115656272728280 010102020303040405050606070703 3 级级4 4 级级%泰素泰素/顺铂顺铂吉西他滨吉西他滨/顺铂顺铂多西紫杉多西紫杉醇醇/顺铂顺铂泰素泰素/卡铂卡铂PS2的病人的的病人的3-4级毒性发生百分比级毒性发生百分比 TAX326 Study Design （泰素蒂铂类泰素蒂铂类Vs NVB+Vs NVB+铂类铂类）RANDOMIZEStratifiication Factors: Stage of DiseaseIIIB vs. IVand RegionUS/Canada South AmericaEurope/LebanonIsraelSouthAfrica/AustraliaNew ZealandResponse assessment every 2 cycles泰素蒂泰素蒂 75mg/m2 IV 卡铂卡铂 AUC 6 IV Q 3 wks(TCb)诺维苯诺维苯 25mg/m2 IV D 1, 8, 15 & 22顺铂顺铂 100mg/m2 IV D 1Q 4 wks(VC)泰素蒂泰素蒂 75mg/m2 IV顺铂顺铂 75mg/m2 IV Q 3 wks（TC）vs.or TAX 326 Overall SurvivalFossella 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 VCRANDOMIZEProtocol SchemaStratification Weight loss in previous 6 months: 5% vs 5% Disease stage: IIIB with effusion, IV Brain metastases: Presence or absenceGemcitabine 1000 mg/m2 d 1,8Paclitaxel 200 mg/m2 d 1q 21 daysGemcitabine 1000 mg/m2 d 1,8Carboplatin AUC 5.5 d 1q 21 daysArm A: 健择健择 + 卡铂卡铂Arm B: 健择健择+ 泰素泰素Arm C: 泰素泰素+ 卡铂卡铂Paclitaxel 225 mg/m2 d 1Carboplatin AUC 6.0 d 1q 21 days 含铂方案含铂方案Vs非铂方案非铂方案ASCO Abstract #7025ASCO Abstract #7025 Coalition TrialSurvival by Treatment ArmMeta-Analysis: 1-Y 生存生存90年代新化疗药物联合作为非铂方案年代新化疗药物联合作为非铂方案 (N = 3,307)dAddario et al. J Clin Oncol. 2005;23:2926-2936.卡铂卡铂Vs顺铂顺铂Does it matter for advanced disease?NSCLC: 90NSCLC: 90年代新化疗药物顺铂或卡铂的随机研究年代新化疗药物顺铂或卡铂的随机研究 N Zojwalla, 2004RegimenRegimenN NMedianMedianSurvivalSurvivalFossella et al, Fossella et al, JCO 2003JCO 2003Cis + DocetaxelCis + DocetaxelCarbo + DocetaxelCarbo + Docetaxel40840840640611.311.39.49.4Rosell et al,Rosell et al,Ann Onc, 2002Ann Onc, 2002Cis + PaclitaxelCis + PaclitaxelCarbo + PaclitaxelCarbo + Paclitaxel3093093093099.89.88.58.5Schiller et al,Schiller et al,NEJM, 2002NEJM, 2002Cis + PaclitaxelCis + PaclitaxelCarbo + PaclitaxelCarbo + Paclitaxel2882882902907.87.88.18.1Mazzanti et al,Mazzanti et al,Lung Ca, 2003Lung Ca, 2003Cis + GemcitabineCis + GemcitabineCarbo + GemcitabineCarbo + Gemcitabine6262585810.410.410.810.8Zatloukal et al,Zatloukal et al,Lung Ca, 2003Lung Ca, 2003Cis + GemcitabineCis + GemcitabineCarbo + GemcitabineCarbo + Gemcitabine878789898.88.88.08.0 NSCLC: 9090年代新化疗药物顺铂或卡铂的随机研究年代新化疗药物顺铂或卡铂的随机研究 N Zojwalla, 2004MONTHS Carboplatin Cisplatin N = 1152 N = 11548.79.8* No other such trials 1992 2003; * 2 trials with paclitaxel, 1 with docetaxel, 2 with gem. Carbo vs. Cis Meta-analysisOverall survival with cisplatin-based compared with carboplatin-based chemotherapyHotta, K. et al. J Clin Oncol; 22:3852-3859 2004Carbo vs. Cis Meta-analysisOverall survival with cisplatin plus new agents compared with carboplatin plus new agentsHotta, K. et al. J Clin Oncol; 22:3852-3859 2004一线化疗一线化疗: : 怎样选择最好的联合方案怎样选择最好的联合方案? ? 疗效与生存疗效与生存? ? 生活质量生活质量? ? 毒性毒性? ? 病人的基础状态病人的基础状态? ? 费用费用? ?Weekly Paclitaxel with Carboplatin Followed by Maintenance Paclitaxel vs.Observation for Advanced NSCLC Arm 3Arm 3Arm 2Arm 2Arm 1Arm 1Paclitaxel 150 mg/mPaclitaxel 150 mg/m2 2 + Carboplatin AUC=2 + Carboplatin AUC=2 (weekly for 6 wks, 2 wks off), (weekly for 6 wks, 2 wks off), then then Paclitaxel 100 mg/mPaclitaxel 100 mg/m2 2 + Carboplatin AUC=2 (weekly + Carboplatin AUC=2 (weekly for 6 wks, 2 wks off )*for 6 wks, 2 wks off )* Paclitaxel 100 mg/m Paclitaxel 100 mg/m2 2 + Carboplatin AUC=2 + Carboplatin AUC=2 (weekly for 3 wks, 4 (weekly for 3 wks, 4thth wk off)* wk off)*Paclitaxel 100 mg/mPaclitaxel 100 mg/m2 2(weekly for 3 wks, 4(weekly for 3 wks, 4thth wk off) wk off) + Carboplatin AUC=6 (d1 )*+ Carboplatin AUC=6 (d1 )*SCHEMABelani et al, JCO 21:2933-39, 2003*Patients with CR, PR or SD randomized to paclitaxel 70 mg/m2/wk or observation Weekly Paclitaxel with Carboplatin Followed by Maintenance Paclitaxel vs.Observation for Advanced NSCLCEfficacy/Toxicity Arm 1 Arm 2 Arm 3Median Survival Time 49 wks 31 wks 40 wks (p=0.077 vs 1) (p0.45 vs 1) Median TTP 30 wks 21 wks 27 wks (p=0.01 vs 1) (p0.73 vs 1) 1-yr. Survival 47% 31% 41% (p0.01 vs 1) (p2 (IDEAL 2)previouschemotherapyregimensContinue gefitinib until diseaseprogression or unacceptable toxicityPrimary endpointsPatientslResponse rate (both trials)lSafety profile (IDEAL 1)lSymptom relief (IDEAL 2)IDEAL 1 global trial including Japan, Europe, Australia, and South Africa (JPN=209)IDEAL 2 USA trialNatale & Zaretsky 2002 RANDOMIZEDDGefitinib (Iressa)Gefitinib (Iressa)治疗晚期治疗晚期NSCLCNSCLC的研的研究究( (IDEAL-1,2)IDEAL-1,2)IDEALIDEAL：Iressa Dose Evaluation in Iressa Dose Evaluation in Advanced Lung CancerAdvanced Lung Cancer IDEAL-1IDEAL-1： 该研究是一随机、双盲、全球该研究是一随机、双盲、全球性研究。在欧洲、日本、南美洲等地进行，性研究。在欧洲、日本、南美洲等地进行，比较不同剂量的比较不同剂量的IrassaIrassa治疗晚期治疗晚期NSCLCNSCLC。IDEAL-2IDEAL-2： IressaIressa作为三线药物单药治疗作为三线药物单药治疗晚期晚期NSCLCNSCLC的研究。该研究在美国的的研究。该研究在美国的3030个试个试验中心下进行。验中心下进行。GefitinibGefitinib作为三线药物治疗作为三线药物治疗晚期晚期NSCLCNSCLC的研究的研究Semin Oncol. 2003;30(1 Suppl 1):30-85154疾病控制率疾病控制率()1918有效率（）有效率（）500mg/d250mg/dIDEAL-1N2103543症状改善率症状改善率()912有效率（）有效率（）500mg/d250mg/dIDEAL- 2N216GefitinibGefitinib作为三线药物治疗作为三线药物治疗晚期晚期NSCLCNSCLC的的期研究期研究Oncologist. 2003;8(4):303-6. 7.04.58.9中位有效期(月)10.67.913.6有效率（）两组合并(n=142)500mg/d (n=76)250mg/d(n=66)结论：结论：GefitinibGefitinib用于铂类和多西紫杉醇治疗失败的晚期用于铂类和多西紫杉醇治疗失败的晚期NSCLCNSCLC病人，推病人，推荐结论是荐结论是250250mg/dmg/d。因为因为500500mg/dmg/d的疗效无增加，但毒性更大。的疗效无增加，但毒性更大。ISEL:IRESSA survival evaluation in lung cancer (Trial 709)曾接受曾接受1-21-2种化疗方案的晚期种化疗方案的晚期NSCLCNSCLC患者患者接受吉非替尼接受吉非替尼( (易瑞沙易瑞沙) )与最佳支持治疗与最佳支持治疗并安慰剂随机对照并安慰剂随机对照IIIIII期临床试验期临床试验ISEL：Bankground共入组1692 NSCLC 病人(2003.7.15-2004.8.2)在28个国家的210个中心开展其中342例病人(22%)为东方人主要终点指标：总体生存期次要终点指标（治疗失败时间，客观缓解和生活质量），2005年2月的安全性情况预先设计对东方人进行亚组分析IRESSA(250 mg/day) 1 end-pointSurvival2 end-pointsTTFORRQoL, symptomsSafetyExploratory end-pointTumour biomarker analysis (eg EGFR)1692 patients in 210 centers across 28 countriesRandomized (2:1 ratio)Placebo + BSCCT, chemotherapy; BSC, best supportive care; EGFR, epidermal growth factor receptor; TTF, time to treatment failure; ORR, objective response rate; QoL, quality of lifePatientsLocally advanced or metastatic NSCLC1 or 2 prior CT regimensIntolerant to most recent CT regimen or progression 90 days of last CT cycleISEL trial design0246810121416Time (months)At risk:1692134787748525210431Median, months1-year survival, %Logrank HR (95% CI), 0.89 (0.77, 1.02); p=0.087Cox regression analysis, p=0.030IRESSA5.627Placebo5.1210.00.20.40.60.81.0ProportionsurvivingIRESSAPlaceboCI, confidence interval; HR, hazard ratioMedian follow-up: 7 months (range 315); 58% deathsISEL: survival in the overall populationMedian, months1-year survival, %Logrank HR (95% CI), 0.84 (0.68, 1.03); p=0.089Cox regression analysis, p=0.033IRESSA6.330Placebo5.418Time (months)At risk:81266944626214566181IRESSAPlacebo02468101214160.00.20.40.60.81.0ProportionsurvivingISEL: Survival in the Adenocarcinoma Population169210515392781294917IRESSAPlaceboIRESSAPlaceboCox analysis (95% CI)LogrankOdds ratio (95% CI)Median TTF, months3.02.60.82 (0.73, 0.92) p=0.0006p=0.002ORR, % (n)8.0 (77/959)1.3 (6/480)7.28 (3.1, 16.9)p0.0001TTF (months)At risk:02468101214160.00.20.40.60.81.0Proportionwithout treatment failureISEL: significant improvement in TTF and ORRReasons for treatment failurePatients (%)IRESSAPlacebo6050403020100肿瘤进展肿瘤进展肿瘤进展肿瘤进展（客观）（客观）（客观）（客观）症状加重症状加重症状加重症状加重不良事件不良事件不良事件不良事件其他其他其他其他Factors predicting Gafitinib Sensitivity IressaTM package insertLynch:NEJM2004 GGCGGGCCAAACTGCTGGGTGCG 100n nEGFR protein expression by immunohistochemistryn nEGFR gene copy number by FISHn nEGFR Mutational statusSelection of Patients for EGFR Inhibitors5/5 patients who responded to gefitinib had EGFR mutations 4/4 patients who progressed on gefitinib had no EGFR mutationsPaez: Science Express Rep 2004.CharacteristicAdenocarcinoma Other NSCLCFemale MaleJapaneseAmerican% with Mutation (n) 21% (15/70) 2% (1/49)20% (1/45)9% (7/74)26% (15/58)2% (1/61)Is a bath and a shower always better than either alone? 贝伐单抗（Bevacizumab） + Chemotherapy晚期晚期NSCLC: 靶向治疗联合化疗靶向治疗联合化疗 有历史意义的一步？有历史意义的一步？ R RA ANND DOOMMI IZ ZE EEligibilityEligibility: : No prior Rx No prior Rx Stage IIIB Stage IIIB or IVor IV Non-SqCCaNon-SqCCa ECOG PS 0- ECOG PS 0-1 1 No CNS metsNo CNS mets卡铂卡铂卡铂卡铂: AUC = 6: AUC = 6泰素泰素泰素泰素: 200 mg/m: 200 mg/m2 2 Q 3 weeks Q 3 weeks卡铂卡铂卡铂卡铂: AUC = 6: AUC = 6泰素泰素泰素泰素: 200 mg/m: 200 mg/m2 2贝伐单抗贝伐单抗贝伐单抗贝伐单抗: 15 mg/kg: 15 mg/kgQ 3 weeksQ 3 weeksECOG Trial (E4599): rhuMab VEGF (ECOG Trial (E4599): rhuMab VEGF (贝伐单抗贝伐单抗Bevacizumab) Bevacizumab) 在晚期在晚期NSCLC (Non-Squamous)NSCLC (Non-Squamous)Sandler: LBA, ASCO 05Sandler: LBA, ASCO 05Sample size of 842 patients for 80% power to detect a 25% improvement in median survival ( 8 to 10 mos.)病人特点病人特点 (eligible patients)90%90%91%91%CaucasianCaucasian50%50%58%58%MaleMale40%40%38%38%ECOG PS 0ECOG PS 043%43%44%44%Age Age 65 6528%28%28%28%Prior wt. loss Prior wt. loss 5% 5%91%91%91%91%Measurable diseaseMeasurable disease13%13%14%14%Stage IIIB Stage IIIB N N = 424= 424N N = 431= 431 PCBPCBPCPC 非血液学毒性非血液学毒性 PC (% n) PCB (% n) Grade 3 Grade 3 p-valueHemorrhage（出血） 3 (0.7) 19 (4.5).001Hemoptysis 1 (0.2)8 (1.9)0.04CNS04 (1.0)0.03GI2 (0.5)5 (1.2)NSOther1 (0.2)4 (1.0)NSHypertension（高血压）3 (0.7)25 (6.0).001Venous Thrombosis（）13 (3.0)16 (3.8)NSArterial Thrombosis4 (1.0)8 (1.9)NS6 mo. 1 yr33% 6%55%15% ECOG Trial (E4599): rhuMab VEGF (Bevacizumab) in Advanced NSCLC (Non-Squamous)ResponseResponseCategoryCategory(Patients)(Patients)PCPC(383(383) )PCBPCB(391(391) )CRCR0.30.3%1.31.3%PRPR9%9%24%24%CR/PRCR/PR9%9%25%25%* *p0.0001*p0.0001Sandler: abstract # ASCO 05Sandler: abstract # ASCO 05 MST 1y 2 yr 10.2 44% 17% 12.5 52% 22% ECOG Trial (E4599): rhuMab VEGF (Bevacizumab) in Advanced NSCLC (Non-Squamous)Sandler: ASCO 05Sandler: ASCO 05Efficacy by Gender ( Subset Analysis)MaleMaleFemaleFemaleOS (HR)OS (HR)0.690.69 p=0.003 p=0.0030.960.96 P=0.80P=0.80PFS (HR)PFS (HR)0.530.53P=0.0001P=0.00010.680.68P=0.002P=0.002RR (%)RR (%)12.2 vs 23.5 12.2 vs 23.5 p=0.006p=0.0067.4 vs 31.77.4 vs 31.7P0.0001P0.0001 ?chance分子靶向药物如何与化疗结合？分子靶向药物如何与化疗结合？运用分子生物学的研究提高患者的选择性量体裁衣运用分子生物学的研究提高患者的选择性量体裁衣(tailor therapy)(tailor therapy)根据肿瘤的生物学体性进行个体危险评根据肿瘤的生物学体性进行个体危险评估估基因表达特征基因表达特征gene expression profiling gene expression profiling (GEP) (GEP) 核苷酸序列核苷酸序列早期早期 NSCLCNSCLC的预后因素的预后因素对化疗药物耐药性的预测对化疗药物耐药性的预测EGF REGF R药物药物VEGFRVEGFR药物药物 任重而道远任重而道远When based on rational considerations, drugs typically do not clinically perform as predicted. We lack sufficient understanding of complex biological systems. SCLCTreatment Chemotherapy Active single Agents(RR25%) Methorexate Cyelo/Ifosfamide Adriamycin/Epirubicin Vincristine Etoposide/teniposide Cis/Carboplatin Taxanes Gomcitabine VinorelbineSCLCSCLC TreatmentEtoposide/cisplatin or CarboplatinEarly concurrent thoracic RT in LDPCI if CR/near CR after chemotherapySCLC Induction chemotherapyEtoposide/cisplatin(EP, 4Cs) equivalent in efficacy to CAV(6Cs) in treat of EDEP has become stand and of care, based on therapeutic index and ease of administration with thoracic irradiationIfosfamide with EP(Vs.EP) conferred median(9 Vs 7months) and two-year(13% Vs 50%) survival benefit in ED patientsPaclitaxel with EP(vs.EP) conferred no benefit and was more toxic in 3 randomized studiesEP vs EP/Paclitaxel as first-line treatment in SCLCCisplatin 80mg/m2 d2Etoposide 80mg/m2 d2-4Paclitaxel 175mg/m2 d1Cisplatin 80mg/m2 d1Etoposide 120mg/m2 d1-3TEP(62)EP B(71)radmjzed133 patients(ED and LD)SCLCTreatmentInduction Chemotherapy(JCOG9511)EDEtoposide 100mg/m2 d1-3Cisplatin(EP) 80mg/m2 d1Irinotecan 60mg/m2 d1,8,15Cisplatin(IP) 60mg/m2 d1RandomizeResultsIrinotecan/Cisplatin for ED SCLC New Standard of Care? 化疗期改善生活质量措施化疗期改善生活质量措施控制呕吐控制呕吐(急、迟晚急、迟晚)刺激食欲，增加体重刺激食欲，增加体重预防继发感染预防继发感染保护骨髓功能保护骨髓功能预防肝功损伤预防肝功损伤预防肾功损伤预防肾功损伤止痛止痛(三级止痛三级止痛)Glutathione(谷胱甘肽谷胱甘肽)保护保护CDDP肾损肾损伤伤原理：原理：Glutathione cell内解毒时需内解毒时需r-谷酰胺转肽谷酰胺转肽酶酶 (r-glutamyltranseptidase) 肾小管细胞含量丰富，肿瘤细胞量极少肾小管细胞含量丰富，肿瘤细胞量极少临床：临床：150例晚期卵巢癌随机例晚期卵巢癌随机 CDDP+Glutathione* CDDP(单单) 6 *CDDP前前3000mg/m2 i.v.点点15分分结果：结果：6次化疗后次化疗后 Glutathione组组 vs 对照对照 CR+PR% 58 39 肾毒性肾毒性% 38 49 贫血贫血% 17 34 听听N% 相似相似 新衍生物新衍生物Ethyol已广泛用于已广泛用于CDDP治疗为主实体瘤治疗为主实体瘤化疗期并用肝得健保护肝功能效应化疗期并用肝得健保护肝功能效应 吴梅娜等中国肿瘤临床