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1、,呼吸病区:王 洁,肺癌内科治疗进展,非小细胞肺癌 内科治疗研究进展,NSCLC: NSCLC的流行病学及诊断分期 早期可手术切除NSCLC的辅助化疗 局部晚期不可手术切除NSCLC同步化放疗 IIIb(胸水)/IV期NSCLC姑息化疗 分子靶向治疗 SCLC的全身治疗,肺癌的分子异常,常见的基因改变,烟草,对细胞外信号异常应答 细胞周期失控 凋亡机制失控 接触抑制丧失 获得转移能力 血管生成 永生化 自分泌生长,肺泡不典型增生,癌前腺瘤,肺癌,原位癌,异型性变,支气管化生,正常上皮,2005 Estimated US Cancer Deaths*,ONS=Other nervous syst
2、em. Source: American Cancer Society, 2005.,Men 295,280,Women 275,000,27% Lung and bronchus 15% Breast 10% Colon and rectum 6% Ovary 6% Pancreas 4% Leukemia 3% Non-Hodgkin lymphoma 3% Uterine corpus 2% Multiple myeloma 2% Brain/ONS 22% All other sites,Lung and bronchus 31% Prostate 10% Colon and rect
3、um 10% Pancreas 5% Leukemia 4% Esophagus 4% Liver and intrahepatic 3% bile duct Non-Hodgkin 3% Lymphoma Urinary bladder 3% Kidney 3% All other sites 24%,高龄肺癌发病概况,肺癌患者年龄70岁占40% 加拿大2002年统计 男:75-79岁肺癌发病达高峰 女:70-74岁肺癌发病达高峰 意大利:65岁以上肺癌患者大约占60% 我国肺癌发病率40岁以后上升,70岁达高峰,鳞癌 (30%) 男性最常见 主要与吸烟相关(剂量相关) 局部播散倾向 痰中较
4、易检出 高表达具有解毒和抗氧化特性的基因编码蛋白,非小细胞肺癌(NSCLC)病理类型,腺癌 (30-50%) 在女性和不吸烟者中最常见的肺癌类型 病变常发于外周 全世界发病率上升 高表达与小气道与免疫相关的基因编码蛋白 K-ras 突变常见 支气管肺泡癌是其一个亚型,NSCLC 分期,淋巴结,主支气管,对侧淋巴结,远处器官转移,胸壁侵犯,NSCLC: 分期及生存,Mountain. Chest. 1997;1710-1717.,Stage at Diagnosis,St I,St II,St IIIA,St IIIB,St IV,肺癌 内科治疗研究进展,NSCLC: NSCLC的流行病学及诊断
5、分期 早期可手术切除NSCLC的辅助化疗 局部晚期不可手术切除NSCLC同步化放疗 IIIb(胸水)/IV期NSCLC姑息化疗 分子靶向治疗 SCLC的全身治疗,NSCLC:复发形式,背景,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,使用的药物有效率不高。 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。,IALT临床研究设计,R,Chemotherapy,Control, Thoracic Radiotherapy 60 Gy* *optional, but predefin
6、ed by N stage at each center,完全切除 NSCLC,ASCO, Chicago, June 2, 2003,化疗方案,顺铂 80 mg/m q 3 weeks x 4 or 100 mg/m q 4 weeks x 3 or 4 or 120 mg/m q 4 weeks x 3 + Vp-16 100 mg/m x 3 days per cycle or NVB 30 mg/m weekly or 长春新碱 4 mg/m weekly or 长春地辛 3 mg/m weekly,结 果,化疗 对照 N 932 935 中位生存期 50.8 months 44.4
7、months 中位无病生存期 40.2 months 30.5 months 5-年生存率 44.5 % 40.4 % 5-年无病生存率 39.4 % 34.3 %,总生存期,Control,Chemotherapy,Years,无病生存,Control,Chemotherapy,Years,总 结,5年总生存率提高4.1% ( 40.4% Vs 44.5%) p0.03,5年无病生存提高5.1 % ( 34.3% VS 39.4%,p0.003) 致死性毒性 0.8%,Correlation between stage and activity of Chemotherapy,- posit
8、ive,- negative,- not tested,早期(I-IIIa)完全切除的NSCLC,基于4组随机对照研究结果,对IB-III完全切除的NSCLC, 辅助化疗是标准的治疗方法,ASCO 2003 IALT (Le havalier) ASCO 2003 JLCRG (Kato) ASCO 2004 JBR 10 (Winton) ASCO 2004 CALGB (Strauss),有待解决的问题,选择哪些患者? 选择何种化疗方案? 化疗的时机? 化疗周期? 分子靶向药物如何与化疗结合?,选择哪些患者?,适应症: 1.IB,II,IIIA期患者 2.PS评分0-1 3. 高危因素的I
9、A期 肿瘤 2cm 低分化 分子标记物指标Dr.Strass 的个人观点 禁忌症: 1.IA期 2.全肺切除术? 3.年龄75岁? 4.细支气管肺泡癌 5.有合并症 6.术后恢复慢,化疗的时机?,一般术后4-6周开始化疗。,化疗周期?,推荐4个化疗周期,新辅助治疗,增加肿瘤的手术控制率 减少肿瘤的微转移,新辅助化疗,新辅助治疗:SWOG 9900,泰素 225 mg/m2 卡铂 AUC = 6 X 3 cycles,手术,R A N D O M I Z E,手术,Stage IB, II and IIIA (T3N1) N= 374/600,Primary Endpoint: 33% impr
10、ovement in the expected 2.7 medians survival for surgery alone,Pisters K, et al,ASCO Abstract # 7012:,无疾病进展生存期,HR=0.80 0.59-1.07, p=0.14,median F/U 31 mo,SWOG 9900,总生存,HR=0.84 0.60-1.18, p=0.32,SWOG 9900,Median,1 yr,2 yr,Preop,47 mo,82%,69%,Control,40 mo,79%,63%,Median FU 31 months,可切除的 N2 NSCLC: IN
11、T 0139 Trial,Cisplatin, 50 mg/m2 IVPB d1, 8, 29, 36 Etoposide, 50 mg/m2 IVPB d1-5, 29-33 Thoracic RT, 45 Gy (1.8 Gy/d), begin d1,疾病无进展者,手术,继续放疗至 61 Gy,巩固化疗 cisplatin plus etoposide X 2 cycles,诱导治疗,Albain KS et al,ASCO Abstract #7014,INT 0139 Update,Overall Survival,Median FU 81 months,Overall Surviv
12、al by Pathologic Nodal Status,No surgery (n=38),Pathologic N0 (n=76),Pathologic N1-3, unknown (n=88),p 0.0001,% Alive,0,25,50,75,100,Months from Randomization,0,20,40,60,80,100,120,INT 0139 Update,肺叶切除的总生存 Subset VS Matched CT/RT Subset,% Alive,0,25,50,75,100,Months from Randomization,0,12,24,36,48,
13、60,/,/,/,/,/,/,/,/,/,/,/,/,/,/,/,/,/,/,/,/,/,/,/,MS,34 mos. 22 mos.,5 yr OS 36% 18%,CT/RT/S,CT/RT,INT 0139,Months from Randomization,全肺切除的总生存 Subset VS Matched CT/RT Subset,MS 3 yr OS 5 yr OS,19 mos. 36% 22%,CT/RT/S,CT/RT,% Alive,0,25,50,75,100,0,12,24,36,48,60,/,/,/,/,/,/,/,/,/,/,29 mos. 45% 24%,IN
14、T 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? Restaging mediastinoscopy/VATS/EUS?,N2 病人是否外科治疗需肺癌多学科讨论决定,局部晚期 (N2 )NSCLC,Message: Surgical resection does not offer a survival advantage over radiotherapy in patients with clinically operable (INT 0
15、319) or inoperable (EORTC 8941) stage III N2 disease. Concurrent chemoradiotherapy is the standard of care. Pneumonectomies should be avoided.,Locally Advanced N2 Lung Cancer,2005 NCCN临床肿瘤指南 多学科治疗:辅助化疗,基于IALT研究,对术后辅助化疗进行修订 IA期: T1N0 不进行辅助治疗 IB期: T2N0 推荐术后进行辅助化疗 II期:T1-2N1 推荐术后辅助化疗或放疗(2B)+化疗 期 术后可选择单
16、用化疗或放疗(2B)+化疗,2005 NCCN临床肿瘤指南 多学科治疗:辅助化疗,对于临床分期N2阴性而术后病理分期N2阳性者, 术后可以选择化疗或观察(2B)或联合放化疗(2B) T4N0-1同叶内卫星结节者,术后需辅助化疗 辅助化疗应选择含铂的二药联合方案,术后辅助化疗,基于CALGB9633和BR10研究 对于术后辅助化疗的推荐级别:2004 2A 2005 1级 对IA(T1N0)者完全切除术后: 2004 观察 2005 高危者:化疗(2B) 化疗方案 含铂二药联合方案,肺癌 内科治疗研究进展,NSCLC: NSCLC的流行病学及诊断分期 早期可手术切除NSCLC的辅助化疗 局部晚期
17、不可手术切除NSCLC同步化放疗 IIIb(胸水)/IV期NSCLC姑息化疗 分子靶向治疗 SCLC的全身治疗,不能手术局部晚期NSCLC化放疗结合的方式,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
18、63 Gy/7 wks Arm 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-Treat
19、ment Characteristics,CT RT CT CT+RT CT+RT CT (N=92) (N=74) (N=92) Age: 70 74(80%) 53(72%) 69(75%) 70+ 18(20%) 21(28%) 23(25%) Gender: Male 63(68%) 54(73%) 62(67%) Female 29(32%) 20(27%) 30(33%) KPS: 70-80 25(27%) 23(31%) 22(24%) 90-100 67(73%) 51(69%) 70(76%) % Weight Loss 5% 67(73%) 47(64%) 66(72%)
20、 5-10% 25(27%) 27(36%) 26(28%) Stage: IIIA 33(36%) 28(38%) 35(38%) IIIB 59(64%) 46(62%) 57(62%),T/CRT Historical 1 yr 59% 58% 2 yr 31% 31% Median 13.0 mo 14.5,T/CT/C/RT Historical 1 yr 53% 58% 2 yr 22% 31% Median 12.8mo 14.5mo,_,_,-,-,T/C/RTT/C Historical 1 yr 64% 58% 2 yr 33% 31% Median 16.1mo 14.5
21、mo,_,-,Arm 1,Arm 3,Arm 2,SWOG 9504: Treatment,Concurrent Chemoradiation PE: Cisplatin 50 mg/m2 IV d 1, 8, 29, 36 Etoposide 50 mg/m2 IV d 1-5, 29-33 RT: 45 Gy (1.8 Gy/fraction) 16 Gy boost (2 Gy/fraction),Consolidation Docetaxel 75 mg/m2 IV X 1 cycle Docetaxel 75-100 mg/m2 IV X 2 cycles (every 3 week
22、s),Gaspar LE, et al. Proc Am Soc Clin Oncol 2001;20:315a. (abstr & poster 1255),Phase II SWOG Trial (S9504): Results,Survival Median 27 mos 18 - 43 mos 1-year survival 76% 67% - 85% 2-year survival 54% 43% - 64% 3-year survival 40% 24% - 55%,0%,20%,40%,60%,80%,100%,0,12,24,36,48,Months After Registr
23、ation,SWOG 9504 Progression-Free Survival,Median N Events in Months 83 56 16,100%,SWOG 9504 Overall Survival,Gaspar: ASCO 2001,SWOG 9504 (PE/RT TXT) vs SWOG 9019 (PE/RT PE): Patient Characteristics,SWOG 9504 SWOG 9019 No. Patients 83 50 Median age 60 58 Male/Female 61/22 41/9 PS: 0-1 78 50 2 5 0 Sta
24、ge: n (%) T4 N0-1 31 (37) 18 (36) T4 N2 22 (27) 12 (24) N3 30 (36) 20 (40),SWOG 9504 (PE/RT TXT) vs SWOG 9019 (PE/RT PE): Survival (median f/u 28 mos),SWOG 9504 SWOG 9019 Med Surv 27 mos 15 mos 95% CI 18 43 mos 10 22 mos Survival rates 1 year 76% 67-85 58% 44-72 2 year 54% 43-64 34% 21-47 3 year 40%
25、 24-55 17% 7-27 4 year 39% 17%,Gaspar LE, et al. Proc Am Soc Clin Oncol 2001;20:315a. (abstr & poster 1255),Current Status of Chemoradiotherapy in Stage III NSCLC,Adapted from Pisters: ASCO, 2000 * S9504,2005 NCCN临床肿瘤指南 多学科治疗:辅助化疗,对于临床分期N2阴性而术后病理分期N2阳性者,术后可以选择化疗或观察(2B)或联合放化疗(2B) T4N0-1同叶内卫星结节者,术后需辅助
26、化疗 辅助化疗应选择含铂的二药联合方案,肺癌 内科治疗研究进展,NSCLC: NSCLC的流行病学及诊断分期 早期可手术切除NSCLC的辅助化疗 局部晚期不可手术切除NSCLC同步化放疗 IIIb(胸水)/IV期NSCLC姑息化疗 分子靶向治疗 SCLC的全身治疗,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NSCLC的一线治疗,Good PS Patients 1990s: Platinum-based CT standard NSCLC Collaborative Group BMJ. 1995;311:899-909 Current ASCO Guidelines: Pla
27、tinum doublets or non-platinum doublets are standard for advanced NSCLC pts with good PS Pfister et al. J Clin Oncol. 2004;22:330-353,Advanced NSCLC US FDA Approved Therapies,1994 vinorelbine/cisplatin and vinorelbine 1998 gemcitabine/cisplatin 1998 paclitaxel/cisplatin 1999 docetaxel (after platinu
28、m) 2003 docetaxel/cisplatin 2003 gefitnib (after platinum and docetaxel) 2004 pemetrexed (after platinum) 2004 erlotinib (after 1 prior chemotherapy),NSCLC: 一线化疗,化疗 Vs BSC? 有无最好的铂类联合方案? 含铂方案Vs非铂方案? 卡铂 Vs 顺铂? 化疗靶向治疗Vs化疗,治 疗,长春瑞滨 30 mg/m2,第1、8天 每3周 + 最佳支持治疗 最佳支持治疗 (BSC),紫杉醇 200 mg/m2 第1天 每3周 + BSC 最佳支
29、持治疗,泰索帝 100 mg/m2 第1天 每3周 + BSC 最佳支持治疗,吉西他滨 1000 mg/m2 第1、8和15天 每4周 + BSC 最佳支持治疗,月,概率,Log-rank p = 0.03,吉西他滨,最佳支持治疗,月,概率,Log-rank p = 0.84,ECOG 1594: Study Design,Stratification: Stage: IIIB vs IV PS: 01 vs 2 Wt Loss: 5% vs 5% CNS Mets: no vs yes,Arm A: Cisplatin + Paclitaxel Paclitaxel: 135 mg/m2/2
30、4 h Day 1 Cisplatin: 75 mg/m2 day 2,q3wk,Arm D: Carboplatin + Paclitaxel Paclitaxel: 225 mg/m2/3 h Day 1 Carboplatin: AUC 6 Day 1,Arm C: Cisplatin + Docetaxel Docetaxel: 75 mg/m2 Day 1 Cisplatin: 75 mg/m2 Day 1,Arm B: Cisplatin + Gemcitabine Gemcitabine: 1000 mg/m2 Days 1, 8, 15 Cisplatin: 100 mg/m2
31、 Day 1,q4wk,q3wk,q3wk,Schiller 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 A N D O M I Z E,E1594,ECOG 1594:Analysis of Toxicity,22,66,7,62,11,56,27,28,0,10,20,30,40,50,60,70,3 级,4 级,%,泰素/顺铂,吉西他滨/顺铂,多西紫杉醇/顺铂,泰素/卡铂,PS2的病人的3-4级毒性发生百分比,T
32、AX326 Study Design (泰素蒂铂类Vs NVB+铂类),R A N D O M I Z E,Stratifiication Factors: Stage of Disease IIIB vs. IV and Region US/Canada South America Europe/Lebanon Israel SouthAfrica/Australia New Zealand,Response assessment every 2 cycles,泰素蒂 75mg/m2 IV 卡铂 AUC 6 IV Q 3 wks (TCb),诺维苯 25mg/m2 IV D 1, 8, 15
33、 & 22 顺铂 100mg/m2 IV D 1Q 4 wks (VC),泰素蒂 75mg/m2 IV 顺铂 75mg/m2 IV Q 3 wks (TC),vs.,or,TAX 326 Overall Survival,Fossella et al. J Clin.Oncol. 2003;21:3016-3024.,100,80,60,40,20,0,Survival (%),0,3,6,9,12,15,18,21,24,27,30,33,Time (months),TC,VC,100,80,60,40,20,0,Survival (%),0,P = .657, adjusted log-r
34、ank test,TCb,VC,1-y survival 46% vs 41% with VC 2-y survival 21% vs 14% with VC Median survival: 11.3 vs 10.1 mo,P = .044, adjusted log-rank test,1-y survival 38% vs 40% with VC 2-y survival 18% vs 14% with VC,R A N D O M I Z E,Protocol Schema,Stratification Weight loss in previous 6 months: 5% vs 5
35、% Disease stage: IIIB with effusion, IV Brain metastases: Presence or absence,含铂方案Vs非铂方案,ASCO Abstract #7025,Coalition Trial,Survival by Treatment Arm,Meta-Analysis: 1-Y 生存 90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Vs顺铂,Does it matter for advanced disease?,NSCL
36、C: 90年代新化疗药物顺铂或卡铂的随机研究 N Zojwalla, 2004,NSCLC: 90年代新化疗药物顺铂或卡铂的随机研究 N Zojwalla, 2004,M O N T H S,Carboplatin Cisplatin N = 1152 N = 1154,8.7,9.8,* No other such trials 1992 2003; * 2 trials with paclitaxel, 1 with docetaxel, 2 with gem.,Carbo vs. Cis Meta-analysis Overall survival with cisplatin-base
37、d compared with carboplatin-based chemotherapy Hotta, K. et al. J Clin Oncol; 22:3852-3859 2004,Carbo vs. Cis Meta-analysis Overall survival with cisplatin plus new agents compared with carboplatin plus new agents Hotta, K. et al. J Clin Oncol; 22:3852-3859 2004,一线化疗: 怎样选择最好的联合方案?,疗效与生存? 生活质量? 毒性? 病
38、人的基础状态? 费用?,Weekly Paclitaxel with Carboplatin Followed by Maintenance Paclitaxel vs.Observation for Advanced NSCLC,Arm 3,Arm 2,Arm 1,Paclitaxel 150 mg/m2 + Carboplatin AUC=2 (weekly for 6 wks, 2 wks off), then Paclitaxel 100 mg/m2 + Carboplatin AUC=2 (weekly for 6 wks, 2 wks off )*,Paclitaxel 100 m
39、g/m2 + Carboplatin AUC=2 (weekly for 3 wks, 4th wk off)*,Paclitaxel 100 mg/m2 (weekly for 3 wks, 4th wk off) + Carboplatin AUC=6 (d1 )*,SCHEMA,Belani 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 Followe
40、d by Maintenance Paclitaxel vs.Observation for Advanced NSCLC,Efficacy/Toxicity Arm 1 Arm 2 Arm 3 Median 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) (p0.20 vs 1) Neutropenia grade 4
41、22% 8% 19% Thrombocytopenia grade 4 5% 2% 1% Neuropathy grade 3 5% 3% 13% Belani et al, JCO 21:2933-39, 2003,S T R A T I F Y,ECOG PS 0&1 vs 2 Stage IIIB vs IV,R A N D O M I Z E,Weekly Paclitaxel 100 mg/m2/week x 3 Carboplatin AUC=6 (Cycle duration 4 weeks, Total 4 cycles) Standard Paclitaxel 225 mg/
42、m2 3 Carboplatin AUC= 6 day 1 (Cycle duration 3 weeks, Total 4 cycles),TAXMEN 12 : Phase III Study Schema,*Maintenance Therapy Paclitaxel 70 mg/m2/week 3 weeks on, 1 week off Until Disease Progression,* For patients with CR/PR or SD on both arms,Taxmen 12: Kaplan-Meier Estimates Patient Survival,1.0
43、,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0,8,16,24,32,40,48,56,64,72,80,88,96,104,112,120,128,136,144,152,160,Weekly,Standard,Proportion of Patients Who Survived,Time (Weeks),Message: First set of evidence suggesting we are moving toward customized chemotherapy in lung cancer. Dilemma: Will predictive markers of response to the original treatment translate into a survival benefit in the era of second and third line t
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