1、 非小细胞肺癌的规范性治疗非小细胞肺癌的规范性治疗肺癌 NSCLC 80%，腺/鳞癌比例 ，III/IV期 65% 占恶性肿瘤死亡人数1/3 死亡人数较乳腺癌、前列腺癌和结肠癌的总和还多 80%-90%的肺癌病人最终死于肺癌UICC肺癌肺癌TNM分期分期(1997)T：原发肿瘤 T0：无原发肿瘤证据 TX：仅痰癌细胞 T1：3cm，未累及主支气管 T2：任何一条，3cm、累及主支气管但距隆突2cm、累及脏层胸膜、扩 展到肺门的肺不张或阻塞性肺炎 T3：侵犯胸壁、膈肌、纵隔胸膜、心包、距隆突 2：最佳支持治疗STANDARD THERAPY OF NSCLCSTAGESTANDARDINVEST
2、IGATIONALISurgeryNeo/Adj. chemotherapychemopreventionIISurgery + radiationNeo/Adj. chemotherapychemopreventionIII ASurgery + radiationNeo/Adj. chemotherapychemoradiotherapyinduction therapyIII BChemoradiotherapyInduction therapyIVChemotherapy +/-New Drugs radiationReasons for inoperability in patien
3、ts with lung cancer Distant metastasis Involvement of trachea or contralateral main bronchus with carcinoma Mediastinal lymph node metastasis Superior vena cava obstruction Malignant cell in pleural effusion Recurrent laryngeal nerve paralysis from carcinoma Histologic diagnosis of small cell carcin
4、omaCHEMOTHERAPY OF NSCLC Options Palliative chemotherapy Adjuvant chemotherapy Neo-adjuvant chemotherapy Experimental treatment in Stage I to III A In combination with surgery and/or radiotherapy Curative intention Standard treatment in Stage III B and IV - palliative Improvement of tumor-related sy
5、mptoms Improvement of quality of life Prolongation of Survival对对NSCLC有效的化疗药物有效的化疗药物90年代以前 90年代以后Cisplatin/Carboplatin VinorelbineEtoposide/Teniposide Paclitaxel/DocetaxelVinblastine/Vindesine GemcitabineMitomycin-C Irinotecan/TopotecanIfosfamide Edetvexate(ETX)Doxorubicin单药对单药对NSCLC的疗效的疗效(90年代年代) 药物
6、 有效率(RR)% 药物 有效率(RR)% DDP 15-20 ADM 13 CBP 9-20 5-FU 13 IFO 20 HMM 11 VP16 5-15 MTX 10 MMC 20 CTX 12 VDS 16-25 HN 8 VLB 16-20 CCNU 10 对对NSCLC有效的新药有效的新药 阻止DNA合成的药物 双氟脱氧胞苷(健择、Gemcitabine、GEM) 乙基脱氮氨喋呤(依打曲沙、Edetvexate、ETX) 抑制纺锤体功能的药物 失碳长春碱(诺维本、Navelbine、NVB) 紫杉醇(泰素、Paclitaxel、Taxol、PTX) 紫杉特尔(泰素蒂、Decatax
7、el、Taxotere、DTX) 拓扑异构酶抑制剂 伊立替康(Innotecan、CPT-11) 拓扑替康(Topotecan、TPT)新药单药对新药单药对NSCLC的疗效的疗效药物与剂量 病例数 RR(%) MST 1年生存率PTX250mg/m2/ 24 21 24.1w 41.7%PTX200mg/m2 25 24 40w 40%DTX100mg/m2 105 23-38 6.3-11m 21-45%GEM1000mg/m2 268 20-22 7m NAGEM1250mg/m2 76 20 9.2m 35%CPT-11100mg/m2 72 31.9 42w NATPT0.5-1.5m
8、g/m2 37 14 NA NANVB30mg/m2 391 12-33 30-33w 25-30%Supportive CareversusSupportive Care+Chemotherapy No. MST(wks) 1Yr. SurvivalStudy Chemo Pts. Chemo SC Chemo SCRapp et al CAP 137 24.7 17 21% 14% VP 32.6 26% 14%Woods et al VP 188 27 17 24% 17%Quoix et al VP 46 28 10 24% 11%Ganz et al VP 48 20.4 13.6
9、19% 12%Kassa et al VP 87 22 16.5 21% 13%Cartel et al MCP 102 36.6 17.2 38% 12%Cellerino et al CEP 115 34.3 21.1 30% 20% MECCullerino et al MIP 359 29.7 18.6 28% 18%Heising et al VpCarbo 48 29 11 28% 18%n Improves survival versus BSCl Median, 2 mol 1-yr, 10%l Hazard Rate Reduction of 26%n Relieves sy
10、mptoms: 66%78% in stage III/IVn Improves QOLn Cost-effectiveCISPLATIN-BASED THERAPY IN ADVANCED NSCLCTaxanes vs BSC in Unteated Advanced NSCLC Arms MS 1YS 2YS PTX 7M 36% 10% BSC 6M 28% 1% DTX 6M 25% 12% BSC 4.6M 15% 0IV期期NSCLC随机临床试验随机临床试验治疗方案 1年生存率支持治疗 15%90年代前DDP 25%联合化疗新药单药化疗 25%DDP+NVB/PTX/GEM 35
11、%Carbo+PTX治疗后复发和转移的再处理治疗后复发和转移的再处理PS 0-2：全身化疗 PS 2：最佳支持治疗 弥漫性脑转移：姑息性全脑外照射 孤立转移灶：手术切除或外照射NSCLC联合化疗方案联合化疗方案(1) CAP CTX 500mg/m2 iv d 1、2 ADM 40mg/m2 iv d 1 DDP 50mg/m2 iv d 3、4 21天为一周期 EP VP16 80-100mg/m2 iv d 1-3 DDP 60-120mg/m2 iv d 1 21天为一周期NSCLC联合化疗方案联合化疗方案(2) MVP MMC 8mg/m2 iv d 1 VDS 3mg/m2 iv d
12、 1、8 DDP 50mg/m2 iv d 3、4 21天为一周期 MIP MMC 6mg/m2 iv d 1 IFO 3g/m2 iv d 1 (加Mesna) DDP 50mg/m2 d 1 21天为一周期NSCLC联合化疗方案联合化疗方案(3) ICE IFO 1.2g/m2 iv d 1-3 CBP 300mg/m2(AUC 5-6) iv d 1 VP16 80mg/m2 iv d 1-3 21天为一周期NSCLC联合化疗方案联合化疗方案(4) NP NVB 30mg/m2 iv d 1、8 DDP 120mg/m2 iv d 1 21天为一周期 TP Taxol 135-175mg
13、/m2 iv d 1 DDP 60mg/m2 iv d 3 21天为一周期NSCLC联合化疗方案联合化疗方案(5) GP GEM 1250mg iv d 1、8 DDP 80-100mg/m2 iv d 2 21天为一周期 DP DTX 65mg/m2 iv d 1 DDP 60mg/m2 iv d 3 21天为一周期Cumulative Phase II Data of New Drugs Combined with Platinum Pt No RR MST 1 Year*Gemzar 436 45 10.061*Vinorelbine 328 41 8.8 37*Paclitaxel 6
14、19 42 9.338 Docetaxel 255 35 8.2 58 Irinotecan 185 44 7.9 NRBunn et al, Clin Cancer Res 1998, 5:1087-1100* FDA Approved 1st Line TreatmentRANDOMIZEStratification Performance status0-1 vs. 2 Weight loss inprevious 6 months5% Disease stage IIIB or IV Presence or absence of brain metsArm A: Cisplatin +
15、 PaclitaxelTaxol: 135 mg/m2 over 24 hours, day 1Cisplatin: 75 mg/m2 day 2, 3-week cycleArm B: Cisplatin + GemcitabineGemcitabine: 1,000 mg/m2 days 1,8,15Cisplatin: 100 mg/m2 day 1, 4-week cycleArm C: Cisplatin + DocetaxelTaxotere: 75 mg/m2 day 1Cisplatin: 75 mg/m2 day 1 3-week cycleArm D: Carboplati
16、n + PaclitaxelTaxol: 225 mg/m2 over 3 hours, day 1Carboplatin: AUC 6.0 day 1 3-week cycleSchiller JH, et al, NEJM 2002; 346(2):92-98ORR (%)21%22%17%17%TTP (m) 3.44.2*3.73.1 MST (m) 7.88.17.48.11-yr Survival 31%36%31%34%2-yr survival (%) 10%13%11%11%ECOG 1594 - Efficacy Company ConfidentialCopyright
17、2000 Eli Lilly & Company*p=0.02 TC GC TxC TCbNeutropenia 18/57 24/39 21/48 20/43Thrombocytopenia 4/2 22/28 2/1 8/2Anemia 12/1 27/1 13/2 9/1Febrile neutropenia 2/14 1/3 1/10 0/4Bleeding 1/0 2/0 0/0 1/0Vomiting 3/21 7/28 3/18 2/6Neuropathy 5/0 9/0 5/0 10/0Hypersensitivity 2/1 0/0 5/2 1/1 Renal 3/0 6/2
18、 3/0 1/0ECOG 1594 - Toxicities (G3%/G4%)Company ConfidentialCopyright 2000 Eli Lilly & Company( Time To Progression ) TTP延长意味着总生存期延长 TTP是指病人随机入组到疾病进展的时间，纯粹反映了药物的疗效，TTP的延长直接改善了病人的无症状生存期和生存质量。 TTP和ST都是评价抗肿瘤药物的重要指标。 Richard Pazdur,MD. FDA药物评价中心肿瘤产品主任 对于同一病人，在二、三线治疗给予病人生存机会相同的情况下，一线治疗的TTP将直接影响总生存期，TTP延长
19、意味着总生存期的延长。一一 线治线治 疗疗 TTP二线治疗二线治疗三线三线治疗治疗疾病进展疾病进展 疾病进展疾病进展 疾病进展疾病进展 疾病进展疾病进展 一一一线治疗一线治疗TTP二线治疗二线治疗三线三线治疗治疗总生存期总生存期药物药物A药物药物 A 总生存期总生存期Phase II studies of new drugs + DDP or CBP No.of No.of Total Median Survival Agent studies patients CR+PR(%) (Weeks)NVB+DDP 7 328 135(41) 38PTX+DDP 8 286 121(42) 42PT
20、X+CBP 8 333 137(46) 38DTX+DDP 5 255 88(35) 35GEM+DDP 6 245 114(47) 57CPT-11+DDP 7 185 81(44) 34TPT+DDP 1 22 3(22) 32 Standard 1stLine Regimens in NSCLC Comparison of Efficacy No. Total No. Response Med.Surv 1 yr Trials Pts. Rate (mos) SurvCBP+PTX 4 889 24% 8.6 37%DDP+GEM 6 1144 30% 8.7 37%DDP+DTX 3
21、843 29% 9.1 39%DDP+NVB 5 1215 28% 8.9 37%Platinum-Based Regimens in NSCLC Comparison of Toxicities No. No. Gr 4 Gr 4 Gr 3 Gr 3 Gr 1 Trials Pts. WBC Plt Neu Ar-Myal Alop CBP+PTX 4 889 15% 0% 15% 10% 80%DDP+GEM 6 1144 25% 18% 11% 1% 10% DDP+DTX 3 843 35% 0% 6% 4% 70% DDP+NVB 5 1215 30% 0% 9% 5% 10%Com
22、parison of carboplatin-based Regimens in NSCLC (Efficacy) No. No. ORR MS 1-y Surv Trials Pts. (%) (mos) (%)CBP+PTX 4 889 24 8.6 37CBP+GEM 3 450 40 9.9 40CBP+DTX 1 412 28 9.1 38Comparison of Carboplatin-based Regimens in NSCLC (Toxicities) No. Gr 4 Gr 4 Gr 3 Gr 3 Gr 1 Trials AGC Plt Neuro Ar-Myal AlopCBP+PTX 4 15% 0% 15% 10% 80%CBP+GEM 3 8% 12% 0% 0% 12%CBP+DTX 1 25% 2% 1% 4% 70%循证医学循证医学Meta分析分析 III期临床试验期临床试验随机随机III期临床试验期临床试验II期临床试验期临床试验I期临床试验期临床试验体内体内/体外试验体外试验个案报道个案报道高水准的循证医学是基于随机高水准的循证医学是基于随机III期临床研究资料的数量及确切的疗效期临床研究资料的数量及确切的疗效
