非小细胞肺癌的化疗进展.ppt

1、非小细胞肺癌的化疗进展,2005 US Cancer Deaths*,ONS=Other nervous system. Source: American Cancer Society, 2005.,Men295,280,Women275,000,27%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

2、 and bronchus31% Prostate10% Colon and rectum10% Pancreas5% Leukemia4% Esophagus4% Liver and intrahepatic3%bile duct Non-Hodgkin Lymphoma 3% Urinary bladder3% Kidney3% All other sites 24%,2002年上海市男性肺癌发病水平,2002年上海市女性肺癌发病水平,Relative Survival* (%) during Three Time Periods By Cancer Site,*5-year relati

3、ve survival rates based on follow up of patients through 2001. Recent changes in classification of ovarian cancer have affected 1995-2000 survival rates Source: Surveillance, Epidemiology, and End Results Program, 1975-2001, Division of Cancer Control and Population Sciences, National Cancer Institu

4、te, 2004.,Site,1974-1976,1983-1985,1995-2000,All sites505364 Breast (female)757888 Colon 505863 Leukemia344146 Lung and bronchus131415 Melanoma of the skin808591 Non-Hodgkin lymphoma475459 Ovary3741 44 Pancreas334 Prostate677599 Rectum495564 Urinary bladder737882,2002-2004年上海市肺癌相对生存率,男性16801例中位生存期28

5、2天 女性 6918例中位生存期308天,20世纪30年代 上海的烟草广告,肺癌晚期非小细胞美国 FDA 批准的治疗方案,1994 长春瑞滨 /顺铂 和长春瑞滨 1998 吉西他滨/顺铂 1998 泰素/顺铂 1999 多西他赛 (使用铂类后) 2003 多西他赛 /顺铂 2003 吉非替尼 (使用铂类和泰索帝后) 2004 培美曲唑 (使用铂类后) 2004 埃罗替尼 (在一线化疗后) 2006 贝伐单抗,Chemotherapy of NSCLC,Treatment adapted to each stage of the disease,Resectable disease I, II,

6、 IIIA,Unresectable disease IIIB,Unresectable disease IV,Adjuvant CT Pre-operative CT,CT+RT combination,Palliative CT Platinum-based or Platinum-free regimens,Recent CT evolutions of Non Small Cell Lung Cancer,Arrival of new oral formulations Development of multimodal treatments Development of chemot

7、herapy for early stages,State of the ArtStage Ib/II/III NSCLC,Operable patients Pre-operative CT / CT-RT Adjuvant CT Inoperable patients CT-RT,Place of adjuvant CT in Non Small Cell Lung Cancer,Patients population: - Stage I, II, eventually III - Completely resected - N+,Ref: Stewart, BMJ 1995,1995

8、Cambridge meta-analysis suggests: 5% benefit in survival at 5y for CDDP based CT,新的随机临床研究,IALTNEJM: 350:330, 2004,1,867例患者入选 (148 中心 33个国家)肺癌辅助化疗中最大样本的随机临床试验 原来目标 3,300 病例 实际入选 57% 来自原来目标人群 包括 IA IIIB NSCLC 随机分为化疗组 3 or 4 周期顺铂加鬼臼乙叉甙, 长春碱, 长春瑞滨, 或长春酰胺 NVB + CDDP (27% pts) 顺铂剂量：80mg/m2*4，100mg/m2*4 ，1

9、000mg/m2*3，120mg/m2*4 两药联用的化疗方案 术后放疗,IALT: Place of adjuvant CT in Non Small Cell Lung Cancer,Ref: Le Chevalier T., ASCO 03,p0.003,p0.03,350:351-360, 2004,INTERNATIONAL ADJUVANT LUNG CANCER TRIAL总体生存率,HR = 0.86, 95% CI:0.76 - 0.98,5年生存率 化疗组44.5% 对照组 40.4%,结果支持以顺铂为基础的化疗方案对术后的非小细胞肺癌有效 但是不能确定亚组患者均从以顺铂为

10、基础的辅助化疗中受益,NVB-CDDP: the only new schedule tested,主要结果,在III期患者中观察到 显著降低死亡危险比 在 I 或 II 期NSCLC没有显著降低死亡危险比,IALT: Place of adjuvant CT in Non Small Cell Lung Cancer, The difference in survival observed is coherent with the results of the meta-analysis published in 1995 and significant enough to recommen

11、d chemotherapy after surgery. 7000 deaths per year worldwide could be avoided. T. Le Chevalier Plenary session, ASCO 03,长春瑞滨 + Cisplatin in early stagesIntergroup JBR.1O trial,(Winton T. et al, ASCO 04),“ANITA: Phase III Adjuvant Navelbine and Cisplatin Versus Observation in Completely Resected (Sta

12、ge I-III) NSCLC Patients: Final Results After 70-Months of Follow-up” Douilard, J, on behalf of Adjuvant Navelbine International Trialists AssociationProceedings ASCO, 23: 624s (Abstract #7013), 2005,840 patients randomized (from 104 centers) stage IB 35% stage II 30% stage IIIA 35% median survival

13、65.8 months versus 43.7 months (chemotherapy NVB: 30 mg/m I.V. Weekly x 16/20 ，CDDP: 100 mg/m I.V. D1, D29, D57, D85 vs. observation) HR=0.79; 95% CI: 0.66-0.95; p=0.013,SURVIVAL,ANITA: SURVIVAL BY STAGE,OVERALL EFFECT adjuvant chemotherapy significantly improves survival in completely resected NSCL

14、C SUBGROUP ANALYISIS stage IB NSCLC no effect “should be considered standard of care after total resection of stages IIA, IIB, and IIIA”,ANITA CONCLUSIONS,Adjuvant CT- NSCLC Meta-analysis Lung Adjuvant Cisplatin Evaluation,5 studies：ALPI、 ANITA、 BLT、 IALT、 JBR10 4 584 patients (individual data) Sign

15、ificant benefit of CT in OS and PFS (p=0,004) OS absolute difference at 5 years : 5,3% +/- 1,5%,LACE. JP Pignon et al. oral #7008,Adjuvant CT - NSCLC,Which patients ? Stage II, IIIa : significant impact, detrimental for stage Ia (LACE) Not mandatory for Stage Ib : CALGB 9963 update failure in OS obj

16、ective significant advantage in PFS and for patients with tumor 4 cm Elderly 60 years (C. Pepe et al. oral #7009) no differences in G-CSF use no differences in hospitalizations 1 treatment related death in both young and elderly groups despite similar tox. elderly patients received sign. less CT,Adj

17、uvant CT NSCLC,Which drugs ? Effect of Navelbine is marginally better but interaction with the associated drugs may be confounded by cisplatin alone (LACE) Navelbine impact is known (Schiller comment) Taxol Carbo : questionable partner in adjuvant from CALGB trial (Schiller comment) Others Combinati

18、ons Multivariate analysis were not able to study the respective role of the associated drug and cisplatin dose (LACE) “we dont know “(Schiller comment),早期NSCLC辅助化疗：总结,辅助化疗是B-A期NSCLC患者的标准治疗方式。研究最多的药物是长春瑞宾/顺铂 胸部放疗仍然被认为有害，没有临床获益的证据 除了日本UFT外，没有数据支持辅助化疗用于A期NSCLC患者.,Is Adjuvant therapy useful for all rese

19、cted patients in NSCLC?,Stade I B Stade IIStade III A CALGB JBR-10,IALT / ANITA,Several approaches are possible to sequence CT and RT Sequential Concurrent Induction concurrent Concurrent consolidation,Inoperable patients Stage IIIB,Mornex ECCO 01,Phase III study,Efficacy of 长春瑞滨 + CDDP in sequentia

20、l CT+RT,Induction with 长春瑞滨 + CDDP RT High efficacy confirmed in Phase III,n=212 24% IIIA N2, 76% IIIB,Felip, ASCO 97; Viallet, Cancer 99; Zatloukal, IASLC 03; Ishikura, ECCO 03;,长春瑞滨 + CDDP in sequential CT+RT,* Sequential arm,OR MS Distant Survivalafter CTafter RT-CT relapses Felip 48% - 13 m- (n=

21、 33) Viallet46%74% 12.2 m3 YS: 26%(n= 42) 24.2 m 67% 22% for responders non resp. responders Zatloukal* -47% 12.9 m- 1 YS: 53% (CR=17%) Ishikura -83% 24 m-1 YS: 70%(n= 30) 2 YS: 50%,Stage III patients,Improved distant control and survival for responding patients,(n=50),Zatloukal, ASCO 02; Viallet, C

22、ancer 99; Felip, ASCO 97; Mornex, ECCO 01; Ishikura ECCO 03; Douillard, Lung Cancer 00,Phase II studies,Good tolerance profile: no risk of delayed RT,Tolerance of 长春瑞滨 + CDDPin sequential CT+RT,WHO G/4, % pts Sequential NP RT Neutropenia38-88% rare complications Febrile Neutropenia2-12% Thrombocytop

23、enia4-7% no risk of haemorrage Oesophagitis0-17% Pneumonitis1-10%,Zatloukal, IASLC 03,Randomised Phase II,Sequential vs concomitant CT+RT,Concomitant CT- RT is more effective than sequential CT-RT,p= 0.02,COX study,Cox, Lung Cancer 00,p= 0.02,p= 0.001,Enhanced benefit by using both approaches: Reduc

24、tion of distant metastases + loco-regional control.,Sequential vs concomitant CT+RT,长春瑞滨 Vokesstudy EFFICACY,The only randomised study with 3 different schedules in stage III,Vokes,JCO 02,长春瑞滨 Vokesstudy Toxicity G3-4; % pts,Vokes,JCO 02,Tolerance WHO G3/4, % pts,Vokes,JCO 02,长春瑞滨 + CDDP in concomit

25、ant CT+RT,长春瑞滨 + CDDP: the best efficacy/tolerability ratio,Unresectable stage III patients : ASCO Guidelines for CT+RT,CT plus RT prolongs survival compared to RT alone CT may best be started soon after the diagnosis of unresectable NSCLC has been made Delaying CT may negate the survival benefits o

26、f treatment The duration of CT should be 2 to 4 cycles of initial platinum-based CT,(Pfister, JCO 04),Which CT in metastatic Non Small Cell Lung Cancer?,Fit for polyCTFit for monoCT,Patients population: Stage IV,PSComorbiditiesNeed for QOLAge,With CDDPWithout CDDPElderly pts,NSCLC细胞毒化疗的“疗效平台”,二药 vs

27、单药方案；二药 vs 三药方案在生存期、缓解率方面的比较,Delbaldo C. et al., JAMA 2004; 292:470,Le Chevalier, JCO 94; Wozniak, JCO 98 ; Kelly, JCO 01; Fossella, JCO 03 Scagliotti, JCO 02; Souquet, Annals 02; Gebbia, Lung Cancer 03 ; Martoni, ASCO 2003,Phase III studies *,ComparatorReference NVB-CDDPVDS-CDDPLe Chevalier NVB-CDD

28、P CDDPWozniak TXL-CBDCANVB-CDDPKelly NVB-IFO-CDDP NVB-CDDPSouquet TXL-CBDCA NVB-CDDPScagliotti GEM-CDDP NVB-CDDPScagliotti TXT-CDDP NVB-CDDPFossella GEM-CDDP NVB-CDDPGebbia GEM-CDDP NVB-CDDPMartoni,1994,1998,2001,2002,2002,2002,2003,2003,2003,*Endpoint: Median survival :Significant improvement :No s

29、ignificant improvement,长春瑞滨 + CDDP,Martoni phase III EJC 2005 (NVB-cis vs Gem-cis),Very similar results, no details on maintenance therapy Even with sub optimal doses of NVB vs GEM,New in 2005,NVB-CDDP,CIS vs. Cab meta-analysis: An individual patient data (9 studies: 2 968 pts) Comparing cisplatin v

30、ersus carboplatin-based chemotherapy in first-line treatment of advanced NSCLC.,NSCLC Metastatic or Locally Advanced,A. Ardizzoni , PASCO 2006; #7011,Ardizzoni A. ASCO 2006, Abs #7011,Are cisplatin and carboplatin equivalent ?,CISCA(CISplatin vs. CAboplatin)meta-analysis of randomized studies compar

31、ing cisplatin to carboplatin,Overall CIS CAR in terms of RR but not of survival Subgroup analyses suggest that CISCAR in terms of survival when combined with 3rd generation agents (80% of overall study population) Grade 3/ 4 thrombocytopenia and anemia were significantly more frequent in Carbo arm,

32、while grade nausea, vomiting and renal toxicities were more frequent in Cis arm,Substitution of cisplatin for carboplatin Improves toxicity profile Reduces response rate With a significant survival reduction in trials including stage IIIB and Non Squamous patients Without affecting survival in trial

33、s including only stage IV patients,Are cisplatin and carboplatin equivalent ?,NSCLC含铂方案 vs. 非铂方案 : 一项汇萃分析,N=6.504 含铂方案1年生存率提高了5% (34% vs. 29%) (OR 1.21, P=.0003) 含铂方案与第三代化疗药物为基础的联合方案 相比未见优势 (OR 1.11, P=.17),DAddario G et al. J. Clin. Oncol. 2005, 10 mo MS: not far from platin-doublets,* Italic = ASC

34、O 2005,Many non-platinum doublet results last year,长春瑞滨 + CDDP Recommended schedules,NVB i.v. 30 mg/m2 D1, D8 GEM 1000 mg/m D1, D8 every 3 weeks,Recommended Schedulesof 长春瑞滨 non-CDDP based regimens,长春瑞滨 - GEMCITABINE,Recommended dose of 长春瑞滨 in Non Small Cell Lung Cancer,STAGE IV: For patients fit f

35、or monochemotherapy,NVB i.v. 30 mg/m2 D1, D8 every 3 weeks,长春瑞滨 i.v., , , ,2nd line,长春瑞滨 ORAL in NSCLC,Which indication? Which perspectives?,20%,stage,IA 60%,IIA 34%,IB 38%,IIB 23%,IIIA 9-13%,IIIB 3-7%,IV 1%,wet,5YS, 1997,% at diagnosis,Update in 2005,minimal increase in 5YS,% at diagnosis,Current Treatment of NSCLC: 2006,Stage,Primary treatment,Adjuvant therapy,Outcome,IA,Surgery,5 yr SR 60-70%,IB,C/T,II,5 yr SR 40-50%,IIIA (resectable),Neoadjuvant C/T Surgery