胃癌治疗现状及2008ASCO进展.ppt

胃癌治疗现状及 2008ASCO进展,Rui-hua Xu (徐瑞华） Sun Yat-sen University Cancer Center xurhmail.sysu.edu.cn Tel: 020-8734 3468,胃癌治疗有效的化疗药物,Old Drugs Fluoropyrimidines 5-FU Platinum Cisplatin Anthracyclines Doxorubicin Epirubicin Etoposide Methotrexate,New Drugs Fluoropyrimidines Capecitabine S-1 Platinum Oxaliplatin Taxanes Paclitaxel Docetaxel Irinotecan,FP vs FAM vs UFTM: JCOG 9912 trial,Ohtsu et al 2003,FP 5-FU UFTM p value,No. Patients 105 105 70,Response (%) 34.8 11.4 8.6 0.0001,PFS (weeks) 3.9 1.9 2.4 0.001,MS (weeks) 7.1 7.3 6.0 NS,UFTM, tegafur uracil / mitomycin,Waters et al 1999,ECF vs FAMTX: UK Trial,Chemotherapy for gastric cancer in the past,FP regimen has been the standard or reference regimen in Asia ECF is recommended mostly in Europe,Where we have been in AGC 我们所知道的胃癌化疗,Eloxatin: REAL-2, phase III Xeloda: ML17032, phase III Taxotere: TAX 325, phase III CPT-11 V306, phase III Eloxatin: FLO vs FLP, phase III S1: JCOG 9912, phase III S1: SPIRITS, phase III 2008 ASCO DC vs FLP phase III Phase II clinical trials,E Epirubicin 50 mg/m2 iv C Cisplatin 60 mg/m2 iv F PVI 5-FU 200 mg/m2/day q3w,REAL-2: 研究设计,2 x 2 randomisation Planned treatment duration 24 weeks,E Epirubicin 50 mg/m2 iv C Cisplatin 60 mg/m2 iv X Capecitabine 625 mg/m2/bid q3w,E Epirubicin 50 mg/m2 iv O Oxaliplatin 130 mg/m2 iv F PVI 5-FU 200 mg/m2/day q3w,E Epirubicin 50 mg/m2 iv O Oxaliplatin 130 mg/m2 iv X Capecitabine 625 mg/m2/bid q3w,PVI, portal vein infusion,Cunningham D, et al. ASCO 2006 (Abstract LBA4017).,Hazard ratio (95% CI): 0.86 (0.800.99),Time (years),Probability (%),0,1,2,3,4,5,6,0,20,40,60,80,100,8,206,178,37,52,12,No. at risk,484,480,28,3,1,5-FU,Capecitabine,5-FU,Capecita-bine,Cunningham D, et al. ASCO 2006 (Abstract LBA4017).,REAL-2: overall survival for fluoropyrimidine comparison (per protocol),REAL-2: overall survival for platinum comparison (per protocol),Hazard ratio (95% CI): 0.92 (0.801.10),Probability (%),0,1,2,3,4,5,6,0,20,40,60,80,100,10,198,187,41,48,10,490,474,1,4,1,Cisplatin,Oxaliplatin,Cisplatin,Oxaliplatin,Time (years),No. at risk,Cunningham D, et al. ASCO 2006 (Abstract LBA4017).,ECF EOX,Probability (%),Time (years),Cunningham D, et al. ASCO 2006 (Abstract LBA4017).,REAL-2: overall survival for ECF and EOX (ITT),*p0.05 vs ECF; *p0.01 vs ECF,Cunningham D, et al. ASCO 2006 (Abstract LBA4017).,REAL-2: grade 34 血液学毒性,Phase III Trial in AGC with 5Fu/LV Plus Either oxaliplatin or Cisplatin (FLO vs FLP),Al-Batran. J Clin Oncol 2008; 26(9),Best Overall Response (ITT),Time to Treatment Failure (ITT),FLO vs FLP: subgroup of patients over 65 years,Grade ¾ Hematological and Neurosensory toxicities,R A N D O M I S A T I O N,ML17032 : Phase III study: XP vs FP Xeloda + cisplatin vs 5-FU + cisplatin,FP 5-FU c.i. 800mg/m2 d15 q3w Cisplatin 80mg/m2 3-hour i.v. infusion,XP Xeloda 1 000mg/m2 bid d114 q3w Cisplatin 80mg/m2 3-hour i.v. infusion,Advanced and/or metastatic gastric cancer n=316,n=156,n=160,Primary end-point: non-inferiority in PFS,Kang Y et al. Proc Am Soc Clin Oncol 2006 (Abst LBA4018),XP vs FP: non-inferior PFS,Estimated probability,Per-protocol analysis,XP (n=139) FP (n=137),Median PFS months (95% CI) 5.6 (4.97.3) 5.0 (4.26.3),0,Months,2,4,6,8,10,12,14,16,18,20,22,24,26,1.0,0.8,0.6,0.4,0.2,0.0,HR=0.81 (95% CI: 0.631.04) Compared to HR upper limit 1.25, p=0.0008,Kang Y et al. Proc Am Soc Clin Oncol 2006 (Abst LBA4018),XP vs FP: trend to superior PFS,Estimated probability,Intent-to-treat analysis,XP (n=160) FP (n=156),Median PFS months (95% CI) 5.6 (4.86.9) 5.0 (3.95.7),0,2,4,6,8,10,12,14,16,18,20,22,24,26,1.0,0.8,0.6,0.4,0.2,0.0,HR=0.80 (95% CI: 0.631.03) Test for superiority p=0.0801,Kang Y et al. Proc Am Soc Clin Oncol 2006 (Abst LBA4018),Months,Superior response rate with XP vs FP,Kang Y et al. Proc Am Soc Clin Oncol 2006 (Abst LBA4018),22,DCF Docetaxel 75 mg/m2 over 1 h, Day 1 Cisplatin 75 mg/m2 over 13 h, Day 1 5-FU 750 mg/m2/day over 5 days, q3w (n=227),CF Cisplatin 100 mg/m2 over 13 h, Day 1 5-FU 1000 mg/m2/day over 5 days, q4w (n=230),Measurable/evaluable metastatic or measurable locally recurrent gastric adenocarcinoma Age 18 years KPS 70 Adequate hematologic/ biochemical parameters No prior palliative chemotherapy,RANDOM I S A T I ON,Treatment until PD, consent withdrawn or unacceptable toxicity; tumor assessments q8w,Docetaxel-based chemotherapy in advanced gastric cancer: Phase III trial (TAX 325),Van Cutsem E, et al. J Clin Oncol (accepted for publication).,Log-rank p=0.0004 Hazard ratio: 1.47 (95% CI: 1.191.83) Risk reduction: 32.1%,0,0,10,20,30,40,50,60,70,80,90,100,DCF,CF,3,6,9,12,15,18,21,24,Probability (%),TAX 325: time to progression (primary endpoint),Time (months),Van Cutsem E, et al. J Clin Oncol (accepted for publication).,Log-rank p=0.0201 Hazard ratio: 1.29 (95% CI: 1.041.61) Risk reduction: 22.7%,0,10,20,30,40,50,60,70,80,90,100,DCF,CF,TAX 325: overall survival,Time (months),Van Cutsem E, et al. J Clin Oncol (accepted for publication).,Probability (%),DCF,CF,(n=221),(n=224),CR (%),2,1,PD (%),17,26,ORRa (%),37,25,95% CI,30.343.4,19.931.7,p-value,0.01,95% CI,Responders with response duration 9 months (%),26,14,TAX 325: best overall response,Response parameter,SD (%),30,31,Median response duration (months),6.1 5.08.3,5.6 4.26.4,0.32,0.02,aConfirmed and independently reviewed,Van Cutsem E, et al. J Clin Oncol (accepted for publication).,TAX 325 Clinical Benefit: time to definitive worsening of KPSa,0 3 6 9 12 15 18 21 24 27,100,90,80,70,60,50,40,30,20,10,0,Time (months),Probability (%),DCF,CF,p=0.0088 HR: 1.38 (95% CI: 1.081.76) Risk reduction: 27.5%,aWorsening defined as a definitive decrease in PS by 1 KPS category vs baseline,Moiseyenko V, et al. WCGIC 2005 (Abstract O-013).,Patients (%),DCF (n=221),CF (n=224),Lethargy,19,14,Stomatitis,21,27,Diarrhea,19*,8,Infection,13,7,Nausea,14,17,Vomiting,14,17,Anorexia,10,9,Neurosensory,8*,3,1 event,69,59,Adverse eventsa,aPossibly or probably related to study treatment; treatment-emergent non-hematologic toxicities occurring at grade 3 to 4 in 5% of patients in either group *p0.05 vs CF,TAX 325: main grade 34 non-hematologic adverse events,Van Cutsem E, et al. J Clin Oncol (accepted for publication).,% of evaluable patients,DCF,CF,Neutropenia Anemia Thrombocytopenia,82.3 18.2 7.7,56.8 25.6 13.5,(n=221),(n=224),Adverse events regardless of secondary prophylactic treatment,28.3,12.2,13.1,15.0,% of patients with febrile neutropenia/ neutropenic infection,(n=219),(n=41),(n=222),(n=20), / + secondary prophylactic G-CSF,+,+,Van Cutsem E, et al. WCGIC 2005 (Abstract O-012).,TAX 325: grade 34 hematologic adverse events,TAX325: Conclusions and interpretations,T + CF CF The TCF regimen is the proof of the concept that docetaxel provides the benefit our patients need Docetaxel should be incorporated in safer regimen using oxaliplatin, S-1 or capecitabine Develop a regimen to allow addition of a biologic,V306: FUFIRI vs FP as 1st Line Chemotherapy for AGC,N=170 CPT-11 80mg/m2 CF 500mg/m2 5FU 2000mg/m2 civ 1/W x 6w,N=163 CDDP 100mg/m2 d1 5FU 1000mg/m2/d d1-5 Q4W,N=333 AGC,RR 54（31.8%） 42（25.8%） TTP 5.0m 4.2m (p=0.088) TTF 4.0m 3.4m (p=0.002) OS 9.0m 8.7m p0.53,M. Dank 2005 ASCO abs 4003,V306: FUFIRI vs FP as 1st Line Chemotherapy for AGC,Dank, et al. ASCO 2005,- Center - PS - Unresectable vs recurent, adj Crx vs recurrent, no adj Crx,R A N D O M I S A T I O N,ARM A (Control) 5-FU civ 800 mg/m2 D1-5 q 4 weeks,ARM B S-1 80 mg/m2 D1 - 28 q 6 weeks,U N T I L P D,Primary endpoint: Overall survival A vs B: non-inferiority, A vs C: superiority,ARM C CPT-11 70 mg/m2 D1,15 CDDP 80 mg/m2 D1 q 4 weeks,JCOG 9912 Trial,Boku N, et al. Proc Am Soc Clin Oncol 2007 (#4513),JCOG 9912 Trial; Results,Boku N, et al. Proc Am Soc Clin Oncol 2007 (#4513),R A N D O M I S A T I O N,ARM A S-1 40-60 mg bid for 28 d q 6 weeks,ARM B Cisplatin 60 mg/m2 on D8 S-1 40-60mg bid for 21 d q 5 weeks,U N T I L P D,Primary endpoint: Overall survival (Superiority),Center PS Unresectable vs. recurrent,SPIRITS Trial,Narahara H et al. ASCO 2007,Results of SPRITS Trial,Narahara H et al. ASCO 2007,Country: 23 (US, Europe, South America, Ukraine) Primary Endpoint: Overall survival (Superiority) Patient accrual 1050 (completed in March, 2007),FLAGS Trial (First-Line Advanced Gastric Cancer Study),Type of disease (Locally advanced vs Metastatic 1 metastasis vs Metastatic 1 metastases) - Prior adjuvant CT Measurable disease - Centers,Cisplatin 75 mg/m2 IV Day 1,S-1 25mg/m2 bid po Day 1-21,Cycles repeated every 4 weeks,Cisplatin 100 mg/m2 IV Day 1,Cycles repeated every 4 weeks,5-FU 1000 mg/m2/day CIV Day 1-5 (over 120 hours ),R A N D O M I S A T I O N,ARM A Taxotere 40 mg/m2 D1 S-1 80 mg/m2 D1-14 q 3 weeks,ARM B S-1 80 mg/m2 D1-28 q 6 weeks,U N T I L P D,START Trial (S-1 and Taxotere for Advanced Gastric Cancer Randomized Phase III Trial) Collaborative Japan-Korea Trial,Patient accrual: 628 Primary endpoint: Overall survival,Center Measurable ds (by RECIST),Docetaxel-cisplatin (DC) versus 5-fluorouracil-leucovorin-cisplatin (FLC) as first-line treatment for locally advanced or metastatic gastric cancer: Preliminary results of a phase III study.,K. Ridwelski 2008ASCO #4512,Ramdomized 3-armed phase III study of S-1 monotherapy versus S-1/CDDP (SP) versus 5-FU/CDDP (FP) in patients (pts) with advanced gastric cancer (AGC): SC-101 study,M. Jin, H. Lu, J. Li, L. Shen, Z. Chen, Y. Shi, S. Song, S. Qin, J. Liu, X. Ouyang #4533,Reported by Jin ML and He YJ,Meta-analysis of chemotherapy in advanced gastric cancer,All randomized trials closed to accrual by end of 2004 eligible Trials with neoadjuvant or adjuvant treatment excluded Endpoint: OS,Meta-analysis of chemotherapy in advanced gastric cancer,Cisplatin versus no cisplatin 7 RCTs, n=1677, HR=0.98, p=0.59 Irinotecan versus no irinotecan 3 RCTs, n=550, HR=0.89, p=0.36 Anthracycline versus no anthracycline 7 RCTs, n=1501 pts, HR=0.94, 95%CI=0.84-1.06, p=0.31 Taxane versus no taxane 3 RCTs, n=572, HR=0.82, 95%CI=0.68-0.99, p=0.03,GATE phase II trial of first-line docetaxel oxaliplatin in advanced gastric cancer,N=270 Patients with advanced gastric and gastrooesophageal junction adenocarcinoma,R,TE Docetaxel 75 mg/m2 + Oxaliplatin 130 mg/m2 q 3 wk,TEF Docetaxel 50 mg/m2 + Oxaliplatin 85 mg/m2 + folinic acid 400 mg/m2 + 5-FU 2400 mg/m2/46h (no bolus), q 2 wk,TEX Docetaxel 50 mg/m2 + Oxaliplatin 100 mg/m2 q 3 wk + Capecitabine 625 mg/m2 bid continuously,Median TTP: 5.4 months,Overall survival : 12.3 months,A Pilot study of FOLFOX6 in AGC,ORR 41.0%, SD 21.6%,Xu RH. Chemotherpay 2008 in press,5.4 months (95% CI, 2.4-8.4 months),12.1 months (95% CI, 10.0-14.2months),TTP,OS,Ruihua Xu1, Bing Han1, Feng Wang1, Huiyan Luo1,Yanxia Shi1, Yuhong Li1, Miaozhen Qiu1, Wenqi Jiang1, Youjian He1, Zhong-zhen Guang1 1. Department of Medical Oncology, Sun Yat-sen University Cancer Center,Guangzhou GD, CHINA 2. Nan-chang University 1st affiliated hospital, Nanchang, CHINA,Phase II Clinical Trail of XELOX as first line treatment in patients with unresectable or metastatic gastric cancer,XELOX,Oxaliplatin 130mg/ d1 3hr Xeloda 1g/ d1-14 bid po Every 3 weeks,Primary endpoint: OR, TTP (ITT) Secondary endpoints: OS and safety profiles,Response rates in XELOX （ITT）,疾病控制率为 76%（ITT）,TTP and OS of eligible patients receiving XELOX,),中位OS 11.1 months (95% CI, 5.6-16.5 months),中位TTP 5.8 months (95% CI, 3.4 to 8.2 months,Table 3. Toxicities According to NCI-CTC,TCX for AGC (1st line): Phase I / II study,Chemotherapy (every 3 weeks) Docetaxel 60 mg/m2 iv D1 Xeloda 937.5 mg/m2 po bid D1-14 Cisplatin 60 mg/m2 iv D1 Efficacy (N = 40) Response: 4 CRs, 23 PRs: 68% 10 Op: 4 pathologic CRs TTP: 7.8 mo, OS: 16.9 mo Toxicity G3/4 neutropenia 63%, neutropenic fever 10%, 1 death G3 asthenia 38%, G3 HFS 2.5%, G3 diarrhea 2.5%,Kang YK, et al. Proc ASCO 2004,CT in AGC 2008,Advanced Gastric Cancer: Targeted Agents,1. Shah et al. J Clin Oncol. 2006;24:5201; 2. Di Fabio et al. ESMO, 2006. Abstract 1077PD; 3. Pinto et al. ASCO, 2006. Abstract 4031; 4. Lordick et al. ESMO, 2006. Abstract 1076PD. 5. Bang et al ASCO 2007. 6 Enzinger Annals of Oncology 2006.,Advanced Esophago Gastric Cancer: Targeted Agents: GI Symposium 2008,Targeted Agents: Phase II CALGB 80403/ECOG 1206 Trial,At: http:/www.clinicaltrials.gov. Accessed November 9, 2006.,Metastatic Esophagogastric Cancer,Irinotecan + Cisplatin + Cetuximab,ECF + Cetuximab,FOLFOX + Cetuximab,Primary end point: Response rate,EGFr Tyrosine Kinase Inhibitors: Phase II, Adenocarcinoma,Doi 1036 Proc ASCO 22, 2003; Ferry Clin Can Res 132:5869; 2007 Janmaat JCO 24: 1612; 2006;Tew GI ASCO 2005; Dragovich JCO 24: 4922; 2006,Favorite frontline off clinical trial in MD Anderson Cancer Center,DOX Docetaxel 35-45 mg/m2 every 2 weeks Oxaliplatin 85 mg/m2 every 2 weeks Capecitabine 1500-1800 mg/m2 every 2 weeks OR 5-FU 1800-2200 mg/m2 every 2 weeks We add a biologic if it can be approved,How should we proceed?,Biologics are already being added to reference regimens,Future Directions: Targeted Agents,Molecular Targeted Therapies VEGF, EGFR pathways Phase II and III development with chemo, chemoRT DNA Array Spectrum of genes in tumor Prognostic of survival Predictive of response to therapy,Future Directions: Tailoring of Therapy,Chemotherapy targets (TS, ERCC-1) in tumors Pharmacogenetics Genetic polymorphisms of tumor targets vary in each patient Immunohistochemistry target expression Impact on tumor response Pharmacogenomics Patient drug catabolism, toxicity, activity,Conclusion,5-Fluorouracil infusion is being replaced with 5-FU prodrugs such as capecitabine or S1. Cisplatin will be replaced by oxaliplatin. Taxotere seems to be a useful third drug. Non-cisplatin regimens are available. Role of targeted agents should be defined.,存在的问题 今后的临床研究方向,标准治疗的一线方案：DCF (或改良的DCF）、XP、XELOX？ 临床研究的对照组方案的选择：ECF、DCF、XP？ 腹腔内播散病人姑息切除术在胃癌中的作用? 如何更好的化放疗联合? 个体化?,Thank you!,