胃癌治疗现状及2008asco进展

胃癌治疗现状及 2008ASCO进展,Rui-hua Xu (徐瑞华） Sun Yat-sen University Cancer Center 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 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: . 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,D