1、胃癌治療現狀及2008ASCO進展Rui-hua Xu (徐瑞華）Sun Yat-sen University Cancer CenterTel: 020-8734 3468胃癌治療有效的化療藥物Old DrugsFluoropyrimidines5-FUPlatinumCisplatinAnthracyclinesDoxorubicinEpirubicinEtoposideMethotrexateNew DrugsFluoropyrimidinesCapecitabineS-1PlatinumOxaliplatinTaxanesPaclitaxelDocetaxelIrinotecanFP

2、vs FAM vs UFTM: JCOG 9912 trialOhtsu et al 2003FP5-FUUFTMp valueNo. Patients10510570Response(%)PFS(weeks)MS(weeks)NSUFTM, tegafur uracil / mitomycinWaters et al 1999ECF vs FAMTX: UK TrialECFFAMTXp valueNo. pts137137Response46%21%0.00003FFS7.4 mo3.3 mo0.0001MST8.7 mo6.1 mo0.00052-yr SR14%5%0.03Chemot

3、herapy for gastric cancer in the pastFP regimen has been the standard or reference regimen in AsiaECF is recommended mostly in EuropeWhere we have been in AGC我們所知道的胃癌化療Eloxatin: REAL-2, phase IIIXeloda: ML17032, phase IIITaxotere: TAX 325, phase IIICPT-11 V306, phase IIIEloxatin: FLO vs FLP, phase I

4、IIS1: JCOG 9912, phase IIIS1: SPIRITS, phase III2008 ASCO DC vs FLP phase IIIPhase II clinical trialsEEpirubicin 50 mg/m2 ivCCisplatin 60 mg/m2 ivFPVI 5-FU 200 mg/m2/dayq3wREAL-2: 研究設計2 x 2 randomisationPlanned treatment duration 24 weeksEEpirubicin 50 mg/m2 ivCCisplatin 60 mg/m2 ivXCapecitabine 625

5、 mg/m2/bid q3wEEpirubicin 50 mg/m2 ivOOxaliplatin 130 mg/m2 ivFPVI 5-FU 200 mg/m2/dayq3wEEpirubicin 50 mg/m2 ivOOxaliplatin 130 mg/m2 ivXCapecitabine 625 mg/m2/bid q3wPVI, portal vein infusionCunningham D, et al. ASCO 2006 (Abstract LBA4017). RegimennMedian(months)1-year(%)95% CI5-FU4849.639.435.044

6、.0Capecitabine48010.944.640.149.0Hazard ratio (95% CI): 0.86 (0.800.99)Time (years)Probability (%)01234560204060801008206178375212No. at risk48448028315-FU Capecitabine5-FU Capecita-bineCunningham D, et al. ASCO 2006 (Abstract LBA4017). REAL-2: overall survival for fluoropyrimidine comparison (per p

7、rotocol)REAL-2: overall survival for platinum comparison (per protocol)RegimennMedian(months)1-year(%)95% CICisplatin49010.040.135.748.4Oxaliplatin47410.443.939.449.0Hazard ratio (95% CI): 0.92 (0.801.10)Probability (%)012345602040608010010198187414810490474141CisplatinOxaliplatinCisplatinOxaliplati

8、nTime (years)No. at riskCunningham D, et al. ASCO 2006 (Abstract LBA4017). ArmMedian OS (months) 1-year survival (%) 95% CIp-valueHazard ratio95% CIECFEOX9.911.237.7 31.843.646.8 40.452.90.02010.80 0.660.970130204060801002ECFEOXProbability (%)Time (years)Cunningham D, et al. ASCO 2006 (Abstract LBA4

9、017). REAL-2: overall survival for ECFand EOX (ITT)Toxicity(% of patients)ECF (n=236)ECX (n=229)EOF (n=231)EOX (n=232)Leucopenia19.521.013.413.8Anaemia*8.6Thrombocytopenia5.2Neutropenia41.751.1*29.9* 27.6* Febrile neutropenia7.8*p0.05 vs ECF; *p70Adequate hematologic/bio

10、chemical parametersNo prior palliative chemotherapyRANDOMISATIONTreatment until PD, consent withdrawn or unacceptable toxicity; tumor assessments q8wDocetaxel-based chemotherapy in advanced gastric cancer: Phase III trial (TAX 325)Van Cutsem E, et al. J Clin Oncol (accepted for publication).22Log-ra

11、nk 1.83)Risk reduction: 32.1%00102030405060708090100DCFCF3691215182124Probability (%)TTPDCFCFMedian (months)5.63.795% CI4.865.913.454.47Any event (%)167 (75.6)174 (77.7)TAX 325: time to progression(primary endpoint)Time (months)Van Cutsem E, et al. J Clin Oncol (accepted for publication).OSDCFCFMedi

12、an (months)9.28.695% CI8.3810.587.169.461-year (%)40.231.62-year (%)18.48.8Log-rank 1.61)Risk reduction: 22.7%03691215182124273033360102030405060708090100DCFCFTAX 325: overall survivalTime (months)Van Cutsem E, et al. J Clin Oncol (accepted for publication).Probability (%)DCFCF(n=221)(n=224)CR (%)21

13、PD (%)1726ORRa (%)372595% CI30.343.4 19.931.7 p-value95% CIResponders with responseduration 9 months (%)2614TAX 325: best overall responseResponse parameterSD (%)3031Median response duration (months)5.08.3 aConfirmed and independently reviewed Van Cutsem E, et al. J Clin Oncol (accepted fo

14、r publication).TAX 325 Clinical Benefit: time to definitive worsening of KPSa0 3 6 9 12 15 18 21 24 27 100 90 80 70 60 50 40 30 20 10 0Time (months)Probability (%)DCFCF1.76)Risk reduction: 27.5%DCFCFMedian (months)6.14.895% CI4.997.753.425.55Any event (%)128 (58)141 (63)1-year (%)33.115.8aWorsening

15、defined as a definitive decrease in PS by 1 KPS category vs baselineMoiseyenko V, et al. WCGIC 2005 (Abstract O-013).Patients (%)DCF(n=221)CF(n=224)Lethargy1914Stomatitis2127Diarrhea19*8Infection137Nausea1417Vomiting1417Anorexia109Neurosensory8*31 event6959Adverse eventsaaPossibly or probably relate

16、d to study treatment; treatment-emergent non-hematologic toxicitiesoccurring at grade 3 to 4 in 5% of patients in either group*p CFThe TCF regimen is the proof of the concept that docetaxel provides the benefit our patients needDocetaxel should be incorporated in safer regimen using oxaliplatin, S-1

17、 or capecitabineDevelop a regimen to allow addition of a biologicV306: FUFIRI vs FP as 1st Line Chemotherapy for AGCN=170CPT-11 80mg/m2CF 500mg/m25FU 2000mg/m2 civ1/W x 6w N=163CDDP 100mg/m2 d15FU 1000mg/m2/d d1-5Q4WN=333 AGCRR 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

18、 8.7m pM. Dank 2005 ASCO abs 4003V306: FUFIRI vs FP as 1st Line Chemotherapy for AGCDank, et al. ASCO 2005Hematologic G3/4NeutropeniaNeutropenic feverNonhematologic G3/4AnyDiarrheaVomitingStomatitisRenalFOFIRI25%5%40%22%7%2%0.6%PF52%10%44%7%8%17%6%- Center- PS- Unresectable vs recurent, adj Crx vs r

19、ecurrent, no adj CrxRANDOMISATIONARM A (Control)5-FU civ 800 mg/m2 D1-5 q 4 weeksARM BS-1 80 mg/m2 D1 - 28 q 6 weeksUNTILPD Primary endpoint: Overall survival A vs B: non-inferiority, A vs C: superiorityARM CCPT-11 70 mg/m2 D1,15 CDDP 80 mg/m2 D1 q 4 weeksJCOG 9912 TrialBoku N, et al. Proc Am Soc Cl

20、in Oncol 2007 (#4513) JCOG 9912 Trial; Results5FU S1CPNo.234234236Off-treatment (PD/Toxicity)199/18203/22143/75Response rate9%28%38%PFS2.9 m4.2 m*4.8 m*OS10.8 m11.4 m12.3 mBoku N, et al. Proc Am Soc Clin Oncol 2007 (#4513) RANDOMISATIONARM A S-1 40-60 mg bid for 28 d q 6 weeksARM B Cisplatin 60 mg/m

21、2 on D8 S-1 40-60mg bid for 21 d q 5 weeksUNTILPD Primary endpoint: Overall survival (Superiority) Center PS Unresectable vs. recurrentSPIRITS TrialNarahara H et al. ASCO 2007Results of SPRITS TrialS1S1/CisP-valueResponse31%54%.0018PFS4.0 mo6.0 mo 1050 (completed in March, 2007)FLAGS Trial(First-Lin

22、e Advanced Gastric Cancer Study)RANDOMIZEType of disease(Locally advanced vsMetastatic 1 metastasis vs Metastatic 1 metastases) - Prior adjuvant CT Measurable disease - CentersCisplatin 75 mg/m2 IV Day 1S-1 25mg/m2 bid po Day 1-21Cycles repeated every 4 weeksCisplatin 100 mg/m2 IV Day 1Cycles repeat

23、ed every 4 weeks5-FU 1000 mg/m2/day CIV Day 1-5 (over 120 hours ) RANDOMISATIONARM A Taxotere 40 mg/m2 D1 S-1 80 mg/m2 D1-14 q 3 weeksARM B S-1 80 mg/m2 D1-28 q 6 weeksUNTILPDSTART Trial(S-1 and Taxotere for Advanced Gastric Cancer Randomized Phase III Trial) Collaborative Japan-Korea Trial Patient

24、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 R

25、amdomized 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#4533Reported by Jin ML and He YJ Meta-analysis of chem

26、otherapy inadvanced gastric cancerAll randomized trials closed to accrual by end of 2004 eligibleTrials with neoadjuvant or adjuvant treatment excludedEndpoint: OSMeta-analysis of chemotherapy inadvanced gastric cancerCisplatin versus no cisplatin 7 RCTs, n=1677, , Irinotecan versus no irinotecan 3

27、RCTs, n=550, , Anthracycline versus no anthracycline 7 RCTs, n=1501 pts, , 95%CI=0.84-1.06, Taxane versus no taxane 3 RCTs, n=572, , 95%CI=0.68-0.99, GATE phase II trial of first-line docetaxel oxaliplatin in advanced gastric cancerN=270Patients withadvanced gastricand gastrooesophagealjunctionadeno

28、carcinomaRTEDocetaxel 75 mg/m2 +Oxaliplatin 130 mg/m2 q 3 wkTEFDocetaxel 50 mg/m2 +Oxaliplatin 85 mg/m2 +folinic acid 400 mg/m2 +5-FU 2400 mg/m2/46h (no bolus), q 2 wkTEXDocetaxel 50 mg/m2 +Oxaliplatin 100 mg/m2 q 3 wk +Capecitabine 625 mg/m2 bid continuouslyMedian TTP: 5.4 months Overall survival :

29、 12.3 months A Pilot study of FOLFOX6 in AGCORR 41.0%, SD 21.6%Xu RH. Chemotherpay 2008 in press5.4 months (95% CI, 2.4-8.4 months) 12.1 months (95% CI, 10.0-14.2months) TTPOS Ruihua Xu1, Bing Han1, Feng Wang1, Huiyan Luo1,Yanxia Shi1, Yuhong Li1, Miaozhen Qiu1, Wenqi Jiang1, Youjian He1, Zhong-zhen

30、 Guang1 1. Department of Medical Oncology, Sun Yat-sen University Cancer Center,Guangzhou GD, CHINA 2. Nan-chang University 1st affiliated hospital, Nanchang, CHINAPhase II Clinical Trail of XELOX as first line treatment in patients with unresectable or metastatic gastric cancer XELOXOxaliplatin 130

31、mg/ d1 3hrXeloda 1g/ d1-14 bid po Every 3 weeksPrimary endpoint: OR, TTP (ITT)Secondary endpoints: OS and safety profilesResponse rates in XELOX （ITT）ResponseNo. of patientsResponse rate (%)CR24PR1938SD1734PD918NA36疾病控制率為 76%（ITT）TTP and OS of eligible patients receiving XELOX) 中位OS 11.1 months (95%

32、 CI, 5.6-16.5 months)中位TTP 5.8 months (95% CI, 3.4 to 8.2 monthsTable 3. Toxicities According to NCI-CTCToxicities Grade 1-2 (n =50) Grade 3-4 (n =50) Patient No. % Patient No. %Hematologic Neutropenia1224612 Thrombocytopenia61236 Anemia91812Gastrointestinal Nausea132600 Vomiting81612 Diarrhea4812 S

33、tomatitis102000Neurosensory*91800Hand-foot syndrome*153036*According to an oxaliplatin specific scale (grade0-3)* Only grade 0-3TCX for AGC (1st line): Phase I / II studyChemotherapy (every 3 weeks)Docetaxel 60 mg/m2 iv D1Xeloda 937.5 mg/m2 po bid D1-14Cisplatin 60 mg/m2 iv D1Efficacy (N = 40)Respon

34、se: 4 CRs, 23 PRs: 68% 10 Op: 4 pathologic CRsTTP: 7.8 mo, OS: 16.9 moToxicityG3/4 neutropenia 63%, neutropenic fever 10%, 1 deathG3 asthenia 38%, G3 HFS 2.5%, G3 diarrhea 2.5%Kang YK, et al. Proc ASCO 2004CT in AGC 2008Phase II StudyRegimenNResponse (%)TTPY. Sato #4537S1+TAX+DDP3187.1%7.4H. Iwase #

35、4539S1+Taxol+DDP 4265%8.0P. Comella #4542FOLFOXIRI4640%7.6 Advanced Gastric Cancer: Targeted AgentsPhase II StudyRegimenNResponse (%)Shah. 20061Bevacizumab + DDP + Irinotecan3465%Di Fabio et al. 20062Cetuximab + FOLFIRI2752%Pinto et al. 20063Cetuximab + FOLFIRI2556%Lordick et al. 20064Cetuximab + FU

36、FOX2864%Bang et al 20075Sunitinib425%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 Gast

37、ric Cancer: Targeted Agents: GI Symposium 2008Phase II StudyRegimenNResponse (%)Jhawer 2008Bevacizumab + Modified DCF1471%Enzinger et al. 2008Bev + Irinotecan/Docetaxel/DDP2268%Gold 2008Cetuximab555%Pinto 2008Cetuximab + Docetaxel/Cisplatin3441%Hecht 2008Lapatinib250% Targeted Agents:Phase II CALGB

38、80403/ECOG 1206 TrialAt: :/ . Accessed November 9, 2006.Metastatic Esophagogastric CancerIrinotecan +Cisplatin +CetuximabECF +CetuximabFOLFOX +Cetuximab Primary end point: Response rate EGFr Tyrosine Kinase Inhibitors: Phase II, AdenocarcinomaGastric Number Patients% ResponseDragov

39、och (Erlotinib)250%Doi (Gefitinib)751%GE JunctionFerry (Gefitinib)2711%Janmaat (Gefitinib)260%Tew (Erlotinib)170%Dragovich(Erlotinib)439%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 CenterDOXDocetaxel 35-45 mg/m2 every 2 weeksOxaliplatin 85 mg/m2 every 2 weeksCa