局部进展期胰腺癌治疗新进展CSCO年会文档资料.ppt

Pancreas,Liver,GB,Duodenum,Liver,Pancreas,Stomach,Duo,A,胰臟癌(Pancreatic Cancer)Adenocarcinoma of the exocrine pancreas,Pancreas is a retro-peritonum organRelatively symptom-free in early stageEarly dissemination,small tumor does not have to early diseaseEasily metastasize to liver or encase great vesselMost common symptoms,obstructive jaundice,BW loss and back painUsually diagnosed at advanced stage,International Agency for Cancer Research.GLOBOCAN 2002.Available at:http:/www-dep.iarc.fr.Accessed Septemberr 8th,2009.,胰臟癌之流行病學,胰臟癌之臨床分期與預後,Selected T4,SMV/PV partially involvedSMA/CA,上腸繫動脈(superior mesenteric artery)/celiac axisSMV/PV,上腸繫靜脈(superior mesenteric vein)/門靜脈(portal vein),Management of pancreatic cancer.Current opinion 18:vii1-vii10,Deoxycytidine,Cytosine arabinoside,Gemcitabine（吉西他賓）,HO,HO,HO,NH2,NH2,NH2,HOH2C,HOH2C,HOH2C,O,O,O,N,O,O,O,N,N,N,N,N,F,F,HO,Structure of deoxycytidine,cytosine arabinoside and gemcitabine,Burris HA 3rd et al.JCO 1997;15:2403,Gem 1,000 mg/m2,q week x7/8 week then x 3/4 week5-FU 600 mg/m2,weekly*p=0.0022;*p=0.0002;#p=0.0025,Gemcitabine5-FUNo.of patients6363Metastatic diseases72%76%Objective tumor response rate:5.4%0%Clinical Benefit response rate:23.8%4.8%*Median time to tumor progression:2.3 mo0.9 mo*Median overall survival:5.7 mo4.4 mo#6-month survival rate:46%29%12-month survival rate:18%2%,第三期隨機分組臨床試驗比較吉西他賓(Gemcitabine)與 5-FU 治療晚期胰臟癌,Platinum,N=625623Louvet 7.19.0Heinemann 6.07.5Colucci 5.07.5Viret 6.78.0Poplin 4.95.9Subtotal,Fluoropyrimidine,N=912901Riess 6.25.8Berlin 5.46.7Dicostanzo 7.87.5Cunningham 6.07.4Hermann 7.3 8.4Scheithauer 8.2 9.5Subtotal,Others,N=706698Oettle 6.36.2OReilly 6.26.7Rocha Lima 6.66.3Stathopoulos 6.56.4SubtotalTotal,N=2,243/2,222,0.82 0.64 1.050.80 0.59 1.080.87 0.58 1.290.92 0.59 1.450.88 0.73 1.060.85 0.76-/0.96,1.04 0.86 1.250.82 0.65 1.031.05 0.67 1.630.79 0.65 0.970.89 0.70 1.120.82 0.50 1.350.90 0.81 0.99,0.98 0.82 1.180.93 0.74 1.171.04 0.84 1.300.99 0.67 1.460.99 0.88 1.100.91 0.85 0.97,0.5 0.7 1 1.5,Heinemann V et al,BMC Cancer 2008;8:82,OS(Gem vs Gem+X),評估含吉西他賓(Gemcitabine)複方與單方化學治療對晚期胰臟癌之療效-隨機分組臨床試驗之總合分析-,Median OS(months),%of patients with metastatic diseases,*Randomized phase II trial,*,*,第三期隨機分組臨床試驗中晚期胰臟癌接受吉西他賓(Gemcitabine)單方化學治療患者之中位數存活期,R.R.6-11%22%33%33%,Gem+HDFL:800 mg/m2/wk+5-FU/LV 2,000/300 mg/m2/wk,x 3/4 wk GOFL:Gem 800 mg/m2+Oxaliplatin 85 mg/m2+5-FU/LV 3,000/300 mg/m2,q 2 wk,Gem alonePhase IPhase II-IIIGem+HDFL Phase I/II(1997)GOFL Phase I(2002)Phase II(2004)Phase II(2004),US/EuropeCCW/NICR/NHRIin VGH&NTUHCCW/NICR/NHRIin VGH&NTUHCCW/NICR/NHRI+University HospitalsTCOGT1204:CCRT following Induction GOFL in locally advanced Pancreatic Cancer,晚期胰臟癌吉西他賓(Gemcitabine)複方化學治療之臨床試驗,吉西他賓(Gemcitabine)的代謝及其作用機轉,Giovannetti E,et al.Mol Cancer Ther 2006;5:1387-95,MTD in phase I:790 mg/m2as 30-min i.v.,weekly x 3/4,Intracellular dFdCTP saturatedWith dFdC 350 mg/m2,30-min i.v.,GOFL in PCA:Phase I/II,Gemcitabine,Oxaliplatin,5-FU/Leucovorin,Gem+L.OHP q 2w:30.6%RRGemOx q 2w:26.8%RR,OS 9 months,Gem-FL24 q wk:22%RRFOLFUGEM q 2w:22.6%RRFOLFUGEM2 q 2w:19%RR,FOLFUGEMOX:29.0%RR,Median OS,8 months,Gem-L.OHP-HDFL:median OS,12.5 months,Synergism,Louvet C et al.J Clin Oncol 2002;20:1512;Louvet C et al.J Clin Oncol 2005;23:3509-16Louvet C et al.Ann Oncol 2001;12:675;Andre T et al.Gastroenterol Clin Biol 2004;28:645Shiah HS et al.JGH 2006;21:874;Carnier C et al.2001 ASCO,#620,隔週投與吉西他賓(Gemcitabine),奧沙利鉑(Oxaliplatin)及48小時連續灌注高劑量5-FU/CF(leucovorin)GOFL治療晚期胰臟癌之第一期臨床試驗:理論基礎,隔週投與吉西他賓(Gemcitabine),奧沙利鉑(Oxaliplatin)及48小時連續灌注高劑量5-FU/CF(leucovorin)GOFL治療晚期胰臟癌之第一期臨床試驗:試驗設計與結果,c.i.x 48 hrs,GOFL in PCA:Phase I/II,Chang HJ et al.JGH 2006,Regimen:Q 2 weeks,4 weeks/cycleGemcitabine 800 mg/m2,iv x 80 minOxaliplatin 65,75,85 mg/m2,iv x 2 hoursLeucovorin 300 mg/m2,5-FU 3,000 mg/m2,Oxaliplatin dose(mg/m2)65 7585Case No.6 3 6DLT 1 0 1CR/PR 1/2 1 1MTD of oxaliplatin:85 mg/m2;Overall RR:33.3%(95%CI:6.3-60.4%),A 56y/o man presented with neck LAP and BW loss,Pre-treatment Post-GOFL48 x 8 weeks(left panel)pancreatic body cancer with liver and neck LN metastases at presentation;(right panel)after 2 cycles of GOFLOS,2004-07-10-2004-12-10(TF)-2006-05-29(death),Phase I/II GOFL in Pancreatic Cancer,案例,Carnier C et al.2001 ASCO,#620Chang HJ et al.Cancer Chemother Pharmacol 2009Correale P et al.J Chemother 2008;20:19-25,Carnier Chang Correale FOLFOGEMOX GOFLGOLFNo.of patients 30 45 27 dFdC/L-OHP(mg/m2)800/100,D3 800/85,D1 1000/85,D25-FU bolus/48-hr IV(mg/m2)400/2,000 0/3,000 0/3,000Treatment cycle(weeks)Q 3 Q 2 Q 2Metastatic diseases(%)63 80 60ORR(%):29 33 33 Median PFS(months):7.2 5.1 5.5Median OS(months):8.0 8.7 8.0 Grade 3/4 neurotoxicity(%)1 14?Grade 3/4 neutropenia(%)28 21?,隔週投與吉西他賓(Gemcitabine),奧沙利鉑(Oxaliplatin)及48小時連續灌注高劑量5-FU/CF(leucovorin)GOFL治療晚期胰臟癌之第二期臨床試驗:結果,A,B,C,D,2004-08-12,GOFL x 5,SD,2005-03,post-CCRT x 1 m,2005-09,post-CCRT x 7 m,2006-03,post-CCRT x 12 m,M,65 y/o with locally advanced pancreatic cancer,Metastatic diseases,chemotherapy until disease progressionLocally advanced disease,chemotherapy x 3 cycles*or treatment failure followed by CCRT,Carnier C et al.2001 ASCO,#620Chang HJ et al.Cancer Chemother Pharmacol 2009,隔週投與吉西他賓(Gemcitabine),奧沙利鉑(Oxaliplatin)合併48小時連續灌注高劑量5-FU/CF(leucovorin)GOFL治療晚期胰臟癌之第二期臨床試驗:轉移性與局部進展性患者之預後,Carnier Chang FOLFOGEMOX*GOFL轉移性(Metastatic)Case No.19 36Median PFS(months):5.4Median OS(months):6.9 7.8局部進展性(Locally advanced)Case No.119Median PFS(months):11.5Median OS(months):11.5 15.9,Krzyzanowska MK et al.JCO 2003;21:3409-14,*age,sex and co-morbidity adjusted median survival,1,696 patients(from Medicare data bank)between 1991 and 1996,Median OS*Untreated56%15 weeksC/T 7%27 weeksR/T13%29 weeksCCRT24%47 weeks,“真實世界”局部晚期胰臟癌之治療-美國紐約醫療保險資料庫之分析結果-,Gemcitabine:400 mg/m2/week 1000 mg/m2/week,Median:50.4 Gy(39.6-61.2/22-34 fraction),x 3/4 weeks x 3,Huang PI et al.2007 ASCO GI Cancer Symposium Abs#154Huang PI,et al.Int J Radiat Oncol Biol Phys 2009;73:159-65,PR/SD(%)44/27Median TTP(months)5.2Median OS(months)10.5 non-responders/responders 7.0/18.51-yr survival rate(%)42.22-yr survival rate(%)14.6Grade 3-4 neutropenia 24.0,局部進展期胰臟癌接受第一線含吉西他賓(Gemcitabine)同步化學放射治療之預後-台北榮民總醫院之經驗-,Unresectable,locally advanced PanCa,N=74,Gemcitabine 1,000 mg/m2/wk x 3/4 wk,CCRT:Gemcitabine 600 mg/m2/wk x 6 R/T 5,040Gy/28 fx,Gemcitabine 1,000 mg/m2/wk x 3/4 wkUntil tumor progressionor unacceptable toxicity,Loehrer PJ et al 2008 ASCO#4506,*P=0.044,Response rate:9%3%Median PFS:6.3 months 6.1 monthsMedian OS*:11.0 months 9.2 months12m OS rate:NA NAGr 4 AE 41%6%,ineligible in 3assigned Tx(-)in 5,比較第一線含吉西他賓(Gemcitabine)同步化學放射治療與全身性化學治療局部進展期胰臟癌之第三期臨床試驗:E4201,Unresectable,locally advanced PanCa,N=119,Gemcitabine 1,000 mg/m2/wk X 7/8 wk,CCRT:5-FU 1,500 mg/m2 x 120h/wk x 6Cisplatin 20 mg/m2/d,D1-5,wk 1&5 R/T 6,000Gy/30 fx,Gemcitabine 1,000 mg/m2/wk x 3/4 wkUntil tumor progression or unacceptable toxicity,Cauffert B,et al Ann Oncol 2008;19:1592-99,*In Coxs regression,HR=0.54(95%CI,0.31 0.96,P=0.006),Compliance rate:83%73%12m PFS:12%32%Median OS*:8.6 months13.0 months12m OS rate:32%53%Gr 3-4 AE 65%40%,比較局部晚期胰臟癌接受第一線同步5-FU/cisplatin化學放射治療與全身性吉西他賓(Gemcitabine)化學治療療效之第三期臨床試驗2000-01 FFCD/SFRO試驗,Unresectable,locally advanced PanCaN=181,Huguet F et al.J Clin Oncol 2007;25:326-31,3 months of CT*,Progression ds53(29.3%),Disease controlled128(70.3%),CCRT,N=72,Continue CT,N=56,Gemcitabine alone 24.9%GEMOX 51.4%FOLFUGEM 23.7%,#p=0.005,#p=0.0009,Median PFS#10.8 months 7.4 monthsMedian OS#15.0 months11.7 months1-year survival rate 65.3%47.5%,同步化學放射治療可改善接受第一線全身性化學治療無法切除局部晚期胰臟癌患者之存活-GERCOR第二及三期臨床試驗之次群分析-,Cyto-/histology proven,Unresectable,locally advanced PanCa,CR/PR/SD,PD,SurgicalResection,CCRT:gemcitabine or 5-FU-basedR/T 5,040 cGy/28fx,Doublet/triplet CTUntil tumor progressionor unacceptable toxicity,Salvage C/T,Doublet/Triplet ICT x 2-3 months,Resectable,Unresectable,Ko AH,et al.Int J Radiat Oncol Biol Phys 2007;68:809-16Marti JL,et al.Ann Surg Oncol 2008;15:3521-31Moureau-Zabotto L et al.J Clin Oncol 2008;26:1080-5Chang HJ et al.2009 ASCO,Rationales:1.Treating micro-metastases 2.Selecting patients for CCRT,前導性(Inductional)全身性化學治療併同步化學放射治療於局部進展期胰臟癌患者之第二期臨床試驗,Ko AH,et al.Int J Radiat Oncol Biol Phys 2007;68:809-16Marti JL,et al.Ann Surg Oncol 2008;15:3521-31Moureau-Zabotto L et al.J Clin Oncol 2008;26:1080-5Chang HJ et al.2009 ASCO,前導性(Inductional)全身性化學治療併同步化學放射治療於無法切除局部進展期胰臟癌患者之第二期臨床試驗,Cyto-/histology proven,Unresectable,locally advanced PanCa,CR/PR/SD,PD,SurgicalResection,CCRT:Gemcitabine 400mg/m2 QwR/T 5,040 cGy/28fx,GOFL48Until tumor progressionor unacceptable toxicity,Salvage C/T,GOFL,Q 14d x 6,Resectable,Unresectable,前導性(Inductional)全身性化學治療併同步化學放射治療於無法切除局部進展期胰臟癌患者之第二期臨床試驗:TCOG1204,No.of patients50Median age61Gender,M/F(%)52/48ECOG P.S:0/1/2(%)12/72/16Histology:WD+MD/PD+UD/?(%)44/14/42Location:Head/Body-tail(%)58/46T stage:T2/T3-4(%)12/88N stage:N0/N1/UD(%)58/30/12Resectability(%)Borderline resectable 4Unresectable96,前導性(Inductional)全身性化學治療併同步化學放射治療於無法切除局部進展期胰臟癌患者之第二期臨床試驗:TCOG1204,Locally advanced pancreatic cancer&have inductional GOFL,N=50,Disease-controlled,N=33(66%)Objective response,N=11(22%)Stable ds,N=22(44%),Ds Progression,N=17(35%),Undergo gem-based CCRT,N=30(60%),CCRT not done,3(6%)Surgical resection,N=1 Patient refusal,N=2,Mortality,N=1(2%),Complete CCRT,N=29,前導性(Inductional)全身性化學治療併同步化學放射治療於無法切除局部進展期胰臟癌患者之第二期臨床試驗:TCOG1204,Pre-treatment,Post-GOFL x 6,F/38,Locally advanced pancreatic cancer,aorto-caval LN+,2006-06,2006-09,2007-05,Post-GOFL-CCRT-GOFL,Post-GOFL+CCRT,2006-11,A,B,D,C,Post-CCRT+GemIri x 6,2006-01,Post-GOFL+CCRT,2005-10,Post-GOFL x 6,2005-08,Post-CCRT+GemIri+S-1,2006-12,Pre-Treatment,2006-03,Post-GOFL x 6+CCRT,2006-09,r/o liver and retroperitoneal metastases at 2007-04,Treatment group N median(95%CI)OS,MCCRT/surgery3020.5(15.43-25.57)No CCRT 3 9.6(4.48-14.72)PD/UE 17 8.4(6.15-10.65)Overall5014.3(11.98-16.62)P=0.0005(log-rank test),前導性(Inductional)全身性化學治療併同步化學放射治療於無法切除局部進展期胰臟癌患者之第二期臨床試驗:TCOG1204,Small Jr W,et al.JCO 2008;26:942-7,Week,Gem 1.0 g/m2/wkR/T 2.4 Gy/daySurgery:4 6 weeks after neo-adjuvant therapy,前導性(Inductional)全劑量dFdC化學治療併同步化學放射治療對於未轉移胰臟癌患者之療效 可切除率及一年存活率,可切除(resectable)T1-2(OP w/o adjuvant)T1-2(OP+Adjuvant CT)T3-4(OP w/o adjuvant)T3-4(OP+Adjuvant CT)局部晚期(locally advanced)Borderline resectable(Neo-adjuvant+OP)無法切除(unresectable)(Neo-adjuvant+OP)(ICT+CCRT)(Gem-based CT)(CCRT+CT)轉移性(metastatic),/,I I I I I I5 10 15 20 25 30,27.6,19.1,50.2,20.5,14.0,14.3,18.0,20.5,13.0,11.0,7.0,ITTPer protocol,Our data suggested inductional chemotherapy followed by CCRT could achieve encouraging survival in unresectable LAPCRole in earlier stage PC deserves further exploration,結論,Have a Nice Week-end,