局部进展期胰腺癌治疗新进展CSCO年会课件

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1、局部进展期胰腺癌治疗新进展CSCO年会陳立宗陳立宗 M.D.,Ph.D國立成功大學附設醫院國立成功大學附設醫院 血液腫瘤內科血液腫瘤內科高雄醫學大學附設醫院高雄醫學大學附設醫院 胃腸內科胃腸內科臺灣臺灣局部进展期胰腺癌治疗新进展CSCO年会PancreasLiverGBDuodenumLiverPancreasStomachDuoA胰臟癌胰臟癌Pancreas is a retro-peritonum organRelatively symptom-free in early stageEarly dissemination,small tumor does not have to early

2、 diseaseEasily metastasize to liver or encase great vesselMost common symptoms,obstructive jaundice,BW loss and back painUsually diagnosed at advanced stage局部进展期胰腺癌治疗新进展CSCO年会 International Agency for Cancer Research.GLOBOCAN 2002.Available at:.Accessed Septemberr 8th,2009.Case No.MaleFemale Total(%

3、)Global124,84110,465 232,306(100.00)Asia 52,63438,448 91,082(39.21)North America 17,46817,454 34,922(15.03)South America 6,685 6,76213,447(5.79)Western Europe 10,603 9,80320,406(8.78)Eastern Europe 15,86013,463 29,323(12.62)Northern Europe 5,588 5,82811,416(4.91)Southern Europe 8,945 7,98316,928(7.2

4、9)Africa 3,647 3,768 7,415(3.19)胰臟癌之流行病學胰臟癌之流行病學局部进展期胰腺癌治疗新进展CSCO年会胰臟癌之臨床分期與預後胰臟癌之臨床分期與預後UICCstageClinical/radiological criteriaLong-term survivalMedian OSI II可切除可切除（Resectable,T1-3,selected T4,NX,M0)No SMA/CA encasement Patent SMV-PV confluence20%1320 mIII局部進展期局部進展期（Locally advanced,T4,NX-1,M0)SMA/

5、CA involvement or Occlusion of SMV/SMPV confluenceNA610 mIV轉移性轉移性（Metastatic,any T,any N,M1)NA36 mSelected 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&recommenda

6、tion derived from the 8th WCGC,Barcelona,2006.Versylpe C,et al.Ann Oncol 2007;18:vii1-vii10局部进展期胰腺癌治疗新进展CSCO年会DeoxycytidineCytosine arabinosideGemcitabine（吉西他賓）（吉西他賓）HOHOHONH2NH2NH2HOH2CHOH2CHOH2COOONOOONNNNNFFHOStructure of deoxycytidine,cytosine arabinoside and gemcitabine局部进展期胰腺癌治疗新进展CSCO年会Burris

7、 HA 3rd et al.JCO 1997;15:2403Gem 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

8、 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第三期隨機分組臨床試驗比較吉西他賓比較吉西他賓(Gemcitabine)與與 5-FU 治療晚期胰臟癌治療晚期胰臟癌局部进展期胰腺癌治疗新进展CSCO年会Platinum,N=625623Louvet 7.19.0Heinemann 6.07.5Colucci 5.07.5Viret 6.78.0Poplin 4.95.9Subtotal,Fluoropyrimidin

9、e,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 /2,2220.82 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

10、.961.04 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 0.990.98 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 0.970.5 0.7 1 1.5Heinemann V et al,BMC Cancer 2008;8:82OS(Gem vs Gem+X)評估含評估含吉西他賓吉西他賓(Gemcitabine)複方與單方化學治療複方與單方化學治療對晚期

11、胰臟癌之療效對晚期胰臟癌之療效-隨機分組臨床試驗之總合分析隨機分組臨床試驗之總合分析-局部进展期胰腺癌治疗新进展CSCO年会4567850%60%70%80%90%100%Gem vs 5FU 97Gem+/-5FU 02Gem+/-5FU/LVGem+/-XelodaGem+/-AlimtaGem vs ExatecanGem+/-ExatecanGem+/-CPT-11Gem+/-CPT-11Gem+/-CisplatinGem+/-CisplatinGem+/-Eloxatin 05ECOG 6201Gem+/-Tarceva 05Gem+/-Marimastat 02Gem+/-Ava

12、stin 07Gem+/-Axitinib 08Gem+/-Cetuximb 07Median 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第三期隨機分組臨床試驗中晚期胰臟癌接受吉西他賓接受吉西他賓(Gemcitabine)單方化學治療患者之中位數存活期單方化學治療患者之中位數存活期局部进展期胰腺癌治疗新进展CSCO年会R.R.6-11%22%33%33%Gem+HDFL:800 mg/m2/wk+5-FU/LV 2,000/300 mg/m2/wk,x 3

13、/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 Inductio

14、n GOFL in locally advanced Pancreatic Cancer晚期胰臟癌吉西他賓晚期胰臟癌吉西他賓(Gemcitabine)複方化學治療之臨床試驗複方化學治療之臨床試驗 局部进展期胰腺癌治疗新进展CSCO年会吉西他賓吉西他賓(Gemcitabine)的代謝及其作用機轉的代謝及其作用機轉Giovannetti E,et al.Mol Cancer Ther 2006;5:1387-95MTD in phase I:790 mg/m2as 30-min i.v.,weekly x 3/4 Intracellular dFdCTP saturatedWith dFdC 35

15、0 mg/m2,30-min i.v.局部进展期胰腺癌治疗新进展CSCO年会GOFL in PCA:Phase I/IIGemcitabineOxaliplatin5-FU/LeucovorinGem+L.OHP q 2w:30.6%RRGemOx q 2w:26.8%RR,OS 9 monthsGem-FL24 q wk:22%RRFOLFUGEM q 2w:22.6%RRFOLFUGEM2 q 2w:19%RRFOLFUGEMOX:29.0%RR,Median OS,8 monthsGem-L.OHP-HDFL:median OS,12.5 months Synergism Louvet

16、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隔週投與吉西他賓隔週投與吉西他賓(Gemcitabine),(Gemcitabine),奧沙利鉑奧沙利鉑(Oxaliplatin)(Oxaliplati

17、n)及及4848小時連續灌注高劑量小時連續灌注高劑量5-FU/CF(leucovorin)GOFL5-FU/CF(leucovorin)GOFL治療治療晚期胰臟癌之第一期臨床試驗晚期胰臟癌之第一期臨床試驗:理論基礎理論基礎局部进展期胰腺癌治疗新进展CSCO年会隔週投與吉西他賓隔週投與吉西他賓(Gemcitabine),(Gemcitabine),奧沙利鉑奧沙利鉑(Oxaliplatin)(Oxaliplatin)及及4848小時連續灌注高劑量小時連續灌注高劑量5-FU/CF(leucovorin)GOFL5-FU/CF(leucovorin)GOFL治療治療晚期胰臟癌之第一期臨床試驗晚期胰臟癌

18、之第一期臨床試驗:試驗設計與結果試驗設計與結果 c.i.x 48 hrs,GOFL in PCA:Phase I/IIChang HJ et al.JGH 2006Regimen: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 oxali

19、platin:85 mg/m2;Overall RR:33.3%(95%CI:6.3-60.4%)局部进展期胰腺癌治疗新进展CSCO年会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)-

20、2006-05-29(death)Phase I/II GOFL in Pancreatic Cancer 案例局部进展期胰腺癌治疗新进展CSCO年会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 10

21、00/85,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?隔週投與吉西他賓隔週投與吉西他賓(Gemcitabine),(Gemcitabin

22、e),奧沙利鉑奧沙利鉑(Oxaliplatin)(Oxaliplatin)及及4848小時連續灌注高劑量小時連續灌注高劑量5-FU/CF(leucovorin)GOFL5-FU/CF(leucovorin)GOFL治療治療晚期胰臟癌之第二期臨床試驗晚期胰臟癌之第二期臨床試驗:結果結果局部进展期胰腺癌治疗新进展CSCO年会ABCD2004-08-12,GOFL x 5,SD2005-03,post-CCRT x 1 m2005-09,post-CCRT x 7 m2006-03,post-CCRT x 12 mM,65 y/o with locally advanced pancreatic c

23、ancer局部进展期胰腺癌治疗新进展CSCO年会Metastatic diseases,chemotherapy until disease progressionLocally advanced disease,chemotherapy x 3 cycles*or treatment failure followed by CCRTCarnier C et al.2001 ASCO,#620Chang HJ et al.Cancer Chemother Pharmacol 2009隔週投與吉西他賓隔週投與吉西他賓(Gemcitabine),(Gemcitabine),奧沙利鉑奧沙利鉑(Oxa

24、liplatin)(Oxaliplatin)合併合併4848小時連續灌注高劑量小時連續灌注高劑量5-FU/CF(leucovorin)GOFL5-FU/CF(leucovorin)GOFL治療治療晚晚期胰臟癌之第二期臨床試驗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轉移性與局部進展性患者之預後 Carnier Chang FOLFOGEMOX*GOFL轉移性轉移性 (Metastatic)Case No.19 36Median PFS(months):5.4Median OS(months):6.9 7.8局部進展性局部進展性(Locally advanced)Case No.11

25、9Median PFS(months):11.5Median OS(months):11.5 15.9局部进展期胰腺癌治疗新进展CSCO年会Krzyzanowska MK et al.JCO 2003;21:3409-14*age,sex and co-morbidity adjusted median survival1,696 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

26、真實世界”局部晚期胰臟癌之治療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美國紐約醫療保險資料庫之分析結果 -局部进展期胰腺癌治疗新进展CSCO年会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 3Huang 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(%)44/2

27、7Median 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局部進展期胰臟癌接受第一線含吉西他賓吉西他賓(Gemcitabine)同步化學放射治療之預後同步化學放射治療之預後-台北榮民總醫院之經驗台北榮民總醫院之經驗-局部进展期胰腺癌治疗新进展CSCO年会Unresectable,locally advanced PanC

28、a,N=74 Gemcitabine 1,000 mg/m2/wk x 3/4 wkCCRT:Gemcitabine 600 mg/m2/wk x 6 R/T 5,040Gy/28 fxGemcitabine 1,000 mg/m2/wk x 3/4 wkUntil tumor progressionor unacceptable toxicityLoehrer PJ et al 2008 ASCO#4506*P=0.044Response rate:9%3%Median PFS:6.3 months 6.1 monthsMedian OS*:11.0 months 9.2 months12m

29、 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局部进展期胰腺癌治疗新进展CSCO年会Unresectable,locally advanced PanCa,N=119 Gemcitabine 1,000 mg/m2/wk X 7/8 wkCCRT: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

30、fxGemcitabine 1,000 mg/m2/wk x 3/4 wkUntil tumor progression or unacceptable toxicityCauffert 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比較局

31、部晚期胰臟癌接受第一線同步5-FU/cisplatin化學放射治療化學放射治療與全身性與全身性吉西他賓吉西他賓(Gemcitabine)化學治療療效之第三期臨床試驗化學治療療效之第三期臨床試驗2000-01 FFCD/SFRO試驗試驗局部进展期胰腺癌治疗新进展CSCO年会Unresectable,locally advanced PanCaN=181Huguet F et al.J Clin Oncol 2007;25:326-313 months of CT*Progression ds53(29.3%)Disease controlled128(70.3%)CCRT,N=72Continu

32、e CT,N=56Gemcitabine alone 24.9%GEMOX 51.4%FOLFUGEM 23.7%#p=0.005,#p=0.0009Median 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第二及三期臨床試驗之次群分析-局部进展期胰腺癌治疗新进展CS

33、CO年会Cyto-/histology proven,Unresectable,locally advanced PanCaCR/PR/SDPDSurgicalResectionCCRT:gemcitabine or 5-FU-basedR/T 5,040 cGy/28fxDoublet/triplet CTUntil tumor progressionor unacceptable toxicitySalvage C/TDoublet/Triplet ICT x 2-3 monthsResectableUnresectableKo AH,et al.Int J Radiat Oncol Bi

34、ol 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 ASCORationales:1.Treating micro-metastases 2.Selecting patients for CCRT前導性前導性(Inductional)全身性化學治療併同步化學放射治療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於局部進展期胰臟癌患者之第二期臨床試驗局

35、部进展期胰腺癌治疗新进展CSCO年会NICT regimenXRT(Gy/fx)Complete ICT+CCRTMedian OS(M)ICT/CCRTALLUCSF 0725GC x 650.4/2812(48%)17.013.5NYU 0826GC x 250.4/2818(74%)NA11.0GERCOR 0859GEMOX x 4 55/33 44(74%)12.612.2TCOG.0950GOFL x 650.4/2830(60%)18.514.0Ko AH,et al.Int J Radiat Oncol Biol Phys 2007;68:809-16Marti JL,et a

36、l.Ann Surg Oncol 2008;15:3521-31Moureau-Zabotto L et al.J Clin Oncol 2008;26:1080-5Chang HJ et al.2009 ASCO前導性前導性(Inductional)全身性化學治療併同步化學放射治療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於無法切除局部進展期胰臟癌患者之第二期臨床試驗局部进展期胰腺癌治疗新进展CSCO年会Cyto-/histology proven,Unresectable,locally advanced PanCaCR/PR/SDPDSurgicalR

37、esectionCCRT:Gemcitabine 400mg/m2 QwR/T 5,040 cGy/28fxGOFL48Until tumor progressionor unacceptable toxicitySalvage C/TGOFL,Q 14d x 6ResectableUnresectable前導性前導性(Inductional)全身性化學治療併同步化學放射治療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於無法切除局部進展期胰臟癌患者之第二期臨床試驗:TCOG1204局部进展期胰腺癌治疗新进展CSCO年会No.of patients50Media

38、n 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前導性前導性(Inductional)全身性化學治療併同步化學放射治療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於無法切除局部進

39、展期胰臟癌患者之第二期臨床試驗:TCOG1204局部进展期胰腺癌治疗新进展CSCO年会Locally advanced pancreatic cancer&have inductional GOFL,N=50Disease-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=2Mort

40、ality,N=1(2%)Complete CCRT,N=29前導性前導性(Inductional)全身性化學治療併同步化學放射治療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於無法切除局部進展期胰臟癌患者之第二期臨床試驗:TCOG1204局部进展期胰腺癌治疗新进展CSCO年会Pre-treatmentPost-GOFL x 6F/38,Locally advanced pancreatic cancer,aorto-caval LN+2006-062006-092007-05Post-GOFL-CCRT-GOFLPost-GOFL+CCRT 2006-11A

41、BDC局部进展期胰腺癌治疗新进展CSCO年会Post-CCRT+GemIri x 6,2006-01Post-GOFL+CCRT,2005-10Post-GOFL x 6,2005-08Post-CCRT+GemIri+S-1,2006-12局部进展期胰腺癌治疗新进展CSCO年会Pre-Treatment,2006-03Post-GOFL x 6+CCRT,2006-09r/o liver and retroperitoneal metastases at 2007-04 局部进展期胰腺癌治疗新进展CSCO年会Overall Survival(months)50403020100Surviva

42、l Rate(%)1.0.8.6.4.20.0Treatment 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)前導性前導性(Inductional)全身性化學治療併同步化學放射治療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於無法切除局部進展期胰臟癌患者之第二期臨床試驗:TCOG1204局部进展期胰腺

43、癌治疗新进展CSCO年会Inductional Gemcitabine+CCRT NSurgical resection rate12-month OS rateResectable1681%94(82 100)%Borderline resectable 933%76(47 100)%Definitive unresectable147%47(19 75)%All3944%73(58 87)%Small Jr W,et al.JCO 2008;26:942-712345678910WeekGem 1.0 g/m2/wkR/T 2.4 Gy/daySurgery:4 6 weeks after

44、 neo-adjuvant therapy前導性前導性(Inductional)全劑量全劑量dFdC化學治療併同步化學放射治療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率及一年存活率局部进展期胰腺癌治疗新进展CSCO年会可切除可切除(resectable)T1-2(OP w/o adjuvant)T1-2(OP+Adjuvant CT)T3-4(OP w/o adjuvant)T3-4(OP+Adjuvant CT)局部晚期局部晚期(locally advanced)Borderline resectable(Neo-adjuva

45、nt+OP)無法切除無法切除(unresectable)(Neo-adjuvant+OP)(ICT+CCRT)(Gem-based CT)(CCRT+CT)轉移性轉移性(metastatic)/I I I I I I5 10 15 20 25 3027.619.150.220.514.014.318.020.513.011.07.0ITTPer protocol局部进展期胰腺癌治疗新进展CSCO年会 Our data suggested inductional chemotherapy followed by CCRT could achieve encouraging survival in unresectable LAPC Role in earlier stage PC deserves further exploration結論局部进展期胰腺癌治疗新进展CSCO年会