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1、局部進展期胰臟癌治療之新進展,陳立宗 M.D., Ph.D,國家衛生研究院 癌症研究所 國立成功大學附設醫院 血液腫瘤內科 高雄醫學大學附設醫院 胃腸內科 臺灣,Pancreas,Liver,GB,Duodenum,Liver,Pancreas,Stomach,Duo,A,胰臟癌 (Pancreatic Cancer) Adenocarcinoma of the exocrine pancreas,Pancreas is a retro-peritonum organ Relatively symptom-free in early stage Early dissemination, sma
2、ll tumor does not have to early disease Easily metastasize to liver or encase great vessel Most common symptoms, obstructive jaundice, BW loss and back pain Usually diagnosed at advanced stage, International Agency for Cancer Research. GLOBOCAN 2002. Available at: http:/www-dep.iarc.fr. Accessed Sep
3、temberr 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 involved SMA/CA, 上腸繫動脈(superior mesenteric artery)/celiac axis SMV/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
4、（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 week 5-FU 600 mg/m2, weekly * p = 0.0022; * p = 0.0002; # p = 0.0025,Gemcit
5、abine 5-FU No. of patients 63 63 Metastatic diseases 72 % 76 % Objective tumor response rate: 5.4 % 0 % Clinical Benefit response rate: 23.8 % 4.8 % * Median time to tumor progression: 2.3 mo 0.9 mo* Median overall survival: 5.7 mo 4.4 mo# 6-month survival rate: 46% 29% 12-month survival rate: 18% 2
6、%,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= 625 623 Louvet 7.1 9.0 Heinemann 6.0 7.5 Colucci 5.0 7.5 Viret 6.7 8.0 Poplin 4.9 5.9 Subtotal,Fluoropyrimidine, N= 912 901 Riess 6.2 5.8 Berlin 5.4 6.7 Dicostanzo 7.8 7.5 Cunningham 6.0 7.4 Hermann 7.3 8.4 Scheithauer 8.2 9.5 Subtotal,Oth
7、ers, N= 706 698 Oettle 6.3 6.2 OReilly 6.2 6.7 Rocha Lima 6.6 6.3 Stathopoulos 6.5 6.4 Subtotal Total, N= 2,243 / 2,222,0.82 0.64 1.05 0.80 0.59 1.08 0.87 0.58 1.29 0.92 0.59 1.45 0.88 0.73 1.06 0.85 0.76 -/0.96,1.04 0.86 1.25 0.82 0.65 1.03 1.05 0.67 1.63 0.79 0.65 0.97 0.89 0.70 1.12 0.82 0.50 1.3
8、5 0.90 0.81 0.99,0.98 0.82 1.18 0.93 0.74 1.17 1.04 0.84 1.30 0.99 0.67 1.46 0.99 0.88 1.10 0.91 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,* R
9、andomized 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 alone Phase I Phase II - III Gem + HDFL Phase I / II
10、(1997) GOFL Phase I (2002) Phase II (2004) Phase II (2004),US / Europe CCW/NICR/NHRI in VGH & NTUH CCW/NICR/NHRI in VGH & NTUH CCW/NICR/NHRI + University Hospitals TCOG T1204: 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
11、其作用機轉,Giovannetti E, et al. Mol Cancer Ther 2006;5:1387-95,MTD in phase I: 790 mg/m2 as 30-min i.v., weekly x 3/4,Intracellular dFdCTP saturated With 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% RR GemOx q 2w: 26.8% RR, OS 9 mo
12、nths,Gem-FL24 q wk: 22% RR FOLFUGEM q 2w: 22.6% RR FOLFUGEM2 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;23:3509-16 Louvet C et al. Ann Oncol 2001;12:675; Andr
13、e T et al. Gastroenterol Clin Biol 2004;28:645 Shiah 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
14、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/cycle Gemcitabine 800 mg/m2, iv x 80 min Oxaliplatin 65, 75, 85 mg/m2, iv x 2 hours Leucovorin 300 mg/m2, 5-FU 3,000 mg/m2, Oxaliplatin dose (mg/m2) 65 75 85 Case No. 6 3 6 DLT 1 0 1 CR / PR 1
15、 / 2 1 1 MTD 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 GOFL OS, 2004-07-10
16、- 2004-12-10 (TF) - 2006-05-29 (death),Phase I/II GOFL in Pancreatic Cancer,案例,Carnier C et al. 2001 ASCO, #620 Chang HJ et al. Cancer Chemother Pharmacol 2009 Correale P et al. J Chemother 2008;20:19-25,Carnier Chang Correale FOLFOGEMOX GOFL GOLF No. of patients 30 45 27 dFdC/L-OHP (mg/m2) 800/100,
17、D3 800/85,D1 1000/85,D2 5-FU bolus/48-hr IV (mg/m2) 400/2,000 0/3,000 0/3,000 Treatment cycle (weeks) Q 3 Q 2 Q 2 Metastatic diseases (%) 63 80 60 ORR (%): 29 33 33 Median PFS (months): 7.2 5.1 5.5 Median OS (months) : 8.0 8.7 8.0 Grade 3/4 neurotoxicity (%) 1 14 ? Grade 3/4 neutropenia (%) 28 21 ?,
18、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 d
19、isease progression Locally advanced disease, chemotherapy x 3 cycles* or treatment failure followed by CCRT,Carnier C et al. 2001 ASCO, #620 Chang 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,C
20、arnier Chang FOLFOGEMOX* GOFL 轉移性 (Metastatic) Case No. 19 36 Median PFS (months): 5.4 Median OS (months): 6.9 7.8 局部進展性 (Locally advanced) Case No. 11 9 Median PFS (months): 11.5 Median OS (months): 11.5 15.9,Krzyzanowska MK et al. JCO 2003;21:3409-14,* age, sex and co-morbidity adjusted median sur
21、vival,1,696 patients (from Medicare data bank) between 1991 and 1996,Median OS* Untreated 56% 15 weeks C/T 7% 27 weeks R/T 13% 29 weeks CCRT 24% 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,Hua
22、ng PI et al. 2007 ASCO GI Cancer Symposium Abs#154 Huang PI, et al. Int J Radiat Oncol Biol Phys 2009;73:159-65,PR / SD (%) 44 / 27 Median TTP (months) 5.2 Median OS (months) 10.5 non-responders / responders 7.0 / 18.5 1-yr survival rate (%) 42.2 2-yr survival rate (%) 14.6 Grade 3-4 neutropenia 24.
23、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 wk Until tumor progression or unacceptable toxicity,Loehrer PJ et al
24、 2008 ASCO #4506,* P = 0.044,Response rate: 9% 3% Median PFS: 6.3 months 6.1 months Median OS*: 11.0 months 9.2 months 12m OS rate: NA NA Gr 4 AE 41% 6%,ineligible in 3 assigned 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,G
25、emcitabine 1,000 mg/m2/wk X 7 / 8 wk,CCRT: 5-FU 1,500 mg/m2 x 120h/wk x 6 Cisplatin 20 mg/m2/d, D1-5, wk 1 & 5 R/T 6,000Gy / 30 fx,Gemcitabine 1,000 mg/m2/wk x 3/4 wk Until tumor progression or unacceptable toxicity,Cauffert B, et al Ann Oncol 2008; 19:1592-99,* In Coxs regression, HR = 0.54 (95% CI
26、, 0.31 0.96, P = 0.006),Compliance rate: 83% 73% 12m PFS: 12% 32% Median OS*: 8.6 months 13.0 months 12m 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 PanCa N = 181,Huguet F et al. J Clin
27、 Oncol 2007;25:326-31,3 months of CT*,Progression ds 53 (29.3%),Disease controlled 128 (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 months Median OS# 15.0 months 11.7 months 1-year survival rate 65.3% 47
28、.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,Surgical Resection,CCRT: gemcitabine or 5-FU-based R/T 5,040 cGy / 28fx,Doublet/triplet CT Until tumor progression or unacceptable toxicity,Salvage C/T,D
29、oublet /Triplet ICT x 2-3 months,Resectable,Unresectable,Ko AH, et al. Int J Radiat Oncol Biol Phys 2007;68:809-16 Marti JL, et al. Ann Surg Oncol 2008;15:3521-31 Moureau-Zabotto L et al. J Clin Oncol 2008;26:1080-5 Chang HJ et al. 2009 ASCO,Rationales: 1. Treating micro-metastases 2. Selecting pati
30、ents 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;68:809-16 Marti JL, et al. Ann Surg Oncol 2008;15:3521-31 Moureau-Zabotto L et al. J Clin Oncol 2008;26:1080-5 Chang 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
31、之第二期臨床試驗,Cyto-/histology proven, Unresectable, locally advanced PanCa,CR / PR / SD,PD,Surgical Resection,CCRT: Gemcitabine 400mg/m2 Qw R/T 5,040 cGy / 28fx,GOFL48 Until tumor progression or 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
32、切除局部進展期胰臟癌患者之第二期臨床試驗: TCOG1204,No. of patients 50 Median age 61 Gender, M / F (%) 52 / 48 ECOG P.S: 0 / 1 / 2 (%) 12 / 72 / 16 Histology: WD+MD / PD+UD / ? (%) 44 / 14 / 42 Location: Head / Body-tail (%) 58 / 46 T stage: T2 / T3-4 (%) 12 / 88 N stage: N0 / N1 / UD (%) 58 / 30 / 12 Resectability (%)
33、Borderline resectable 4 Unresectable 96,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
34、 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 +,2
35、006-06,2006-09,2007-05,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 g
36、roup N median (95% CI) OS, M CCRT/surgery 30 20.5 (15.43-25.57) No CCRT 3 9.6 (4.48-14.72) PD/UE 17 8.4 (6.15-10.65) Overall 50 14.3 (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/wk R/T
37、 2.4 Gy/day Surgery: 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(
38、unresectable) (Neo-adjuvant + OP) (ICT + CCRT) (Gem-based CT) (CCRT + CT) 轉移性(metastatic),/,I I I I I I 5 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,ITT Per protocol,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,Have a Nice Week-end,