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1 mg 4 6 C 15 H 22 FN 3 O β-D--5--1,
2 A B B A m 2 900mg 1.31m m 2 1,200mg 1.64m 2 1,500mg B m 2 1,500mg 1.33m m 2 1,800mg 1.57m m 2 2,100mg 1.81m 2 2,400mg 2
3 mg m 2 1,500mg 1.33m m 2 1,800mg 1.57m m 2 2,100mg 1.81m 2 2,400mg FU 5'-deoxy-5-fluorocytidine 5 -DFCR 5 -DFUR 5-FU mg/m 2 /
4 1 1.31m 2 900mg 1.31m m 2 1,200mg 1.64m 2 1,500mg F. Hoffmann-La Roche Ltd.2,500mg/m 2 / ,500mg/m 2 /2 1 EU ,500mg/m 2 / JO JO ,500mg/m 2 / in vivo Cancer Res 58: , 1998 Biol Pharm Bull 21: , ZR-75-1 MCF-7 MAXF401 MX-1 MDA-MB CXF280 HCT116 LoVo COLO205 HT-29 DLD-1 WiDr 1.5mmol/kg/5 -DFUR 0.75mmol/kg/5-FU 0.15mmol/kg/ 0.1mmol/kg/ 5 -DFUR FU % 2 MAXF401 MX-1 CXF280 HCT DFUR 33% mmol/kg/ 50% mmol/kg/maxf MX CXF HCT HCT
5 mmol/kg/ mmol/kg/ mmol/kg/ mmol/kg mmol/kg mm 3 % 8/ > / > / > / / / > / > / > / / > / > / /8 764 >83 6/8 12 2/8 20% 0.44mmol/kg mmol/kg mmol/kg mmol/kg 56.3mmol/kg mmol/kg 56.0mmol/kg mmol/kg/ mmol/kg mmol/kg mmol/kg/ mmol/kg 2 5
6 1 24.6mmol/kg PK 1 JO15951 Jpn J Clin Oncol 2006; 36: ,500mg/m 2 / 3,000mg/3,600mg/4,200mg/ 4,800mg/ PK DFCR 5 -DFUR 5-FU FBAL PK 5 -DFCR 5 -DFUR 5-FU 3 C max t 1/2 FBAL C max 5 -DFUR 5 -DFUR 5 -DFCR 5 -DFUR 14 ± ± C max µg/ml ± ± 2.55 t max h ± ± 1.40 AUC 0-t µg h/ml ± ± 1.92 AUC µg h/ml ± ± 1.71 t 1/2 h ± ± CL/F L/h ± ± 61.9 C max µg/ml ± ± 1.90 t max h ± ± 1.27 AUC 0-t µg h/ml ± ± 4.58 AUC µg h/ml ± ± 4.60 t 1/2 h ± ± CL/F L/h ± ± 32.6 C max µg/ml ± ± 2.83 t max h ± ± 1.21 AUC 0-t µg h/ml ± ± 3.31 AUC µg h/ml ± ±
7 14 ± ± 5 -DFUR t 1/2 h ± ± CL/F L/h ± ± 32.2 C max µg/ml ± ± t max h ± ± FU AUC 0-t µg h/ml ± ± AUC µg h/ml ± ± t 1/2 h ± ± CL/F L/h ± ± 418 C max µg/ml ± ± 1.20 t max h ± ± 1.31 FBAL AUC 0-t µg h/ml ± ± 6.50 AUC µg h/ml ± ± 7.84 t 1/2 h ± ± CL/F L/h ± ± 7.29 AUC t 1/2 CL/F AUC C max R obs 5-FU ,250mg/m FU AUC C max R obs % 5 -DFCR 5 -DFUR 5-FU FUPA FBAL 3% 5 -DFCR PK 14 AUC C max Grade 3 4 Grade 1 PK 2 SO14695 J Clin Oncol 2001; 19: SO14796 J Clin Oncol 2001; 19: FU/LV Mayo 61 SO SO ,500mg/m 2 / SO14695 SO SO SO DFUR 5-FU FBALPPK PPK 1,250mg/m 2 5 -DFUR 5-FU 7
8 FBAL AUC C max PPK CLcrALP AST ALT KPS PK ALP 2 5-FU CL 11%5-FU AUC 12% ALP 5 5-FU CL 24%5-FU AUC 31% CLcr 50%FBAL CL 35%FBAL AUC 53% CLcr 50%FBAL 24%C max 41% 1.3 FBAL 24%FBAL C max 19% SO14693 SO DFUR 5-FU FBAL AUC C max Dose Limiting Toxicity: DLT AUC C max Grade 3 4 Grade 3 Grade 3 4 Cox AUC C max 3 JO15951 PK SO14794 SO14798 SO15304 WP15811 PK JO DFCR 5 -DFUR 5-FU FBAL AUC C max 1,255 1,250mg/m 2 AUC JO % 90%CI 5 -DFUR AUC FU AUC C max AUC C max PK AUC C max 90% JO15951 AUC C max 90%CI 5 -DFCR 14 ± ± JO ± ± 1.71 SO ± ± SO ± ± SO ± ± WP ± ± * 90%CI , , 1.05 JO ± ± 4.60 SO ± ±
9 14 ± ± SO ± ± DFCR SO ± ± WP ± ± * 90%CI , , 2.16 JO ± ± 3.40 SO ± ± DFUR SO ± ± SO ± ± WP ± ± * 90%CI , , JO ± ± SO ± ± FU SO ± ± SO ± ± WP ± ± * 90%CI , , JO ± ± 7.84 SO ± ± FBAL SO ± ± SO ± ± WP ± ± * 90%CI , , * JO15951 SO14794 SO14798 SO15304 WP15811 JO15951 JO15951 SO14695 SO14796 PK SO14695 SO14796 PPK 1,250mg/m 2 5 -DFUR 5-FU FBAL AUC 1,250mg/m JO15951 PK JO15951 AUC C max 5 -DFUR 5-FU FBAL PK BP15831 PK PK 5 -DFUR 5-FU FBAL AUC 5 -DFUR 5-FU FBAL AUC JO mg/m BP DFUR 5-FU FBAL AUC PK AUC AUC/ng h/ml/mg/m 2 JO15951 BP15831 ± ± 5 -DFUR ± ± FU ± ± FBAL ± ±
10 14 AUC/ng h/ml/mg/m 2 JO15951 BP15831 ± ± 5 -DFUR ± ± FU ± ± FBAL ± ± PK DFCR AUC 5 -DFUR 5-FU AUC 3 SO14794 SO14798 SO15304 WP15811 PK PK 5 -DFCR 5 -DFUR PK PK JO DFCR 5 -DFUR 5-FU FBALSO14695 SO DFUR 5-FU FBAL PK AUC C max Grade 1 3 PK JO15951 Wilcoxon P<0.05 PK 12 SO14695 SO14796 PK PK PK PK JO15951 SO14695 SO14796 PK PK PK PK CDA CDA SNPs 3 6 Pharmacogenetics 2003;13: Hum Genet 2006; 119: Exp Hematol 1998; 26:
11 3 SNPs G208A A70T CDA 32 40% SNP 4.3% Pharmacogenetics 2003; 13: Hum Genet 2006; 119: SNP SNP A79C CDA Exp Hematol 1998; 26: Pharmacogenetics 2003; 13: SNPs SNP Hum Genet 2006; 119: CDA SNPs Hum Genet 2006; 119: CDA G208A 4.3% CDA SNPs SNPs CDA SNPs PK JO15951 SO14794 SO14798 SO15304 WP15811 PK JO DFCR AUC µg h/ml 5 -DFCR AUC µg h/ml 3 SO14794 SO14798 SO15304 WP15811 JO DFCR AUC BP DFCR AUC PK PK CDA PK CDA CDA PK PK 11
12 PK 61 PK 54 SO14799 PK CV% 5 -DFUR AUC µg h/ml C max µg/ml FU C max µg/ml AUC µg h/ml FBAL AUC µg h/ml C max µg/ml PK PK PK 2 PK JO15951 SO14794 SO14798 SO15304 WP DFUR 5-FU AUC C max 3 SO14794 SO14798 SO15304 WP DFUR 5-FU PK JO DFUR 5-FU AUC C max JO15951 SO14695 SO14796 PK BP DFUR 5-FU AUC C max AUC C max 3 PK 5 -DFUR 5-FU PK CDA PK PK PK 3 PK 12
13 PK 5 -DFUR 5-FU AUC / %CI 0.39, %CI 0.50, %CI 0.53, JO15156 JO15951 JO14865 JO15153 JO15950 JO15156 JO15751 JO15153 JO17219 JO15951 SO14695 SO14796 M66001 Dukes C SO14693 SO ,657mg/m 2 / ,500mg/m 2 / ,004 1,657 2,510mg/m 2 / 16 1,657mg/m 2 / ,657mg/m 2 / ,657mg/m 2 / ,500mg/m 2 / ,500mg/m 2 / FU/LV Mayo 303 2,500mg/m 2 / FU/LV Mayo 301 2,500mg/m 2 / FU/LV Mayo ,004 1,331 1,657 2,083mg/m 2 / ,004 1,657 2,510 3,000 3,514mg/m 2 /
14 SO14797 JO15155 JO16526 JO ,331mg/m 2 / 39 2,510mg/m 2 / ,657mg/m 2 /LV 60mg/ JO15151 JO15742 JO15151 JO ,657mg/m 2 / 3 1 2,500mg/m 2 / 2 1 1,650 1,900mg/m 2 / mg/m 2 3 1,657mg/m 2 / 3 1 1,657mg/m 2 / 3 1 1,657mg/m 2 / 3 1 JO15949 JO15154 JO ,657mg/m2 / 3 1 2,500mg/m 2 / JO17905 JO SO14697 NO15542 SO14799 SO15179 SO ,510mg/m 2 / 2 1 2,510mg/m 2 / 2 1 2,510mg/m 2 / CPA600mg/m 2 MTX 40mg/ m 2 5-FU 600mg/m ,331mg/m 2 / 2 2,510mg/m 2 / mg/m ,510mg/m 2 / mg/m mg/m
15 1 1 JO15156 Anticancer Drugs 2004; 15: ,657mg/m 2 / 1,800mg/2,400mg/ 3,000mg/ /56 CR 0 PR % 95%CI 15.8, 40.3% JO15951 Jpn J Clin Oncol 2006; 36: ,500mg/m 2 / 3,000mg/3,600mg/4,200mg/ 4,800mg/ RECIST 21/60 CR 0 PR % 95%CI 23.1, 48.4% 3 JO Int J Clin Oncol 2005;10: JO Jpn J Clin Oncol 2004; 34: JO JO JO JO JO JO
16 8 SO14695 J Clin Oncol 2001; 19: FU/LV Mayo 61 2,500mg/m 2 / FU/LV 20mg/m 2 5-FU 425mg/m Mayo FU/LV 303 PD FU/LV FU/LV 294 IRC 5-FU/LV 28.3% 95%CI 23.0, 34.0% 76/269 CR 1 PR % 95%CI 9.0, 17.4% 34/266 CR 1 PR % 95%CI 8.6, 22.0%95%CI 10% 29 5-FU/LV FU/LV / %5-FU/LV 157/ % 149/ % 5-FU/LV 137/ % 9 SO14796 J Clin Oncol 2001;19: SO FU/LV FU/LV FU/LV 299 IRC 5-FU/LV 21.1% 95%CI 16.4, 26.6% 56/265 CR 1 PR % 95%CI 12.0, 21.0% 44/273 CR 2 PR % 95%CI %95%CI 10% 21 5-FU/LV FU/LV / % 5-FU/LV 161/ % 143/ %5-FU/LV 146/ % 16
17 10 M66001 Ann Oncol 2003; 14: N Engl J Med 2005; 352: Dukes C FU/LV ,500mg/m 2 / FU/LV 20mg/m 2 5-FU 425mg/m Mayo 6 Disease Free Survival: DFS 95%CI hierarchical test Per protocol population PPP DFS FU/LV 983 All randomized population ARP 1 Extended per protocol population EPPP FU/LV PPP FU/LV 974 DFS %CI 0.76, %CI 1.2 ARP EPPP DFS %CI 0.75, %CI 0.75, FU/LV DFS Kaplan-Meier PPP
18 DFS ARP %CI 0.77, 1.01 PPP %CI 0.80, 1.06 EPPP %CI 0.78, 1.03 ARP % 5-FU/LV 56.7% ARP PPP EPPP %CI 0.74, %CI 0.79, %CI 0.76, 1.04 ARP % 5-FU/LV 68.4% ARP OS Kaplan-Meier OS Kaplan-Meier ARP / %5-FU/LV 10/ % FU/LV /995 20%5-FU/LV 221/974 23% 169/995 5-FU/LV 192/ SO14693 J Clin Oncol 1998; 16: SO14794 J Clin Oncol 1998; 16: SO14797 J Clin Oncol 2000; 18:
19 2 1 JO ,657mg/m 2 / 1,800mg/2,400mg/3,000mg/ /55 CR 1 PR % 95%CI 10.4, 33.0% 1 2 JO ,500mg/m 2 / SD RECIST 7/32 CR 0 PR 7 RECIST 21.9% 95%CI 9.3, 40.0% 3 JO ,650 1,900mg/m 2 / mg/m JO Brest Cancer 2006;13: JO JO
20 6 JO ,657mg/m 2 / JO JO15154 JO JO JO SO14697 J Clin Oncol 1999; 17: ,510mg/m 2 / WHO 27/135 CR 3 PR % 95%CI 13.6, 27.8% 22/ % NO15542 Cancer 2001; 92: ,510mg/m 2 / WHO 17/ % 95%CI 15.1, 36.5% 3 11 SO14799 Ann Oncol 2001; 12: SO15179 Br J Cancer 2002; 86:
21 13 SO14999 J Clin Oncol 2002; 20: M66001 M66001 JO15156 JO15951 SO14695 SO14796 JO15156 JO M66001 JO15951 SO14695 SO14796 M National Comprehensive Cancer Network NCCNNCCN 2006 ver. 2 National Cancer Institute Physician Data QueryNCI-PDQGuideline for Colon and Rectal Cancer Surgery Dukes AJCC/UICC TNM Dukes M66001 Dukes C Stage AJCC/UICC TNM Stage Stage Stage Stage 10cm NCI 5cm origin of primary feeding vessel 21
22 NCCN 2006 ver. 2 NCI-PDQ Stage Stage 5-FU/LV NCCN 2006 ver. 2 5-FU/LV5-FU/LV+ 5-FU/LV 3 RPMI Mayo MachoverPDQ Stage 6 5-FU/LV Mayo RPMI 5-FU/LV RPMI Mayo 5 DFS Overall Survival: OS 10 J Clin Oncol 2005; 23: Machover Machover Lancet 1995; 345: FU/LV 6 5-FU/LV RPMI bolus LV 500mg/m 2 day 1 5-FU bolus 500mg/m 2 day FU/LV Mayo bolus LV 20mg/m 2 day FU bolus 425mg/m 2 day FU/LV Machover bolus LV 400mg/m 2 day FU bolus mg/m 2 day NCCN 2500mg/m 2 2 day ver FU/LV + FOLFOX4 85mg/m 2 day 1 LV 200mg/m 2 day FU 400mg/m 2 bolus 5-FU 600 mg/m 2 22h.infusion day FU/LV + mfolfox6 85mg/m 2 day 1 LV 400mg/m 2 day 1 5-FU 400mg/m 2 bolus day 1 5-FU 2400 mg/m h infusion 2 Stage Stage Stage % Int J Clin Oncol 2001; 6: % J Natl Cancer Inst 2004; 96: Stage a 76.1% Stage b 62.1% TNM Stage 7 TNM 22
23 Stage Stage 5FU/LV M Stage 1 M66001 DFS OS 18 20,898 DFS marginally significant DFS improvements may not translate into significant OS benefits 2 3 DFS 5 OS J Clin Oncol 2005; 23: J Clin Oncol 2007; 25: DFS OS OS Mayo Stage M M66001 DFS %CI 0.76, 1.04PPP 95%CI FU/LV ARP EPPP RFS OS 5-FU/LV 95%CI 3 DFS % ARP , 1.00 PPP* ,
24 5-FU/LV 95%CI EPPP** , RFS % ARP , 0.99 PPP* , 1.02 EPPP** , % ARP , 1.01 PPP* , 1.10 EPPP** , 1.05 * 12 ** 1 M66001 Roche FDA M66001 JO SO14695 SO14796 JO15951 SO14695 SO14796 GOT Grade 3 GOT JO Grade % Grade 3/4 % SO14695 SO
25 GOT * * SO14695 SO14796 M FU/LV 28 M FU/LV FU/LV / 0.54 / / / / % Grade 3/4 % Grade 3/4 % Grade 4 % Grade 4 % % % % % % % 28 % SO14695 SO14796 M66001 Grade 2 M66001 M FU/LV 91% 910/995 91% 885/ % 89%
26 4830 Grade 3/4 36% 35% FU/LV % % 85 9% 85 9% % % % % % % % % % % % % % % % % % % % % % % % % 99 10% 97 10% 92 9% 89 9% 96 10% 89 9% 95 10% 88 9% 91 9% 87 9% % % 86 9% 63 6% % 69 7% 63 6% 62 6% % % 5-FU/LV Grade 3/4Grade 3/4 5-FU/LV 10 Grade 3/4 16 2% 5-FU/LV % 21 Grade 3/4 54 5% % Grade 3/4 995 Grade 4 5-FU/LV 974 Grade 3/4 Grade % 24 2% % 35 4% % 15 2% % 11 1% 18 2% 2 <1% % 5 <1% 17 2% % % % 1 <1% 18 2% % 0 1 <1% 0 1 <1% 0 1 <1% <1% 0 1 <1% 1 <1% <1% % 0 5 <1% % 1 <1% 4 <1% 0 3 <1% 1 <1% 20 2% 6 <1% 6 <1% 2 <1% 47 5% 4 1% 2 <1% 1 <1% 0 1 <1% 0 3 <1% 26
27 995 5-FU/LV 974 Grade 3/4 Grade 4 Grade 3/4 Grade <1% 1 <1% <1% 0 1 <1% 1 <1% 0 1 <1% <1% 0 1 <1% 1 <1% 1 <1% 1 <1% <1% 0 1 <1% 1 <1% 0 8 <1% % 0 6 <1% % % 0 1 <1% 0 5-FU/LV Grade 3/4 1% M FU/LV 4 NCCN 2006 ver. 2 Stage StageNCCN 2006 ver. 2 Stage 12 T4 NCI-PDQ 5-FU/LV Stage Stage Stage M66001 Stage 5-FU/LV 5 M66001 Dukes C Stage 27
28 JO EU SO14695 SO14796 M mg 500mg 300mg 2,500mg/m 2 / 150mg 500mg 300mg 1,657mg/m 2 / 300mg Grade 300mg 1,657mg/m 2 / 300mg 300mg 500mg 150mg JO % JO % 8.3% SO14695 SO % 5.6% M % 5.3% 2,500mg/m 2 / JO15951 SO14695 SO14796 M mg 150mg 500mg JO15951 SO14695 SO % 5 0% 05%5% JO mg 2500mg/m 2 /day % JO15951 SO14695 SO % 28.6% 4/14 20% 2/10 10% 1/10 5 0% 46.2% 6/ % 42/ % 43/152 28
29 2500mg/m 2 /day % JO15951 SO14695 SO % 31.8% 7/ % 30/ % 31/122 5% 36.4% 4/11 0% 0/ % 5/13 25% 1/4 0% 0/4 JO15951 SO14695 SO % 0 5% 05%5% 2500mg/m 2 /300mg JO15951 SO14695 SO % 5 0% 0 5% 5% 5% 5 0% 0 5% 5% 5% 5 0% 0 5% 5% % % % % % % % % % % % % Grade Grade 3 JO15951 SO14695 SO % % % % % % % % % Grade JO15951 SO14695 SO mg JO15951 SO14695 SO mg JO mg 500mg 29
30 SO14695 SO mg 1 150mg 500mg 300mg PK 300mg 300mg M mg 500mg 2,500mg/m 2 / m 2 1,500mg 1.25m 2 1,500mg 1.25m m 2 1,650mg 1.33m m 2 1,800mg 1.38m m 2 1,800mg 1.52m m 2 2,000mg 1.57m m 2 2,100mg 1.66m m 2 2,150mg 1.78m m 2 2,300mg 1.81m 2 2,400mg 1.92m m 2 2,500mg 2.06m m 2 2,650mg 2.18 m mg 300mg 150mg 500mg go.jp/shinyaku/ g030408/ _21500amy00080_q100_1.pdf mg 300mg 7 30
31 550 70% 95%CI 3% 890 Pearson-Clopper 10% 1,000 1, %95% 1 8 M JO16526 SO14697 NO CR+PR % %CI 9.3, 40% 20 95%CI 13.6, 27.8% %CI 15.1, 36.5% RECIST WHO WHO JO % 11/55 95%CI 10.4, 33.0% % 7/43 31
32 JO16526 JO15155 JO ,657mg/m 2 /3 1 JO ,500mg/m 2 /2 1 2 JO16526 Grade 3 Grade Grade JO15155JO JO15155 JO16526 JO15155 JO16526 Grade Grade 3 Grade Grade 3 36/6060.0% 8/6013.3% 29/3582.9% 5/3514.3% 16/6026.7% 1/601.7% 14/3540.0% 1/352.9% 22/6036.7% 0/600% 21/3560.0% 1/352.9% 14/6023.3% 0/600% 13/3537.1% 1/352.9% 13/6021.7% 0/600% 10/3528.6% 1/35 2.9% 24/6040.0% 1/601.7% 19/3554.3% 1/352.9% 10/6016.7% 0/600% 16/3545.7% 0/350% 0/60 0% 0/60 0% 1/352.9% 1/352.9% JO15155 JO16526 JO15155 JO Grade 3 Grade 1 Grade 3 Grade 21/6035.0% 0/60 0% 15/3542.9% 1/352.9% 21/ % 0/60 0% 18/3551.4% 2/35 5.7% * 20/ % 0/60 0% 16/3545.7% 2/35 5.7% 10/6016.7% 0/60 0% 7/3520.0% 3/358.6% 2/603.3% 0/600% 1/352.9% 1/352.9% 17/ % 0/60 0% 7/3520.0% 1/352.9% * JO JO15951Grade3 JO15951 Grade Grade JO15156JO
33 AST JO15156 JO15951 JO15156 JO15951 Grade Grade 3 Grade Grade 3 37/5962.7% 4/596.8% 44/6073.3% 8/6013.3% * 4/596.8% 0/590% 23/6038.3% 0/600% 14/5923.7% 0/590% 26/6043.3% 1/601.7% 8/5913.6% 0/590% 21/6035.0% 0/600% 7/5911.9% 0/590% 13/6021.7% 0/600% 20/5933.9% 1/591.7% 21/6035.0% 4/606.7% 4/596.8% 0/590% 21/6035.0% 0/600% * JO15156 JO15156 JO15951 JO15156 JO Grade 3 Grade 1 Grade 3 Grade AST GOT 23/5939.0% 1/591.7% 34/6056.7% 3/605.0% * 13/5922.0% 0/590% 27/6045.0% 3/60 5.0% 13/5922.0% 0/59 0% 5/608.3% 1/601.7% * JO15156 * AST GOT * ** Grade 3 QOL 2 Grade 4 Grade 3 JO16526 SO14697 NO15542 JO16526 SO14697 NO15542 SO14697 NO15542 JO16526 Grade 2 3 Grade 4 JO16526 SO14697 NO15542 JO16526 SO14697 NO Grade % % % 43 Grade 4 5.7% % % 5 33
34 JO16526 SO14697 NO % % % % 4 8% % % 56.8% 62.2% 60.0% 57.4% 62.2% 54.3% 11.1% 14.9% 45.7% 9.3% 33.8% NOS 40.0% 57.4% 59.5% NOS 37.1% 45.1% 40.5% 31.4% 4.9% 0% 28.6% 2.5% 2.7% JO Grade JO Grade SO Grade NO Grade 5.7% 2.5% 6.8% 5.7% 2.5% 8.1% 3.7% 6.8% 2.9% 1.2% 2.7% 8.6% 3.1% 5.4% 5.7% 8.6% 1.4% ALT 0.6% 2.9% 2.9% 0.6% 2.9% 0.6% 1.9% 2.7% JO SO14695 SO14796 Grade 3 Grade
35 ,650mg/m 2 / mg/m 2 SO
36 5 3 1, JO ,180 Grade 3/4 42/ / % % 40/ % 37/ %LDH 34/ % 33/ % 31/ % 26/ %AlP 24/ %GOT 22/ % 21/ % 20/ % 19/ % 18/ % GPT 17/ % 15/ % 14/ % 13/ % 12/ % 11/ %BUN 10/ % 9/ % 8/ % 7/ % 6/ % Grade 3 21/ % 18/ % 15/ %LDH 9/ % 4/59 6.8% 3/59 5.1% 5% 38/ % 37/ % 28/ % 26/ %LDH 25/ % 19/ %AlP 17/ %16/ % 14/ % GOT 13/ %GPT 12/ %10/ % 9/ % BUN 8/ % 7/ % 6/ % 5/59 8.5% 36
37 BUN 4/59 6.8% 3/59 5.1% %1 BUN 1 1 BUN JO / % 458 Grade 3/4 30/ % 50 55/ % % % NOS % NOS % % % NOS % % NOS % % % % NOS % Grade % 4 6.7% 3 5.0% 5% % NOS % NOS % % % NOS % NOS % % % NOS 5 8.3% NOS 4 6.7% NOS NOS NOS 3 5.0% NOS NOS 1 5 8% C NOS 1 Grade 3 1 Grade SO14695 Safety 294/299 98% 3,003 5-FU/LV 290/294 99% 3, /299 93% 1,771 5-FU/LV 285/290 97% 2,039 10% 5% 10% FU/LV 294 Grade Grade 3 Grade Grade % % % 2 0.7% % % % % % % % % 37
38 299 5-FU/LV 294 Grade Grade 3 Grade Grade % % % % NOS % % % % NOS % % % % % 9 3.0% % % % 3 1.0% % 5 1.7% % 5 1.7% % 4 1.4% % 1 0.3% % 3 1.0% % 3 1.0% % 5 1.7% NOS % 1 0.3% % 0 0% % 3 1.0% % 3 1.0% % 5 1.7% % 3 1.0% % 6 2.0% % 6 2.0% % 7 2.3% % 8 2.7% NOS % 5 1.7% % 0 0% % 1 0.3% % 0 0% % % % % % 5 1.7% % 1 0.3% % 6 2.0% % 3 1.0% % 0 0% % 0 0% 5% FU/LV 294 Grade Grade 3 Grade Grade % % % 20.7% % % % % % % % % % 6 2.0% % 8 2.7% NOS % % % % % 9 3.0% % % NOS % % % 6 2.0% NOS % 1 0.3% % 0 0% % 1 0.3% % 3 1.0% % 1 0.3% % 4 1.4% % 2 0.7% % 4 1.4% % 3 1.0% % 5 1.7% % 0 0% % 0 0% % 1 0.3% % 1 0.3% % 0 0% % 0 0% % 0 0% % 0 0% % 1 0.3% % 2 0.7% % 2 0.7% % 1 0.3% % 0 0% % 0 0% % 7 2.3% % % % 0 0% % 0 0% % 3 1.0% % 3 1.0% % 0 0% % 1 0.3% NOS % 2 0.7% % 0 0% 38
39 299 5-FU/LV 294 Grade Grade 3 Grade Grade % 0 0% 93.1% 0 0% % 0 0% 82.7% 0 0% % 0 0% % 0 0% Grade 1 Grade 3 Grade Grade FU/LV Grade 3 Grade 1 Grade 3 Grade % % % % % 5 1.7% % 0 0% % % % % % 1 0.3% % 3 1.0% % 2 0.7% % 0 0% % 1 0.3% % 1 0.3% Al-p % 0 0% % 1 0.3% % 3 1.0% % 0 0% AST GOT % 1 0.3% % 0 0% % 2 0.7% % 1 0.3% % 5 1.7% % % % 1 0.3% % % % 1 0.3% % 0 0% ALT GPT % 1 0.3% % 0 0% % 2 0.7% % 1 0.3% 82.7% 1 0.3% % % 82.7% 0 0% 62.0% 0 0% 110/ %5-FU/LV 119/ % 44/ %5-FU/LV 69/ % % % % %5-FU/LV % % % % % % 40/ %5-FU/LV 32/ % 27/ %5-FU/LV 19/ % % 5 1.7% 5 1.7% 4 1.3% 3 1.0% 5-FU/LV 8 2.7% 4 1.4% 3 1.0% 4 SO14796 Safety 280/297 94% 1,916 5-FU/LV 269/299 90% 1, /299 93% 1,771 5-FU/LV 285/290 97% 2,039 Grade 3/4 109/297 37% FU/LV 82/299 27% % 5% 39
40 10% FU/LV 299 Grade Grade 3 Grade Grade % % % 1 0.3% % % % % % 8 2.7% % 2 0.7% % 4 1.3% % % NOS % % % 6 2.0% NOS % 9 3.0% % 6 2.0% % 3 1.0% % 5 1.7% % 4 1.3% % 0 0% % 2 0.7% % 1 0.3% % 4 1.3% % 4 1.3% % 5 1.7% % 3 1.0% 5% FU/LV 299 Grade Grade 3 Grade Grade % % % 1 0.3% % % % % % 5 1.7% % 2 0.7% % 4 1.3% % % NOS % 6 2.0% % 5 1.7% % 1 0.3% % 1 0.3% % 2 0.7% % 1 0.3% NOS % 4 1.3% % 2 0.7% % 2 0.7% % 1 0.3% % 0 0% % 1 0.3% % 0 0% % 0 0% NOS % 0 0% % 0 0% % 3 1.0% % 0 0% % 0 0% % 3 1.0% % 0 0% % 3 1.0% Grade 1 Grade 3 Grade Grade FU/LV Grade 3 Grade 1 Grade 3 Grade % % % % % % % % % 1 0.3% % 0 0% % 3 1.0% % 2 0.7% AST GOT % 1 0.3% % 1 0.3% % 2 0.7% % 2 0.7% Al-p % 0 0% % 1 0.3% % 4 1.3% % 1 0.3% ALT GPT % 1 0.3% % 3 1.0% % 3 1.0% % 1 0.3% % 7 2.4% % % % 3 1.0% % 0 0% 40
41 297 5-FU/LV Grade 3 Grade 1 Grade 3 Grade % 6 2.0% % % % 0 0% % 1 0.3% % 4 1.3% % 1 0.3% % 0 0% % 0 0% 31.0% 0 0% 3 1.0% 00% 97/ %5-FU/LV 100/ % 37/ %5-FU/LV 53/ % % 5 1.7%5-FU/LV % % 9 3.0% 7 2.3% 5 1.7% 38/ %5-FU/LV 31/ % 30/ %5-FU/LV 21/ % 6 2.0% 5 1.7% 3 1.0% 5-FU/LV 6 2.0% 5 1.7% 5 M Safety 5-FU/LV 910/995 91% 5, /974 91% 5, /995 87% 4, /974 89% 4,830 Grade 3/4 354/995 36% /974 35% % 5% 10% FU/LV 974 Grade Grade 3 Grade Grade % % % 5 0.5% % % % % % % % % % % % % % 6 0.6% % % % % % % % % % % 5% FU/LV 974 Grade Grade 3 Grade Grade % % % 5 0.5% % % % % % % % % % % % % % 6 0.6% % % % % % % % % % % % 6 0.6% % 7 0.7% % 8 0.8% % % % 7 0.7% % 4 0.4% % 0 0% % 0 0% % 2 0.2% % 1 0.1% 41
42 995 5-FU/LV 974 Grade Grade 3 Grade Grade % 0 0% % 4 0.4% % 0 0% % 6 0.6% % 0 0% % 0 0% % 9 0.9% % 4 0.4% % 4 0.4% % 0 0% % 1 0.1% % 0 0% Grade 1 Grade 3 Grade Grade FU/LV Grade 3 Grade 1 Grade 3 Grade % % % % % % % % / % % % % % % % % AST GOT % 7 0.7% % 20.2% % 1 0.1% % 40.4% ALT GPT % % % 60.6% Al-p % 1 0.1% % 10.1% % % % % % 2 0.2% % 30.3% % 4 0.4% % 30.3% % 5 0.5% % 20.2% % 0 0% % 40.4% % 8 0.8% % 50.5% % 40.4% % 10.1% % 30.3% % 60.6% 181/995 18% FU/LV 182/974 19% /974 11% 5-FU/LV 115/974 12% 57 6%5-FU/LV 32 3% 25 3% 17 2% 4 112/995 11%5-FU/LV 73/974 7% 94/995 9% 5-FU/LV 62/974 6% 29 3% 32 3%5-FU/LV 28 3% 16 2% 2 1 JO / % 713 Grade 3/ % %GOT LDH % %AlP % % % %GPT % % % % 42
43 % % % % % % % % Grade % % %GOT LDH 5 8.3% 3 5.0% 5% %GOT % LDH % % % % AlP %GPT % % % % % % % % % 5 8.3% 4 6.7% 3 5.0% JO % 292 Grade 3/ % 33 10% % % % % NOS % NOS % % % % % NOS NOS % 5% Grade 3/ % 3 8.6% 2 5.7% % % % % % NOS % NOS % % % % NOS NOS % NOS NOS 3 8.6% NOS 2 5.7%Grade 3/ % % 3 8.6% 2 5.7%
44 NOS 2 3 SO / % 1, / % 1,056 Grade 3/4 68/ % 10% NOS % % NOS % % % % NOS % % NOS % NOS % % % % % NOS NOS % % Grade 3 NOS % % % % NOS 9 5.6% 5% % NOS % % NOS % % NOS % NOS % % % % NOS % % % % % % 9 5.6% 54/ % 93 18/ % /162 8% 3 11/13 4 NO / % / % 326 Grade 3/4 36/ % % % NOS % % % % % % NOS % NOS % % NOS % Grade % % % 7 9.5% 6 8.1% NOS 5 6.8% 4 5.4% 5% % % % NOS % % % % % NOS 6 8.1% 5 6.8% NOS 4 5.4% 29/ % 89 44
45 16/ % % % 6 8.1% 5 6.8% 5 6.8% 2 2.7% 8/ % 2 7/74 9.5% 1 2 GCP GCP 45
46 Dukes C Stage M66001 Disease Free Survival: DFS 5-FU / LV M66001 M66001 M66001 M66001 Dukes C Stage Stage J Natl Cancer Inst 2001; 93: Dukes C 46
47 M M66001 Dukes C Stage Stage Stage Dukes 47
48 Dukes C 4 1 2,500mg/m 2 / mg 500mg 300mg m 2 1,500mg 1.25m 2 1,500mg 1.33m m 2 1,800mg 1.25m m 2 1,650mg 1.57m m 2 2,100mg 1.38m m 2 1,800mg 1.81m 2 2,400mg 1.52m m 2 2,000mg 1.66m m 2 2,150mg 1.78m m 2 2,300mg 1.92m m 2 2,500mg 2.06m m 2 2,650mg 2.18 m 2 2,800mg 300mg ,500mg/m 2 / mg 300mg 300mg 300mg 300mg 300mg 48
49 150mg 500mg 150mg 500mg 150mg 500mg 150mg 500mg ,000 8 M FU/LV 49
50 Roche Dukes C 8 1,000 Stage 4 6 1,000 Stage 12 Roche Stage Stage XELOX + FOLFOX4 5-FU/LV+ XELOX+ FOLFOX4+ FOLFOX4 3,450 DFS OS M66001 M66001 Roche Roche
51 A B B A m 2 900mg 1.31m m 2 1,200mg 1.64m 2 1,500mg B m 2 1,500mg 1.33m m 2 1,800mg 1.57m m 2 2,100mg 1.81m 2 2,400mg
52 Dukes C B 1 B NCI Grade Grade 1 Grade Grade Grade 4 Grade 0-1 Grade 0-1 Grade 0-1 Grade 0-1 Grade 0-1 Grade m 2 900mg 1.13m m m m m m m m ,200mg 1,500mg 1.77m 2 1,800mg 2 600mg 900mg 1,200mg 52
53 NCI-CTC Ver.2.0 Grade Grade Grade Grade 1 (mm 3 ) (mm 3 ) mmol/kg mmol/kg /8 2/ t max h t max h SO SO DFCR SO DFCR SO FU/LV FU/LV ** 1 ** 1 SO14796 SO FU/LV 5-FU/LV Grade 4 % 4 Grade 4 % 3 27 Grade 4 Grade 4 1 <1% SO14697 NO SO14697 NO
54 SO % SO % 34 JO16526 JO % 5.7% 2.9% 2.9% , , /299 93% 1, /297 85% 1,238 5-FU/LV 285/290 97% 2,039 5-FU/LV 243/299 81% 1,
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第 5 回福岡大学病院と院外薬局とのがん治療連携勉強会 ベバシズマブ併用 FOLFOX/FOLFIRI 療法 福岡大学病院腫瘍 血液 感染症内科 田中俊裕 本日の講演内容 大腸がんの治療方法について概説 アバスチン併用 FOLFOX/FOLFIRI 療法の治 療成績について 2005 年にがんで死亡した人は 325,941 例 ( 男性 196,603 例 女性 129,338 例 ) 2 位 4
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