DIF 2

TS-1 20 25 TS-1 Product Introduction JIMSVAA) 1

DIF 2

TS-1 20 25 3

TS-1 F O H N O NH O CI N OH OH KO2C N H N O NH O Tegafur Gimeracil Oteracil potassium FT CDHP Oxo 1 0.4 1 4

S-1 5

Mechanism of TS-1 Tegafur TS-1 (S-1) Liver and Tumor (CYP 2A6) Tegafur 1 Oteracil 1 Gimeracil 0.4 Tumor Antitumor activity DPD F-β-Ala Gimeracil 5 - FU Oteracil Oteracil GI tract GI toxicity Neurotoxicty Oteracil Oteracil (HFS) Degradation Bone marrow Myelotoxicity Phosphorylation pathway 6

TS-1 Phase II Studies in Japan 2. TS-1 1, 46.5%(60/129 ), 32.6%(30/92 ), 32.6%(42/129 ), 34.8%(8/23 ), 34.1%(29/85 ), 48.1%(23/52 ) ( taxane ), 21.8%(12/55 ), 32.2%(19/59 ), 30.5%(18/59 ), 24.1%(7/29 ) 2, CDDP 47.3%(26/55 ), 43.1%(22/51 ) 7

TS-1 20 25 TS-1 8

1. TNM Stage II ( T1) IIIA IIIB 2. 1. TS-1 2. TS-1 3. (1)TS-1/ (2)TS-1anthracycline taxanes (3) TS-1 9

, 2, : ( Tegafur ) ( Tegafur ) <1.25 m 2 40 mg/ 80 mg/ 1.25 m 2 ~1.5 m 2 50 mg/ 100 mg/ 1.5 m 2 60 mg/ 120 mg/ 28 14 28 14 10

40mg/dose 2 2 / cm Kg 135 140 145 150 155 160 165 170 175 180 185 190 35.0 1.113 1.140 1.167 1.194 1.220 1.246 1.272 1.297 1.322 1.347 1.372 1.396 37.5 1.148 1.176 1.203 1.231 1.258 1.285 1.311 1.337 1.363 1.389 1.414 1.440 40.0 1.181 1.210 1.238 1.267 1.294 1.322 1.349 1.376 1.403 1.429 1.455 1.481 42.5 1.213 1.243 1.272 1.301 1.330 1.358 1.386 1.414 1.441 1.468 1.495 1.522 45.0 1.245 1.275 1.305 1.335 1.364 1.393 1.422 1.450 1.478 1.506 1.534 1.561 47.5 1.275 1.306 1.337 1.367 1.397 1.427 1.456 1.485 1.514 1.543 1.571 1.599 50.0 1.304 1.336 1.367 1.398 1.429 1.460 1.490 1.519 1.549 1.578 1.607 1.636 52.5 1.333 1.365 1.397 1.429 1.460 1.492 1.522 1.553 1.583 1.613 1.642 1.672 55.0 1.360 1.394 1.426 1.459 1.491 1.523 1.554 1.585 1.616 1.646 1.677 1.706 57.5 1.388 1.421 1.455 1.488 1.521 1.553 1.585 1.617 1.648 1.679 1.710 1.740 60.0 1.414 1.449 1.483 1.516 1.550 1.583 1.615 1.648 1.680 1.711 1.743 1.774 62.5 1.440 1.475 1.510 1.544 1.578 1.612 1.645 1.678 1.710 1.743 1.774 1.806 65.0 1.465 1.501 1.536 1.571 1.606 1.640 1.674 1.707 1.740 1.773 1.806 1.838 67.5 1.490 1.526 1.562 1.598 1.633 1.668 1.702 1.736 1.770 1.803 1.836 1.869 70.0 1.514 1.551 1.588 1.624 1.659 1.695 1.730 1.764 1.799 1.832 1.866 1.899 72.5 1.538 1.576 1.613 1.649 1.686 1.721 1.757 1.792 1.827 1.861 1.895 1.929 75.0 1.561 1.599 1.637 1.674 1.711 1.748 1.784 1.819 1.854 1.889 1.924 1.958 77.5 1.584 1.623 1.661 1.699 1.736 1.773 1.810 1.846 1.882 1.917 1.952 1.987 80.0 1.607 1.646 1.685 1.723 1.761 1.798 1.835 1.872 1.908 1.944 1.980 2.015 40mg/ 20mg capsules cap/ 50mg/ 25mg capsules cap/ 60mg/ 20mg capsules cap/ 学会, 23(5), 443-450, 1968 = 0.444 0.663 88.83 10-4 m 2 kg cm 11

1) 40 mg/ 40 mg/ 50 mg/ 40 mg / 50 mg / 60 mg / 増 50 mg/ 60 mg/ 75 mg/ 増 2) ( 査 ) 7 ( ) 12

3) 2 1 () ( ) 4) ( ) oteracil potassium TS-1 13

mono) 2814 ( 4w 2w),. 1 2 3 4 1 2 28 14 ( 査 ) 7 ( ) oteracil potassium TS-1 ( ) 14

Proper Use of TS-1 Single Agent in Advanced Gastric and in the Adjuvant Treatment ( ) 15

TS-1 1 28 14 TS-1 D7 D14 D21 D28 D35 D42 内 状 観 14 ( ) 7 : 16

PS 4 <8.0g/dL <2000/mm 3 <1000/mm 3 <7. 5 /mm 3 AST(GOT) ALT(GPT) 3mg/dL 150 IU/L 1.5mg/dL 17

Proper Use of TS 1 晚 ( 2 1 cisplatin 60mg/m 2 ) TS-1 21 14 Cisplatin TS-1 8 60mg/m 2 TS-1 21 cisplatin 8 60mg/m 2 TS-1 14 TS-1 Cisplatin 60mg/m 2 1 2 3 1 2 21 8 14 薬 18

Proper Use of TS 1 Combining Cispla6n in AGC and NSCLC 19

Cisplatin 1 TS-1 Cisplatin 60mg/m2) 2 TS-1 Cisplatin 21 8 7 14 21 28 14 薬 検査 35 内 状 観 ( 状 14 ( ) 7 20

TS-1 20 25 21

1. 12 TS-132-40mg/dose 72 gimeracil (CDHP) 52.8% tegafur (FT) 7.8% oteracil potassium (Oxo) 2.2%cyanuric acid (CA) 11.4% (5-FU) 7.4% 2. 28 32-40mg/dose TS-1 1 7 14 28TS-1 TS-1 (Ura) CDHP DPD 1,2) 3. TS-1 5-FU FT 49-56% CDHP 32-33% Oxo 7-10% 5-FU 17-20% () 4. 12 T S - 1 (FT CDHP Oxo)(5-FU CA) 72 CDHP 52.8% CA 11.4% FT 7.8% 5-FU 7.4% Oxo 2.2% 12 CDHPCDHP 1 1.25m 2 ~1.5m 2 満 TS-1 50mg 25mg 2 1.5m 2 60mg 20mg 3 CA 2 Oxo 22

Mechanism of adverse events in patients with renal dysfunction Liver CDHP Renal Cell Cell disorder 23

TS-1 ng/ml 10000 1000 100 10 1 Mean SD, 12 FT 5-FU CDHP Oxo CA Uracil 0.1 0 6 12 18 24 30 36 42 48 hr 24

TS-1 Cmax ng/ml Tmax hr AUC 0-48hr ng hr/ml T1/2 hr FT 1971.0±269.0 2.4±1.2 28216.9±7771.4 13.1±3.1 5-FU 128.5±41.5 3.5±1.7 723.9±272.7 1.9±0.4 CDHP 284.6±116.6 2.1±1.2 1372.2±573.7 3.0±0.5 Oxo 78.0±58.2 2.3±1.1 365.7±248.6 3.0±1.4 CA 117.9±184.4 3.4±1.0 892.0±1711.7 3.8±1.6 Mean±SD 25

TS-1 20 25 TS-1 (Phase III) 26

Phase III Data in TS-1 Postoperative Gastric Cancer ACTS-GC Study (NEJM 2007) Advanced Gastric Cancer JCOG 9912 Study (Lancet 2009) SPIRITS Study (Lancet Oncology 2008) 27

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TS-1 In house data 100 90 % 80 70 60 50 40 30 20 12M 340 6-12M 40 6M 108 Surgery alone 530 12 S-1 12 10 0 0 1 2 3 ACTS-GC 37

TS-1 薬 Compliance In house data 100 90 % 80 70 60 50 40 30 20 10 Dose Intensity (% 90 168 70-90 108 70 64 Surgery alone 530 dose intensity 70% 0 0 1 2 3 ACTS-GC 38

Phase III Data in S-1 Postoperative Gastric Cancer ACTS-GC Study (NEJM 2007) Advanced Gastric Cancer JCOG 9912 Study (Lancet Oncology 2009) SPIRITS Study (Lancet Oncology 2008) 39

Combination Chemotherapy for treating advanced/metastatic GC Kim et al. 1993 FAM FAM < Wils et al. 1991 < Kelsen et al. 1992 CF FAMTX Before the platinum era: first-generation regimens EAP < FAMTX The platinum era: secondgeneration regimens FAMTX Webb et al. 1997 < ECF 40

Phase III studies with novel agents (Pre-S1 Era) Study Regimen Response Rate Time to progression REAL 2 (Oxalipla>n) German (FLO v.s FLP) V325 (Docetaxel) Epirubicin 50 mg/m 2 iv Oxa 130 mg/m 2 iv Capecitabine 625 mg/ m 2 /bd q3w Oxa 85 mg/m2 LV 200 mg/m2 5 FU 2,600 mg/m2 24 hour con6nuous infusion, Q2W Docetaxel 75mg/m 2 day1 CDDP 75mg/m 2 day1 5 FU 750mg/m 2 day1~5, q3w Overall Survival 1 yr survival 47.9% 7.0 mos 11.2 mos 46.8% 34.8% 41.3% (> 65yr) 5.8 mos 6.0 mos (> 65yr) 10.7 mos 13.9 mos (> 65yr) 45% 37% 5.6 mos 9.2 mos 40% V306 (Irinotecan) FA: 500 mg/m 2, 5 FU 2000 mg/m 2 as 22h CI, Irinotecan 80mg/m 2 31.8% 5.0 mos 9.0 mos NA 41

JCOG (Japan Clinical Oncology Group) 9912 Patients: Advanced/ metastatic gastric cancer 5-FU ci 800 mg/m 2 24 hr civ (d1-5), q4wks R Stratifications; PS, institutions, prior surgery, adjuvant chemotherapy CPT+CDDP CPT-11 70 mg/m 2 iv (d1,15) CDDP 80 mg/m 2 iv (d1), q4wks S-1 40-60 mg, bid ( 4 weeks on/ 2weeks off ) Primary endpoint: OS Secondary endpoints: adverse events, response, TTF, etc. No. of patients to be included: 689 pts Lancet Oncology 2009 42

43

Toxicity (grade 3/4) 5-FU (%) S-1 (%) CPT-11+CDDP (%) Neutropenia 1 6 65 Diarrhea 0 8 9 Stomatitis 3 2 0 Nausea 7 6 21 Anorexia 13 12 33 Lancet Oncology 2009 44

Conclusion Oral S-1 showed a significant noninferiority to 5-FU in survival with mild toxicities. S-1 should be considered for the standard chemotherapy for unresectable or recurrent gastric cancer Lancet Oncology 2009 45

Phase III Data in S-1 Postoperative Gastric Cancer ACTS-GC Study (NEJM 2007) Advanced Gastric Cancer JCOG 9912 Study (Lancet Oncology 2009) SPIRITS Study (Lancet Oncology 2008) 46

S-1/CDDP vs S-1 (SPIRITS) Patients: unresectable/recurrent gastric cancer R S-1+CDDP S-1: 40-60 mg, bid for 21 days q5wks CDDP: 60 mg/m 2 iv on day 8 N = 298 S-1 40-60 mg, bid (28 days q6wks) Primary endpoint: OS Secondary endpoints: PFS, TTF, Response, Safety. No. of patients: 298 pts Narahara: Lancet Oncology 2008 47

Estimated probability (%) 100 80 60 40 20 0 Overall Survival 11.0 13.0 S-1 S-1+CDDP No. of pts 150 148 Response Rate 31% 54% MST 11.0 13.0 1 yr survival 46.7 % 54.1 % 2 yr survival 15.3 % 23.6 % Log-rank p-value: 0.04 HR: 0.77 [ 95% CI: 0.61 0.98] Median follow-up time (M): 34.7 0 6 12 18 24 30 36 42 48 54 Months 48

Toxicity (grade 3/4) S-1/CDDP (%) S-1 (%) Neutropenia 40 11 Diarrhea 4 3 Stomatitis 1 0 Nausea 11 1 Anorexia 30 6 Narahara: Lancet Oncology 2008 49

Conclusions High efficacy was observed both in S-1 and S-1+CDDP arm The median survival time of S-1 was 11.0 M, moreover, that of S-1+CDDP was 13.0 M S-1+CDDP regimen can be regarded as the first-line standard treatment for AGC 50

S-1 PK in Chinese (Taiwanese) 51

A multi-center phase II and pharmacokinetic study of S-1 as first-line chemotherapy in Taiwanese advanced gastric cancer patients (TTYTG0501) Jen-Shi Chen, M.D 1., Yee Chao, M.D., Ph.D 2., Ruey-Kuen Hsieh, M.D. 4, Li-Tzong Chen, M.D 3., Ann- Lii Cheng, M.D., Ph.D 5., Po-Min Chen, M.D 6., Ph.D., Tzeon-Jye Chiou, M.D 6., Tsu-Yi Chao, M.D 7., Kun-Huei Yeh, M.D., Ph.D 5,8., Jacqueline Whang-Peng, M.D 3., 1. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Lin-Kuo, Taiwan 2. Cancer Center, Veterans General Hospital-Taipei, Taiwan 3. Cancer Cooperative Ward in Veterans General Hospital, Division of Cancer Research., National Health Research Institutes 4. Division of Hematology Oncology, Department of Internal Medicine, MacKay Memorial Hospital-Taipei 5. Division of Oncology and Hematology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan 6. Division of Medical-Oncology, Department of Internal Medicine, Veterans General Hospital-Taipei, Taiwan 7. Division of Hematology-Oncology, Department of Internal Medicine,Tri-Service General Hospital 8. Division of Oncology and Hematology, Department of Internal Medicine,Far Eastern Memorial Hospital 52

Study Design Study Design Open-label, non-comparative, multi-center phase II study Patient Number Simon s two stage optimal design P0=0.1 and P1=0.3 α = 0.05 and β = 0.20 Stage Stage I Stage II Requirement to Pass 2/10 6/29 53

Summary Efficacy Results End Points All Subjects (N=34) Evaluable Subject (N=29) Objective Response Rate (%) 35.3% (95% CI:19.2, 51.3) 41.4% (95% CI:23.4, 59.3) Median Time to progression (Days) 88 (95% CI:72.0, 176.0) 119 (95% CI:79.0, 221.0) Overall Survival (Days) 261 (95% CI:124.0, 408.0) 299 (95% CI:216.0, NA) Five subjects were not evaluable for response. 1 not eligible for study; 1 violation for protocol; 3 early withdraw (1 withdraw due to poor compliance, 2 early withdraw due to early death.) Follow-up on Jan. 2008, there are 3 patients continuing receiving study therapy in the extend study. 54

Study result : Summary of Adverse effect Grade 1 Grade 2 Grade 3 Grade 4 % of G3/4 Hematologic Leukopenia 5 (14.7%) 5 (14.7%) 4 (11.8%) 1 (2.9%) 14.7 Neutropenia 4 (11.7%) 6 (17.6%) 3 (8.8%) 1 (2.9%) 11.7 Anemia 8 (23.5%) 12(35.3%) 6 (17.6%) 2 (5.9%) 23.5 Thrombocytopenia 5 (14.7%) 0 (0.0%) 0 (0.0%) 2 (5.9%) 5.9 Non Hematologic Stoma>>s 6 (17.6%) 3 (8.8%) 2 (5.9%) 0 (0.0%) 5.9 Diarrhea 5 (14.7%) 8 (23.5%) 2 (5.9%) 0 (0.0%) 5.9 Nausea Vomi>ng 8 (23.5%) 5 (14.7%) 3 (8.8%) 2 (5.9%) 1 (2.9%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Pigmenta>on 1 (2.9%) 2 (5.9%) 0 (0.0%) 0 (0.0%) 0.0 Asthenia 15 (44.1%) 6 (17.6%) 4 (11.8%) 0 (0.0%) 11.8 Liver SGOT increase SGPT increase 7 (20.6%) 4 (11.8%) 4 (11.8%) 6 (17.6%) 4 (11.8%) 1 (2.9%) 0 (0.0%) 0 (0.0%) Renal Crea>nine increase 3 (8.8%) 0 (0.0%) 1 (2.9%) 0 (0.0%) 2.9 2.9 0.0 11.8 2.9 Maximal Adverse Events, n=34 (CTC v3.0, 2003) Cancer Chemo Pharm 2010 55

PK Comparison :Taiwan vs Japan S-1 components and its metabolite multiple dose pharmacokinetics after Dose normalization Parameters Taiwan Mean SD CV(% ) Japan Mean SD Day 1 n=12 n=12 5FU CDHP FT207 Oxo CV(%) P value* AUC 0-inf 15.14 6.08 40.1 13.67 5.77 42.2 0.460 C max 2.56 0.91 35.3 2.40 0.82 34.2 0.840 AUC 0-inf 30.83 14.07 45.6 26.60 11.92 44.8 0.229 C max 6.15 2.79 45.4 5.42 2.51 46.3 0.504 AUC 0-inf 572.07 125.66 22.0 591.95 204.08 34.5 0.857 C max 45.56 12.17 26.7 37.20 7.54 20.3 0.092 AUC 0-inf 8.49 6.28 73.9 7.25 5.16 71.3 0.478 C max 1.38 1.35 98.0 1.49 1.19 79.6 0.995 Day 28 n= 7 n=11 5FU CDHP FT207 Oxo AUC 0-τss 14.44 3.61 25.0 11.46 3.76 32.8 0.117 C max,ss 2.55 0.69 27.2 2.09 0.80 38.1 0.251 AUC 0-τss 28.48 9.78 34.3 24.28 8.47 34.9 0.348 C max,ss 6.44 2.11 32.8 5.14 2.84 55.2 0.313 AUC 0-τss 694.65 257.54 37.1 779.94 171.16 21.9 0.408 C max,ss 88.31 31.11 35.2 77.56 18.92 24.4 0.372 AUC 0-τss 12.60 9.43 74.8 11.83 18.08 152.8 0.921 C max,ss 2.46 1.82 74.3 2.34 3.68 157.1 0.949 56

Conclusion The present study demonstrates similarity between Taiwan and Japan patients in the PK of S-1 components and supports the use of Japan data in the evaluation of PK, safety, and efficacy for Taiwan patients. 57

Treatment of Advanced Gastric Cancer Median survival Best supportive care 5-FU FAM FAMTX DCF (V325) ECF Oxa+HDFL XP (ML17032) EOX (Real 2) S-1 monotherapy S-1+CDDP 3 4 mo 4 5 mo 4 5 mo 6.7 mo 9.2 mo 9.4 mo 10 mo 10.5 mo 11.2 mo 11.4 mo 13 mo 58

TS-1 20 25 59

TS-1 Tegafur Disseminated Intravascular Coagulation (DIC) Stevens-Johnson ) 壊 Lyell ( ) Nephrotic syndrome 60

( 2 ) mm 3 (300-2,990/mm 3 ) hemoglobin g/dl (3.5-7.9 g/dl) mm 3 (1.0-7.4/mm 3 ) Diarrhea Rash Stomatitis 61

# 578 55 59 59 55 (CTC 3 ) #2 87.2 (22.5 ) 96.4 30.9 98.3 (42.4 ) 94.9 (30.5 ) 100 (61.8 ) ( 2000/mm3 ) 45.8 ( 2.8 ) 69.1 9.1 32.2 ( 0.0 ) 49.2 ( 3.4 ) 52.7 ( 5.5 ) ( 1000/mm3 ) 43.9 ( 8.5 ) 72.7 10.9 27.1 ( 6.8 ) 42.4 ( 5.1 ) 65.5 (29.1 ) ( 8 g/dl) 38.1 ( 5.7 ) 45.5 3.6 50.8 ( 5.1 ) 50.8 ( 6.8 ) 90.9 (21.8 ) ( 5 104/mm3) 10.9 ( 1.6 ) 38.2 1.8 33.9 ( 1.7 ) 23.7 ( 0 ) 60.0 ( 1.8 ) AST GOT 11.1 34.5 18.6 37.3 14.5 ALT GPT 11.1 29.1 16.9 27.1 14.5 (CTC 3 ) 33.9 ( 3.5 ) 54.5 ( 5.5 ) 61.0 (13.6 ) 33.9 ( 6.8 ) 78.2 (12.7 ) (CTC 3 ) 22.3 ( 0 ) 47.3 ( 0 ) 55.9 (10.2 ) 32.2 ( 3.4 ) 65.5 (10.9 ) (CTC 3 ) 7.8 ( 0.5 ) 30.9 ( 0 ) 35.6 ( 5.1 ) 20.3 ( 1.7 ) 38.2 ( 7.3 ) (CTC 3 ) 18.7 ( 2.9 ) 38.2 ( 5.5 ) 37.3 ( 6.8 ) 22.0 ( 1.7 ) 34.5 ( 7.3 ) #3 22.3 47.3 47.5 35.6 内 17.1 41.8 25.4 27.1 25.5 21.3 47.3 39.0 42.4 23.6 11.8 16.4 22.0 22.0 9.1 #1 #2 CTC NCI-CTC (Japan Society for Clinical Oncology) #3 (fatigue) 62

(All grades) 5% 0.1% ~ 5% ( ) 増 増 酶 (GOT) 酶 (GPT) 酶 / 内 疱 疱 / 酶 酶 値 酶 ( 酶 ) ( ) 63

Toxicity (grade 3/4) Phase III Studies and Taiwan Experience Trials ACTS- GC (n=529) JCOG 9912 (n=234) SPIRITS (n=150) (n=148) TW EXP FLAGS (n=521) Grade3/4 (%) (%) (%) (%)* (%) (%)* Leukopenia 1.2 0.9 2 11 14.7 13.7 Neutropenia NA 5.6 11 40 11.7 32.3 Anemia 1.2 12.8 4 26 23.5 20.7 Thrombocytopenia 0.2 1.3 0 5 5.9 NA Diarrhea 3.1 7.7 3 4 5.9 NA Stomatitis 0.2 2 0 0.7 5.9 1.3 Nausea 3.7 5.6 1 11 2.9 NA Anorexia 5.8 12.4 6 30 17.6 NA * S1 + CDDP 64

TS-1 20 25 65

1. TS-1 TS-1 TS-1 TS-1 2. TS-1(dose-limiting toxicity DLT) (fluorouracil) 査 査 3. 査 (malaise) 黄 () 4. TS-1 (fluoropyrimidine) ( (folinate) tegafur-uracil ) flucytosine (severe blood dyscrasia) 5. TS-1 66

( TS-1) 1. TS-1 2. [] 3. [5-FU 酶 gimeracil 5-FU ] 4. [] 5. 6. flucytosine 7. 67

( ) (1) [] (2) [ (5-FU) 酶 gimeracil 5-FU (3) [] (4) [ 髄 ] (5) [] (6) [ ] (7) [ ] (8) [ ] (9) 68

(1) TS-1 7 (washout period) flucytosine (2) flucytosine TS-1 (3) (4) (gonadic) (5) TS-1 TS-1 TS-1 X [ ] 69

(1) (TS-1 ) fluorouracil (5-FU) tegafur/uracil (UFT) tegafur doxifluridine capecitabine Carmofur LV+UFT Levofolinate 5-FU flucytosine (blood dyscrasia) TS-1 7 (washout period) TS-1 TS-1 gimeracil 70

(2) (TS-1 ) phenytoin warfarin potassium phenytoin ( tegafur ) phenytoin 脲 Warfarin potassium 71

TS-1 産 (1) TS-1 [ tegafur/uracil ] [ TS-1 ( tegafur 7mg/kg 1.5mg/kg) ] (2) TS-1[ ( ) ] 72

TS-1 / 20mg/286 NTD/cap, 25mg/344 NTD/cap Total (2.5~3 ) 20 mg: $25,000~30,000/ (TS-1 ) 25 mg: $27,520/ (TS-1) 20 mg: $93,750~112,500/ 25 mg: $102,187/ Total (5 ) 20 mg: $187,500~225,000 25 mg: $206,400 73

TS-1 20 25 Thank you very much for your attention!!! 74

Mechanism of adverse events in patients with renal dysfunction Liver CDHP Renal Cell Cell disorder 75

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(Cisplatin ) 79

(Cisplatin ) 80

(Cisplatin ) 81

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creatinine Cockcroft-Gault ) 値 Ccr 値 FT 5-FT CDHP Oxo AUC AUC 0-8hr Ccr 値 >80 ml/min 50-80 ml/min FT 10060 ± 1842 11320 ± 2717 5-FU 541.2 ± 174.8 812.4 ± 244.9 CDHP 977.8 ± 327.9 1278.0 ± 306.6 Oxo 155.7 ± 97.5 458.2 ± 239.7 n=17 Ccr : >80 ml/min, n=11 Ccr : 50-80 ml/min, mean±s.d. Cockcroft-Gault Ccr = 140 kg / 72 creatinine mg/dl 0.85 85

Leukopenia 86

Diarrhea 87

Management for leukopenia 1W 2W 1M 2M 4M 6M >1Y 2~3 (WBC<2000/mm 3 ) G-CSF (Adenine) 88

Management for thrombocytopenia 1W 2W 1M 2M 4M 6M >1Y 2~3 ; 7 4 (Thrombocytes <7.5 /mm 3 ) DIC() Gabexate Mesilate Nafamostat-Mesilate Antithrombin III 89

Management for anemia 1W 2W 1M 2M 4M 6M > 1Y 8 4 (Hb <8 g/dl) (p-rbc) 90

Management for diarrhea ( ) 1W 2W 1M 2M 4M 6M >1Y 2~371 ~1 Albumin Tannate Loperamide Codeine phosphate () IVH 91

Management for GI bleeding 1W 2W 1M 2M 4M 6M >1Y 6 1 ( ) Carbazochrome Tranexamic acid thrombin 92