Trans-arterial Chemotherapy for advanced HCC 가톨릭의대소화기내과 배시현
간암은진행된병기에서발견되는경우가많다 2004 국립암센터 I 6.5% II 20.1% III 30.9% IVa 25.2% IVb 17.3%
난치성진행성간암 가톨릭 Tx? TAC 계명대 TAC + others conservative 고대 순천향 아주대 6 개연구기관별진행성간암증례 연대
난치성진행성간암의예후
TNM Stage Therapeutic strategies according to stage and liver function Local therapy (RF,PEIT) Transplantation C TACE? C-P class B III IV A I II Resection, LT Local therapy (RF, PEIT)
진행성간암의예후개선을위한대책 기존치료법활용 간동맥화학색전술 간동맥화학주입법 전신항암화학요법 방사선치료법 병합요법 혁신적치료법개발 표적치료제 면역세포치료 유전자치료?? 문제점? 기존치료법들의세부진료지침미정립
간세포암종진료가이드라인대한간암연구회, 국립암센터 ( 대한간학회지 2004;10:88-98)
암정복추진사업 : 2006-2008 다기관공동간암임상연구 진행성간암의표준치료지침개발을위한대한간암연구회공동임상연구 원자력의학원가톨릭의대연세의대한림의대서울의대 한철주배시현성진실김동준한서경
연구목표 진행성간암에대해기존치료법들을잘적용할수있는방안을찾고, 체계적이고구체적이며상세한치료지침을제시하고자함
진행성간암의표준진료 지침개발 2 세부과제 : 간동맥항암주입요법 다기관공동임상연구
6 개기관공동연구자 가톨릭의대 고려대의대 계명대의대 순천향의대 아주대의대 연세대의대
1 단계 1 차연도 : 국내간세포암치료의고찰과다기관임상연구설계 1. 후향적연구를통한자료수집, 기초설계와전향적연구모형개발 2. 항암제효능평가를위한선정기준구축 3. 단기임상연구진행 대한간암연구회협조 1 단계 2 차연도 : 간동맥내항암주입요법의표준치료지침개발 1. 대규모전향적다기관장기임상연구진행 2. 대상환자의임상연구자료및결과에대한통계분석 1 단계 3 차연도 : 대한간암연구회를통한표준치료지침의최종안수립과보급 1. 표준지침의최종안수립 2. 대한간암연구회를통한표준치료지침의보급 2 단계 : 구축된표준치료지침을간세포암치료에다각도로적용 1. 간동맥화학요법과다른치료법병용 : 비교임상연구
연구방법 Regimen: cisplatin/ 5-FU 대상환자수 : 300 명 ( 각기관별 50 명 ) 평가 : 치료반응율, 부작용발생율, 치료순응도 대상환자선정기준 간세포암종확진 i) 간문맥침습진행성간세포암 ( 혈관내단락포함 ) ii) 미만성진행성간세포암 iii) 기존간동맥화학색전술에불응하는진행성간세포암 건강한간기능 (Child-Pugh score 6 점이하 ) 18 세이상 70 세이하 ECOG performance status 0,1 ANC > 1,500, plt > 60k Cr < 1.5, aminotransferase <200 No distant metastasis 본연구계획서에따라치료와추적관찰이가능한환자
간동맥항암주입요법을위한 - Chemoport 장착법 - A B Infusion pump Tumor Tumor CHA Tumor C Chemoport D Catheter
항암제종류및용량 간동맥항암주입요법의치료방법과프로토콜 저용량군 : 7mg/m 2 cisplatin (5 일간 ) + 170mg/m 2 5-FU (5 일간 ), 3-4 주간격 고용량군 : 60mg/m 2 cisplatin (1 일간 ) + 500 mg/m 2 5-FU (3 일간 ), 3-4 주간격 1 cycle(3-4 주간격 ) CF CF 저용량군 고용량군 CF CF
제 2 세부과제환자등록현황 공동연구기관 최종등록 치료중단 * 분석중 + 최종분석 가톨릭대학교 11 1 1 9 계명대학교 8 1 2 5 고려대학교 7 1 6 순천향대학교 10 3 7 아주대학교 9 3 1 5 연세대학교 24 3 2 19 합계 69 8 10 51 * Enroll 되었으나치료는못함 (1 명 ), 1 차치료후간기능악화및부작용으로치료중단 + 1 차치료후반응평가가안된상태
대상환자들의특성 (1) 전체환자수 ( 명 ) 69 연령 ( 세 ) 중앙값 ( 범위 ) 54 (30-69) 성별남성 / 여성 61/ 8 Child 등급 A/ B/ C 63 / 6 / 0 발병원인 HBV/ HCV/ alcohol/ unknown 52 / 8 / 5/ 3 과거치료경력환자 ( 25 명 ) 치료명 간동맥화학색전술 (20) TAC+PEI (2) TAC+OP(3)
대상환자들의특성 (2) 종괴의형태 ( 명 ) nodular/massive/infiltrative/noduloinfitrative 10/23/31/4 종괴의개수 (single/multiple) 8/61 평균종괴크기 (cm) 12 (2.5-24.8cm) 간문맥침범 (61 명 ) Stage (UICC) III IVA 치료전 AFP 중앙값 ( 범위, ng/ml) 20 Main PV 26 Rt or Lt PV 14 Main + Rt or Lt PV 8 61 1477 (2.7-1558000)
고용량 / 저용량군환자들의특성 (N=69) 고용량 (38명) 저용량 (31명) P-value 연령 ( 세 ) 53 (30-69) 54 (32-69) 0.753 원인 HBV/HCV/other 32/3/3 22/4/5 0.327 병기 UICC (III/IVA) 5/33 2/28 0.586 종양크기 12±4 11±4 0.651 AFP 1393 (3.2-1558000) 1920 (2.7-185142) 0.575 치료회수 1 회 /1 회이상중앙값 ( 범위 ) 8/30 2 (1-7) 10/21 2 (0-7) 0.292 항암제용량 Cisplatin 5-FU 102 (60-120) 890 (500-1000) 12 (9-14) 290 (232-340) <0.001 <0.001 Child 등급 (A / B) 35/3 28/3 0.794 평가불가 ( 중단 / 분석중 ) 6 (2/4) 12 (6/6) 0.031
치료반응 (N=51) 치료반응 고용량 저용량 PR + SD 17 (4 PR * ) 6 PD 15 13 Total 32 19 고용량과저용량에서임상적치료반응은 54% 와 31% 였다. *, 4 개기관 1 명씩
생존율 Median follow-up period (range) : 105 (9-333 days) 고용량군에서생존율이좋은경향
치료부작용 고용량저용량 P-value 용량감소 6 5 0.848 부작용 13 11 0.672 Hematologic anemia leukopenia thrombocytopenia Non-hemotologic gastrointestinal hepatic toxicity nephrotoxicity Others Infection renal toxicity 간내합병증 9 7 0.914 0 4 2 6 1 0 2 2 0 4 0 5 2 0 0 1
문제점과요약 연구의한계점 대상환자등록의어려움 (Child A, no metastasis, 병합치료를우선적으로 ) 치료중진행성간세포암환자의임상경과가치료에비해빠르다 현항암제사용량의제한에의한난치성간암의진행으로추가병용요법이필요 1. 고용량군의치료반응이저용량군보다우수 2. 양군의부작용의차이는없었고, 치료순응도는고용량군이좋았음. 3. 3 차년도에최종분석을통한치료지침수립하여다각도의비교임상연구계획 - 표적치료제와병용요법 - 방사선치료와병용요법
Application of Trans-arterial Chemotherapy using Chemoport - metronomic chemotherapy -
What is the metronomic chemotherapy?
Schedules of maximum tolerated dose (MTD) and metronomic chemotherapy -more toxic - frequent drug resistance - same efficient - low toxicity - no drug resistance Nature Reviews Cancer 4, 423-436 (June 2004) Optimal biologic dose (OBD) or a minimally effect concentration (MEC) for the longest time.
angiogenesis Angiogenesis persists during progression to expansive solid tumors and invasive cancer. Angiogenesis is a rate-limiting step not only in tumor growth but also in carcinogenesis. Therapeutic target inhibition of angiogenesis Metronomic therapy > MTD pulsatile therapy Bergers G, et al. Science. 1999;284:808-12. Bolontrade MF, et al. Carcinogenesis 1998;19:2107-2113. Bertolini F, et al. Cancer Res. 2003;63(15):4342-6.
Therapeutic effects of metronomic chemotherapy for HCC rat model Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea Seong Tae Park, Gi Dae Kim, Hyun-Young Woo, Jin-Dong Kim, Jung-Hyun Kwon, Chan-Ran Yoo, Jeong-won Jang, U-Im Jang, Chang-Uk Kim, Chan-kwon Jeong, Eun-Sun Jeong, Si-Hyun Bae, Jong-Young Choi, Seung-Kew Yoon
HCC rat model induced by DEN DEN i.p 50mg/kg(BW) once/week DEN-induced HCC for 16 weeks (week) -2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 16 19 22 25 Maxium Toleratd Dose Group Metronomic Group Metronomic + VEGF Group 3 times per week, during 2 weeks resting, 40mg/kg/day CTX i.p 16 19 22 25 2 times per week, 20mg/kg/day CTX i.p 16 19 22 25 2 times per week, 20mg/kg/day CTX i.p + 5 mg/kg bevacizumb i.p injection every two weeks
Effect of metronomic chemotherapy on anti-angiogenesis Comparison of CEC evaluation by cytometry Comparison of VEGF expression levels in each groups CEC p o p ulation (% ) 0.18 0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0.00 MTD MET MET + VEGF CD31 VEG F levels (pg/m l) 200.00 180.00 160.00 140.00 120.00 100.00 80.00 60.00 40.00 20.00 0.00 MTD group CD31 MTD MET MET + VEGF metronomic group
Effect of metronomic chemotherapy on survival in hepatocellualr carcinoma 120 100 Survival (%) 80 60 40 20 0 P = 0.002 0 10 20 30 40 50 60 (Days) MTD Metronomic Metronomic + bevacizumab
Metronomic chemotherapy for advanced primary hepatocellular carcinoma Department of Internal Medicine, and Radiology*, College of Medicine, WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea Hyun Young Woo, Si Hyun Bae*, Jin Dong Kim, Jung Hyun Kwon, Chan Ran You, Jung Won Jang, Jong Young Choi, Seung Kew Yoon, Sang Wook Choi, Nam Ik Han, Young Suk Lee, Ho Jong Chun*, Byong Kil Choi*
Method Metronomic group (n=20) -35mg/m 2 epirubicin, 15mg/m 2 cisplatin, 50mg/m 2 5-FU 1 cycle: 4 주 ECF ECF D1 D7 D14 D21 D28 D35 D42 D49?? ECF CF CF REST ECF CF CF REST TAC group (n=22) Age, sex matched 35mg/m 2 epirubicin, 45mg/m 2 cisplatin, 150mg/m 2 5-FU Cycle : every 4 week
Result (I) Patients Characteristics Metronomic group (n=20) TAC group (n=22) P-value 53 (36-89) 53 (37-83) 0.384 Sex (M/F) 20/0 20/2 0.489 HBV/HCV/NBNC 18/2/0 19/1/2 0.321 Child score A/B 6 (5-7) 15/5 6 (5-8) 20/2 0.115 0.229 Tumor size (cm) 12.3 (6.3-21) 9.4 (4.7-18.3) 0.028 Tumor stage AJCC (IIIA/IIIC/IV) UICC (III/IVA/IVB) Tumor type (multinodular/massive/ infiltrative) 10/1/9 1/9/10 20/1/1 0/21/1 0.008 0.001 3/0/17 6/1/15 0.362 AFP (ng/ml) 409 (3.06-92320) 168 (3.18-11977) 0.562 PIVKA II (mau/ml) 441 (11-8990) 1875 (22-2000) 0.241 Previous treatment 10/10 4/19 Age (years)
Results (II) Treatment Response P=0.070 P=0.339 TAC :19 (86.4%) Metronomic :12 (60%) metronomic TAC Time to progression(median, days) : 77±21 vs. 69±21 (metronomic vs. TAC) Disease control rate (PR+SD) (overall) (%) Disease control rate (PR+SD) (2 주기이상 ) (%) Metronomic (n=20) TAC (n=22) P-value 16 (80) 10 (45.5) 0.021 13/15 (86.7) 9/17 (52.9) 0.040
CASE: 54/M, HCC with lung metastasis 5-FU syst continuous chemotherapy 1 st TACI (2007/2/2) 3 rd TACI (20074/4) 5 th TACI (2007/6/1) 07-2-2 07-4-4 07-6-1 AFP 72.92 46.31 18.22 PIVKAII 2000 2000 39
Results (III) Survival rate 93.8% P value=0.021 54.7% 43.8% Metronomic 59.1% 40.9% 13.6% TAC Metronomic 20 10 6 4 2 TAC 22 14 10 4 3 3 1 1 Median survival duration (days): 261 vs. 112 (metronomic vs. TAC)
Results (IV) Complication Complication metronomic (n=20) MTD (n=22) P-value Abd discomfort 5 (25%) 3 (13.6%) NS Abnormal LFT 2 (10%) 4(18%) NS Leukopenia 9 (45%) 4 (18%) NS Ulcer bleeding 1 (5%) 2 (9%) NS Tx number 2.5 (1-10) 3 (1-10 ) NS Dose reduction 10 (50%) 7 (31.8%) NS Treatment discontinuation 5 (25%) 10 (45.5%) NS
Summary and Conclusion 1. Metronomic chemotherapy is more effective treatment for advanced HCC with PVT than TAC alone. ( 6mo. TR 80% vs. 45.5%, P value=0.021 ) 2. Metronomic improved survival in our study. (median survival 261 days vs. 112 days, P value=0.021) 3. Metronomic chemotherapy is tolerable treatment method. multicenter, large-scaled clinical trial
Treatment for advanced HCC TACE Additional modalities 1. local therapy 2. Radiotherapy 3. 표적치료제 (sorafenib etc.) dose & method Adv HCC (stage > III and IVa) Improve response and survival
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