肝癌規(guī)范化治療課件

1、肝癌,中國醫(yī)學科學院腫瘤醫(yī)院內(nèi)科依荷芭麗.遲,HCC 數(shù)據(jù),1. Perz JF, et al. J Hepatol. 2006;45:529-38. 2. Jelic S. Ann Oncol. 2009;Suppl 4:iv41-5. 3. Garcia M, et al. American Cancer Society. 2007. www.cancer.org. Accessed Jan 2010.4. Llovet J

2、, J Hepatol. 2000;33:423-9. 5. Marrero CR, Marrero JA. Arch Med Res. 2007;38:612-20.,Subject to PATH Program Disclaimer,3,,男,女,,,數(shù)據(jù)來源：(中國2014年腫瘤登記年報),,,HCC流行病學,El-Serag HB. Clin Liver Dis. 2001;5:87-107.,Subject to PATH

3、Program Disclaimer,El-Serag HB, Rudolph KL. Gastro. 2007;132:2557-76.,HCC地域死亡率 (每100,000人 ),,,Subject to PATH Program Disclaimer,HCC高危因素和發(fā)病率,> 80% HCC 與HBV或 HCV相關(guān),,,,Llovet JM, et al. Lancet. 2003;362:1907-7.Pisani e

4、t al. Cancer Epidemiol Biomarkers Prev. 1997 ;6:387-400.,Subject to PATH Program Disclaimer,肝癌風險合并超重肥胖與正常體重人群對比薈萃分析,El-Serag HB, et al. Gastroenterology. 2004;26:460-8.,肝細胞高位因素: 糖尿病,Subject to PATH Program Disclaimer,肝細胞

5、肝癌: 男性多于女性,,Database ITA.LI.CA, 2008.,Subject to PATH Program Disclaimer,肝細胞肝癌: 人種差別 (USA),遺傳多態(tài)性: 免疫應答 (i.e. HCV) 炎癥反應 酒精代謝, 環(huán)境致癌胰島素抗藥性治療反應(IFN),Thorgeirsson SS, et al. Hepatology. 2006;43(2 Suppl 1):S145-50.Avila

6、 MA, et al. Oncogene. 2006;25:3866-84.,Subject to PATH Program Disclaimer,HBVHCV酒精黃曲霉毒素B1,損傷,,干細胞增殖停止星形細胞活化,,慢性肝病,Liver cirrhosis,Abnormal livernodules,Extensive scarring(collagen),,染色體不穩(wěn)定,,染色體重度不穩(wěn)定和P53缺失,Hepatoc

7、ellularcarcinoma,幼稚細胞結(jié)節(jié),Hyperplasticnodule,分化好的,中等分化的,分化差的,,增殖,壞死,,,,,Farazi PA, DePinho RA. Nat Rev Cancer. 2006;6:674-87.,肝細胞肝癌的組織病理學和分子病理學特征,Subject to PATH Program Disclaimer,結(jié)節(jié)增生,Bruix J, et al. J Hepatol. 2001;35

8、:421-30.,Subject to PATH Program Disclaimer,非轉(zhuǎn)移早期肝癌的診斷標準,,,,,,,肝功能分期 Child-Pugh 分級腫瘤大小分期TNMVauthey (改良的TNM )Izumi (改良的TNM )JS (日本分期)聯(lián)合分期(肝功能和腫瘤) OkudaCancer of the Liver Italian Program (CLIP)Chinese Universit

9、y Prognostic Index (CUPI)Japanese integrated staging score (JIS)Barcelona Clinic Liver Cancer (BCLC),Subject to PATH Program Disclaimer,HCC 分期,Kudo M, et al. J Gastroenterol. 2003;38:207-15;Wildi S, et al. Br J Surg.

10、2004;91:400-8;Dohmen K, et al. J Gastroenterol Hepatol. 2004;19:1227-32;Marrero JA, et al. Hepatology. 2005;41:707-16.,HCC不同分期包含變量指標 (1),腫瘤大小病變數(shù)量血管侵犯病變累及程度遠處轉(zhuǎn)移肝硬化Child-Pugh 分級實驗室檢查其他 (門靜脈血栓, AFP, 腹水等.),Subject

11、to PATH Program Disclaimer,Kudo M, et al. J Gastroenterol. 2003;38:207-15;Wildi S, et al. Br J Surg. 2004;91:400-8;Dohmen K, et al. J Gastroenterol Hepatol. 2004;19:1227-32;Marrero JA, et al. Hepatology. 2005;41:707-1

12、6.,Subject to PATH Program Disclaimer,HCC不同分期包含變量指標(2),Wildi S, et al. Br J Surg. 2004;91:400-8.,日本分期 (JS),UICC 2002 TNM分期,,Subject to PATH Program Disclaimer,Wildi S, et al. Br J Surg. 2004;91:400-8.,T1期評定中的問題 (1),,Subj

13、ect to PATH Program Disclaimer,TNM stage according to UICC 2002,Wildi S, et al. Br J Surg. 2004;91:400-8.,18,Child-Pugh 評分,Pugh RN, et al. Br J Surg. 1973;60:646-9.,Subject to PATH Program Disclaimer,HCC Child-Pugh 分期與生存

14、,Kudo M, et al. J Gastroenterol. 2003;38:207-15.,Subject to PATH Program Disclaimer,CLIP評分系統(tǒng),CLIP Investigators. Hepatology. 1998;28:751-5.,Subject to PATH Program Disclaimer,早期HCC在多種分期中的判定,早期肝癌診斷在不同分期標準中均不夠準確 TNM 分期

15、(獨立病灶, ≦ 5 cm, 未限定肝功能狀態(tài))Child-Pugh 評分 (未限定腫瘤大小)OKUDA 和 CLIP (涉及瘤負荷占肝臟體積 < 50% )JIS 分期較好; 定義了較早期肝癌 (JIS 評分 = 0) 較準確判定早期肝細胞肝癌 (JIS評分 = 1） 包括了門靜脈血栓, 或 Child-Pugh B 或10 cm的大肝癌),Subject to PATH Program Disclaimer,

16、Kudo M, et al. J Gastroenterol. 2003;38:207-15;Llovet JM, et al. Semin Liver Dis. 1999;19:329-38.,BCLC 分期,*Grieco A, et al. Gut. 2005;54:411-18;Llovet JM, et al. Semin Liver Dis. 1999;19:329-38.,Subject to PATH Program

17、 Disclaimer,,Yes,No,3 nodules ≤ 3 cm,,,,,,,,,,,,,,,,,,,,,,,,,,,,,a Presence of vascular invasion or extrahepatic metastasis to be indicated separatelyb Selected when the severity of liver damage is class B and the tumor

18、 diameter is ≤ 2 cmc Tumor diameter ≤ 5 cm, when there is only one tumor,,Japanese HCC guidelines (ctd),Subject to PATH Program Disclaimer,Kokudo N, Makuuchi MJ. Gastroenterology. 2009;44 Suppl XIX:119-21.,,,,,HCC and p

19、ercutaneous ablation (ctd),Hasegawa K, et al. J Hepatol. 2008;49:589-94.,Subject to PATH Program Disclaimer,,,,,Surgical resection vs percutaneous ablation for hepatocellular carcinoma: a preliminary report of the Japa

20、nese nationwide survey,Subject to PATH Program Disclaimer,Hasegawa K, et al. J Hepatol. 2008;49:589-94.,,,,,Surgical resection vs percutaneous ablationfor hepatocellular carcinoma: a preliminary report of the Japanese

21、nationwide survey,Subject to PATH Program Disclaimer,Hasegawa K, et al. J Hepatol. 2008;49:589-94.,,Yes,No,3 nodules ≤ 3 cm,,,,,,,,,,,,,,,,,,,,,,,,,30,Liver transplantation for HCC Results of liver transplantation: ELT

22、R data,,29,31,Liver transplantation for HCC Results of liver transplantation: ELTR data,32,HCC肝臟移植: 生存與腫瘤大小相關(guān),,,,,Single HCC ≤ 5 cm,2–3 HCCs ≤ 3 cm,33,HCC肝臟移植: 生存與腫瘤大小相關(guān),,,,,Single HCC > 5 cm,>3 HCCs > 3 cm,,擴

23、大肝臟移植適應癥的原則: 生存延長：5年生存率>50％ 移植獲益：移植生存獲益優(yōu)于非移植 等待肝源的死亡風險,34,HCC肝臟移植手術(shù): 生存與腫瘤體積呈負相關(guān),35,Subject to PATH Program Disclaimer,,,,,,,,,,,Cucchetti A, et al. Am J Transplant.2010;Jan 29 [Epub ahead of print].,,Y

24、es,No,3 nodules ≤ 3 cm,,,,,,,,,,,,,,,,,,,,,,,,,37,,,細胞熱效應,105°C,,100°C,60°C,46°C,42°C,40°C,,,,,,Subject to PATH Program Disclaimer,沸騰，汽化和炭化瞬時蛋白質(zhì)凝固不可逆的損害增加對化療藥物的敏感性和輻射細胞動態(tài)平衡,38,RF a

25、blation: armamentarium,,,Expandable needle (Radiotherapeutics – RITA),Single needle – cooled tip (Radionics),Catheter needle (Miras),Cluster needle (Radionics),Subject to PATH Program Disclaimer,39,,,小肝癌研究 (1–3 cm),,PEI

26、組: pCR 48/60 (80%)RF組: pCR 47/52 (80%),1. Livraghi T, et al. Radiology. 1999;210:655-61. 2. Livraghi T, et al. Hepatology. 2008;47:82-9.,1,Subject to PATH Program Disclaimer,40,,,Alcohol,胞質(zhì)蛋白的脫水和由此產(chǎn)生的腫

27、瘤細胞凝固性壞死內(nèi)皮細胞，血小板聚集和血管血栓形成，導致腫瘤組織缺血壞死,,經(jīng)皮無水酒精消融作用,Germani G, et al. J Hepatol. 2009;doi:10.1016.,Subject to PATH Program Disclaimer,41,,,PEI-治療的生存結(jié)果(回顧性研究),,,,Author and year,Shiina S, et al.1Livraghi T, et al.2

28、 Child A, single < 5 cm Child B, single < 5 cmLencioni R, et al.3 Child A, single/multiple < 3 cm Child B, single/multiple < 3 cm,8598 93 100 91,627963 8753,No. of patients,

29、982931496441,Survival (%),3 years,5 years,,1 year,524729 5513,1. Shinna S, Am J Roentgenol. 1993;160:1023-8.2. Livraghi T, et al. Radiology. 1995;197:101-8.3. Lencioni R, et al. Cancer. 1995;76:1737-46

30、.,Subject to PATH Program Disclaimer,,,Long-term survival of HCC patientsafter microwave ablation,Liang P, et al. Radiology. 2005;235:299-307.,Subject to PATH Program Disclaimer,,Yes,No,3 nodules ≤ 3 cm,,,,,,,,,,,,,,,,,

31、,,,,,,,,44,藥物+離子載體+栓塞劑 =,Subject to PATH Program Disclaimer,45,中期HCC,single HCC > 5 cm,44,,多發(fā) HCC ≥ 3個腫瘤, 腫瘤大小 ≥ 3 cm,,,無腫瘤相關(guān)癥狀無血管侵犯和/或肝外轉(zhuǎn)移Child-Pugh class A–B,TACE理想選擇,ORR: 30%–60%死亡率 < 4%,12% HCC,Kudo M, et

32、 al. Oncology. 2007;72 Suppl 1:2-15.Llovet JM, et al. J Nat Cancer Inst. 2008;100:698-711.,Subject to PATH Program Disclaimer,,46,TACE治療,射頻消融或無水酒精注射后的鞏固治療術(shù)前新輔助治療術(shù)后輔助治療肝移植手術(shù)等待期治療,45,47,TACE-TAE: 生存延長,RCTTACE vs TA

33、E vs 保守治療,Llovet, Lancet 2002,Lo, Hepatology 2002,RCTTACE vs 保守治療,Llovet JM, et al. Lancet. 2002;359:1734-9. Lo CM, et al. Hepatology. 2002;35:1164-71.,Subject to PATH Program Disclaimer,48,TACE-TAE: survival advantage

34、s,不能手術(shù)切除的肝癌的標準治療: 與對照組相比TACE提高患者2年生存率 客觀率反應率約35％（16％-61％）TACE與順鉑或阿霉素聯(lián)合較單純TAE帶給患者生存獲益,,Llovet JM, Bruix J. Hepatology. 2003;37:429-42.,Subject to PATH Program Disclaimer,,Yes,No,3 nodules ≤ 3 cm,,,,,,,,,,,,,,,,,,,,,,,

35、,,“不能切除的”患者并不代表晚期,HCC,Terminalstage,PST 0-2, Child–Pugh A–B,Multinodular, PST 0,N1, M1, PST 1–2,Intermediate stage,PST > 2,Child–Pugh C,Very early stage,Single < 2 cm,Early stage,Single or 3 nodules,Advanced st

36、age,Portal invasion,,PST 0, Child–Pugh A,,,,,,,,Subject to PATH Program Disclaimer,,,中期或晚期肝癌患者的預后不佳1,70–80% 肝癌患者在確診時已為中晚期 , 失去根治機會1 102 肝癌患者生存分析2患者中不包括接受過根治性治療* 或 終末期患者 ?,*Surgical resection, liver transplantation o

37、r ethanol injection?Okuda stage 3 or performance status ≥3,1. Llovet JM. Gastroenterology. 2005;40:225-35. 2. Llovet JM. Hepatology.1999;29:62-7.,HCC = hepatocellular carcinoma; OS = overall survival,Subject to PATH Pr

38、ogram Disclaimer,化學治療或內(nèi)分泌治療: 晚期肝癌幾乎無效,1. Yeo W, et al. J Natl Cancer Inst. 2005;97:1532-8. 2. Sciarrino E, et al. Cancer. 1985;56:2751-6.3. Leung TW, et al. Clin Cancer Res. 1999;5:1676-81. 4. Okada S, et al. Oncology.

39、 1993;50:22-6. 5. Hochster HS, et al. J Clin Oncol. 1985;3:1535-40. 6. Pohl J, et al. Chemotherapy. 2001;47:359-65.7. Dunk AA, et al. J Hepatol. 1985;1:394-404. 8. O’Reilly EM, et al. Cancer. 2001;91:101-5. 9. Chao Y,

40、et al. Br J Cancer. 1998;78:34-9. 10. Fuchs CS, Cancer. 2002;94:3186-91. 11. Lin DY, et al. Gastroenterology. 1988;94:453-6.12. GETCH. Hepatology. 2004;40:1361-9. 13. Llovet JM, et al. Hepatology. 2000;31:54-8. 14. Yu

41、en MF, et al. Hepatology. 2002;36:687-9; 15. Dalhoff K, et al. British J Cancer. 2003;89:252-57.,PIAF = cisplatin, IFN α-2b, doxorubicin, Adriamycin, and 5-fluorouracil,Subject to PATH Program Disclaimer,晚期肝細胞肝癌治療 (BCLC

42、C期),2005美國肝臟病研究協(xié)會(AASLD) 推薦是： 沒有標準治療. 患者可以入組隨機臨床研究12008更新: sorafenib 為標準治療延長44%肝功能較好患者的生存2,3 Sorafenib 療效在 Asia–Pacific trial同樣被進一步證實延長47% 亞洲肝細胞肝癌患者的生存4,1. Bruix J, et al. Hepatology. 2005;42:1208-36.2. Llove

43、t J et al. N Engl J Med. 2008;359:378-90.3. Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-7114. Cheng A-L et al. Lancet Oncol 2009;10:25-34.,Subject to PATH Program Disclaimer,,,,,,,BCLC staging and treatment stra

44、tegy,HCC,,Stage A–COkuda 1–2, PST 0–2, Child-Pugh A–B,Stage 0PST 0, Child-Pugh A,Stage DPST >2,Child-Pugh C,Very early stage (0)Single <2 cmcarcinoma in situ,Early stage (A)1–3 nodules <3 cm,PS 0,Interme

45、diate stage (B)Multinodular,PS 0,Advanced stage (C)Portal invasion, N1, M1, PS 1–2,End stage (D),Single,3 nodules ≤3 cm,Portal pressure/bilirubin,Increased,Associated diseases,Normal,No,Yes,Resection,Liver transplant

46、ation(CLT/LDLT),PEI/RFA,Chemoembolization,Sorafenib,Curative treatments,,Randomized controlled trials,RFA = radiofrequency ablation;PEI = percutaneous ethanol injection.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Llovet JM, et al.

47、J Natl Cancer Inst. 2008;100:698-711.,Subject to PATH Program Disclaimer,NCCN Guidelines (2009),NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancer. V2.2009; Available at: www.nccn.org. Accessed February

48、 2010.,Subject to PATH Program Disclaimer,,Japan Society of Hepatology:consensus-based treatment algorithm for HCC,Kudo M. Oncology. 2009;75 Suppl 1:1-12.,Subject to PATH Program Disclaimer,,,Extrahepatic metastasis Ma

49、in portal vein tumor thrombus,Resectable,Solitary tumor ≤ 5 cm ≤ 3 tumors ≤ 3 cmNo venous invasion,Child-Pugh A Child-Pugh B Child-Pugh C Child-Pugh A / B Ch

50、ild-Pugh C,Supportive care,HCC,Confined to the liverMain portal vein patent,APASL working committee meeting consensus on treatment guidelines for HCC,Tumor > 5 cm> 3 tumorsInvasion of hepatic / portal vein branc

51、hes,,,,,,,,,,,,,,,,,,,,,,,,,,Yes,No,,,Child –Pugh A / B Child-Pugh C,,,,,,,,,Omata M et al., APASL working committee meeting consensus on HCC, APASL February 13–16, 2009, Hong Kong,Subject to PATH Pr

52、ogram Disclaimer,,肝細胞肝癌的發(fā)病機制與多個信號傳導通路相關(guān),,,細胞膜,,Wnt 受體,,,,,,,,,,,,,,,,,,,,,,,,,,,,,p53,,,RTK: FGFR EGFRIGF-IRc-MET,受體r,,Adapted from Avila MA, et al. Oncogene. 2006;25:3866-84.,Subject to PATH Program Disclaimer,肝細胞

53、肝癌的分子學發(fā)病機制,肝細胞肝癌的發(fā)病機制與多個信號傳導通路相關(guān)肝細胞惡變是基于炎癥、細胞再生、細胞增生、肝硬化、遺傳、后天因素等 肝細胞肝癌多伴有細胞信號通路失調(diào)，主要包括：1,2血管生成信號Ras/Raf/MEK/ERK PI3K/Akt/mTORWnt/β-catenin,分子治療的主要靶點,,1. Thorgeirsson S, et al. Hepatology. 2006;43:S145-50.2. Avi

54、la MA, et al. Oncogene. 2006;25:3866-84.,Subject to PATH Program Disclaimer,肝細胞肝癌靶向治療:臨床研究,肝細胞肝癌臨床研究全面展開 Sorafenib 的有效性，引發(fā)靶向治療臨床研究 主要在早期和晚期患者臨床研究， 一線治療、二線治療及輔助治療方面的研究,Llovet JM , Bruix J. J Clin Oncol. 2009;27:833-35

55、.,Subject to PATH Program Disclaimer,Adapted from Tanaka S, Arii S. Cancer Sci. 2009;100:1-8.,臨床開發(fā): 分子靶向藥物和其主要靶點,Subject to PATH Program Disclaimer,III期臨床研究:分子靶向藥物和其主要靶點,Sorafenib targets both tumor-cell proliferation an

56、d angiogenesis in vitro,KIT/Flt-3/RET,Endothelial cell or pericyte,VEGFR-2,PDGFR-β,Tumor cell,Wilhelm SM, et al. Cancer Res. 2004;64:7099-109 .,,,Ras,Subject to PATH Program Disclaimer,,,,,,,,Primary endpoints: OS, TTSP

57、Secondary endpoints: TTP, DCR, safety,Phase III SHARP and Asia–Pacific studies,Endpoints: OS, TTSP, TTP, DCR, safety (no primary endpoint defined),1. Llovet JM, et al. N Engl J Med 2008;359:378-90. 2. Cheng A-L, et al.

58、Lancet Oncol 2009;10:25-34.,Subject to PATH Program Disclaimer,Sorafenib consistently increased overall survival in different global patient populations,HR = hazard ratio; OS = overall survival; SHARP = Sorafenib Hepato

59、cellular Carcinoma Assessment Randomized Protocol.,Llovet JM et al. N Engl J Med. 2008;359:378-90. Cheng A-L, et al. Lancet Oncol. 2009;10:25-34.,,,,Survival probability,1.00,0.75,0.50,0.25,Months,0,4,6,8,10,12,14,16,2,

60、,,,,,,,,,,0.00,Sorafenib (n=299)Median OS: 10.7 months,Placebo (n=303)Median OS: 7.9 months,,,,,,,,,,,,,18,,,,Survival probability,1.00,0.75,0.50,0.25,Months,0,4,8,12,22,,,,,,,,,,0.00,Sorafenib (n=150)Median OS: 6.5 m

61、onths,Placebo (n=76)Median OS: 4.2 months,,,,,,,,,,,,,,2,6,10,14,16,18,20,,Subject to PATH Program Disclaimer,Asia–Pacific trial1 vs SHARP2:baseline patient characteristics,,1. Cheng A, et al. J Clin Oncol. 2008;26. A

62、bstract 4509. Updated from oral presentation at ASCO; Chicago, IL; June 2008.2. Llovet JM, et al. N Engl J Med. 2008;359:378-90.,Subject to PATH Program Disclaimer,,,SHARP: sorafenib prolongs OS by 44% and TTP by 74% i

63、n patients with advanced HCC,Llovet JM, et al. N Engl J Med. 2008;359:378-90.,1.00,Survival probability,0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17,Sorafenib (n=299) = 10.7 monthsP

64、lacebo (n=303) = 7.9 months,,,Time from randomization (months),Probability of radiologic progression,0 1 2 3 4 5 6 7 8 9 10 11 12,Sorafenib (n=299) = 5

65、.5 monthsPlacebo (n=303) = 2.8 months,,,Time from randomization (months),1.00,0.75,0.50,0.25,0,HR = 0.69 (95% CI: 0.55–0.87) p<0.001,0.75,0.50,0.25,0,HR = 0.58 (95% CI: 0.45–0.74)p<0.001,Overall survival,Time to

66、 progression(independent central review),Subject to PATH Program Disclaimer,Sorafenib prolongs OS by 47% and TTP by 74% in Asia–Pacific patients with advanced HCC,Cheng A-L, et al. Lancet Oncol. 2009;10:25-34.,Overall

67、survival,Time to progression,Subject to PATH Program Disclaimer,Asia–Pacific study1 vs SHARP2: efficacy similar in both patient populations,1. Cheng A, et al. J Clin Oncol. 2008;26. Abstract 4509. Updated from oral prese

68、ntation at ASCO; Chicago, IL; June 2008.2. Llovet JM, et al. N Engl J Med. 2008;359:378-90. 3. Llovet JM et al. Hepatology. 2008;48:1312-27.,Subject to PATH Program Disclaimer,Sorafenib在晚期肝細胞肝癌為標準治療,Sorafenib 是第一個也是迄今為止