1、Comprehensive systemic therapy of HCCHong QiuDigestive Oncology Department, Tongji Hospital郝捷，陈万青。2012中国肿瘤登记年报 ContentHistory of stagingn1964 Child1964 Child分级分级 Child-Child-TurcotteTurcotte首先提出首先提出n1971 1971 肝癌分级肝癌分级 乌干达乌干达KampalaKampala市国际癌症研讨会首先提出市国际癌症研讨会首先提出n1973 Child-Pugh1973 Child-Pugh分级分级 Pu
2、ghPugh对对ChildChild分级提出修正分级提出修正n1977 1977 中国肝癌协会分期中国肝癌协会分期 中国抗癌协会肝癌专业委员会中国抗癌协会肝癌专业委员会n1985 Okuda1985 Okuda分期分期 OkudaOkudan1988 TNM1988 TNM分期分期 美国癌症联合会（美国癌症联合会（AJCCAJCC） 国际抗癌联盟（国际抗癌联盟（UICCUICC）n1994 Izumi 1994 Izumi 改良分期法改良分期法 IzumiIzumin1998 CLIP1998 CLIP评分法评分法 意大利肝癌小组意大利肝癌小组 （the Cancer of the Liver
3、 Italian Programthe Cancer of the Liver Italian Program） n1999 French1999 French评分法评分法 ChevretChevretn1999 BCLC1999 BCLC（巴塞罗那）分期法（巴塞罗那）分期法 巴塞罗那肝癌小组巴塞罗那肝癌小组 （the Barcelona-Clinic Liver Cancer Groupthe Barcelona-Clinic Liver Cancer Group）n2000 2000 中国分期中国分期(CS) (CS) 中国抗癌协会肝癌专业委员会中国抗癌协会肝癌专业委员会n2000 200
4、0 日本日本TNMTNM分期法分期法(4th) (4th) 日本肝癌研究组（日本肝癌研究组（LCSGJLCSGJ）n2001 CUPI2001 CUPI（香港中文大学预后系数）（香港中文大学预后系数） 香港中文大学香港中文大学LeungLeungn2001 CS 2001 CS （中国肝癌协会分期（中国肝癌协会分期 China Staging)China Staging) 中国抗癌协会肝癌专业委员会中国抗癌协会肝癌专业委员会 n2003 JIS2003 JIS评分法评分法 KudoKudon2003 TNM2003 TNM分期分期(6(6thth) ) 美国癌症联合会（美国癌症联合会（AJCC
5、AJCC） 国际抗癌联盟（国际抗癌联盟（UICCUICC）n2000 2000 分子生物学预后因子分子生物学预后因子n2010 TNM2010 TNM分期分期(7(7thth) ) 美国癌症联合会（美国癌症联合会（AJCCAJCC） 国际抗癌联盟（国际抗癌联盟（UICCUICC）History of staging BCLC staging期别期别PSPS评分评分肿瘤状态肿瘤状态 肝功能状态肝功能状态肿瘤数目肿瘤数目 肿瘤大小肿瘤大小0 0期：极早期期：极早期0 0单个单个2cm2cm没有门脉高压没有门脉高压A A期：早期期：早期0 0单个单个3 3个以内个以内任何任何3cm3cmChild-
6、Pugh A-BChild-Pugh A-BChild-Pugh A-BChild-Pugh A-BB B期：中期期：中期0 0多结节肿瘤多结节肿瘤任何任何Child-Pugh A-BChild-Pugh A-BC C期：进展期期：进展期1-21-2门脉侵犯或门脉侵犯或N1N1、M1M1任何任何Child-Pugh A-BChild-Pugh A-BD D期：终末期期：终末期3-43-4任何任何任何任何Child-Pugh CChild-Pugh C分期分期治疗目的治疗目的 首选首选/次选措施次选措施Stage A：早期：早期A1A2A3A4Stage B：中期：中期Stage C：进展期：进
7、展期Stage D：晚期：晚期根治性治疗根治性治疗根治性治疗根治性治疗根治性治疗根治性治疗根治性治疗根治性治疗姑息治疗姑息治疗 姑息治疗姑息治疗对症治疗对症治疗肿瘤切除术肿瘤切除术肿瘤切除或肿瘤切除或OLT/PTOLT/PTOLT/PT TAE或或TACE接受最新开发的抗肿瘤治疗接受最新开发的抗肿瘤治疗支持治疗支持治疗 BCLC staging Child-Pugh Score评分评分1 12 23 3总胆红素总胆红素(mol(molL)L)343434-5134-515151血清白蛋白血清白蛋白(g/L)(g/L)353528-3528-352828凝血酶原时间延长凝血酶原时间延长1-31-
8、3秒秒4-64-6秒秒6 6秒秒腹水腹水无无轻度轻度中等量中等量肝性脑病（级）肝性脑病（级）无无1-21-23-43-4注：按积分法，注：按积分法，5-65-6分为分为A A级，级，7-97-9分分B B级，级，10-1510-15分分C C级。级。Gut and Liver, Vol. 6, No. 2, April 2012, pp. 139-148 Treatment strategy Treatment strategyLancet. 2012 Mar 31;379(9822):1245-55 Treatment strategyLancet. 2012 Mar 31;379(9822
9、):1245-552011版卫生部诊疗规范版卫生部诊疗规范 Treatment strategy MDT of HCCAblationTACEChemotherapy Biologic therapyRadiotherapy TACETranscatheter arterial chemoembolization Normal hepatocytes receive most of their blood supply from the portal vein. Whereas Tumors create new blood vessels from branches of the hepat
10、ic arterial systemMaterials injected ：polyvinyl alcohol（聚乙烯醇）（聚乙烯醇）iodized oil (碘油碘油)collagen（胶原）（胶原）autologous blood clot Chemotherapeutic agents： cisplatindoxorubicin TACEDue to risk of liver failure chemoembolization may be contraindicated in patients: portal vein thrombosis patients with Child-P
11、ugh C most individuals with Child-Pugh B statusOther contraindications: Contrast allergy Uncorrectable bleeding diathesis TACEPostembolization syndrome: (occurs in 50% of patients when a large volume of liver is treated) Feverabdominal painIleus( occasionally)chemotherapeutic agents used may produce
12、 systemic side effects. Meta-analysis of studies indicates a positive impact on overall survival. At 2 years, the overall survival benefit from this procedure ranges from 20% to 60% AblationAblation techniques include RFA（radiofrenquency ablation） 射频消融射频消融 cryotherapy 冷冻治疗冷冻治疗 injection of chemicals
13、 (eg, ethanol)RFA can be performed via laparotomy or percutaneously via CT or ultrasound guidance. It is best suited for lesions 70%. Some recurrence represents undertreatment of lesions, microscopic satellites that were not included in the ablation site, poor imaging due to technical issues, inexpe
14、rience of the ablator, and selection of large tumors. Ablation is safe and effective for patients who cannot undergo resection or who need a bridge to transplant. AblationIntratumoral ethanol injection The direct injection of 95% ethanol into a neoplastic lesion causes cellular dehydration and coagu
15、lation necrosis. This procedure has been largely replaced by RFA, which in several clinical trials has shown superior efficacy to ethanol injection. Radiation therapyAdjuvant treatment There is no evidence however adjuvant radiation therapy can improve local or regional control after adequate resect
16、ion or ablation. Radiation therapy Radiosensitive cancer Radiosensitive organ, toxicity easily achieved Whole liver-palliative Partial liver-definitive(maybe) Conformal radiotherapy Stereotactic radiotherapy(SRT) Proton and carbon ion Radiation therapyUnresectable diseaseWhole-liver radiation therap
17、y can provide palliation in patients with unresectable tumors，but is limited to a total dose of 30 Gy due to the risk of radiation-induced liver disease. Whole-liver irradiation has been combined with chemotherapy and transcatheter arterial chemoembolization, with objective response rates of approxi
18、mately 40% to 50% and median survival rates of about 18 months. Patients with tumor regrowth after chemoembolization may respond to radiotherapy. The Korean Journal of Hepatology 2011;17(3):189 Gastrointestinal cancer research 2012. 5(1):13-17 ChemotherapyThe low response rates to chemotherapy are r
19、elated to the role of the hepatocyte in detoxification. Hepatocytes also have high multidrug resistance expression. Many patients with hepatocellular carcinoma have cirrhosis or hepatic dysfunction, which complicates the administration of chemotherapeutic agents that undergo hepatic metabolism. Agen
20、ts with partial response rates near or above 10% include doxorubicin, fluorouracil (5-FU), and cisplatin. ChemotherapyEACH 研究研究奥沙利铂（乐沙定奥沙利铂（乐沙定）+ 5FU/LV（FOLFOX4）与单药阿霉素在不适合进行手术切除治）与单药阿霉素在不适合进行手术切除治疗或局部治疗的晚期肝细胞癌受试者中进行的姑息性化疗比较的研究疗或局部治疗的晚期肝细胞癌受试者中进行的姑息性化疗比较的研究随机随机、对照、对照、亚太区多国亚太区多国多中心的多中心的期临床试验期临床试验Arm A
21、 (FOLFOX4):- OXA 85mg/m2 iv. h0 h2 Day 1- LV 200mg/m2 iv. h0 h2 Day 1,2- 5FU 400mg/m2 iv. bolus Day 1, 2 then 600 mg/m2 over 22 hours in Day 1 & 2 , every 2 weeksArm B (Doxorubicin):- Doxorubicin 50 mg/m2 iv. on Day 1, every 3 weeks 患者持续接受治疗直至疾病进展、出现不可耐受的毒性反应、死亡或原病灶已适合手术切除。晚期不适合手术/局部治疗的HCC患者至少有一个可测量
22、病灶既往未接受过抗肿瘤治疗（手术除外）或既往局部治疗后进展Child Pugh A/BBCLC分期 B/CKPS70N = 184分层因素- 不同国家和地区， 疾病状态， BCLC 分期N = 187EACH研究研究:研究目的研究目的 主要研究主要研究终点终点: :比较两种方案的比较两种方案的生存获益生存获益 评价评价FOLFOX 4FOLFOX 4与与DOXDOX相比相比, ,是否能够延长晚期是否能够延长晚期HCCHCC患患 者的总生存时间（者的总生存时间（OSOS） 次要研究次要研究终点终点: : 进一步进一步比较两种方案的有效性与安全性比较两种方案的有效性与安全性，包括包括: :无无进展
23、生存期进展生存期 (PFS);(PFS); 有效率（有效率（RRRR）/ /疾病控制率疾病控制率 (DCR(DCR）; ; 二期切除率；生活质量；安全性二期切除率；生活质量；安全性 疗效结果：疗效结果：总总ITT人人群群结果结果FOLFOX4 (n=184)阿霉素 (n=187)P值风险比(95% CI)主要终点中位OS, months (95% CI)（数据锁定的第一截止日期 （266 events）6.40 (5.30, 7.03)4.97 (4.23, 6.03)0.06950.797 (0.625, 1.017)中位OS, months (95% CI)（数据锁定的第二截止日期 （30
24、5 events）6.47(5.33, 7.03)4.90 (4.20, 6.03)0.04250.785 (0.626, 0.985)次要终点 (cut-off May 31, 2009）中位PFS, months (95% CI)2.93(2.43, 3.53) 1.77(1.63, 2.30) 0.00020.620(0.489, 0.787) 缓解率 , %(95% CI)8.15(4.63, 13.09) 2.67(0.87, 6.13) 0.0233 N/A 疾病控制率 (95% CI)52(45, 60)32(25, 39) 0.0001 疗效疗效结果：结果：中国中国患者患者群的
25、群的OSOS曲线曲线 Biologic therapy Biologic therapy Biologic therapyHepatocellular carcinoma is a vascular tumor; increased levels of vascular endothelial growth factor are found in hepatomas compared with normal hepatic tissueincreased endothelial growth factor levels before resection of tumor or TACE are
26、 associated with early relapse, aggressive behavior, and poor prognosis.Other targets include EGFR (which is frequently expressed in hepatoma cells), the mitogen-activated protein kinase (MAPK) pathway, and the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway.
27、Biologic therapy Biologic therapy Biologic therapy Sorafenib is an oral multikinase inhibitor with antiangiogenic and antiproliferative effects. The SHARP trial compared sorafenib (400 mg PO bid) versus placebo in 600 patients with Child-Pugh class A liver disease. About one-third of patients had un
28、dergone embolization, and the disease progressed. In all, 70% of patients had portal vein thrombosis and/or metastatic lesions. Biologic therapyIn spite of a low radiographic response rate (2% of tumors responded by radiographic criteria),median survival for the 300 patients given sorafenib was sign
29、ificantly better than that for the placebo group (10.7 vs 7.9 months; hazard ratio HR, 0.69). The drug was well tolerated, with fatigue, diarrhea, rash, and hand-foot syndrome as manageable side effects. This is the first well-powered trial to convincingly demonstrate a survival benefit with the use
30、 of a systemic agent for this disease. Sorafenib now is the standard of care for hepatocellular carcinoma not amenable to locoregional therapy the first FDA-approved agent for this indication. Biologic therapyAsia-Pacific Trial226 patients with Child-Pugh class A liver disease were randomized to sor
31、afenib and placebo. These patients primarily had HBV infection; compared with SHARP study patients, they had more local therapy before their entry into the trial and, as a whole, more advanced disease. Biologic therapyAsia-Pacific TrialMedian survival was 6.5 months compared with 4.2 months for sora
32、fenib and placebo, respectively (HR, 0.68) (Cheng AL et al: Lancet Oncol 10:2534, 2009)More data are needed to establish the role of sorafenib in treating Child-Pugh class B liver disease SummaryEarly stage HCC ：30 Curative treatment as the first choice: surgery, liver transplantation, local ablatio
33、n Advanced stage HCC：70% Not suitable to receive curative treatment TACE only benefit for part patients with HCC Insensitivity to convention radiotherapy and chemotherapy. molecule target therapy become the new standing treatment. Question1.1. 肝癌非手术治疗的方法有哪些？肝癌非手术治疗的方法有哪些？2.2. 放射治疗在晚期肝癌中的作用？放射治疗在晚期肝癌中的作用？3.3. FDAFDA第一个批准治疗晚期肝癌的药物是什么？第一个批准治疗晚期肝癌的药物是什么？其作用机制是什么？其作用机制是什么？ 谢谢 谢！谢！
