108/02/15-肝臟移植及目前肝癌治療趨勢

肝臟移植及目前肝癌治療趨勢

張文燦 移植外科 高雄醫學大學附設醫院 wtchang@kmu.edu.tw (07)3121101-7651,7097

20160614 National Heath Insurance

3 Year Survival rate :90% No.2 in Taiwan

健保署公告2003~2014肝臟移植術後存活率 醫院排行 全國

案例數 4114

3年存活率 78%

1037 32

91% 90%

3. 義大

25

89%

4. 台大

427

82%

4. 成大

80

82%

1. 高雄長庚 2. 高醫

3

Liver Cirrhosis-End Stage Liver Disease

肝臟移植簡介 (1)肝臟移植的適應症 (2)肝臟移植的禁忌症 (3)器官捐贈及大愛肝臟移植 (4)活體肝臟移植手術

肝癌治療趨勢 (1)肝癌的治療選擇 (2)肝癌的根治性治療: 肝臟移植治療、手術 切除治療、高頻射波燒灼治療、肝癌的微 創手術及大型肝癌的手術治療 (3)肝癌的姑息性治療:經動脈栓塞治療 (4)肝癌的保守性治療:化學治療、標靶治療、 免疫治療、放射線治療

Treatment of HCC-Taiwan Experience Curative Therapy is the Principleďź 1

3

2

4

very early or early stage

1.Chen CH. Eur J Cancer 2009;45:1630-1639, NTUH 2,3,4 Kuo YH .Wang JH. Eur J Cancer 2010;46:744-751,CGMH,Kaohsiung

Treatment of HCC-Taiwan Experience Surgery vs RFA very early

Propensity score matching analysis

Early

very early

very early or early stage

Wang JH. J Hepatology 2012;56:412-418 Surgery: better disease free survival

Treatment of HCC Surgery vs RFA

Surgery: better disease free survival Single lesion: operation is the choice

Wang JH. J Hepatology 2012;56:412-418 Bruix J. Hepatology 2011;53:1020-1022 Bruix J.Hepatology 2005;42:1208-1236

Local Ablation Therapy

肝胆膵 2006；53:776-783 , KMUH 2011 Annual Report MCT: Microwave coagulation therapy RFA:Radiofrequency ablation therapy

肝臟移植的適應症(1)

台灣器官捐贈登錄分配中心 Koffron A, Med Clin North Am. 2008 Jul;92(4):861-88

肝臟移植的適應症(2)

台灣器官捐贈登錄分配中心 Koffron A, Med Clin North Am. 2008 Jul;92(4):861-88

Indication for LT in the pediatric population 1.

Intractable cholestasis

2.

Portal hypertension

3.

Multiple episodes of ascending cholangitis

4.

Failure of synthetic function

5.

Failure to thrive, malnutrition, ( progressive bone disease)

6.

Intractable ascites

7.

Encephalopathy

8.

Unacceptable quality of life

9.

Metabolic defects for which liver transplantation will reverse life-threatening and prevent central nervous damage

Steinman TI. Clinical Practice Committee, American Society of Transplantation Transplantation 2001;71(9):1189-1204

Evaluation for LT in Adults 1.

Life-threatening and progressive irreversible liver disease

2.

New onset of ascites in a cirrhotic patients

3.

Ascites resistant to medical treatment

4.

Spontaneous bacterial peritonitis

5.

Increasing fatigue in cirrhotic patient so daily activities cannot be performed

6.

Onset of hepatic encephalopathy

7.

Progressive malnutrition and muscle wasting

8.

Recurrent bacterial cholangitis

9.

Symptomatic hepatopulmonary syndrome

10.

Onset of hepatorenal syndrome

11.

Fulminant hepatic failure

12.

Worsening synthetic function in a cirrhotic patient a. Decrease serum albumin b. Rising prothrombin time

13.

Development of hepatocellular carcinoma within a cirrhotic liver Steinman TI. Clinical Practice Committee, American Society of Transplantation Transplantation 2001;71(9):1189-1204

Biochemical Indication of LT 1.Choletsatic diseases Serum biribubin > 10 mg/dl or 100 Îźmol/L( 5.8 mg /dL) 2.Parenchymal disease Serum biribubin > 50 Îźmol/L( 3.0 mg /dL) Serum albumin < 3 .0 g/dL Prothrombin time > 3 seconds above control ( or INR >1.5) Serum cholinesterase < 2500 U/L 3.Model for End-Stage Liver Disease Score(MELD) 15-35(40) ( Except for hepatocellular carcinoma) 1.Blumgart LH. Surgery of the Liver, Biliary tract, and Pancreas, 2007, p1721 2.Maddrey WC. Transplantation of the Liver,2001,p.8 3.Bucheler E. Diagnostic and Interventional Radiology in Liver Transplantation, 2003,p72

肝臟移植的禁忌症

台灣器官捐贈登錄分配中心 Koffron A, Med Clin North Am. 2008 Jul;92(4):861-88

人類免疫缺乏病毒傳染防治及感染者權益保障條例 2018 年 06 月 13 日

第 11 條

有下列情形之一者，應事先實施人類免疫缺乏病毒有關檢驗： 一、 採集血液供他人輸用。但有緊急輸血之必要而無法事前檢驗者，不 在 此限。 二、製造血液製劑。 三、施行器官、組織、體液或細胞 移植。 前項檢驗呈陽性反應者，其血液、器官、組織、體液及細胞，不得 使用。 但受移植之感染者於器官移植手術前以書面同意者，不在此 限。 醫事機構對第一項檢驗呈陽性反應者，應通報主管機關。

愛滋患者得登錄為器官待移植者之符合要件有四： 一、CD4數值大於 200 cells/μl 至少6個月。 二、遵循醫囑並穩定接受雞尾酒療法（HAART），且最近6個月內測量不 到HIV的病 毒量（HIV viral load小於50 copies/ml）。 三、排除有未受控制、潛在致命之伺機性感染或腫瘤。 四、日後仍有抗逆轉錄病毒之治療選擇（應事先與感染科醫師討論及確認）。

UNOS MELD/PELD

Change of Allocation: From UNOS Status to MELD/PELD

In USA, on February 27, 2002, the liver allocation system changed from a status-based algorithm to one using a continuous MELD/PELD severity score to prioritize patients on the waiting list.

Only one priority exception: Status 1A Wisener R. Gastroenterology 2003;124:91-96 Freeman RB . Am J Transplant. 2004;4 Suppl 9:114-31

MELD( Model of end stage liver disease) Taiwan Organ registry and Sharing Center 成人肝臟移植等候者疾病嚴重度分級表暨評分標準表

PMELD (Pediatric ELD) Taiwan Organ registry and Sharing Center 兒童肝臟移植等候者疾病嚴重度分級表暨評分標準表

Waiting List Taiwan Organ registry and Sharing Center 肝臟移植等候者疾病嚴重度分級表暨評分標準表

Principle of Allocation of Liver Graft in Taiwan

器官登錄中心(2011 年 11 月 )

Principle of Allocation of Liver Graft in TaiwanPediatric

器官登錄中心(2011 年 11 月 )

Schaubel DE. Am J Transplant 2009;9(part 2):970-981 Feng S. Liver transplantation 2010;16:S60-S64

No benefit in MELD <10 (Except for HCC) Consider OLT in>MELD 15 Severe: MELD >25 D-MELD=Donor Age x Recipient MELD

Principle of Allocation of Liver Graft in Taiwan(1) 一、絕對因素 血型：需符合血型相同 （ identical ） 或相容 （ compatible ） 之規定， 始得接受分配。 1. 血型相同：捐贈者血型O型對應血型O型之等候者；捐贈者血型A型 對應血型A型之等候者；捐贈者血型B型對應血型B 型之等候者；捐贈 者血型AB型對應血型AB型之等候者。 2. 血型相容：捐贈者血型O型對應血型為A型、B型、AB型之等候者； 捐贈者血型A型對應血型AB型之等候者；捐贈者血型B型對應血型AB型 之等候者。 (二)捐贈者B型肝炎表面抗原呈陽性(HBsAg(+))：其捐贈之肝臟僅能分 配予「B型肝炎表面抗原陽性(HBsAg(+))」之等候者。 (三) 捐贈者有C型肝炎 （ Anti-HCV(+) ） ：其捐贈之肝臟僅能分配予 「有C型肝炎 （ Anti-HCV(+) ） 」之等候者。 肝臟移植分配原則 (2010 年 9 月 13 日 修正) NUC,HBIG .DAA therapy after Liver Transplantation

Principle of Allocation of Liver Graft in Taiwan(2) 二相對因素(1) (一)12歲（含）以下或18歲（含）以下且40公斤 （含）以下之捐贈者，優先分配給18歲（含）以下 等候者。 (二)疾病等級：「等級1 」較「非等級1」之等候 者優先。 (三) 相同器官勸募組織(organ procurement organizations)以內的醫院優於不同器官勸募組織 的醫院。 (四) 勸募醫院：肝臟分配採不分區制，其中以「勸 募醫院」較「其他醫院」之等候者優先。

肝臟移植分配原則 (2010 年 9 月 13 日 修正)

Principle of Allocation of Liver Graft in Taiwan(3) 二相對因素 (2) (五) 評分標準: 以「評分高」較「評分低」之等候者優先。 1. 依據UNOS(United Network for Organ Sharing)加權給分原 則，HCC （ Hepatocellular Carcinoma ） 患者，每三個月 重登記，以MELD Score給分加百分之十，直到完成移植或 判定不適合移植。 2. 血型０型者亦比照HCC加權方式。 3. 十八歲以上(含)者：適用MELD Score評分標準表。 4. 十八歲以下者：適用PELD Score評分標準表。 (六) 等候時間：以「等候時間長」較「等候時間短」之等候者 優先。 三、備註 移植醫院應於醫學條件許可下，優先考量採行肝臟分割移植 手術，其第二位受贈者得由該醫院自行選擇

New 1.三等親內曾捐獻者，排序有提升 2.五等血姻親指定捐獻 肝臟移植分配原則 (2010 年 9 月 13 日 修正)

MELD/Na Adult since 2016

UNOS since 2016

器官捐贈及大愛肝臟移植

腦死判定(I) 第一次判定 (1)腦幹反射檢查 (2)能否自行呼吸 第二次判定 兒童: 腦電圖,

腦部血流檢驗, 24-48 hrs 觀察 x2 腦死判定醫師資格 具神經科、神經外科專科醫師資格者 具麻醉科、內科、外科、急診醫學科或小兒科專科醫 師資格，並曾接受腦死判定之訓練，持有證明文件者 病人為足月出生（滿三十七週孕期）未滿三歲者：兒 科專科醫師 移植醫師不得參予腦死判定

腦死判定(II) 第一次判定---能否自行呼吸 Step 1 100%O2 10 min→95%O2+5%CO2 5 min → 抽血PaCO2>40mmHg Step 2 暫時移除 呼吸器 ,由氣管內管給予100%O2 6L/min Step 3 觀察 10 min →抽血PaCO2>60mmHg 完全無自發性呼吸 →重新接回呼吸器

腦死判定(III) 第二次判定 成人四小時後，依相同步驟再測定一次

但滿一歲以上未滿三歲者應至少十二小 時後；足月出生（滿三十七週孕期）未 滿一歲者，應至少二十四小時後。 意外事故致死、他殺、自殺，或死亡原因有 疑義時，除需獲得家屬同意簽署，仍需報請 檢察官相驗同意，方可摘取捐贈器官，在進 行第二次腦死判定時需請檢察官相驗。

Donor-Derived Cancer

Romagnoli R. Am J Transplant 2016;16:1938-1939

Expanded Criteria of Liver GraftKMUH Experience

Bilirubin

GPT 2011-July-23 Donor : Head injury Liver biopsy: Cholestasis only Hyperbilirubinemia: blood transfusion? Hematoma absorption? Sepsis?,

Expanded Criteria of Liver GraftKMUH Experience MELD=35

Bilirubin

GPT

INR 2011-July-23 Recipient: uneventful recovery

Operation of Deceased Donor IVC

Carrel patch

1.Molimenti EP.Atlas of Liver Transplantation,2002,p11 2.Kremer B. Atlas of Liver,Pancreas, and Kidney Transplantation,1994,p63 3.KMUH 2011-Sept-7 Donor

Splitting Liver

Operation of Recipient IVC

Carrel patch

Splitting Liver

KMUH

Operationâ&#x20AC;&#x201D;in Situ Splitting

Graft weight=783 gm, GRWR=1.39% 2016 Nov 11 at KMUH

活體肝臟移植手術

Lee SG.Am J Transplant. 2015 Jan;15(1):17-38

LDLT vs. DDLT

1.Florman S. Liver Transplantation 2006;12:499-510 2. Moon DB, Lee SG. Gut & Liver 2009;3:145-165

The safety of living donor is the first priority of LDLT.

Living Donor Operation

HA ,PV, HV,BD Variation

1.Mazziotti A. Techniques in Liver Surgery,1997,p5 2.Florman S. Liver Transplantation 2006;12:499-510 3.Blumgart LH. Surgery of the Liver, Biliary tract, and Pancreas,2007, p1787

Living Donor Operation

Right lobe graft

Left lateral segment graft

1.Florman S. Liver Transplantation 2006;12:499-510 2. Moon DB, Lee SG. Gut & Liver 2009;3:145-165

Left lobe graft

Intraoperative Sonograhpy & Cholangiography IVC

Carrel patch

KMUH

Prei-Transplantation Desensitization and Immunosupression for ABOi LDLT at KMUH 2018

Rituximab 375 mg/m2

Double filtration x2 Plasma Exchange x8 IA(Isoagglutinin):1:512 >1:64 Song GW.Lee Sg. Am J Transplant 2016;16:157-170

ABO I Donor Operation

Reconstruction of V8 with PTGF graft , KMUH,201804

ABOi Recipient Operation (1)

ABOi Recipient Operation (2)

Recipient 89 Kg

Recipient 80 Kg

Graft

540 ml

540ml

GRWR

0.607%

0.675%

ABOi LDLT at KMUH

201804血型不相 容活體肝臟移植

Emergent LDLT at KMUH

201704緊急活體肝臟移植

肝癌的治療選擇 肝臟移植

Multi- step,centeric Carcinogenesis

Oikawa T. J Hepatol 2005;42:225-229 肝胆膵 2006;53:619-625

Treatment of HCC

Treatment of HCC

Majno PE. Hepatology 2010; Bruix J.Hepatology 2005;42:1208-1236

NHI Criteria for Liver Transplantation for HCC 1.Milian criteria ( DDLT ) Single tumor < 5 cm If multiple HCC, number <3,Maximal Size< 3 cm No Vascular ( macroscopic) Invasion 2. UCSF criteria ( LDLT) Solitary tumor < or = 6.5 cm or < or = 3 nodules with the largest lesion < or = 4.5 cm and total tumor diameter < or = 8cm No Vascular ( macroscopic) Invasion

1.. Mazzaerro V. N Engl J Med. 1996 Mar 14; 334(11):693-9.

2. Yao FY.Hepatology 2001; 33: 1394â&#x20AC;&#x201C;1403.

Milan Criteria for LT for HCC 1.Milian criteria ( DDLT )

. Mazzaerro V. N Engl J Med. 1996 Mar 14; 334(11):693-9.

Liver transplantation for HCC at KMUH

Liver Transplantation for HCC(1)

Sapisochin G. Nat Rev Gastroenterol Heppatol 2017:14(4):203-217.

Liver Transplantation for HCC(2)

Sapisochin G. Nat Rev Gastroenterol Heppatol 2017:14(4):203-217.

Liver Transplantation for HCC(3)

Sapisochin G. Nat Rev Gastroenterol Heppatol 2017:14(4):203-217.

Liver cirrhosis Child A HCC patients

Liver cirrhosis Child A HCC patients

肝癌的治療選擇 手術治療

Liver Resection for BCLC B&C HCC

Chang WT, Surgery, 2012:152:809-820

Surgical Treatment of BCLC Stage B or C HCC -is justified in selected patients

Is justified in patients with Single tumor without vascular invasion Chang WT. Surgery 2012;152:809-820, VGH,KMUH Ho MC, Ann Surg Oncol 2009;16:848-855,NTUH

Surgical Treatment of BCLC Stage B or C HCC -is justified in selected patients

Lin CT. World J Surg.2010;34:2155-2161,TSGH Wang JH.Eur J Cancer 2008;44:1000-1006,CGMH, Kaohsiung Wu CC. Arch Surg 2000:135:1273-1279, VGH, Taichung

Safe Liver resection for Tumor in Normal Liver 1.Colon cancer liver metastases 2.Living liver donor Partial graft 3.In addition to volume , the remnant liver should have adequate inflow, outflow, and bile duct drainage.

4.Steatohepatitis or fatty liver should be excluded.

5. PVE: Portal Vein Embolization

Clavien PA. New Engl J Med 2007;356:1545-1559

Safe Liver resection for HCC Cirrhotic Liver Zurich U

剩餘肝臟比率的安全 ICG15 肝臟狀態

限量 (%) (sFLR ； aFLR)

正常肝臟

肝硬化(Child A)

<10

≥20~30%

<10

≥40%

10-19

≥60%

20-29

≥80%

Clavien PA. New Engl J Med 2007;356:1545-1559 Makuuchi M. Semin Surg Oncol 1993;9:298-304 Asencio JM. J Hepatobiliary Pancreat Sci. 2014 Jun;21(6):399-404

Small Remnant Liver Volume

2012

Portal Vein embolization??

APPLS??

ALPPS: Associating liver partition with portal vein ligation for staged hepatectomy 1.Schnitzbauer AA. Ann Surg 2012;255:405-414 2.Jaeck D. Ann Surg 2004;1037-1051 3.Adam R. Ann Surg 2000;232:777-785 4.Barbaro R .Rad Med 2009;114:553-570

ALPPS

Stage II

Alvarez FA. J Gastrointest Surg 2013;17:814-821

Knock: Complete Partition of Liver parenchyma

PVE

Knock: Arterial embolization and Sequent Embolization of P4 KMUH

KMUH 2016/3/14:HCC, S7-8

Total liver volume: 2051 cm3 Volume of the left hepatic lobe+ S1: 516cm3 Remnant left liver: 25.1% Remnant liver volume to body weight ratio : 0.688% 73

2016/6/21:Right lobectomy without MHV

Excision of Partial Diaphragm and Repaired with Mesh , Disease Free till Now

KMUH ALPPS(1)

ALPPS(2)

ALPPS(3)

ALPPS vs. PVE ALPPS

PVE

兩次手術 兩次處置間隔 左外側葉無法增大 等待期間腫瘤變多 變大 手術併發症

Yes 7-14 days <5% 機會較小

No 30-60days 30% 病人 30% 病人

機會大(0-12% mortality)

較小

長期效益

未知

可接受

肝癌的治療選擇 微創手術治療

KMUH 微創手術治療 Laparosocpic Right Lobectomy

微創手術治療-Robotic

Treatment of Recurrent HCC At recurrence

After RFA

2009 S5 partial Hepatectomy 2012 S6 HCC >>RFA

Still try curative treatment after recurrence :Liver resection or Liver transplantation from Kudo M.

肝癌的治療選擇 Supportive Treatment

Treatment of HCC

2010 JSH Criteria Kudo M. Dig Dis 2011;29:339-364

Systemic and Immune-Treatment of HCC (1)

Chang WT, Kaohsiung J Med 2018;34:391-399 Kudo M. Oncology 2017;93(suppl):135-146

Systemic and Immune-Treatment of HCC (2)

Kudo M. Oncology 2017;93(suppl):147-159

Thank you for your attention ďź