Hee Jung Wang, MD, PhD Division of LT and Hepatobiliary Surgery

Hepatectomy and Liver Transplantation for HCC

extreme sports -2minuts.wmv

Issues in treatment for HCC

According to the staging classification

• Difficulty of early diagnosis in very early stage HCC

• Selection of treatment modality in early stage HCC

• Down staging in intermediate stage HCC

• Role of surgery as clinical trial for advanced stage HCC

• High recurrence rate after hepatectomy

• No effective anticancer regimens

1983 1988 1990

PEIT MCT RF

OLT

Development of diagnostic imaging

Cancer screening program

Early detection rate : 30 - 40%

2000

LDLT

Liver Resection

Omnipotent modality First line therapy Curative therapy (early HCC)

Palliative therapy

One of the bridging modalities

Evidence based practice guideline

History of treatments in HCC

Nexavar

Role of Liver Resection

Role of liver surgery according to BCLC staging classification

OLT

Liver Resection

LDLT Clinical trial

Grey zone of BCLC staging system (Surgeons’ perceptive) : In real life, the majority of patients who are not considered ideal candidates based on the BCLC guideline still were performed

hepatic resection nowadays. (about 50% of Stage B or C patients)

1) Judgement subjectivity of patients’ symptoms or ECOG PS

2) Biliary invasion

3) Ruptured HCC

4) The BCLC Tx recommendation concerning surgery

: too restrictive

5) 5cm-cutoff point between BCLC stage A and B

(Yang T, Lau WY. World J Gastroenterol 21;21(27):8256-8261)

Many other effective or promising Tx modalities:

: Radiotherapy, Yttrium radioembolization,

Cryotherapy, Microwave coagulation therapy,

Laser therapy or Immunotherapy

Applicability of the BCLC staging system to HCC patients

in Korea

(Kim SE, Lee HJ. Korean J Hepatol Hepatol 2011;17:113-119)

Prospectively consecutive enrolled: 160 HCC patients

Asan medical Center: One hepatologist, One year

Conclusions: Donor shortage, financial

problems, the relatively limited efficacy

of molecular targeting agents, and the

presence of an indeterminate nodule

were the main causes of deviation from

BCLC recommendations. Even after

excluding cases in which decisions were

made by patient preference, only 66% of

the HCC patients were treated according

to BCLC recommendations.

Treatment guidelines that reflect the

Korean situation are mandatory for HCC

Diagnosis and curative treatments of early HCC

BCLC stage Stage 0: 108명 (16.5%)

Stage A: 207명 (31.6%)

Stage B: 117명 (17.7%)

Stage C: 187명 (28.6%)

Stage D: 18명 (2.7%)

병기 미정:16명(2.6%)

0

500

Stage0 StageA StageB StageC StageD

(Ajou University: 2016. 1. 1. – 2017. 12. 31.)

48% 18%

29%

162건: 24.8%

104건: 15.9%

184건: 28.1%

31건: 4.7%

193건: 29.5%

0 20 40 60 80 100 120

전원, …

넥사바, …

TACE

RFA

수술

Prospectively consecutive collection n=653

3%

Treatments according to BCLC Staging

(Ajou University: 2016. 1. 1. – 2017. 12. 31.)

n=653

(Llovet JM, Bruix J. J Hepatol 2008;48:s20-s37)

Diagnosis and curative treatments of early HCC

Prognostic factors of Early Stage HCC

Tumor Biology

Liver Function

Treatment selection

(Llovet JM. Lancet 2003;362:1907-17)

The natural history of early HCC is much

different from that of advanced HCC.

MVI

Differentiation

Survival is also determined

by liver function.

ICG R15 or HVPG

Child-Pugh class

Performance status

Hepatectomy vs.Transplantation ( Local Ablation therapy.)

Liver function affects the applicability of

treatment.

High recurrence rate / No effective anticancer drugs

RF LDLT Liver Resection

Treatment selection in Early stage HCC

Tumor Biology

Liver Function

Treatment selection

Unchangable factors

Poor liver function

Worse biology

Comparable other treatment (according to location)

Old age

Poor performance status

Comorbidities

Good liver function

Better biology

Young age, relatively

Liver resection vs. LDLT for early stage HCC

Tumor Biology?

LT

HR

HR

LT

Normal liver

Decompensated LC

Compensated LC

Tumor Biology?

Tumor Biology

Feasibility

(Safety)

밀란 척도 내의 간암에 대한 간절제와 간이식 후의 예후

(아주대병원, 2005-2015)

Hepatic resection (n=648)

Total cases of HCC

(n=728)

tumor recurrence(n=204)

SLT (Tumor recurrence)

(n=22)

Re-resection, local ablation, TACE

beyond MC(n=252) within MC (n=396) within MC(n=61) beyond MC(n=19)

no recurrence(n=187)

5, died within 90 days

SLT(Decompensated LC)

(n=7)

Primary LT (n=80)

Ajou University Hospital

From July 1994 to December 2011

Liver resection vs. LDLT

5 yr, 72.4 %

Oncologic outcome after HR for early stage HCC

5 yr, 77.0 %

SLT group

PLT group

P=0.075

57.6%

77.0%

Overall 5 year survival rates calculated

from the date of LT of SLT group

SLT group

PLT group

P=0.899

77.0%

78.6%

Overall 5 year survival rates calculated

from the date of HR of SLT group

Liver resection vs. LDLT

Conversion 肝切除

肉眼的 切除不能

耐術 不能

RFA 可能

肝切除後 豫後不良 豫測

肝切除 非適應例

生體肝移植

Insult 輕減 (복강경간절제)

(절제와 동등한 결과 기대)

Salvage 肝切除

術後 HAIC

再發

전신상태불량(고령)

간기능불량

간절제 비적응예의 병태와 외과적 치료 가능성

우삼구역절제의 술전 planning

Preopertive planning using 3D-imaging

우삼구역절제의 술전 planning

Preopertive planning using 3D-imaging

조기간암의 술전 planning

Preopertive planning using 3D-imaging

조기간암의 술전 planning

Preopertive planning using 3D-imaging

조기간암의 술전 planning

Preopertive planning using 3D-imaging

Hypothetical course of patients with acute hepatic failure, classified according to residual hepatic function

Posthepatectomy liver failure

(Lee WM, Williams R. Acute liver failure. 1st ed. Cambridge University Press, 1997)

간절제술후 간부전을 예측하기 위한 다중 회귀방정식

(Yamanaka, 1999)

(Makuuchi, 1999)

간기능 평가에 따른 간절제 범위의 결정

65 year-old male patient

Diagnosis: HCC with HCV-CH in 2009

Present Illness: TACE for HCC, segment 8 (7 times; since 2009)

RFA for recurrent HCC, segment 8 (1 time; in Dec. 201

2)

-> Complicated biloma was developed after RFA

Lab. Findings:

Platelet count 84,000/ul

Albumin 2.9 g/dl

Total Bilirubin 0.9 mg/dl

Prothrombin time 82%

INR 1.13 sec

Child –Pugh score 6

ICG-R15 30.3%

Synapse 3D analysis

fuji1_RH_movie.mpgfuji1_RH_movie.mpgfuji1_RH_movie.mpg

Synapse 3D analysis

fuji6_wd_movie.mpgfuji6_wd_movie.mpgfuji6_wd_movie.mpg

1) Septic deterioration (+): PCD insertion with adequate antibiotics

2) Three therapeutic options:

1> Right hemihepatectomy

2> PVE, right liver followed by right hemihepatectomy

3> Liver transplantation

• I think the liver functional reserve may be underestimated by ICG-R15 and albumin

under the stressful state such as cholestasis or/and infection.

Right liver volume: 33%, ICG-R15: 30.3%

Definitely damaged right anterior sectional branch of BD, HA and PV

Diffuse dilatation of the right hepatic duct

Multiple regression equation

Y=-84.6 + (0.933 x resection rate) + (1.11 x ICG R15) + (0.999 x age)

Safe

for post-hepatectomy liver failure

borderline Risky

55 45

63 30.3 33 43.03

(Yamanaka N, Okamoto E. Ann Surg 1999;200:658-663)

Tumor related factor

Host related factor

Surgery related factor

Patient selection

Patient selection

Neoadjuvant Tx

Operative procedure

Surgical device

Stage

Tumor differentiation

Tumor Markers/FDG-PET

Early postop. liver failure

Fibrosis

Hepatitis prevention EPLF prevention

HCC recurrence

Prognosis

간세포암의 술후 예후에 영향을 주는 인자와 예후향상 전략

Adjuvant therapy DCP

The relationship among factors affecting DFS after hepatectomy in HCC patients

Iguchi K et al. World J Surg 2014; 38:150-158

간세포암의 간절제술후 간부전과 간암의 예후의 관계

Kyoto University Hospital Retrospective Cohort study (488 patients)

Iguchi K et al. World J Surg 2014; 38:150-158

153 EPLF group 335 non-EPLF group

EPLF: Early Posthepatectmy Liver Failure (an increase in the INR of PT and concomitant hyperbiliubinemia/POD#5) Grade A: usual managements Grade B: noninvasive – FFP, albumin, diuretics Grade C: invasive – CRRT, intubation

저자 보고년도 환자수 생존율 (%) 1년 3년 5년

Arii et al. 2000

HCC

바르셀로나 간암병기분류

Stage A : Early HCC

A1 0 single I No Portal HiBP, NL Bil.

A2 0 single I Portal HiBP, NL Bilirubin A3 0 single I Portal HiBP, ABN Bil.

A4 0 3 tumors,

HCC

New agents TAE/TACE PEIT/RF OLT Resection

Radical therapy Randomized controlled trials

Symptomatic

treatment

Okuda 1-2

PST 0-2

Okuda 3

PST 3-4

Terminal stage

(Stage D)

Early stage

(Stage A)

Intermediate stage

(Stage B)

Advanced stage

(Stage C)

PST 0 and

large multinodular

PST 1-2 or

Vp(+) / M1

Single 3 nodules

그림 7. 간세포암의 문맥을 통한 간내 전이에 대한 가설 (Makuuchi 등, 1993) a) 간암이 주변 문맥지를 침윤하여 암세포가 문맥의 말초로 이동하게 된다. b) 이 세포들은 현미경적 종양전을 형성하게 되고 비로소 간내전이가 이루어 진다. c) 육안적으로 보이는 문맥내 종양전 역시도 간내전이의 원인이 될 수 있다.

Curative Surgery for HCC

계통적 간절제 (글리슨 접근법)

A B

D C

비해부학적 쐐기상 간절제

Anatomical resection vs. Non-anatomical resection

Korea-Japan collaboration project : 710 patients (single HCC,

육안적 담관침윤 간세포암에 대한 간외담도절제를 동반한 간절제술

Non-curative Surgery for HCC

문맥내 종양전을 동반한 간세포암에 대한 종양전제거를 동반한 간절제술

A B

C D

Non-curative Surgery for HCC

Survival Curve

HCC patents survival rate after hepatectomy (827 cases)

Years 1 3 5

Stage1 (115) 97.1 91.3 87.9

Stage2 (446) 91.9 79.9 72.0

Stage3 (214) 75.2 58.2 51.2

Stage4 (52) 57.0 31.0 19.9

(Follow up time: 36 – 230 months until March 2017)

Consecutive HCC Patients between Apirl 1994 to December 2013

19.9%

One year survival rate:

57.0%

Diagnosis and curative treatments according to BCLC staging

BCLC stage Stage 0: 108명 (16.5%)

Stage A: 207명 (31.6%)

Stage B: 117명 (17.7%)

Stage C: 187명 (28.6%)

Stage D: 18명 (2.7%)

병기 미정:16명(2.6%)

0

500

Stage0 StageA StageB StageC StageD

(Ajou University: 2016. 1. 1. – 2017. 12. 31.)

48% 18%

29%

162건: 24.8%

104건: 15.9%

184건: 28.1%

31건: 4.7%

193건: 29.5%

0 20 40 60 80 100 120

전원, …

넥사바, …

TACE

RFA

수술

Prospectively consecutive collection n=653

3%

Treatments according to BCLC Staging

(Ajou University: 2016. 1. 1. – 2017. 12. 31.)

n=653

Modified UICC Classification

(Ajou University: 2016. 1. 1. – 2017. 12. 31.)

n=653

0

200

Stage

I

Stage

II

Stage

III

Stage

IV

Disease-free survival Curve

(Ajou University: 1995. 4. – 2013. 12.)

Disease free survival rate after hepatectomy (827 cases)

Years 1 3 5

Stage1 (115) 87.1 74.5 49.5

Stage2 (446) 80.3 58.1 48.3

Stage3 (214) 55.2 41.5 34.8

Stage4 (52) 27.6 10.0 7.5

Disease free survival rate after hepatectomy (827)

Years 1 3 5

Stage1 84.0 64.3 52.5

Stage2 60.2 47.2 40.9

Stage3 34.6 26.0 26.0

Stage4 46 31.3 31.3

n=827

mUICC AJCC, 7th

Overall survival Curve

(Ajou University: 1995. 4. – 2013. 12.)

Overall survival rate after hepatectomy (827 cases)

Years 1 3 5

Stage1 (115) 97.1 91.3 87.9

Stage2 (446) 91.9 79.9 72.0

Stage3 (214) 75.2 58.2 51.2

Stage4 (52) 57.0 31.0 19.9

Overall survival rate after hepatectomy (827 cases)

Years 1 3 5

Stage1 92.7 82.9 76.1

Stage2 79.0 61.1 52.0

Stage3 63.8 43.7 29.1

Stage4 66.2 50.0 42.7

n=827

mUICC AJCC, 7th

Take Home Messages

1. 간암의 치료에 있어 문제점은 근치치료 후 높은 재발율과 효과적인 항암제가 없다는 것이다.

2. 간암의 BCLC 병기의 stage A의 빈도가 40%이상으로 늘었다.

3. BCLC병기에 따른 추천 치료는 deviation rate이 높은 편이다. (특히, stage A)

4. 간암의 수술적 치료는 근치적 치료(stage A)와 비근치적 치료(Stage B, C 및 D)로 나눌 수 있다.

5. 조기간암에서 치료법의 선택은 중요한 예후 인자들 중에 하나이다.

6. 간암의 치료법의 선택은 기관마다 매우 큰 편차가 존재한다. 다학제팀의 운영이 필요하다.

7. 간암의 수술적 치료는 안전성이 매우 중요하므로 3D image분석과 간기능 예비력평가가 필요하다.

8. 간절제와 간이식의 치료법의 선택은 간기능에 의하여 결정되나 대상성 간경변이 동반된 간암에서

생체간이식도 고려될 수 있다.

9. 간암 환자 전체의 성적을 개선하기 위해서는 각 병원 별로 간암의 전체 환자의 전향적 data 관리 및

추적조사가 필요하고 이를 통한 객관적 자료를 근거로 합리적인 대책을 세워야 한다.