Review of trans-arterial treatment in unresectable HCC

Dr KP Wong, RHTSKJoint Surgical Grand Round

Introduction

Hepatocellular carcinoma: 3rd most common cause of death in world 2005: Male: 2nd, Female: 4th most common caus

e of cancer death in HK About 1800 new cases per year

Only 10~37% of patient are suitable surgical candidate

Cancer Registry 2005

overall median survival: 3 months1-yr survival: 7.8%

median survival (Okuda stage): I: 5.1 months II: 2.7 months III: 1.0 month

Microwave coagulation therapy

TAC/TACERFA

1900 20001950

PEI

cryoablation

Transarterial chemoembolization (TACE)

Vascular supply: HCC: arterial supply 90~100% Normal: portal vein 75~85%

TACE Targeted chemotherapy Ischemic necrosis by emboliza

tion

HCC Target Tx: 25 Symptomic Tx: 25

Median Survival: TACE: 48 days (1-504) Symptomic: 51 days (0-60

7)

Unresectable HCC 50 chemoembolization 46 conservative treatment

Survival estimated RR of death: 1.3

(95%CI: 0.9-2.2; P=0.13)

estimated survival rates at 1 year: 62% vs 43.5%

Liver failure 30 pts after 47 courses of treatment

P=0.13

Liver failure

no of patient

etiologycirrhosis (with Child

A)

liver failur

e

Madden et al 1993 50 nd nd nd

Bruix et al 1998 80 62%HCV 100(82) nd

GRETCH et al 1995

96 78% alcohol 91 (100) 63%

Pelletier et al 1998

73 53% alcohol 89(76) 51%

Controversy- Survival benefit

- Liver failure

Positive RCT

Differences

Patient selection Chemo-therauptic

regimen Embolization

technique Schedule

Patient selection

Pelletier et al 1990 Ascites: ~ 50%

Yoshikawa et al 1994 Child C class ~ 30%

GRETCH et al 1995 Esophageal varices: ~46%

Madden et al 1993 Okuda stage II/III: 86%

Regimen and technique

Regimen Catherization

Madden et al 1993

5-epidoxorubicin (60mg/m2) 6ml lipiodol,

5 ml meglumine iothalamate

to hepatic artery

GRETCH et al 1995

70mg cisplatin 10 ml lipiodol

just distal to gastroduodenal artery

Pelletier et al 1998

cisplatin 2mg/kg 5ml lipiodol Ultra Flu

ide lecithinjust distal to gastrodu

odenal artery

Schedule

Schedule Exclusion criteriaMadden

et al 1993

Every 4 weeks later if tolerated

Liver function not monitored

GRETCH et al 1995

Every 2 months up to 4 courses

Pelletier et al 1998

Every 3 months in first year,

then every 4 months afterwards unless contra-indicted

Differences

Patient selection Chemo-therauptic

regimen Embolization

technique Schedule

Single center, open label, randomized trial Chemoembolization: 40 Control: 40

Exclusion criteria: poor hepatic function (Child

B/C) serum creatinine level >= 1

80 mol/L; previous Tx for the tumor o

r acute tumor rupture; extrahepatic metastasis vascular contraindications t

o chemoembolization (hepatic artery thrombosis, main portal vein thrombosis or arteriovenous shunting);

poor performance status

Chemoembolization Feeding artery super-selective

catheterized Cisplatin with lipiodol in 1:1 rat

io Injected slowly, volume accord

ing to size of tumor (variable dose)

Up to 60ml (30mg cisplatin) Gelatin sponge embolization

Tumor response: CT αFP

Schedule Repeat every 2~3 months

Withheld when1. Vascular contraindication2. Poor hepatic function 3. Severe adverse effects4. Progressive disease

Results

Chemoembolization:RR of death: 0.49 (95%CI:0.29-0.81, p=0.006)

P= 0.002

Liver function after TACE

Liver function – bilirubin, albumin, ICG test No sign deteroriation

4

4years, 3 centers RCT 37: TAE 40: TACE 35: conservative

Exclude >75 age Child-Pugh C Renal failure

Active GIB Encephalopathy Refractory ascite

Extrahepatic spread Vascular invasion Porto-systemic shunt Hepatofugal blood flow Contra-indictation to arterial

procedure or doxorubicin

4

Schedule: Baseline, 2, 6 months, then

every 6 months

Withheld when1. Exclusion criteria developed

2. Vascular contraindication

3. Progressive disease

Chemoembolization Doxorubicin with 10ml lipio

dol Doxorubicin (adjusted acco

rding to bilirubin) then gelfoams embolization

Tumor response: Clinical exam, blood te

st 3 monthly US or CT 6monthly

Results

Multivariable analysis: Treatment allocation: TACE vs conservative OR: 0.45, p=0.02

TACE lower portal vein invasion TACE vs conservative: 17% vs 58%, p =0.005

Liver Function after TAE or TACE

Liver failure without tumor progression 3/37 (8.1%) in TAE, 2/40 (5%) in TACE

P =0.017

TACE prolong survival in selected group of patient with unresectable

HCC

Who & how ?

Who would be benefit? No standard census

Suggested best target group of patient

Well preserved liver function

Multi-nodular HCC without vascular invasion

How should we apply? No standard treatment

schedule 2 positive RCT:

treatment schedule - 2.8~4.8/patients

No standard embolization agent

Further RCT to explore optimal target population, active therapies

Advance in embolization agent

Radioembolization

Yttirum 90 microsphere (SIR Sphere®,Thera Sphere® ) Rhenium 180 radiolabelled lipiodol I-131 lipiodol

Drug loaded Microsphere

100-900μm microsphere derived from polyvinyl alcohol (PVA) Can be loaded with chemotheraptic agent

Controlled, sustainable release

Drug-Loaded Microspheres for the Treatment of Liver Cancer: Review of Current ResultsJ. Kettenbach et al. Cardiovasc Intervent Radiol 2008

Combination Therapy

Conclusion

Untreated unresectable HCC had a poor prognosis with median survival of 3 months

TACE offer survival benefit in well selected case

Further study was indicted for explore the optimal target patient, treatment schedule and agent

Evaluation of advance in transarterial therapy and combination therapy for unsectable HCC was indicted

Thank you

Reference

Reference

Tumor stage Liver functional stage Response rate

Indication for resection Indication for

transplantation

Treatment strategy

Old RCT Postitive RCT Alcohol related HCC

5 years predictor Advance in transarteria

l therapy

Tumor staging

Staging Proposals in Hepatocellular Carcinoma Classification Type Stages

Okuda stage System 3 Stage 1,2,3

GETCH classification Score 3 A:0 points;

B:1-5 points;

C: ≥ 6 points

CLIP classification Score 7 0,1,2,3,4,5,6

BCLC staging Staging 5 0: Very early

A: Early

B: Intermediate

C: Advanced

D: End-stage

CUPI Index Score 3 Low risk: score ≤ 1

Intermediate: score 2-7

High: score ≥ 8

TNM staging System 3 Stage I,II,III

JIS Score 4 Stage 0,1,2,3,4

ER classification System 2 ER wild-type

ER variant

SLiDe System 4 Stage 0,1,2,3,4

TNM Classification for Hepatocellular Carcinoma, 2002

• Pathological staging (pTNM)

Stage I T1 N0 M0

Stage II T2 N0 M0

Stage IIIA T3 N0 M0

IIIB T4 N0 M0

IIIC Any T N1 M0

Stage IV Any T Any N M1

• T definitions T1: Solitary without vascular invasion

T2: Solitary tumor with vascular invasion or multinodular ≥ 5

T3: Multinodular > 5 cm or tumor with major vascular invasion

T4: Tumor with invasion of adjacent organs.

AJCC Cancer staging 2002

Definitions Used in the Cancer of the Liver Italian Program (CLIP)

Variable 0 1 2

Child-Pugh class

A B C

Tumor morphology

Uninodular Multinodular Massive or

< 50% of liver volume

< 50% of liver volume

> 50% of liver volume

AFP (ng/mL) < 400 ≥ 400 -

Portal vein thrombosis

No Yes -

CLIP group Hepatology 1998

Okuda Staging System

Stage 1: no adverse parameter is present.

Stage 2: 1 or 2 parameters are present.

Stage 3: 3 or 4 parameters are present.Okuda K et al. Cancer 1985

Tumor size Bilirubin (mg/dL)

Ascites Albumin (g/dL)

> 50 % < 50% > 3 < 3 + - < 3 > 3

The Barcelona Clinic Liver Cancer classification

Stage PST HCC (n) Okuda Liver function

A: Early HCC

A1 0 1 Ino PH, bili normal

A2 0 1 I PH, bili normal

A3 0 1 I PH, bili elevated

A4 0 3, <3 cm I–II Child Pugh A–B

B: intermediate HCC

0 >3 cm I–II Child Pugh A–B

C: advanced HCC 1–2 vasc. invas. I–II Child Pugh A–B

Distant metastases

D: End stage 3–4 All Child Pugh C

Median Survivals (months) for theThree Prognostic Systems

CLIP group Hepatology 1998

Liver function staging

World Health Organization Performance Status grades

Stage 0 Fully active, normal life, no symptoms.

Stage 1 Minor symptoms, able to do light activity.

Stage 2 Capable of self-care but unable to carry out work activities. Up for more than 50% waking hours

Stage 3 Limited self care capacity. Confined to bed or chair > 50% waking hours.

Stage 4 Completely disabled. Confined to bed or chair.

Response rate

Response rate

Complete response: complete disappearance of tumor on imaging or normalization of serum -fetoprotein.

Major response: if tumor size or serum-fetoprotein decreased by more than 50% of the baseline measurement and

Minor response: if the reduction was 50% or less but more than 25%.

Stabilization: variations fo 25% of the initial value Progression: increase of more than 25%. Objective response was defined as the sum of complete an

d major responses.

Response rate (WHO)

Complete response: complete disappearance.

Partial response: decreased > 50% No response: decreased < 50%, increased

< 25% Progression: increase > 25%. Objective response = complete + partial

responses.

Indication for resection

Tumor factor: Absence of extra-hepatic metastasis Absence of tumor thrombus in inferior vena cav

a or main portal vein

Liver factor ICG test at 15min: < 20% or 14~20% CT volumetry

General status for patient

Transplantation criteria

Milan Criteria for Transplantation of the liver

1. One nodule 2.0–5.0 cm; 2 to 3 nodules all ≤3.0 cm

2. No gross intrahepatic portal or hepatic vein involvement on imaging

3. No lymph node or distant metastasis or extrahepatic portal or hepatic vein involvement

Mazzaferro et al, NEJM 1996

Liver Transplantation for HCC: Outcomes

Applying Milan Criteria Authors N Selection Criteria Reccurrence 5-yr Survival

Mazzaferro, 1996

48 Single <5 cm3 nodules <3 cm 8% 74%

Bismuth, 1999

45 Single <3 cm3 nodules <3 cm 11% 74%

Llovet, 1999

79 Single <5 cm 4% 75%

Jonas, 2001

120 Single <5 cm3 nodules <3 cm 16% 71%

Myron Schwartz Gastroenterology 2004

Expand criteria

University of California in San Francisoco Solitary tumor <=6.5cm <= 3 tumor, largest <= 4.5 cm

total tumor diameter <= 8cm

Treatment Strategy

Strategy for staging and treatment assignment of HCC according to the BCLC proposal

Treatment strategies for hepatocellular carcinoma based on tumor stage and Child-Pugh class

Old RCT

HCC Target Tx: 25 Symptomic Tx: 25

Okuda stage II/III: 68%/18%

Catherized to hepatic artery

5-epidoxorubicin (60mg/m2) in 6ml lipiodol, 5 ml meglumine iothalamate

Repeat 4 weeks later if tolerated

Median Survival: TOCE: 48 days (1-504) Symptomic: 51 days (0-6

07)

Pain & appetite Did not differ significantly

Unresectable HCC 50 chemoembolization 46 conservative

treatment

Chemoembolization Catheterize just distal t

o gastroduodenal artery or either left of right branches of hepatic artery

70mg cisplatin and 10 ml lipiodol

Total: 4 courses

Unresectable HCC 50 chemoembolization 46 conservative treatment

Survival Adjusted RR of death: 1.3

(95%CI: 0.8-2.1; P=0.31)

estimated survival rates at 1 year: 62% vs 43.5%

Liver failure 30 pts after 47 courses of treatment

P=0.13

review 1 year survival:

Chemoembolization vs controlOdd ratio 2.0; (95% CI: 1.1-3.6)

2 year mortality: Chemoembolization vs control

Odd ratio 0.54; (95% CI: 0.33, 0.89 p=0.15)

Postitive RCT

Single center, open label, randomized trial Chemoembolization: 40 Control: 40

Exclusion criteria: poor hepatic function serum creatinine level >= 1

80 mol/L; previous Tx for the tumor o

r acute tumor rupture; extrahepatic metastasis vascular contraindications to chemoembolization (hep

atic artery thrombosis,main portal vein thrombosis or arteriovenous shunting);

poor performance status

Exclusion criteria

poor hepatic function presence of hepatic encephalopathy, ascites not controlled by diuretics, history of variceal bleeding within three months, total bilirubin > 50 mol/L, albumin < 28 g/L, Prothrombin time of > 4 seconds over the control);

serum creatinine>180 mol/L; history of treatment for the tumor or acute tumor rupture; presence of extrahepatic metastasis vascular contraindications to chemoembolization (hepati

c artery thrombosis, main portal vein thrombosis or arteriovenous shunting);

poor performance status

Chemoembolization Feeding artery super-selective

catheterized Cisplatin with lipiodol in 1:1 rat

io Injected slowly, volume accord

ing to size of tumor (variable dose)

Up to 60ml (30mg cisplatin) Gelatin sponge embolization

Tumor response: CT αFP

Schedule Repeat every 2~3 months

Withheld when1. Vascular contraindication2. Poor hepatic function 3. Severe adverse effects4. Progressive disease

Results Median courses: 4.5 (1-15) Median volume: 20ml (2-

60ml), related to tumor size (r=0.70, p< 0.001)

Estimated survival

TACEcontrol

1 year 57% 32%

2 years

31% 11%

3 years

26% 3%

Results

Estimated survival Multivariable analysis Chemoembolization:

RR of death: 0.49(95%CI:0.29-0.81, p=0.006)

Uni-portal vein obstruction

RR of death: 2.71(95%CI: 1.38-5.32, p=0.04)

Results

Objective response rate (chemoembolization vs control) Radiological

39% vs 6% (p=0.014)

αFP 72% vs10% (p<0.001)

Liver function Bilirubin: lower in 3 mon

ths, otherwise no sign. difference

Albumin: no sign. diff ICG test: no sign. Diff

=> No sign. deterioration

Comparsion of survival

Liver function after TACE

Liver function – bilirubin, albumin, ICG test No sign deteroriation

Difference from previous study

Difference in patient population Technique and regimen

Selective injection to feeding artery Lower dosage of cisplatin Variable dosage according to tumor No limit of number of treatment course

TACE prolong survival of selected group of Asian patient with unresectable HCC

4

4years, 3 centers RCT 37: TAE 40: TACE 35: conservative

Exclude >75 age Child-Pugh C Active GIB Encephalopathy Refractory ascite Vascular invasion Extrahepatic spread Portosystemic shunt Hepatofugal blood flow Renal failure Contra-indictation to arteria

l procedure or doxorubicin

4

Schedule: Baseline, 2, 6 months, then

every 6 months

Withheld when1. Exclusion criteria developed

2. Vascular contraindication

3. Progressive disease

Chemoembolization Doxorubicin with 10ml lipio

dol Doxorubicin (adjusted acco

rding to bilirubin) then gelfoams embolization

Tumor response: Clinical exam, blood te

st 3 monthly US or CT 6monthly

Results

Estimated survival

TAE TACE control

1st yr 75% 82% 63%

2nd yr

50% 63% 27%

3rd yr

29% 29% 17%

Number of session: TAE: 3.08 (0-7) TACE: 2.8 (1-8)

Results

Multivariable analysis: Treatment allocation: TACE vs conservative OR: 0.45, p=0.02

TACE lower portal vein invasion TACE vs conservative: 17% vs 58%, p =0.005

Liver Function after TAE or TACE

Liver failure without tumor progression 3/37 (8.1%) in TAE, 2/40 (5%) in TACE

4

Meta-analysis of 7 RCT, 503 patient

2 year survival Arterial embolization vs conservative:

odd ratio – 0.53, (95%CI: 0.32-89 p=0.017)

Sensitive analysis Chemoembolization (doxorubicin/cisplatin) -> benefit

OR - 0.42 (95%CI: 0.20-0.88) Embolization alone -> no sign. benefit

OR – 0.59 (95%CI: 0.29-1.20)

no of patient

Etiology HCV/HB

V/alcoholic

Cirrohosis(with child A

%)objective re

psonse Survival (%)liver

failure

Pelletier et al 1990 42 -/ 7/70 88 1 year 2 year

TA (adriamycin 21 7 (33%) 24

Symptomic 21 0 33

Madden et al 1994 50

TAC(epidoxirubicin) 25 16%

Symptomic 25 16%

GRETCH et al 1995 96 8/5/78 91 (100) 63%

TACE (cisplatin, gelfoam) 50 7(16%) 62 38

Control 46 2(5%) 43 26

Pelletier et al 1998 73 15/16/53 89(76) 51%

TACE (cisplatin, gelfoam) + tamoxifen 37 9(24%) 51 24

Tamoxifen 36 2(5.5%) 55 26

Lo et al 2002 79 -/80/- 0%

TACE (cisplati, gelfoam) 40 11(27%) 57 31

Conservative 39 1(2.6%) 32 11

Llovet et al 2003 112 85/6/7 100(70) 7%

TAE (Gelfoam) 37 16(43%) 75 50

TACE (doxorubicin, gelfoam) 40 14(35%) 82 63

Conservative 35 0 63 27

Doffoel et al 2008 123 11/5/1976 98(70) 43%

TACE (eprubicin) + Tamoxifen 62 51 25

tamoxifen 61 46 22

Alcohol related HCC

Multicenter RCT (1995-2002) TACE + tamoxifen: 62 tamoxifen: 61

Exclusion > 75 year-old Child pugh C Okuda stage 3 PV thromobsis Av shunting Extra-hepatic metasta

sis Renal failure Contra-indictation to at

erial procedure

Chemoembolization Epirubicin 50mg + 15ml lipiodol

(adjusted according to bilirubin) Gelfoam cubes

Schedule Every 2 month till stabilized Repeat every 4 months till stabil

ized Then repeat every 6 months Up to 10 course

Monitor AFP CT

Withheld: Refusal No lipodol retention after 3rd c

ourse Poor hepatic function Extrahepatic spread Main portal vein occulsion Irreversible arterial occlusion ? 10% decreased in cardiac ej

ection fraction

Result

Estimated survival

TACE control

1 year 51% 46%

2 years 25% 22%P=0.68

Liver failure Hepatic failure higher in French studies

no of patient

etiologycirrhosis (with Child

A)

liver failur

e

Madden et al 1993

50 nd nd nd

GRETCH et al 1995

96 78% alcohol 91 (100) 63%

Bruix et al 1998 80 62%HCV 100(82) nd

Pelletier et al 1998

73 53% alcohol 89(76) 51%

Lo et al 2002 79 80% HBV nd 0%

Llovet et al 2003 112 85% HCV 100(70) 7%

Doffoel et al 2008 123 76% alcohol 98(70) 43%

5 year survival predictor

TACE confirmedbenefit in 2 year survival

? Any predictor of long survivor

Prospective cohort studies 320 patient, 25 5-year survivor (8%)

Predictor = contradindictation?

Long term survival: Tumor status, hepatic function, TACE technique

AFP Reflecting tumor, including size 8/25 long term survivor have HCC>10cm

Albumin – reflection of liver function Liver failure after TACE – sign. Limitation to survival ben

efit Bilobar disease

40% of 5 year survivors had bilobar disease

Advance in embolization agent

Radioembolization

Yttirum 90 microsphere Rhenium 180 radiolabelled lipiodol I-131 lipiodol

Yttirum 90 microsphereSIR Sphere® Thera Sphere®

parameter resin glass

Manufactor Sirtex Medical, Australia

MDS Nordion, Canada

Diameter 20-60μm 20-30μm

Activity per particle

50Bq 2500Bq

Number of microsphere per 3 GBq vial

40-80 x 106 1.2 x 106

Materialresin with bound

yttriumglass with yttrium

in matrix

Yttirum 90 microsphere

Regimenno of patient

objective response

median survival

(Okuda 1)

median survival

(Okuda 2)

Dancy et al 2000

22 20%

Liu et al 2004

Thera Sphere 14 57%

Gulec et al 2007

SIR-Sphere 40 67%

Young et al 2007

41 660 431

Carr et al 2004

Thera Sphere 42 649 302

Control 23 244 64

Yttirum 90 microsphere

Grade 3 to 4 liver toxicity up to 20%

90Y microsphere did not increased risk of liver adverse events with proven PVT

Lipiodol

Doxorubicin lost from lipiodol in short period of time

Lipiodol droplet separate rapidly from aqueous status

Disadv: Penetrate portal venules and hepatic sinusoids Affect hepatic microcirculation Large amount => parenchymal damage or bile duct isch

emia

radioembolization

Drug loaded Microsphere

100-900μm microsphere derived from polyvinyl alcohol (PVA) Can be loaded with chemotheraptic agent

Controlled, sustainable release

Drug-Loaded Microspheres for the Treatment of Liver Cancer: Review of Current ResultsJ. Kettenbach et al. Cardiovasc Intervent Radiol 2008

Drug loaded Microsphere

Hong et al. 2006 Plasma concentration: minimal Tumor level:

DEB – 413.5 nmol/g (day 3) - 116.7 nmol/g (day 7) - 41.76 nmol/g (day14)

Control – peak: 0.09 nmol/g

Drug loaded Microsphere

Stadler et al America Scientific assembly and annual meeting program 2006

30 patient, 82 procedure Objective response: 40 % (CR- 27%; PR -13%) 30 day mortality: 1% Major adverse events: 2%

(temporary liver failure, cholecystitis)

Malgari et al Eur Radiol 2006

42 patients CT: without enhancement 65% No severe disorder of hepatic function

PRECISION trial

Drug-Loaded Microspheres for the Treatment of Liver Cancer: Review of Current ResultsJ. Kettenbach et al. Cardiovasc Intervent Radiol 2008

Others

Experience and protocol in QMH

Protocol

Inclusion criteria: Unresectable HCC Distribution of tumour: bilobe Liver function too poor (ie Child’s B/C; poor ICG in QM

H) Without systemic metastasis

Following are not contra-indicted: Hepatic vein involvement Portal vein branch involvement History of rupture

Protocol

Exclusion criteria: Extrahepatic metastases Vascular contraindications:

Main portal vein thrombosis Hepatic artery thrombosis Significant arteriovenous (av) shunting

Poor LFT (Child’s C) or RFT Bilirubin > 50 umol/L (absolute contraindication) INR > 1.5 (can proceed to TACE if INR corrected after giving

FFP) Plt <50 x 10^9/L (can proceed after giving plt conc) Creatinine > 180 umol/L Hepatic encephalopathy / Hepatorenal syndrome / Hepatopul

monary syndrome / Refractory ascites.

Protocol

Schedule Benigning: 2 courses of TACE, then CT Arrange iv contrast CT after each courses of TACE TACE not repeat within 2 months

On Fu Assess LRFT, AFP, CT results

Continue TACE if LRFT not contra-intradicted AFP and CT suggest partial response or stable disease

responsesize of tumor &

AFPplan

complete 100% decreasestop TACE or continue 1

more course

partial >=50% decrease continue TACE in 4-6

months (or more frequent)

stable <50% decrease

or <25% increase

continue TACE in 2-3 months

progressive>25% increase or

new lesions on CT

stop TACE after 1 or 2 more courses

main portal vein thrombosis/ sign. AV shunt

stop TACE

Others