Recent Advances in Diagnosis, Treatment and Prevention of Hepatocellular Carcinoma (HCC)
Recent Advances in Diagnosis, Treatment and Prevention of Hepatocellular Carcinoma (HCC)
Recent Advances in Diagnosis, Treatment and Prevention of Hepatocellular Carcinoma (HCC)
0-39
40-49
50-59
60-69
70-79
80-
(yr)
5000
10000
15000
20000
25000
30000
35000
30,000
HCV-associated
HBV-associated
1945
1975
25 yrs
Blood transfusion
IV injection
Drug abuse
2000
HCVAb(+)
79.8%
HBsAg(+)
11.0%
HCVAb(-)
HBsAg (-)
8.4%
87.5% HBcAb(+)
HCVAb(+)
HBsAg (+)
0.8%
Cirrhosis (85.4 )
Autopsy (n=1021)
%
100
HCV +
50
HBV +
10
15 (y)
normal
CH
LC
HCC
0.5
1.5
3.0
F1
F2
F3
CH
7.0
20-30%
LC
HCC
CHO
R
80
G
R
Y
MU-3
P
20 L
C
C
I
W
Q L
90
T
T
S 130
P
T
L
R
R
E
Y C W P
120
T
I
S
G
D
P
N
E
R
C
G
C
70
F
140
S
G
V
E
G
L
E
P
A
R
D
A
V
C
110
C
G
G
Q
D
E
S L S A T A F W A K Y T
150
R
L
A
V T V E V I P
40
C
C 60
E
50
E
S
L F G K N A
N
NH2
A
L
R
N
E
P R
K
P
E
100 I
S
T
T
CHO
Hinge domain
C S R
A F
A L
30
L N G K R V
10
R S
160
G G S T T
thrombin
Gla domain
Kringle domain
F1
Thrombin
S
S
230
E
V
A
Q
G
200
Y C W
A
A
A
E
D
K
A
L
Q
E
L
R
P
D
S
G
G
G
274
180
K
D 240
R
D
R
F
D
P
Y
G
E
E
N
Q
Y
E
R
R
D
C
C 220
I
G R
F
N
270 A
210
N
D
L
E
A
N
P
A
P
D
Y
V
P V
P
C
C
L
D
E 250
170 T
P
E
E
D
L
L
E
P
260
G
P
V
S
L
S Q
R
D G
D L G D
T
C
G 190
L A
S
Kringle domain
F2
100
1,000
10,000
75,000 mAU/mL
HCC
196 407
48.2
LC
14 265
5.3
Chr. Hep
2 54
3.7
Acute Hep
13
33.3
50
30
Cases
Cases
10
1
Cases
Cases
(Takatsu)
Number of patients
Positive
<20
59
12 (20.3 %)
21-30
34
13 (38.2 %)
31-50
10
8 (80.0 %)
51<
26
25 (96.2 %)
PIVKA-II
>20 ng/ml
>200 ng/ml
Sensitivity
45.0 %
66.7 %
26.4 %
Specificity
92.8 %
80.7 %
94.0 %
Accuracy
63.7 %
72.5 %
53.1 %
>20
AFP
>100
>500
Sensitivity
86
73
60
32
Specificity
98
86
98
99
(ASLD 52ND Annual Meeting, 2001 University of Michigan, Ann Arbor, MI)
PIVKA-ll (mAU/m )
1000
100
10
10
100
1000
AFP (ng/ml)
P=0.229 (not significant)
n =79
n
=132
70
45
40
35
30
25
20
15
10
5
0
60
50
40
30
20
10
0
PIVKA-ll
AFP
combined
PIVKA-ll
AFP
combined
(Saito)
1000
LC group:57
1000
Detection of HCC
8/21
6/21
100
40
100
40
10
10
-24
PIVKA- (mAU/mL)
PIVKA- (mAU/mL)
9/21
-18
-12
Months
-6
-24
-18
-12
-6
Months
mAU/mL
PIVKA-
104
103
103
102
102
10
before
after
before
after
PIVKA-II
Clinical Utility in Japan
-Diagnosis of HCC
Screening of high-risk group
Liver cirrhosis, Chronic hepatitis
-As a marker in the evaluation of therapeutic effects on HCC
-As a detector of recurrence of HCC
Clinical Comparison to Alpha-fetoprotein(AFP)
AFP:Most common marker of HCC
5-year survival: 69
80
7-year survival: 49
60
40
20
PEIT (n=147)
0
1
9 year
Radiofrequency ablation
Hooked arrays electrode
Conventional
monopolar electrode
1.6 cm
(ablation area)
Cooled-tip electrode
gas gas
PEIT (55)
RFA(56)
Number of session
6.7
Days in hospital
27.1 10.3
Complications
2.6
20
Local recurrence
1.9 0.6
p<0.0001
10.3
3.3
p<0.0001
(38%)
p=0.901
0
(36%)
21
0
p=0.027
Regimen
Before treatment, Mar. 1992
After treatment,
Apr. 1992
After treatment,
Mar. 1993
100
80
p<0.0001
60
CS1(n=41)
40
CS2(n=61)
20
CS3(n=12)
years
Ascites
abscent
present, controlable
present, uncontrolable
total bilirubin
(mg/dl)
<=2.0
2.0< <=3.0
3.0<
Albumin
(g/dl)
ICG R15(%)
prothrombin
time(%)
3.5<=
3.0<= <3.5
<3.0
<=15
15< <=40
40<
80<=
50<= <80
<50
age
Liver function
GOT
GPT
T.bil
<100
<100
Normal
Blood
platellet
>80,000
Renal function
Serum Cr
<1.5
PS
0, 1
Liver function of patients with tumor thrombi in major branches of the portal vein,treated with
a combination of 5-FU arterial chemotherapy and subcutaneous administration of IFN-
Age
(yrs)
42
HCV
2.0
9780
3.0
80
46
HBV
1.5
5450
4.0
88
74
HCV
1.2
4420
3.0
63
70
HCV
1.8
4100
3.5
79
70
HCV
1.8
5640
3.4
78
67
HCV
1.3
4590
3.7
76
64
HCV
1.0
4730
3.7
100
60
HBV
2.3
4690
3.0
89
70
HBV
1.9
8990
3.2
80
10
63
HCV
0.9
3710
3.0
60
11
31
HBV
1.2
7460
2.6
69
Gender
Hepatitis
Platelet
(x105/L)
Leukocyte/L
Albumin
(g/dL)
Hepaplastin Child-Pugh
classification
Test (%)
Case
Clinical outcome of patients with tumor thrombi in major branches of the portal vein, treated with
a combination of 5-FU arterial chemotherapy and subcutaneous administration of IFN-
Case
1
2
3
4
5
6
7
8
9
10
11
Tumor
pathology
Tumor
Diameter
(cm)
Treatment
cycles
PIVKA-II
(mAU / mL)
(pre / post)
Response
Side effects
Outcome (mos)
4.5
9900 / <5
7140 / < 40
CR
4.0
448 / <5
8988 / < 65
PR
Leukopenia
Vp3, multiple
5.5
32 / 9
7056 / 630
PR
Depression,
metastases
Vp3, Vv3
3.5
5/5
<65 / < 65
PR
5.0
12 / 5
3750 / 14,637
SD
15, alive
6.0
191 / 5
448 / < 40
CR
13, alive
5.0
4400 / <5
4430 / <40
CR
8, alive
Vp3, multiple
Right lobe
10 / 12
40,110 / 195,300
PD
6, alive
Vp3
6.0
336 / 364
ND
PR
Vp3, multiple
Right lobe
28,700 / 28,100
5635 / 11,739
PD
Vp3, B2
5.0
Vp3, multiple
Vp3, multiple
Vp3, multiple
Vp3/Vv2
Vp3, multiple
Diffuse type
5, alive
Depression
-
Diffuse type
5, alive
5, dead
70,000 / 41,200
790 / <40
PR
3, alive
Author
Drugs
One term
2 mos
Nair, et al
Sachs, et al
Creagan, et al
GTSG
Kardinal ,et al
IFN- 12 MU, I.m. (daily, Day 1-5 / week) doxorubicin 25-40 mg / m , I.v. (Day 1)
Feun, et al
IFN- 20 MU, I.m. (weekly, 1st 3 weeks) doxorubicin 20 mg / m 2, I.v. (weekly, 1st 3 weeks)
Patt, et al
IFN- 5 MU, I.m. (3 time / week) 5-FU 750 mg / m 2, continous I.v. (5 days, 1st week)
Lai, et al
Leung, et al
CDDP (20 mg / m2, I.v. Days 1-4, every week) doxorubicin (40 mg / m 2, I.v., Day 1),
12 wks
5-fluorouracil (400 mg / m2 I.v., Days 1-4) IFN- (5 MU / m2 s.c., Days 1-4) I.m.
Urabe, et al
IFN- 3 MU, I.m. (3 times / week), 5-FU 750 mg / m 2, I.a. (weekly), CDDP 75 mg / m2 , I.a. (every
2 weeks), MTX 30 mg / m2 , I.a. (every 4 weeks) leucovorin 30 mg / m 2 , I.v. (every 4 weeks)
Llovet, et al
Chung, et al
5 MU / m , I.m. (3 time / week), CDDP 2 mg / kg, continuous I.a. (ever 8 weeks)IFN- 3 MU, I.m.
2
4 wks
1-3 wks
4 wks
5 wks
2 wks
1 wk
3 wks
Response CR
+ PR / total
(%)
0 / 2 (0)
0 / 30 (0)
1 / 7 (17)
2 / 30 (7)
1 / 30 (3)
2 / 21 (10)
6 / 28 (21)
11 / 35 (31)
13 / 50 (26)
4 wks
7 / 15 (47)
1 yr
2 / 30 (7)
8 wks
6 / 18 (33)
20
NR N=585
10
IR N=145
0
10
CR N=461
15
(y)
Complete responder
(HCV RNA (-))
(ALT normalized)
10%
Biochemical responder
(HCV RNA (+))
(ALT normalized)
30%
significantly lower
1/2 in occurrence
Responder rate
10 20 % increase
KL-6
21,000
(Y Otsuki)
Antibiotic
Syou-saiko-tou
1,600
1,400
1,200
1,000
800
600
400
200
IFN
Cut-Off Value
500U/mL
Healthy
N=44
IIP*
Radiation
pneumonia
Drug induced
pneumonia
80
60
44.0 %
40
20
0
8.0 %
ALT< 80u
(n=25)
ALT> 80u
(n=27)
(Tarao)
Anti-inflammatory agents
1. Glycyrrhizin prevalation (IV)
2. Sho-Saiko-to (herbal medicine)
3. Ursodeoxycholic acid
4. etc.
50
SNMC(-)
SNMC(+)
0
0
10
15
(year)
80
60
67%
40
27%
(n=281)
20
0
9 years
88%
cumulative
incidence100
of distant
recurrence
80
(%)
Non-IFN group
(n=22)
p<0.01
60
40
20
IFN group
(n=18)
0
0
10
cumulative
survival 1.0
rate
IFN group
(n=18)
0.5
Non-IFN group
(n=22)
p<0.01
0
0
10
1995
1995
1995
1995
Development of PVI
1yr
2yr
2%
13%
21%
55%
Vit K(-)
(Koike 2002)
recurrence
1yr
2yr
Vit K (+)
9%
37%
Vit K(-)
37%
84%
(Mizuta 2002)
IFN + Vitamin K2
Conclusion
*Prevention of HCC in chronic liver diseases by IFN
*Early detection and treatment
*Prevention of the second primary HCC by IFN, Vit K
*Treatment of advanced HCC by chemotherapy with IFN