Beruflich Dokumente
Kultur Dokumente
OF THE
The clinical outcome of cirrhotic patients with hepatocellular carcinoma (HCC) depends both on the residual liver
function and tumor characteristics. However, the relative
prognostic weight of these variables is not well defined. The
aims of this study were to verify the value of known
prognostic factors and to devise a prognostic index more
sensitive than the commonly used Okuda stage. A retrospective analysis of the cases of HCC diagnosed at 16 Italian
institutions from 1990 to 1992 was performed. Overall
survival was the only end point used in the analysis. The
Cox model, stratified by locoregional treatment, was used
for multivariate analyses. The final model was derived from
10 randomly chosen training samples, and the prognostic
validity of the Cancer of the Liver Italian Program (CLIP)
score was assessed on the corresponding testing samples.
Four hundred thirty-five cases of HCC were collected. As of
January 1997, 313 patients (72%) were deceased. Overall
median survival was 20 months. At multivariate analysis,
independent predictive factors of survival were Child-Pugh
stage, tumor morphology, a-fetoprotein (AFP), and portal
vein thrombosis. A simple scoring system (CLIP score) was
thus produced, assigning linear scores (0/1/2) to the covariates. Compared with Okuda stage, the CLIP score, structured as a six-category tool, has a greater discriminant
ability, revealing a class of patients with an impressively
more favorable prognosis and another class with a relatively
shorter life expectancy. The CLIP score is a new prognostic
system that accounts for both liver function and tumor
characteristics. It is easy to calculate and appears to give
more precise information than the Okuda stage. (HEPATOLOGY 1998;28:751-755.)
751
752
GALLO ET AL.
diagnosis and either the date of death or the date of last follow-up
information. Univariate survival curves were estimated using the
Kaplan-Meier method3 and compared by means of the log rank test.4
The observed/expected death ratio for each category is reported. For
each variable, missing data were not used in the analysis if they
accounted for less than 10% of cases.
A stratified Cox proportional hazard regression model5 was used
for multivariate analyses, using Child-Pugh stage, tumor type,
Okuda stage, portal vein thrombosis, and AFP level as covariates.
Locoregional therapy (yes/no) was the stratification factor. Treatment choice strongly depends on the prognostic assessment of
patients, and a retrospective comparison of treated and untreated
patients is accordingly biased. Furthermore, locoregional treatment
may be considered as a proxy for the severity of the disease, and,
stratifying by it, we assumed a different baseline survival for treated
and untreated subjects. Cases with missing values for one or more
variables in the model were excluded from multivariate analysis.
An internal cross-validation procedure was applied, splitting the
whole sample in a training (67%) and in a testing sample (33%). The
process was repeated 10 times; thus, we had 10 training samples and
10 corresponding testing samples. The best-fitting model was
estimated for each training sample. During the analysis, we noticed
an impaired prognostic ability of the Okuda categories caused by the
strict correlation (P , .0001) of the Okuda with the Child-Pugh
stage. Therefore, we replaced the Okuda stage with its single
constitutive variables. A composite variable (tumor morphology)
was further defined by combining together tumor type and tumor
extension. Median value and interquartile range of the 10 estimates
of the relative risks are reported for each covariate retained in the
final model.
A simple scoring system (CLIP score) was derived assigning
linear scores (0/1/2) to the covariates of the final model. Prognostic
validity of the CLIP score was assessed on the 10 testing samples and
compared with the Okuda and Child-Pugh stages. Median values
and interquartile ranges of overall survival for each prognostic
category are presented.
All analyses were performed with the BMDP statistical software.6
RESULTS
Year of diagnosis
1990
1991
1992
Age (yr)
Median
Range
Sex
Male
Female
Modality of diagnosis
Cytological/histological
Imaging 1 AFP . 400
Imaging 1 AFP , 400 or unknown
Cirrhosis
Absent
Present
n (%)
118 (27.1)
128 (29.4)
189 (43.4)
64
19-89
333 (76.6)
102 (24.4)
338 (77.7)
48 (11.0)
49 (11.3)
14 (3.2)
421 (96.8)
O/E Death
166
192
69
0.69
1.12
2.40
129
193
100
0.78
0.93
1.88
204
181
42
0.71
1.28
5.26
331
89
0.82
3.54
161
175
46
53
0.63
1.41
4.06
0.79
361
46
0.92
2.42
421
14
0.98
1.93
182
247
12
138
75
22
2.35
0.68
0.48
0.62
0.87
0.66
348
80
1.02
1.00
,.0001
,.0001
,.0001
,.0001
,.0001
,.0001
.03
,.0001
.89
GALLO ET AL.
RR (training samples)
Covariates
Median Value
Child-Pugh stage
A
B
C
Tumor morphology
Uninodular and #50%
Multinodular and #50%
Massive or .50%
Portal vein thrombosis
No
Yes
AFP (ng/dL)
,400
$400
IQ Range
1
1.72
3.92
1.66-1.92
3.51-4.21
1
1.74
3.18
1.65-1.96
2.78-3.79
1
1.58
1.47-1.97
1
1.79
1.43-1.74
Child-Pugh stage
A
B
C
Tumor moruninodular and
multinodular and massive or extenphology
extension #50%
extension #50%
sion .50%
AFP (ng/dL)
,400
$400
Portal vein
no
yes
thrombosis
753
CLIP Score
Testing
Sample
516
1 (n 5 114)
2 (n 5 110)
3 (n 5 110)
4 (n 5 120)
5 (n 5 107)
6 (n 5 105)
7 (n 5 112)
8 (n 5 123)
9 (n 5 127)
10 (n 5 128)
*
38
44
42
38
*
50
37
43
28
38
38
35
34
25
30
28
38
21
26
19
14
22
20
15
19
14
14
12
18
3
4
5
5
4
5
4
5
5
4
2
2
3
4
6
3
1
3
1
2
1
1
1
1
2
1
0
1
1
1
CLIP score
0 (13.7)
1 (29.4)
2 (29.8)
3 (13.5)
4 (8.2)
5 1 6 (8.0)
Okuda stage
I (43.0)
II (44.7)
III (14.4)
Child-Pugh stage
A (36.3)
B (46.0)
C (16.2)
Median
Interquartile
Range
42.5
32.0
16.5
4.5
2.5
1.0
37.5-*
25.5-38
14-19.5
4-5
1.5-3.5
1-1
32.5
12.0
1.5
30-35.5
11-16.5
1-3
29
19
3.5
25.5-29.5
16-20.5
2-5
754
GALLO ET AL.
GALLO ET AL.
755
15. Tublin ME, Dodd GD III, Baron RL. Benign and malignant portal vein
thrombosis: differentiation by CT characteristics. Am J Roentgenol
1997;168:719-723.
16. Dodd GD III, Memel DS, Baron RL, Eichner L, Santiguida LA. Portal vein
thrombosis in patients with cirrhosis: does sonographic detection of
intrathrombus flow allow differentiation of benign and malignant
thrombus? Am J Roentgenol 1995;165:573-577.
17. Cedrone A, Rapaccini GL, Pompili M, Aliotta A, Trombino C, De Luca F,
Caturelli E, et al. Portal vein thrombosis complicating hepatocellular
carcinoma. Value of ultrasound-guided fine-needle biopsy of the thrombus in the therapeutic management. Liver 1996;16:94-98.
18. De Sio I, Castellano L, Calandra M, Romano M, Persico M, Del Vecchio
Blanco C. Ultrasound-guided fine needle aspiration biopsy of portal vein
thrombosis in liver cirrhosis: results in 15 patients. J Gastroenterol
Hepatol 1995;10:662-665.
19. Chlebowski RT, Tong M, Weissman J, Block JB, Ramming KP, Weiner JM,
Bateman JR, et al. Hepatocellular carcinoma. Diagnostic and prognostic
features in North American patients. Cancer 1984;53:2701-2706.
20. Attali P, ProdHomme S, Pelletier G, Papoz L, Ink O, Buffet C, Etienne JP.
Prognostic factor in patients with hepatocellular carcinoma. Cancer
1987;59:2108-2111.
21. Vauthey JN, Klimstra D, Franceschi D, Tao Y, Fortner J, Blumgart L,
Brennan M. Factors affecting long-term outcome after hepatic resection
for hepatocellular carcinoma. Am J Surg 1995;169:28-35.
22. Akashi Y, Koreeda C, Enomoto S, Uchiyama S, Mizuno T, Shiozaki Y,
Sameshima Y, et al. Prognosis of unresectable hepatocellular carcinoma:
an evaluation based on multivariate analysis of 90 cases. HEPATOLOGY
1991;14:262-268.
23. Shijo H, Okazaki M, Higashihara H, Koganemaru F, Okumura M.
Hepatocellular carcinoma: a multivariate analysis of prognostic features
in patients treated with hepatic arterial embolization. Am J Gastroenterol
1992;87:1154-1159.
24. Nomura F, Ohnishi K, Tanabe Y. Clinical features and prognostic of
hepatocellular carcinoma with reference to serum alpha-fetoprotein
levels. Cancer 1989;64:1700-1707.
25. Trevisani F, Caraceni P, Bernardi M, DIntino PE, Arienti V, Amorati P,
Stefanini GF, et al. Gross pathologic types of hepatocellular carcinoma in
Italian patients. Cancer 1993;72:1557-1563.
26. Trevisani F, DIntino PE, Grazi GL, Caraceni P, Gasbarrini A, Colantoni
A, Stefanini GF, et al. Clinical and pathologic features of hepatocellular
carcinoma in young and older Italian patients. Cancer 1996;77:22232232.
27. Nagasue N, Yukaya H, Hamada T, Hirose S, Kanashima R, Inokuchi K.
The natural history of hepatocellular carcinoma. Cancer 1984;54:14611465.
28. Yamasaki T, Kurokawa F, Kato A, Irie K, Yutoku K, Terai S, Matsuzaki Y,
et al. Clinicopathologic features of early hepatocellular carcinoma.
Hepatogastroenterology 1996;43:926-931.