Int J Clin Oncol (1998) 3:299-303
© The Japan Society of Clinical Oncology 1998
Satoru Kakizaki • Hitoshi Takagi • Kenji Katakai Daisuke Kanda - Takashi Kosone • Akira Kojima Mariko Kurosaki • Hisashi Takayama Y o s h i a k i H a s h i m o t o • S h u u i c h i Saito • K e i i c h i r o u Y u a s a Toshihiko Yamada • Takehiko Abe • Takeaki Nagamine Masatomo Mori
The natural history of untreated hepatocellular carcinoma
Received: September 1, 1997 / Accepted: April 22, 1998 Abstract
Background. Although
early diagnosis and treatment of hepatocellular carcinoma (HCC) has become available through advances in diagnostic imaging and therapeutic modalities, there is still a need for recent data on the prognosis of untreated HCC. Therefore, we evaluated the natural history of patients with untreated H C C from various clinical viewpoints. Methods. D a t a from 70 untreated H C C patients (57 men, 13 women; aged 43-94 years) diagnosed from June 1992 to May 1997 at seven hospitals in G u n m a Prefecture, Japan, were analyzed. Results. The overall mean survival was 5.3 + 7.6 months from diagnosis to death. The median survival was 2.0 months from diagnosis to death; 12.0 months for tumor stage I, 6.8 months for tumor stage II, 8.6 months for tumor stage III, 2:0 months for tumor stage IV-A, and 2.0 months for tumor stage IV-B. According to clinical stage, the median length of survival of clinical stage I patients was 4.3 months; stage II, 4.3 months; and stage III, 1.4 months. In the 15 patients who refused any anti-cancer treatment, the median survival was 15.2 months and in the 55 patients who could not be given anti-cancer treatment because of poor liver function or advanced cancer the median survival was 1.6 months. The prognosis of patients with H C C complicated by portal thrombus was extremely poor. Multivariate analysis showed that portal thrombus and hypoalbuminemia were significant indicators of poor prognosis. Older patients with H C C had a poor prognosis, although the difference from prognosis in younger patients was not significant.
s. Kakizaki ([~) • H. Takagi • K. Katakai - D. Kanda • T. Kosone • A. Kojima • M. Kurosaki • H. Takayama - Y. Hashimoto - S. Saito • K. Yuasa - T. Yamada • T. Abe • T. Nagamine • M. Mori First Department of Internal Medicine, Gunma University School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan Tel. +81-27-220-8127;Fax +81-27-220-8136 e-mail:
[email protected]
Conclusions. Both tumor stage and clinical stage were correlated with duration of survival from diagnosis in these patients with HCC. The prognosis of untreated patients with H C C was extremely poor. All untreated patients died within 3 years of diagnosis. K e y w o r d s Hepatocellular carcinoma . Natural course •
Prognosis
Introduction In recent years, although early diagnosis and treatment of hepatocellular carcinoma (HCC) has become available through advances in screening of high-risk groups by diagnostic imaging and the presence of tumor markers, the overall prognosis of H C C is not satisfactory. Many therapeutic modalities are available for HCC, such as hepatic resection, transcatheter arterial embolization, ethanol injection, and microwave coagulation. To determine the prognosis of recent patients with untreated HCC, we evaluated the natural course of the disease in 70 such untreated patients, from various clinical viewpoints, during a 5-year period.
Patients and methods From June 1992 to May 1997, 70 patients with untreated primary H C C were identified at seven hospitals in G u n m a prefecture, Japan. No specific therapy for H C C was employed in any of these patients. Fifty-five patients (group P) were not offered treatment; the reasons varied but major causes were a tumor that was too advanced and poor liver function. In the remaining 15 patients (group R), either the patient or the family had refused treatment. H C C was diagnosed by needle biopsy or by imaging such as computed tomography or angiography. Patients in w h o m tumor tissue was taken by fine needle biopsy were diagnosed histologically. Those patients who were not able to be
300 Table 1. Classification of patients with untreated HCC according to tumor stage of HCC" and clinical stage of hepatic functional reserve1 Clinical stage
Table 2. Median survival time (months) of 70 patients with untreated HCC according to tumor stage of HCC and clinical stage of hepatic functional reserve Clinical stage
I
II
III
Total I
II
III
Median survival
12" 18 2 2 1.5 4.3
21 21 15.2 4 3.3 4.3
i 2.4 -1.4 1.4 1.4
12 6.8 8.6 2 2 2
Tumor stage of HCC I
II III IV-A IV-B Total
1
3
1
5
3 1 6 3 14
1 3 15 1 23
5 0 22 5 33
9 4 43 9 70
HCC, Hepatocellular carcinoma. aAccording to Union Internationale Contre Le Cancer
Tumor stage of HCC I
II III IV-A IV-B Median survival
~Died for reason other than liver disease (renal failure)
(%)
biopsied because of p o o r liver function and/or a d v a n c e d tumor, or p e r s o n a l reasons, were diagnosed by imaging studies. Images of dynamic or helical c o m p u t e d t o m o graphy were d i a g n o s e d by at least two e x p e r i e n c e d radiologists. A n g i o g r a p h y or magnetic resonance imaging were also used for diagnosis in some patients. L e n g t h of survival was calculated from the time of diagnosis of H C C . A g e , relevant l a b o r a t o r y data, t u m o r m a r k ers, accompanying p o r t a l thrombus, and e x t r a h e p a t i c metastasis were r e c o r d e d at the time of diagnosis of H C C . Findings of p o r t a l t u m o r thrombus involving the p o r t a l trunk or the first m a i n branch of the p o r t a l vein on comp u t e d t o m o g r a p h y or e c h o g r a p h y were considered to be positive. T u m o r stage was designated according to T N M classification of the U n i o n I n t e r n a t i o n a l e Contre le Cancer criteria and clinical stage, according to hepatic functional reserve, was designated according to the criteria of the Liver Cancer Study G r o u p of J a p a n J Survival rates were calculated by the K a p l a n - M e y e r m e t h o d and the generalized W i l c o x o n test was used for statistical analysis. Differences were considered significant when P < 0.05. Multivariate analysis was p e r f o r m e d by multiple linear regression analysis with the c o m p u t e r system N A P Ver.4.0 for Macintosh (Igaku-Shoin, T o k y o , Japan). Survival time was the d e p e n d e n t variable. I n d e p e n d e n t variables were age, sex, albumin, lactic d e h y d r o g e n a s e ( L D H ) , p r o t h r o m bin time, a m m o n i a , alpha f e t o p r o t e i n ( A F P ) , p r o t e i n induced by vitamin k absence-II ( P I V K A - I I ) , p o r t a l thrombus, and e x t r a h e p a t i c metastasis. Qualitative variables, such as sex and p o r t a l t h r o m b u s were conventionally defined as follows: male, 1 and female, 0; positive, 1 and negative, 0. The p a r t i a l regression coefficient was calculated and differences were considered significant when P < 0.05. T h e 70 patients were g r o u p e d according to t u m o r stage and clinical stage, as shown in T a b l e 1.
Results T h e r e were 57 m e n and 13 w o m e n in the series ( m e a n age, 67.7 +- 11.5 years). T h e 15 patients in group R had a m e a n
1oo
--
........
i
i ......
[._, 5 0 - -
i ........
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
Fig. 1. Survival curves of 70 patients with untreated hepatocellular
carcinoma (HCC). Group P, patients unable to receive anti-cancer treatment because of poor liver function or advanced cancer; group R, patients who refused anti-cancer treatment. --, total (n = 70); :.., group P (n = 55); ---, group R (n = 15)
age of 68.7 _+ 10.9 years and the 55 patients in group P had a m e a n age of 67.4 + 11.7 years. T h e r e was no significant difference in age b e t w e e n the two groups. The m e a n survival of the 70 patients from diagnosis to d e a t h was 5.3 _+ 7.6 months (range, 0.1-32.6 months); their m e d i a n survival was 2.0 months. T h e m e d i a n survival of group R was 15.2 months and that of group P was 1.6 months. The survival curves of the groups are shown in Fig. 1. The overall survival rate of the 70 patients was 17.1% at i year, 8.7% at 2 years, and 0% at 3 years. Survival rates in group R patients were 66.0%, 33.5%, and 0% at 1, 2 and 3 years, respectively, while these rates for group P patients were 2.3%, 0%, and 0%, respectively, over the 3 years. T h e longest surviving patient was a 60-year-old m a n in group R with stage I I I t u m o r and clinical stage II, and no metastasis or p o r t a l thrombus. H e survived for 32.6 months. O n e patient in group R with stage I t u m o r and clinical stage I died of a reason o t h e r than liver disease, r e n a l failure. A l l 70 of the u n t r e a t e d patients died within 3 years of diagnosis Survival was e x a m i n e d in relation to t u m o r stage, and the m e d i a n survival of stage I t u m o r patients was 12.0 months; stage II, 6.8 months; stage III, 8.6 months; stage IVA , 2.0 months; and stage IV-B, 2.0 months. T h e m e d i a n survival of clinical stage I patients was 4.3 months; stage II, 4.3 months; and stage III, 1.4 months (Table 2 ). Survival of
301 (%)
(%)
100
100
50
50
............
....... ; C 2 Z L Z I I
tlllll
0
2
4
6
lillllll 8
10
12
14
16
18
20
O 22
24
26
28
30
32
Fig. 2. Survival curves of the 70 patients with untreated HCC according to Union Internationale Cortre le Cancer tumor stage. --, stage I (n = 5); ..., stage II (n = 9); ---, stage III (n = 4); .... ; stage IV-A (n = 43);--, stage IV-B (n = 9)
(%) 100
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
Fig. 4. Survival curves of the 70 patients with untreated HCC according to presence of portal thrombus involving the portal trunk or the first main branch of portal vein (Vp3). '", Vp3 (n = 29); --, others (n 41) =
Table 3. Multivariate linear regression analysis of survival in 70 patients with untreated HCC according to clinical data
--
5 0 - -
L__]
.......
L""[ ............... [ L.. "[
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
Factor
Partial regression coefficient
Age (years) Sex (male) T-Bil (mg/dl) Alb (g/dl) LDH (U/l) PT (%) NH 3 (Fmol/1) AFP (ng/ml) PIVKA-II (AU) Portal thrombus (+) Extrahepatic metastasis (+)
-0.154 -0.045 -0.06 0.22* -0.095 0.042 -0.12 -0.132 -0.028 -0.491"* - 0.098
Fig. 3. Survival curves of the 70 patients with untreated HCC according to clinical stageJ --, clinical stage I (n = 14); ..., clinical stage II (n = 23); ---, clinical stage III (n = 33)
*P < 0.05; **P < 0.01 R2 = 0.36
patients with stage I V - A t u m o r was significantly shorter than that of stage I t u m o r patients (Fig. 2; P < 0.05). Survival of patients in clinical stage I I I was significantly shorter than that of patients in clinical stage I (Fig. 3; P < 0.05). T u m o r stage and clinical stage were closely correlated with prognosis. A c c o r d i n g to survival rates of each factors calculated by the K a p l a n - M e y e r method, the prognosis of patients with H C C complicated by portal t h r o m b u s was extremely p o o r (Fig. 4; P < 0.01). T h e multivariate analysis showed that portal t h r o m b u s ( P < 0.01) and h y p o a l b u m i n e m i a ( P < 0.05) were significant factors for p o o r prognosis (Table 3). A l t h o u g h the difference was n o t significant, older patients with H C C had a p o o r e r prognosis than younger patients. Causes of d e a t h were cancer death caused by H C C (n = 39); hepatic failure due to liver cirrhosis (n = 21) (death of hepatic failure due to progression of H C C was included in cancer deaths); gastrointestinal ( G I ) bleeding (n = 9) ( G I bleeding caused by the r u p t u r e of esophageal varices was
classified as G I bleeding, and oozing of the G I tract due to hepatic failure was classified as hepatic failure) and renal failure due to diabetes mellitus (n = 1).
Discussion In recent years, the early diagnosis and t r e a t m e n t of H C C has b e c o m e possible through advances in diagnostic imaging techniques and t u m o r biopsy. T r e a t m e n t for the liver cirrhosis that accompanies H C C has also improved. Nagasue et al. 2 r e p o r t e d 100 patients with u n t r e a t e d H C C in 1984. Their m e a n survival was 4 months from the onset of initial symptoms to death and 2 months from hospital admission to death. O k u d a et al. 3 r e p o r t e d a large study of the prognosis of H C C in 1985. The m e d i a n survival of 229 patients who received no specific t r e a t m e n t was 1.6 months from diagnosis. A t t a l i et al. 4 r e p o r t e d in 1987 that
302 Table 4. Summary of previous reports of untreated HCC Authors
Period Country No. of patients with untreated HCC Mean survival (months) ~ Median survival (months) Maximum survival (months) Prognostic factors
Nagasue et al.2
Falkson et al.5
Okuda et al.3
Attali et al.4
Olnbuyide6
Stuart et al.7
Our study
1970-1982 Japan
1974-1979 b
1976-1983 Japan
1974-1982 France
1989-1992 Nigeria
1986-1995 USA
1992-1997 Japan
100
Not shown Not shown
229 Not shown
127
89
81 Not shown
70
2.4 Not shown
0.8 Not shown
c
Not shown
2 Not shown 14 Symptoms Jaundice Ascites
4 Not shown
1.6
