Prognostic Factors of Hepatocellular Carcinoma in the West: A Multivariate Analysis in 206 Patients &VIER
CALVE", JORDI BRUJX,PERE GINI%, CONCEPCI6 BRU,MANEL sOLI3, RAM6N VILANA AND JOAN ROD&
Liver Unit and Departments of Radiology and Pathology, Hospital Clinic i Provincial, Barcelona 08036, Spain
To investigate the prognostic factors in Western patients with hepatocellular carcinoma, 206 patients with condjrmeddiagnoses of hepatocellular carcinoma were etadied in terms of survival. All patients were dialplosed between 1983 and 1987. A multivariate survival analysis (Coxregreesionmodel) usingclinical, biochemical, ultrasonographical and pathological data obtained at diagnosis dieclosed that bilirubin (p = O.OOOl), aecitea (p = O.OOOl), toxic syndrome (defined by the preaence of weight loss >lo%premorbid weight, malabe and anorexia) (p = 0.0091, b l d urea nitrogen (p = 0.0261, tumor size (p = 0.001), yglutamyltranmpeptidase(p = O.OOOS), age (p = 0.0006), serum d u m (p = 0.003) and presence of metaetasee (p = 0.002) were independent predictore of survival. According to the contribution of each of these factors to the final model, a pragmatic index was condructed allowing division of patients in different groups according to their relative rielr of death: RRD = EXP (Age x 0.03 + Ascites x 0.8281 +BUN x 0.0137 + Serum sodium x (-0.0638) + y-Glutamyltranspeptidase x 0.0019 + Bilirubin x 0.0734 + Tumor size x 0.33 + Toxic syndrome x 0.4966 + Metaetases x 0.66). These d t s facilitate the stratification of hepatocellular carcinoma patients to design and evaluate future controlled trials. (HEPATOLOGY 19w);12:763-760.)
Hepatocellular carcinoma (HCC) usually occurs in a background of cirrhosis and is considered to have a dismal prognosis (1).Although in the past 10 y-r several studies have defined the prognostic factors that affect survival in patients with compensated (2)or decompensated (3-6)cirrhosis, factors & d i n g prognosis in HCC are less well known. Most of the prognostic studies published up to now in patients with HCC were made to define histological (7,8) or surgical (9-11) factors and/or applied only univariate analysis (1, 12, 13). The only studies applying multivariate analysis including large numbers of patients and wide sets of variables were Received December 5, 1989;accepted May 21, 1990. This study w a supported ~ in part by the Fundaci6 Catalana per a L'Estudi de lea Malaltiee del Fetge. Dr. Calvet had a reeearch grant from the Hospital Clinic i Provincial of Barcelona.
Address reprint requests to: J. Bruiu, M.D.,Liver Unit, Hospital Clinic i Provincial, C W i l , 170, Barcelona 08036, Spain. 31/1/%8606
performed by Attali et al. (14)and Chlebowski et al. (15). However, some important variables, such as tumor size, presence of portal thrombosis and the differentiation degree, were not analyzed in these studies. This study, which reports the results of follow-up investigation, was designed to determine the prognostic factors in a large series of Western patients with unequivocally confirmed HCC, taking into account clinical, biochemical and tumor variables. PATIENTS AND METHODS This study included 258 consecutive adult patients with confirmed HCC diagnosed between January 1983 and December 1987. Patients coming from foreign countries (two cases) and/or subjects with insufficient clinical data (nine cases) were excluded from the study. In addition, to meet the dugnostic criteria used by several authors (12-14,16-21), those ~ 8 8 8 8without pathological confirmation or increased a-fetoprotein (AFP)(n = 41)were also excluded, leaving 206 cases for the analysis. Accordingly, this series represents all patients with unequivocally confirmed HCC admitted to the Liver Unit of the Hospital Clinic i Provincial of Barcelona between January 1983 and December 1987. Diagnosis was made in 87 patients by liver biopsy or necropsy and by cytology in 103 patients. In another 16 cases the dugnosis was based at least on ultrasonographic (US) findings associated with diagnostic levels of AFP. In most of the patients HCC was deteded by US during a hospital admission for treatment of liver disease decompensation. In a few cases HCC was detected in an outpatient basis by routine US screening or because of a toxic syndrome, d e h e d by the presence of weight loss > 10% of premorbid weight, malaise and anorexia. All of these patients had complete clinical records, includmg histories, physical examinations and laboratoryanalyses, which included standard liver function tests, prothrombin time, platelet and blood cell counts, AFT, HBaAg and protein electrophoresis. The existence of ascites was assessed by paracentesis and US. The presence of metastases was ascertained by chest radiograph and, when bone involvement was clinically suspected, by bone scintigraphy. Tumor sue and the presence of portal thrombosis were investigated by US. To analyze the value of tumor size, HCCs were divided into four semiquantitative groups based on their US appearance: uninodular 5 5 cm (group 11, uninodular > 5 cm (group 21, multinodular (group 3)or diffuee tumors (group 4). The differentiation degree was available to be reviewed in 156 of the 190 cases with anatomopathological confirmation. In patients with needle biopsy (n = 471,tumor Merentiation was graded accordingto the criteria of Edmondson and Shiner
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CALVET ET AL.
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- 6 0 5
I
I
10
20
30
1
40
50
'
1
60
t
wins
FIG.1. Actuarial survival rate of the whole series of HCC patients.
(22). In those patients in whom only cytological smears were available for review (n = 1091, classification according to Edmondson and Steiner was not feasible. In such cases tumor differentiation was graded according to previously published criteria (231, which are based on the parallelism between the magnitude of the cell abnormalities and the degree of the differentiation of the tumor (24): (a)good differentiation: the neoplastic cells resemble normal or reactive hepatocytes and contain abundant cytoplasm with or without bile thrombi. (b) Moderate differentiation: the nuclei of the cells are larger and more hyperchromatic than in well-differentiated tumors, occupying a large portion of the tumor cells. (c) Poor differentiation: the nuclei are intensely hyperchromatic, whereas the cytoplasm is markedly reduced and contains few granules. The cells are largely different from nontumoral hepatocytes. The specimens were reexamined by one pathologist or by one cytologist, both unaware of the final outcome of the patients. To group patients stratified by these criteria and those divided by the criteria of Edmondson and Steiner, cases with grades I and I1 from the classification of Edmondson and Steiner were considered well differentiated, grade I11 as moderately differentiated and grade IV as poorly differentiated. Of the 206 patients studied, 156 were men and 50 were women. The mean age was 62.2 2 0.7 (range = 22 to 89) yr. Cirrhosis underlay HCC in 188 patients, whereas liver biopsy disclosed normal livers in seven patients and chronic hepatitis in another four. In seven patients the presence or absence of underlying liver disease could not be ascertained from the available data. Alcoholic cirrhosis was diagnosed in patients with constant ethanol intakes > 80 gm/day for > 10 yr (25). Cryptogenic cirrhosis was diagnosed in nonalcoholic patients when HBsAg was not detected in the serum. Seventy-seven patients (41%)were found to have alcoholic cirrhosis, 13 (8%) HBsAg-associated cirrhosis and 94 (50%) cryptogenic cirrhosis. In four patients cirrhosis was related to porphyria cutanea tarda. Only 58 HCC patients were treated. Tumor resection was performed in 13. Thirty-eight received chemotherapy (13 patients took mitoxantrone, 10 took adriamycin, 11 took VP-16 and cyclophosphamide and 4 patients took other
HEPATOLOGY
treatments) and seven were treated with percutaneous intratumoral ethanol injection. In the remaining 148 patients only symptomatic support was provided. At the time of analysis (June 1988) 30 patients were alive and 176 had died. Survival was obtained from clinical records in 111 patients. The survival and the data of death of the remaining 95 subjects were learned by telephone (66 cases) or by consulting population registries (29 cases). Statistical Methods. Tlmty-five variables (Tables 1 and 2) were considered from the history, physical examination, standard liver function tests, US and cytological examination. All data were obtained at the time of diagnosis. Univariate analysis of survival was performed by computing survival curves according to the Kaplan-Meier method (26). Survival curves were statistically compared using the Mantel-Cox test. For continuous variables, the cutoff level chosen was its median value. Variables that achieved statistical significance (p < 0.05) or were close to significance (p < 0.1) in the univariate analysis were subsequently included in a multivariate analysis using a stepwise forward Cox regression procedure (27).The univariate and multivariate analyses were performed using the BMDP statistical package, 1L and 2L, respectively (28). With the significant prognostic variables obtained in the multivariate analysis, the relative risk of death (RRD) was calculated for each patient using the equation hi(t)/XO(t)= exp (gl x xli
+ . . . . . . + pp x xpi)
where hz(t) is the hazard rate for survival of a particular patient at time t, AO(t) is the hazard computed at the average values of the variable in the model, pl to /3p are the regression coefficients of the variables and xli to xpi are the values of the variable of a particular patient. Higher values for RRD indicate a worse prognosis and lower values mean a better prognosis. Detailed information about this method was provided in a previous report (2). Because this analysis requires that all patients be represented by a complete set of variables, missing data were replaced by the mean values obtained in the whole series as suggested by Rosenman et al. (29). Nevertheless, the regression coefficient was also calculated for each variable without inclusion of mean values; in no case was a significant difference found. The assumption of proportionality hazards was checked by observing a constant vertical difference between plots of log-integrated hazard against t for various levels of each variable (30). The effects of treatment on prognosis were evaluated by including treatment as a variable in the multivariate study, thus comparing treated and untreated patients. In addition, the regression coefficients of the whole series were compared with those of untreated patients. The predictive power of the model was tested using the split-sample technique (6). The X2 test was used for other statistical analysis of the results. Data are presented as mean 5 S.E.M.
RESULTS Survival. The survival curve after diagnosis in all patients studied is shown in Figure 1. The median survival time in the whole series of patients was 3.3 mo (range = 0.1 to 65 mo). Twenty-three percent of the patients survived longer than 1yr. Factor8 Correlating with Survival. As shown in
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PROGNOSIS OF HCC
TABLE 1. Variables without prognostic significance in the univariate analysis Variable
No. of patients
3 mo
lyr
156 50
52 52
27 15
86 120
53 53
30 18
15 189
65 53
12 26
90 113
48 55
20 28
42 164
43 55
20 26
31 172
40 55
18 25
150 33
52 52
25 21
162 15
57 57
22
102 99
57 57
20 26
103 101
58 46
28 20
104 100
58 48
23 23
101 99
48 58
20 23
104 95
50 57
20 22
101 86
60 50
23 23
43 83 30
58 50 50
25 20 15
188 11
53 72
25 27
28 178
52 61
28 12
Sex (n = 206) Male Female Alcoholism in = 206)
Y N HBsAg (n = 204) Positive Negative Previously decompensated liver disease (n = 203) Y N Gastrointestinal bleeding a t admission ( n = 206) Y N Encephalopathy at admission (n = 203) Y N Hepatic stigmata ( n = 183) Y N Hepatomegaly (n = 177) Y N Blood glucose level In = 201 I 5 98 mg/d >98 mg/d AST (n = 204) 5 8 9 IU/L >89 I U L ALT (n = 204) 171 I U L > 7 1 IU/L Cholesterol (n = 2001 5 155 mg/dl > 155 mg/dl Triglycerides (n = 199) I 89 mg/dl >89 mg/d y-globulin (n 187) 5 2 1 gm/L > 2 1 gm/L Degree of differentiation (n 156) I I1 111 Associated cirrhosis ( n = 199)
Y N
0.40
0.23
0.57
0.22
0.20
0.21
0.72
0.61
0.16
0.06
0.22
0.20
0.51
0.62
0.07
0.65
Metastases (n = 206)
Y N
Tables 1 and 2, 18 of the 35 parameters obtained at diagnosis were found to be of value in predicting prognosis in the univariate analysis. Among these 18 variables, the stepwise Cox regression analysis disclosed nine that independently correlated with survival: bili-
p Value
0.06
rubin, m i t e s , toxic syndrome (defined by the presence of weight loss > 10% of premorbid weight, malaise and anorexia), blood urea nitrogen, tumor size, yglutamyltranspeptidase (GGT), age, serum sodium and presence of metastases (Table 3).
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TABLE 2. Variables with prognostic significance in the univariate analysis % surviving
Variable
Ascites (n
No. of patients
3 mo
1Yr
105 100
32 75
12 37
63 142
32 63
8 28
69 116
35 65
8 36
109 88
34 70
12 33
105 98
68 38
34 12
102 101
66 40
36 10
83 83
68 38
41 13
32 41 38 86
69 60 51 37
49 47 16 10
73 111
40 65
7 33
124 79
70 43
31 15
107 88
38 67
15 36
106 85
46 68
15 33
110 87
64 40
26 18
103 100
60 45
27 17
100 99
60 45
32 18
104 102
60 45
30 20
102 101
60 45
26 18
94 93
50 62
20 31
0.0001
= 205)
Y N
0.0001
Jaundice (n = 205)
Y N Toxic syndrome (n
0.0001
= 185)
Y N Serum sodium (n = 197) a 137 mEqL > 137 mEqL Bilirubin (n = 203) 5 1.8 mg/d > 1.8 mddl Alkaline phosphatase (n = 203) 1351 I U L >351 IUL AFP (n = 166) I 151 n g / d > 151 nghd Tumor size (n = 197) Uninodular ( I 5 an) Uninodular ( > 5 cm) Multinodular Diffise Portal thrombosis (n = 184)
Y N Serum creatinine (n = 203) s 1.1mg/dl > 1.1mgtdl Hematocrit (n = 195) I 37%
> 37% Hemoglobin level (n = 191) I12gmn >12 gm/L BUN (n = 197) a20 mg/d > 20 mddl
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0004
0.0013
0.0008
0.007
Platelet count (n = 203) 5112 x 10E9L >112 x 10E9L GGT (n = 199) a 109.5 1UL > 109.5 IUD, Age (n = 206) a 62 > 62
0.0005
0.04
0.02
Prothrombin index (n = 203) I 72%
> 72% Serum albumin (n = 187) 5 30
>30 gm/L
p Value
0.02
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1
10
757
PROGNOSIS OF HCC
\
20
30
I
M
I M
60
10
20
,
w ,
30
40
I 50
60 nowins
D17HS
FIG.2. Actuarial survival rate of HCC patients divided into three groups according to RRD.
The effect of treatment on survival was evaluated by comparing the survival of treated patients with that of untreated ones. The univariate analysis showed that treated patients had longer survival than did untreated patients (p < 0.001). However, when treatment was included in a multivariate analysis with the remaining prognostic variables obtained in the univariate analysis, it was not selected as an independent variable in predicting prognosis. Furthermore, the regression coefficients of the prognostic variables in the final model were calculated for the 148untreated patients, and in no case was a difference found between these regression coefficients and those obtained in the whole series. RRD was calculated for each patient according to the following equation:
FIG.3. Validation of the final model by the split-sample technique. No sigruficant differences are seen between the survival curves of patients of groups A and B when dividing them into three subgroups according to RRD. TABLE 3. Prognostic variables in the fkal model Variable
Bilirubin Toxic syndrome Ascites BUN Tumor size GGT Age Serum sodium Metastases
Relp.ession d c i e n t
0.0734 0.4965 0.8281 0.0137 0.3300 0.0019 0.0300 - 0.0538 0.5500
p Value
0.0001 0.009 0.0001 0.025 0.0001 0.0006 0.0005 0.0024 0.0022
The validation of the final model was tested by the split-sample technique, as done in previous reports (2). This consists of obtaining the regression coefficients for the variables in the final model in a random sample of 66% of the population studied (139patients, group A). In this formula, ascites, toxic syndrome and me- Then the regression coefficient is calculated for this tastases were introduced as dichotomous variables subgroup and the patients are divided into three risk (present = 1, absent = 01,tumor size (uninodular a5 subgroups of equal size using a de nouo calculated RRD. cm = 1, uninodular > 5 cm = 2, multinodular = 3 or Survival curves are calculated using the method of diffuse = 4) as a semiquantitative variable and the Kaplan and Meier (26)for each of the three subgroups. remaining items as continuous variables. The regression coefficients obtained in group A are used RRD ranged between 0.004 and 2.73;it was feasible to to calculate RRD in the remaining 33%of the patients divide the series into three groups with significantly (67patients, group B).These patients are also divided different survivals (Fig. 2). Patients with RRD ~0.025 into three risk subgroups using identical RRD boundhad relatively good prognoses (median survival time = aries as in group A. Finally, each survival curve for the 12.8 & 2.9 mo), whereas patients with RRD between subgroups of group B is compared with the corre0.025 and 0.085 had markedly shorter life expectancies sponding curve for group A. The validation of the final (median survival = 3.9 & 0.5 mo). Finally, patients model is assessed by the absence of differences between with RRD >0.085 had extremely poor prognoses (me- the survival curves. As shown in Figure 3, the applidian survival = 1 +- 0.2mo). cation of this statistical technique confirmed the validity
RRD = EXP (Age x 0.03 + Ascites x 0.8281 + BUN x 0.0137 + Serum sodium x ( - 0.0538) + GGT x 0.0019 + Bilirubin x 0.0734 + Tumor size x 0.33 + Toxic syndrome x 0.4965 + Metastases x 0.55).
CALVET ET AL.
758
of the final model, there being no differences between the survival curves of each pair of patient subgroups divided according to the same RRD boundaries. DISCUSSION
This study reports the results of a follow-up investigation using multivariate analysis to assess the prognostic factors in a large series of European patients with unequivocally confirmed HCC. The study was carried out retrospectively. However, because only survival was considered as the endpoint of the study, it is unlikely that our results could be distorted by loss of follow-up information. As previously known, our results show that patients with HCC have poor prognoses with very short median survivals after diagnosis. This reduced survival is not markedly different from the data found by most authors when describing series with both treated and untreated patients (7, 8, 12-18, 20, 31-37). The main difference of our study is that it includes a large number of patients diagnosed over 5 yr in only m e liver unit receiving all kinds of liver patients for diagnosis and treatment. This characteristic is especially relevant because it guarantees the absence of a previous selection of patients, which may occur with studies done in surgical departments or in centers devoted to cancer treatment not receiving patients with advanced disease. In that regard, our study includes patients diagnosed in early stages and patients with end-stage disease. The univariate analysis disclosed that multiple variables had prognostic significance (Table 2). However, the multivariate analysis selected only nine variables as independent predictors of survival. Three (tumor size, metastases and toxic syndrome) were related to the tumor, whereas the other six reflected the severity of the underlying liver disease (presence of ascites, plasma levels of bilirubin and GGT, BUN and serum sodium) or the patient characteristics (age). Interestingly, some variables previously shown to have prognostic significance such as differentiation degree (12, 361, nature of the underlying liver (31, 37), concentration of AFP (38) and the presence of encephalopathy (14) were not selected as prognostic variables in our study. Probably some of these differences may be justified in part by the design of the studies. Thus some of the series do not determine the role of a large number of variables and others do not include early and advanced cases. As in most of the neoplasms, tumor size and metastases constitute independent prognostic factors. Surprisingly, tumor size was not evaluated in most of the studies (7, 14, 15, 32) and is only reported in patients subjected to surgical treatment (9-111, namely tumor resection. In the classification proposed by Okuda et al. (18), tumor size is taken into account and introduced as a percentage of the total liver volume. In our study HCC size was entered as a semiquantitative variable following the findings of US and, as expected, tumor size greatly influenced the patients’ prognoses, thus being one of the
HEPATOLOGY
most important parameters in determining the outcome of HCC patients. An interesting finding of this study is the predictive power of the presence of toxic syndrome. This term is widely used in our country to describe the impairment of the patient’s clinical status (35) and is defined by the appearance of weight loss > 10%of premorbid weight, malaise and anorexia. Probably, this easily evaluated clinical parameter reflects the advanced stage of HCC patients and might offer the same information as the performance status test (39),which has also been shown to have prognostic implications in the studies by Ihde et al. (37) and Primack et al. (12). Therefore the simple assessment of the patient’s physical condition continues to be very useful to roughly appraise the patient’s prognosis. Because cirrhosis frequently underlies HCC, it is not surprising that these two conditions share the same prognostic factors. The presence of ascites, increased bilirubin levels and impaired renal function (reflected by BUN and serum sodium) are known to be independent predictors of survival in patients with compensated and decompensated cirrhosis (2-4, 6). We have found that these parameters also have prognostic significance in HCC patients, probably reflecting the deleterious effects of the tumor on liver function. The importance of bilirubin coincides with the results obtained by Primack et al. (12), Attali et al. (14) and Chlebowski et al. (15). The fact that the latter two studies also apply a multivariate analysis further reinforces the prognostic value of bilirubin. Furthermore, bilirubin is one of the four parameters taken into account in the staging system proposed by Okuda et al. (13). By contrast, there are some discrepancies about the importance of albumin concentration, ascites and encephalopathy. Ascites and albumin concentration, which are also included in the Okuda staging system, were not selected as prognostic parameters in the previous multivariate investigations (14, 15). However our study found survival to be correlated with the presence of ascites and not with albumin concentration. On the other hand, the presence of encephalopathy at admission was not selected as a progr.ostic variable in our series. In most of the investigations the possible importance of encephalopathy was not reported, whereas in the study by Attali et al. (14) encephalopathy was the best variable for predicting the 60-day survival of HCC patients. This difference with our investigation could be due to the shorter follow-up time of their study and to the fact that Attali’s patients probably had more advanced disease, as reflected by shorter median survival (about 1 mo) and higher incidence of encephalopathy. The prognostic significance of GGT can be explained by the combination of two aspects. Increases of this enzyme are highly nonspecific and may be due to the increase of the hepatoma-specific isoenzyme (40) or to cholestasis induced by the tumor. In this sense, it has been shown that alkaline phosphatase, another enzyme reflecting cholestasis, is an independent predictor of
PROGNOSIS OF HCC
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survival, not only in HCC patients but also in compen sated cirrhotic patients ( 2 ) . In fact, both alkaline phosphatase and GGT were found to be variables with prognostic sigmficance in the univariate analysis, yet alkaline phosphatase lost its significance in the multivariate analysis. The last variable with prognostic implications was age, thus placing us in agreement with several studies showing that advanced age is associated with shorter survival (8, 15). One finding of our study that should be tempered by several considerations is the nonselection of treatment as an independent prognostic variable when comparing treated and untreated patients. In fact, the only subgroup of HCC patients with a worldwide-acceptedbetter prognosis is made up of subjects subjected to tumor resection. However, the low resection rate (6%)of our series cannot induce significant differences between treated and untreated patients. In addition, because intratumoral ethanol injection - another potentially curative procedure (41)-was not applied until the end of 1987 (421,most of this reduced group of treated patients received chemotherapy. Because treatment was not selected as an independent prognostic variable in the multivariate analysis, it can be suggested that the improved survival of our treated patients is related to factors other ke., better liver function or less advanced disease) than the treatment itself. The main interest of this investigation is that the results permit the division of HCC patients according to their expected survival. This mathematical staging system facilitates the design and evaluation of controlled trials to assess the usefulness of different therapeutic approaches for HCC.
Acknowledgments: We are indebted to Eulalia Ventura for her secretarial assistance. We are also grateful to the personnel of the population registries and in particular to Maria Bach-Esteve and Pepita Talavera from the Index del Registre Civil of the Barcelona Council. REFERENCES
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31. Sutton FM, Russell NC, Guinee VF,Alpert E. Factors affecting the prognosis of primary liver carcinoma. J Clin Oncol 1988;6:321328. 32. Inouye AA,Whelan TJ. Primary liver cancer: a review of 205 cases in Hawaii. Am J Surg 1979;138:53-61. 33. Lai CL, Lam KC, Wong KP, Wu PC, Todd AD. Clinical features of hepatocellular carcinoma: review of 211 patients in Hong Kong. Cancer 1981;47:2746-2755. 34. McBride CM. Primary carcinoma of the liver. Surgery 1976;80: 323-327. 35. Garrigues V, Prieto M, Berenguer J . An&is clinicopatologicode una serie de 80 hepatocarcinomas primarios. Gastroenterol Hepatol 1985;8:291-295. 36. McDemott WV, Cady B, Georgi B, Steele G, Khettry U. Primary cancer of the liver: evaluation, treatment and prognosis. Arch Surg 1989;124:552-555. 37. Ihde DC, Matthews MJ, Makuch RW, McIntire KR, Eddy JL. Prognostic factors in patients with hepatocellular carcinoma receiving chemotherapy. Am J Med 1985;78:399-406.
HEPATOLOGY
38. Nomura F, Ohnishi K, Tanabe Y. Clinical features and prognosis of hepatocellular carcinoma with reference to serum alphafetoprotein levels: analysis of 606 patients. Cancer 1989;64:17001707. 39. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207-214. 40. Sawabu N, Hattori N. Serological markers in hepatocellular carcinoma. In: Okuda K, Ishak KG, eds. Neoplasms of the liver. Tokyo: Springer-Verlag, 1987:227-237. 41. Livraghi T, Festi D, Monti F, Salmi A, Vettori C. US-guided percutaneous alcohol injection of small hepatic and abdominal tumors. Radiology 1986;161:309-312. 42. Bru C, Bruix J , Bianchi L, Gilabert R, Calvet X, ViIana R, Rod& J. Tratamiento del carcinoma hepatocelular mediante inyeccidn intratumoral de alcohol etilico: resultados preliminares. Gastroenterol Hepatol 1988;ll:lll-115.
CALVE", JORDI BRUJX,PERE GINI%, CONCEPCI6 BRU,MANEL sOLI3, RAM6N VILANA AND JOAN ROD&
Liver Unit and Departments of Radiology and Pathology, Hospital Clinic i Provincial, Barcelona 08036, Spain
To investigate the prognostic factors in Western patients with hepatocellular carcinoma, 206 patients with condjrmeddiagnoses of hepatocellular carcinoma were etadied in terms of survival. All patients were dialplosed between 1983 and 1987. A multivariate survival analysis (Coxregreesionmodel) usingclinical, biochemical, ultrasonographical and pathological data obtained at diagnosis dieclosed that bilirubin (p = O.OOOl), aecitea (p = O.OOOl), toxic syndrome (defined by the preaence of weight loss >lo%premorbid weight, malabe and anorexia) (p = 0.0091, b l d urea nitrogen (p = 0.0261, tumor size (p = 0.001), yglutamyltranmpeptidase(p = O.OOOS), age (p = 0.0006), serum d u m (p = 0.003) and presence of metaetasee (p = 0.002) were independent predictore of survival. According to the contribution of each of these factors to the final model, a pragmatic index was condructed allowing division of patients in different groups according to their relative rielr of death: RRD = EXP (Age x 0.03 + Ascites x 0.8281 +BUN x 0.0137 + Serum sodium x (-0.0638) + y-Glutamyltranspeptidase x 0.0019 + Bilirubin x 0.0734 + Tumor size x 0.33 + Toxic syndrome x 0.4966 + Metaetases x 0.66). These d t s facilitate the stratification of hepatocellular carcinoma patients to design and evaluate future controlled trials. (HEPATOLOGY 19w);12:763-760.)
Hepatocellular carcinoma (HCC) usually occurs in a background of cirrhosis and is considered to have a dismal prognosis (1).Although in the past 10 y-r several studies have defined the prognostic factors that affect survival in patients with compensated (2)or decompensated (3-6)cirrhosis, factors & d i n g prognosis in HCC are less well known. Most of the prognostic studies published up to now in patients with HCC were made to define histological (7,8) or surgical (9-11) factors and/or applied only univariate analysis (1, 12, 13). The only studies applying multivariate analysis including large numbers of patients and wide sets of variables were Received December 5, 1989;accepted May 21, 1990. This study w a supported ~ in part by the Fundaci6 Catalana per a L'Estudi de lea Malaltiee del Fetge. Dr. Calvet had a reeearch grant from the Hospital Clinic i Provincial of Barcelona.
Address reprint requests to: J. Bruiu, M.D.,Liver Unit, Hospital Clinic i Provincial, C W i l , 170, Barcelona 08036, Spain. 31/1/%8606
performed by Attali et al. (14)and Chlebowski et al. (15). However, some important variables, such as tumor size, presence of portal thrombosis and the differentiation degree, were not analyzed in these studies. This study, which reports the results of follow-up investigation, was designed to determine the prognostic factors in a large series of Western patients with unequivocally confirmed HCC, taking into account clinical, biochemical and tumor variables. PATIENTS AND METHODS This study included 258 consecutive adult patients with confirmed HCC diagnosed between January 1983 and December 1987. Patients coming from foreign countries (two cases) and/or subjects with insufficient clinical data (nine cases) were excluded from the study. In addition, to meet the dugnostic criteria used by several authors (12-14,16-21), those ~ 8 8 8 8without pathological confirmation or increased a-fetoprotein (AFP)(n = 41)were also excluded, leaving 206 cases for the analysis. Accordingly, this series represents all patients with unequivocally confirmed HCC admitted to the Liver Unit of the Hospital Clinic i Provincial of Barcelona between January 1983 and December 1987. Diagnosis was made in 87 patients by liver biopsy or necropsy and by cytology in 103 patients. In another 16 cases the dugnosis was based at least on ultrasonographic (US) findings associated with diagnostic levels of AFP. In most of the patients HCC was deteded by US during a hospital admission for treatment of liver disease decompensation. In a few cases HCC was detected in an outpatient basis by routine US screening or because of a toxic syndrome, d e h e d by the presence of weight loss > 10% of premorbid weight, malaise and anorexia. All of these patients had complete clinical records, includmg histories, physical examinations and laboratoryanalyses, which included standard liver function tests, prothrombin time, platelet and blood cell counts, AFT, HBaAg and protein electrophoresis. The existence of ascites was assessed by paracentesis and US. The presence of metastases was ascertained by chest radiograph and, when bone involvement was clinically suspected, by bone scintigraphy. Tumor sue and the presence of portal thrombosis were investigated by US. To analyze the value of tumor size, HCCs were divided into four semiquantitative groups based on their US appearance: uninodular 5 5 cm (group 11, uninodular > 5 cm (group 21, multinodular (group 3)or diffuee tumors (group 4). The differentiation degree was available to be reviewed in 156 of the 190 cases with anatomopathological confirmation. In patients with needle biopsy (n = 471,tumor Merentiation was graded accordingto the criteria of Edmondson and Shiner
753
754
CALVET ET AL.
70
- 6 0 5
I
I
10
20
30
1
40
50
'
1
60
t
wins
FIG.1. Actuarial survival rate of the whole series of HCC patients.
(22). In those patients in whom only cytological smears were available for review (n = 1091, classification according to Edmondson and Steiner was not feasible. In such cases tumor differentiation was graded according to previously published criteria (231, which are based on the parallelism between the magnitude of the cell abnormalities and the degree of the differentiation of the tumor (24): (a)good differentiation: the neoplastic cells resemble normal or reactive hepatocytes and contain abundant cytoplasm with or without bile thrombi. (b) Moderate differentiation: the nuclei of the cells are larger and more hyperchromatic than in well-differentiated tumors, occupying a large portion of the tumor cells. (c) Poor differentiation: the nuclei are intensely hyperchromatic, whereas the cytoplasm is markedly reduced and contains few granules. The cells are largely different from nontumoral hepatocytes. The specimens were reexamined by one pathologist or by one cytologist, both unaware of the final outcome of the patients. To group patients stratified by these criteria and those divided by the criteria of Edmondson and Steiner, cases with grades I and I1 from the classification of Edmondson and Steiner were considered well differentiated, grade I11 as moderately differentiated and grade IV as poorly differentiated. Of the 206 patients studied, 156 were men and 50 were women. The mean age was 62.2 2 0.7 (range = 22 to 89) yr. Cirrhosis underlay HCC in 188 patients, whereas liver biopsy disclosed normal livers in seven patients and chronic hepatitis in another four. In seven patients the presence or absence of underlying liver disease could not be ascertained from the available data. Alcoholic cirrhosis was diagnosed in patients with constant ethanol intakes > 80 gm/day for > 10 yr (25). Cryptogenic cirrhosis was diagnosed in nonalcoholic patients when HBsAg was not detected in the serum. Seventy-seven patients (41%)were found to have alcoholic cirrhosis, 13 (8%) HBsAg-associated cirrhosis and 94 (50%) cryptogenic cirrhosis. In four patients cirrhosis was related to porphyria cutanea tarda. Only 58 HCC patients were treated. Tumor resection was performed in 13. Thirty-eight received chemotherapy (13 patients took mitoxantrone, 10 took adriamycin, 11 took VP-16 and cyclophosphamide and 4 patients took other
HEPATOLOGY
treatments) and seven were treated with percutaneous intratumoral ethanol injection. In the remaining 148 patients only symptomatic support was provided. At the time of analysis (June 1988) 30 patients were alive and 176 had died. Survival was obtained from clinical records in 111 patients. The survival and the data of death of the remaining 95 subjects were learned by telephone (66 cases) or by consulting population registries (29 cases). Statistical Methods. Tlmty-five variables (Tables 1 and 2) were considered from the history, physical examination, standard liver function tests, US and cytological examination. All data were obtained at the time of diagnosis. Univariate analysis of survival was performed by computing survival curves according to the Kaplan-Meier method (26). Survival curves were statistically compared using the Mantel-Cox test. For continuous variables, the cutoff level chosen was its median value. Variables that achieved statistical significance (p < 0.05) or were close to significance (p < 0.1) in the univariate analysis were subsequently included in a multivariate analysis using a stepwise forward Cox regression procedure (27).The univariate and multivariate analyses were performed using the BMDP statistical package, 1L and 2L, respectively (28). With the significant prognostic variables obtained in the multivariate analysis, the relative risk of death (RRD) was calculated for each patient using the equation hi(t)/XO(t)= exp (gl x xli
+ . . . . . . + pp x xpi)
where hz(t) is the hazard rate for survival of a particular patient at time t, AO(t) is the hazard computed at the average values of the variable in the model, pl to /3p are the regression coefficients of the variables and xli to xpi are the values of the variable of a particular patient. Higher values for RRD indicate a worse prognosis and lower values mean a better prognosis. Detailed information about this method was provided in a previous report (2). Because this analysis requires that all patients be represented by a complete set of variables, missing data were replaced by the mean values obtained in the whole series as suggested by Rosenman et al. (29). Nevertheless, the regression coefficient was also calculated for each variable without inclusion of mean values; in no case was a significant difference found. The assumption of proportionality hazards was checked by observing a constant vertical difference between plots of log-integrated hazard against t for various levels of each variable (30). The effects of treatment on prognosis were evaluated by including treatment as a variable in the multivariate study, thus comparing treated and untreated patients. In addition, the regression coefficients of the whole series were compared with those of untreated patients. The predictive power of the model was tested using the split-sample technique (6). The X2 test was used for other statistical analysis of the results. Data are presented as mean 5 S.E.M.
RESULTS Survival. The survival curve after diagnosis in all patients studied is shown in Figure 1. The median survival time in the whole series of patients was 3.3 mo (range = 0.1 to 65 mo). Twenty-three percent of the patients survived longer than 1yr. Factor8 Correlating with Survival. As shown in
Vol. 12, No. 4, 1990
755
PROGNOSIS OF HCC
TABLE 1. Variables without prognostic significance in the univariate analysis Variable
No. of patients
3 mo
lyr
156 50
52 52
27 15
86 120
53 53
30 18
15 189
65 53
12 26
90 113
48 55
20 28
42 164
43 55
20 26
31 172
40 55
18 25
150 33
52 52
25 21
162 15
57 57
22
102 99
57 57
20 26
103 101
58 46
28 20
104 100
58 48
23 23
101 99
48 58
20 23
104 95
50 57
20 22
101 86
60 50
23 23
43 83 30
58 50 50
25 20 15
188 11
53 72
25 27
28 178
52 61
28 12
Sex (n = 206) Male Female Alcoholism in = 206)
Y N HBsAg (n = 204) Positive Negative Previously decompensated liver disease (n = 203) Y N Gastrointestinal bleeding a t admission ( n = 206) Y N Encephalopathy at admission (n = 203) Y N Hepatic stigmata ( n = 183) Y N Hepatomegaly (n = 177) Y N Blood glucose level In = 201 I 5 98 mg/d >98 mg/d AST (n = 204) 5 8 9 IU/L >89 I U L ALT (n = 204) 171 I U L > 7 1 IU/L Cholesterol (n = 2001 5 155 mg/dl > 155 mg/dl Triglycerides (n = 199) I 89 mg/dl >89 mg/d y-globulin (n 187) 5 2 1 gm/L > 2 1 gm/L Degree of differentiation (n 156) I I1 111 Associated cirrhosis ( n = 199)
Y N
0.40
0.23
0.57
0.22
0.20
0.21
0.72
0.61
0.16
0.06
0.22
0.20
0.51
0.62
0.07
0.65
Metastases (n = 206)
Y N
Tables 1 and 2, 18 of the 35 parameters obtained at diagnosis were found to be of value in predicting prognosis in the univariate analysis. Among these 18 variables, the stepwise Cox regression analysis disclosed nine that independently correlated with survival: bili-
p Value
0.06
rubin, m i t e s , toxic syndrome (defined by the presence of weight loss > 10% of premorbid weight, malaise and anorexia), blood urea nitrogen, tumor size, yglutamyltranspeptidase (GGT), age, serum sodium and presence of metastases (Table 3).
756
CALVET ET AL.
HEPATOLOGY
TABLE 2. Variables with prognostic significance in the univariate analysis % surviving
Variable
Ascites (n
No. of patients
3 mo
1Yr
105 100
32 75
12 37
63 142
32 63
8 28
69 116
35 65
8 36
109 88
34 70
12 33
105 98
68 38
34 12
102 101
66 40
36 10
83 83
68 38
41 13
32 41 38 86
69 60 51 37
49 47 16 10
73 111
40 65
7 33
124 79
70 43
31 15
107 88
38 67
15 36
106 85
46 68
15 33
110 87
64 40
26 18
103 100
60 45
27 17
100 99
60 45
32 18
104 102
60 45
30 20
102 101
60 45
26 18
94 93
50 62
20 31
0.0001
= 205)
Y N
0.0001
Jaundice (n = 205)
Y N Toxic syndrome (n
0.0001
= 185)
Y N Serum sodium (n = 197) a 137 mEqL > 137 mEqL Bilirubin (n = 203) 5 1.8 mg/d > 1.8 mddl Alkaline phosphatase (n = 203) 1351 I U L >351 IUL AFP (n = 166) I 151 n g / d > 151 nghd Tumor size (n = 197) Uninodular ( I 5 an) Uninodular ( > 5 cm) Multinodular Diffise Portal thrombosis (n = 184)
Y N Serum creatinine (n = 203) s 1.1mg/dl > 1.1mgtdl Hematocrit (n = 195) I 37%
> 37% Hemoglobin level (n = 191) I12gmn >12 gm/L BUN (n = 197) a20 mg/d > 20 mddl
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
0.0004
0.0013
0.0008
0.007
Platelet count (n = 203) 5112 x 10E9L >112 x 10E9L GGT (n = 199) a 109.5 1UL > 109.5 IUD, Age (n = 206) a 62 > 62
0.0005
0.04
0.02
Prothrombin index (n = 203) I 72%
> 72% Serum albumin (n = 187) 5 30
>30 gm/L
p Value
0.02
Vol. 12, No. 4, 1990
-
1
10
757
PROGNOSIS OF HCC
\
20
30
I
M
I M
60
10
20
,
w ,
30
40
I 50
60 nowins
D17HS
FIG.2. Actuarial survival rate of HCC patients divided into three groups according to RRD.
The effect of treatment on survival was evaluated by comparing the survival of treated patients with that of untreated ones. The univariate analysis showed that treated patients had longer survival than did untreated patients (p < 0.001). However, when treatment was included in a multivariate analysis with the remaining prognostic variables obtained in the univariate analysis, it was not selected as an independent variable in predicting prognosis. Furthermore, the regression coefficients of the prognostic variables in the final model were calculated for the 148untreated patients, and in no case was a difference found between these regression coefficients and those obtained in the whole series. RRD was calculated for each patient according to the following equation:
FIG.3. Validation of the final model by the split-sample technique. No sigruficant differences are seen between the survival curves of patients of groups A and B when dividing them into three subgroups according to RRD. TABLE 3. Prognostic variables in the fkal model Variable
Bilirubin Toxic syndrome Ascites BUN Tumor size GGT Age Serum sodium Metastases
Relp.ession d c i e n t
0.0734 0.4965 0.8281 0.0137 0.3300 0.0019 0.0300 - 0.0538 0.5500
p Value
0.0001 0.009 0.0001 0.025 0.0001 0.0006 0.0005 0.0024 0.0022
The validation of the final model was tested by the split-sample technique, as done in previous reports (2). This consists of obtaining the regression coefficients for the variables in the final model in a random sample of 66% of the population studied (139patients, group A). In this formula, ascites, toxic syndrome and me- Then the regression coefficient is calculated for this tastases were introduced as dichotomous variables subgroup and the patients are divided into three risk (present = 1, absent = 01,tumor size (uninodular a5 subgroups of equal size using a de nouo calculated RRD. cm = 1, uninodular > 5 cm = 2, multinodular = 3 or Survival curves are calculated using the method of diffuse = 4) as a semiquantitative variable and the Kaplan and Meier (26)for each of the three subgroups. remaining items as continuous variables. The regression coefficients obtained in group A are used RRD ranged between 0.004 and 2.73;it was feasible to to calculate RRD in the remaining 33%of the patients divide the series into three groups with significantly (67patients, group B).These patients are also divided different survivals (Fig. 2). Patients with RRD ~0.025 into three risk subgroups using identical RRD boundhad relatively good prognoses (median survival time = aries as in group A. Finally, each survival curve for the 12.8 & 2.9 mo), whereas patients with RRD between subgroups of group B is compared with the corre0.025 and 0.085 had markedly shorter life expectancies sponding curve for group A. The validation of the final (median survival = 3.9 & 0.5 mo). Finally, patients model is assessed by the absence of differences between with RRD >0.085 had extremely poor prognoses (me- the survival curves. As shown in Figure 3, the applidian survival = 1 +- 0.2mo). cation of this statistical technique confirmed the validity
RRD = EXP (Age x 0.03 + Ascites x 0.8281 + BUN x 0.0137 + Serum sodium x ( - 0.0538) + GGT x 0.0019 + Bilirubin x 0.0734 + Tumor size x 0.33 + Toxic syndrome x 0.4965 + Metastases x 0.55).
CALVET ET AL.
758
of the final model, there being no differences between the survival curves of each pair of patient subgroups divided according to the same RRD boundaries. DISCUSSION
This study reports the results of a follow-up investigation using multivariate analysis to assess the prognostic factors in a large series of European patients with unequivocally confirmed HCC. The study was carried out retrospectively. However, because only survival was considered as the endpoint of the study, it is unlikely that our results could be distorted by loss of follow-up information. As previously known, our results show that patients with HCC have poor prognoses with very short median survivals after diagnosis. This reduced survival is not markedly different from the data found by most authors when describing series with both treated and untreated patients (7, 8, 12-18, 20, 31-37). The main difference of our study is that it includes a large number of patients diagnosed over 5 yr in only m e liver unit receiving all kinds of liver patients for diagnosis and treatment. This characteristic is especially relevant because it guarantees the absence of a previous selection of patients, which may occur with studies done in surgical departments or in centers devoted to cancer treatment not receiving patients with advanced disease. In that regard, our study includes patients diagnosed in early stages and patients with end-stage disease. The univariate analysis disclosed that multiple variables had prognostic significance (Table 2). However, the multivariate analysis selected only nine variables as independent predictors of survival. Three (tumor size, metastases and toxic syndrome) were related to the tumor, whereas the other six reflected the severity of the underlying liver disease (presence of ascites, plasma levels of bilirubin and GGT, BUN and serum sodium) or the patient characteristics (age). Interestingly, some variables previously shown to have prognostic significance such as differentiation degree (12, 361, nature of the underlying liver (31, 37), concentration of AFP (38) and the presence of encephalopathy (14) were not selected as prognostic variables in our study. Probably some of these differences may be justified in part by the design of the studies. Thus some of the series do not determine the role of a large number of variables and others do not include early and advanced cases. As in most of the neoplasms, tumor size and metastases constitute independent prognostic factors. Surprisingly, tumor size was not evaluated in most of the studies (7, 14, 15, 32) and is only reported in patients subjected to surgical treatment (9-111, namely tumor resection. In the classification proposed by Okuda et al. (18), tumor size is taken into account and introduced as a percentage of the total liver volume. In our study HCC size was entered as a semiquantitative variable following the findings of US and, as expected, tumor size greatly influenced the patients’ prognoses, thus being one of the
HEPATOLOGY
most important parameters in determining the outcome of HCC patients. An interesting finding of this study is the predictive power of the presence of toxic syndrome. This term is widely used in our country to describe the impairment of the patient’s clinical status (35) and is defined by the appearance of weight loss > 10%of premorbid weight, malaise and anorexia. Probably, this easily evaluated clinical parameter reflects the advanced stage of HCC patients and might offer the same information as the performance status test (39),which has also been shown to have prognostic implications in the studies by Ihde et al. (37) and Primack et al. (12). Therefore the simple assessment of the patient’s physical condition continues to be very useful to roughly appraise the patient’s prognosis. Because cirrhosis frequently underlies HCC, it is not surprising that these two conditions share the same prognostic factors. The presence of ascites, increased bilirubin levels and impaired renal function (reflected by BUN and serum sodium) are known to be independent predictors of survival in patients with compensated and decompensated cirrhosis (2-4, 6). We have found that these parameters also have prognostic significance in HCC patients, probably reflecting the deleterious effects of the tumor on liver function. The importance of bilirubin coincides with the results obtained by Primack et al. (12), Attali et al. (14) and Chlebowski et al. (15). The fact that the latter two studies also apply a multivariate analysis further reinforces the prognostic value of bilirubin. Furthermore, bilirubin is one of the four parameters taken into account in the staging system proposed by Okuda et al. (13). By contrast, there are some discrepancies about the importance of albumin concentration, ascites and encephalopathy. Ascites and albumin concentration, which are also included in the Okuda staging system, were not selected as prognostic parameters in the previous multivariate investigations (14, 15). However our study found survival to be correlated with the presence of ascites and not with albumin concentration. On the other hand, the presence of encephalopathy at admission was not selected as a progr.ostic variable in our series. In most of the investigations the possible importance of encephalopathy was not reported, whereas in the study by Attali et al. (14) encephalopathy was the best variable for predicting the 60-day survival of HCC patients. This difference with our investigation could be due to the shorter follow-up time of their study and to the fact that Attali’s patients probably had more advanced disease, as reflected by shorter median survival (about 1 mo) and higher incidence of encephalopathy. The prognostic significance of GGT can be explained by the combination of two aspects. Increases of this enzyme are highly nonspecific and may be due to the increase of the hepatoma-specific isoenzyme (40) or to cholestasis induced by the tumor. In this sense, it has been shown that alkaline phosphatase, another enzyme reflecting cholestasis, is an independent predictor of
PROGNOSIS OF HCC
Vol. 12, No. 4, 1990
survival, not only in HCC patients but also in compen sated cirrhotic patients ( 2 ) . In fact, both alkaline phosphatase and GGT were found to be variables with prognostic sigmficance in the univariate analysis, yet alkaline phosphatase lost its significance in the multivariate analysis. The last variable with prognostic implications was age, thus placing us in agreement with several studies showing that advanced age is associated with shorter survival (8, 15). One finding of our study that should be tempered by several considerations is the nonselection of treatment as an independent prognostic variable when comparing treated and untreated patients. In fact, the only subgroup of HCC patients with a worldwide-acceptedbetter prognosis is made up of subjects subjected to tumor resection. However, the low resection rate (6%)of our series cannot induce significant differences between treated and untreated patients. In addition, because intratumoral ethanol injection - another potentially curative procedure (41)-was not applied until the end of 1987 (421,most of this reduced group of treated patients received chemotherapy. Because treatment was not selected as an independent prognostic variable in the multivariate analysis, it can be suggested that the improved survival of our treated patients is related to factors other ke., better liver function or less advanced disease) than the treatment itself. The main interest of this investigation is that the results permit the division of HCC patients according to their expected survival. This mathematical staging system facilitates the design and evaluation of controlled trials to assess the usefulness of different therapeutic approaches for HCC.
Acknowledgments: We are indebted to Eulalia Ventura for her secretarial assistance. We are also grateful to the personnel of the population registries and in particular to Maria Bach-Esteve and Pepita Talavera from the Index del Registre Civil of the Barcelona Council. REFERENCES
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Okuda K, Ishak KG, eds. Neoplasms of the liver. Tokyo: SpringerVerlag, 1987:3-19. Gines P, Quintero E, Arroyo V, Teres J, Bruguera M, Rimola A, Caballeria J , e t al. Compensated cirrhosis: natural history and prognostic factors. HEPATOLOCY 1987;7:122-128. Llach J , Gines P, Arroyo V, Rimola A, Tit6 LL, Badalamenti S, Jimenez W, et al. Prognostic value of arterial pressure, endogenous vasoactive systems and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites. Gastroenterology 1988;94:482-487. Infant-Rivard C, Esnaola S, Villeneuve J P . Clinical and statistical validity of conventional prognostic factors in predicting short-term 1987;7:660-664. survival among cirrhotics. HEPATOLOGY Gluud C, Henriksen JH,Nielsen G, the Copenhagen Study Group for Liver Diseases. Prognostic indicators in alcoholic cirrhotic 1988;8:222-227. men. HEPATOLOGY Schlichting P, Christensen E, Andersen PK, Faureholdt L, Juhl E, Poulsen H, Tygstrup N, et al. Prognostic factors in cirrhosis identified by Cox’s regression model. HwAromw 1983;3:889-895.
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