Patient demographics
A total of 120 patients (22 females and 98 males) were included in the analysis, with a median age of 61 years (Q1, Q3: 54.7, 65.4). Twenty-six patients underwent transplantation before the MELD scoring system was implemented in Germany. The calculated median MELD score was 11 (Q1, Q3: 8, 15). The most frequent causes of liver cirrhosis were alcoholic liver disease (ALD) and viral hepatitis (n=75 and 21, respectively). The median waiting time was 222 days (Q1, Q3: 72.5, 347 days) (Table 1).
Table 1: Patient Demographics
|
[ALL] N=120
|
N
|
Age
|
61 [54.7;65.4]
|
120
|
<65
|
91 (75.8%)
|
|
>65
|
29 (24.2%)
|
|
Sex:
|
|
120
|
f
|
22 (18.3%)
|
|
m
|
98 (81.7%)
|
|
Disease
|
|
|
ALD
HCV
HBV
Cryptogen
Other
|
75 (62.5%)
14 (11.7%)
7 (5.8%)
12 (10%)
12 (10%)
|
|
AFP (ng/ml)
|
8.00 [4.10;70.0]
|
105
|
Waiting_time (days)
|
212 [72.5;347]
|
120
|
D (mm)
|
33.2 (20.8)
|
120
|
MELD:
|
11 [8; 15]
|
97
|
Meld <= 15
|
71 (73.2%)
|
|
Meld = 15 - 30
|
17 (17.5%)
|
|
Meld > 30
|
9 (9.28%)
|
|
preTreat:
|
|
120
|
no pre Treatment
|
45 (37.5%)
|
|
pre Treatment
|
75 (62.5%)
|
|
N:
|
|
100
|
N = 1
|
59 (59.0%)
|
|
N = 1 - 3
|
30 (30.0%)
|
|
N > 3
|
11 (11.0%)
|
|
Grade:
|
|
59
|
1
|
23 (39.0%)
|
|
2
|
33 (55.9%)
|
|
3
|
3 (5.08%)
|
|
Asan:
|
|
120
|
Exceeding
|
35 (29.2%)
|
|
Fulfilling
|
85 (70.8%)
|
|
AFP Score:
|
|
105*
|
> 2
|
26 (24.8%)
|
|
≤ 2
|
79 (75.2%)
|
|
MC:
|
|
120
|
Exceeding
|
46 (38.3%)
|
|
Fulfilling
|
74 (61.7%)
|
|
UTS:
|
|
120
|
Exceeding
|
34 (28.3%)
|
|
Fulfilling
|
86 (71.7%)
|
|
ALD: Alcoholic liver disease; HCV: Hepatitis C virus; HBV: Hepatitis B virus; AFP: Alpha-feto protein in ng/ml; D: Diameter of the largest tumor in mm; MELD: Model of end-stage liver disease; N: Number of tumors; MC: Milan Criteria; UTS: Up-to-seven Criteria; * Missing AFP values for 15 patients. Data are shown as the average and standard deviation (round brackets) for normally distributed data and as the median and quantiles (square brackets) for nonnormally distributed data.
HCC diagnosis
Eighty-nine patients received a diagnosis of HCC prior to transplantation based on a biopsy or MRI and CT scan, and the diagnosis was proven by postoperative pathology. Incidental HCC was detected in 31 patients according to the postoperative pathological examination. In our population, biopsy was performed preoperatively in 46 cases, proving HCC in 36 patients with 78.2% accuracy, followed by MRI with 68.6% accuracy (35 out of 51 patients) and CT with 64.3% accuracy (72 out of 112 patients). In total, 62.5% of all patients received transarterial chemoembolisation as bridging therapy, followed by radio frequency ablation or both. According to the postoperative histological results, 74 of 120 patients met the MC, 86 patients met the UTS criteria, and 85 patients met the Asan criteria. Out of 46 MC exceeding patients, 12 patients fulfilled UTS and 11 patients fulfilled the Asan criteria.
The AFP score could be calculated only for 105 patients due to the missing AFP values of 15 patients. A total of 79 patients had an AFP score equal to or less than 2. Only five patients exceeding the MC had an AFP score equal to or less than 2.
HCC recurrence-free survival
Seventeen of the 120 patients (14.2%) developed HCC recurrence after a median of 28 months following transplantation (range 5-63 months). According to the univariate analyses, the parameters sex, age (≤ or >65 years), underlying disease, MELD score and pretreatment were not associated with HCC recurrence in our cohort. Only the AFP level (p=0.009), number of tumors (p=0.012), maximum diameter of the largest tumor (p=0.015), and tumor grade (p=0.045) were related to HCC recurrence.
Four of 74 (5.4%) patients fulfilled the MC criteria, four of 86 (4.7%) patients met the UTS criteria, and five of 85 (5.9%) patients fulfilled the Asan criteria and developed HCC recurrence. Five of 79 (6.3%) patients with an AFP score of 2 or less experienced HCC recurrence. These criteria were highly significant in the distinction between patients according to disease recurrence (MC: p=0.001, UTS criteria: p<0.001, Asan criteria: p<0.001, AFP score p=0.009). For the prediction of HCC recurrence, the sensitivity and specificity for the MC were 76% and 68%, respectively; for the UTS criteria, 76% and 80%, respectively; for the Asan criteria, 71% and 78%, respectively; and for the AFP score, 71% and 84%, respectively (Table 2). However, in the multivariate analyses, none of the parameters nor the scoring systems reached statistical significance (data not shown). According to the Kaplan-Meier curves, patients fulfilling UTS but exceeding the MC showed no significant changes in HCC recurrence (Figure 1).
Table 2: Univariate Analyses for HCC Recurrence
|
HCC N=17
|
no HCC N=103
|
p.overall
|
age65:
|
|
|
0.357
|
<65
|
11 (64.7%)
|
80 (77.7%)
|
|
>65
|
6 (35.3%)
|
23 (22.3%)
|
|
sex:
|
|
|
0.735
|
f
|
2 (11.8%)
|
20 (19.4%)
|
|
m
|
15 (88.2%)
|
83 (80.6%)
|
|
AFP (ng/ml)
|
165 [6.70;435]
|
7.10 [4.00;39.1]
|
0.009
|
Waiting-time (days)
|
230 [31.0;394]
|
211 [75.5;344]
|
0.934
|
D (mm)
|
43.4 (20.0)
|
31.5 (20.6)
|
0.035
|
MELD:
|
|
|
1.000
|
Meld <= 15
|
12 (80.0%)
|
59 (72.0%)
|
|
Meld = 15 - 30
|
2 (13.3%)
|
15 (18.3%)
|
|
Meld > 30
|
1 (6.67%)
|
8 (9.76%)
|
|
preTreat:
|
|
|
1.000
|
no pre Treatment
|
6 (35.3%)
|
39 (37.9%)
|
|
pre Treatment
|
11 (64.7%)
|
64 (62.1%)
|
|
N:
|
|
|
0.012
|
N = 1
|
1 (12.5%)
|
58 (63.0%)
|
|
N = 1 - 3
|
5 (62.5%)
|
25 (27.2%)
|
|
N > 3
|
2 (25.0%)
|
9 (9.78%)
|
|
grade:
|
|
|
0.045
|
1
|
0 (0.00%)
|
23 (43.4%)
|
|
2
|
5 (83.3%)
|
28 (52.8%)
|
|
3
|
1 (16.7%)
|
2 (3.77%)
|
|
Asan:
|
|
|
<0.001
|
Exceeding
|
12 (70.6%)
|
23 (22.3%)
|
|
Fulfilling
|
5 (29.4%)
|
80 (77.7%)
|
|
AFP Score:
|
|
|
<0.001
|
> 2
|
12 (70.6%)
|
14 (15.9%)
|
|
≤ 2
|
5 (29.4%)
|
74 (84.1%)
|
|
MC:
|
|
|
0.001
|
Exceeding
|
13 (76.5%)
|
33 (32.0%)
|
|
Fulfilling
|
4 (23.5%)
|
70 (68.0%)
|
|
UTS:
|
|
|
<0.001
|
Exceeding
|
13 (76.5%)
|
21 (20.4%)
|
|
Fulfilling
|
4 (23.5%)
|
82 (79.6%)
|
|
AFP: Alpha-feto protein in ng/ml; D: Diameter of the largest tumor in mm; MELD: Model of end-stage liver disease; N: Number of tumors; MC: Milan Criteria; UTS: Up-to-seven Criteria. Data are shown as the average and standard deviation (round brackets) for normally distributed data and as the median and quantiles (square brackets) for nonnormally distributed data.
Overall survival
The overall survival rates were 76.7% for 1 year, 67.2% for 3 years and 55.6% for 5 years. In total, 53 patients died during the follow-up period, most of them (n=17) due to HCC recurrence. Fifteen patients died from sepsis and multiorgan failure. The third most common cause of death was cardiopulmonary complications. The univariate analyses of sex, age (≤ or > 65 years), primary disease, MELD score, pretreatment, tumor diameter, number of tumors, and grade showed no statistically significant difference between survivors and nonsurvivors. Only AFP levels (p<0.001) showed significant differences between the groups.
The 1-, 3- and 5-year survival rates for patients fulfilling the MC were 82%, 77%, and 69%, respectively; those for patients fulfilling the UTS criteria were 81%, 76% and 71%, respectively; those for patients fulfilling the Asan criteria were 81%, 74% and 70%, respectively; and those for patients with an AFP score ≤2 were 82%, 75% and 52%, respectively. Similar to HCC recurrence, the criteria were also highly significant regarding survival (MC: p=0.001 UTS criteria: p<0.001, Asan criteria: p<0.001, AFP score: p=0.002). The sensitivity and specificity were 57% and 76%, respectively, for the MC, 49% and 88%, respectively, for the UTS criteria, 47% and 85%, respectively, for the Asan criteria and 41% and 87%, respectively, for the AFP score (Table 3). Again, according to the Kaplan-Meier curves, patients fulfilling UTS but exceeding the MC showed no significant changes in survival (Figure 1). However, in the multivariate analyses, none of the parameters nor the scoring systems reached statistical significance (data not shown).
Table 3. Univariate Analyses of Survival
|
Non Survivor N=53
|
Survivor N=67
|
p.overall
|
age65:
|
|
|
0.248
|
<65
|
37 (69.8%)
|
54 (80.6%)
|
|
>65
|
16 (30.2%)
|
13 (19.4%)
|
|
sex:
|
|
|
1.000
|
f
|
10 (18.9%)
|
12 (17.9%)
|
|
m
|
43 (81.1%)
|
55 (82.1%)
|
|
AFP (ng/ml)
|
36.1 [5.40;234]
|
6.20 [3.50;26.5]
|
<0.001
|
Waiting_time (days)
|
236 [77.0;370]
|
198 [64.5;316]
|
0.319
|
D (mm)
|
36.8 (20.1)
|
30.3 (21.1)
|
0.091
|
MELD:
|
|
|
0.703
|
Meld <= 15
|
29 (69.0%)
|
42 (76.4%)
|
|
Meld = 15 - 30
|
9 (21.4%)
|
8 (14.5%)
|
|
Meld > 30
|
4 (9.52%)
|
5 (9.09%)
|
|
preTreat:
|
|
|
0.319
|
no pre Treatment
|
23 (43.4%)
|
22 (32.8%)
|
|
pre Treatment
|
30 (56.6%)
|
45 (67.2%)
|
|
N:
|
|
|
0.109
|
N = 1
|
18 (48.6%)
|
41 (65.1%)
|
|
N = 1 - 3
|
12 (32.4%)
|
18 (28.6%)
|
|
N > 3
|
7 (18.9%)
|
4 (6.35%)
|
|
grade:
|
|
|
0.559
|
1
|
8 (32.0%)
|
15 (44.1%)
|
|
2
|
15 (60.0%)
|
18 (52.9%)
|
|
3
|
2 (8.00%)
|
1 (2.94%)
|
|
Asan:
|
|
|
<0.001
|
Exceeding
|
25 (47.2%)
|
10 (14.9%)
|
|
Fulfilling
|
28 (52.8%)
|
57 (85.1%)
|
|
AFP Score:
|
|
|
0.002
|
> 2
|
18 (40.9%)
|
8 (13.1%)
|
|
≤ 2
|
26 (59.1%)
|
53 (86.9%)
|
|
MC:
|
|
|
0.001
|
Exceeding
|
30 (56.6%)
|
16 (23.9%)
|
|
Fulfilling
|
23 (43.4%)
|
51 (76.1%)
|
|
UTS:
|
|
|
<0.001
|
Exceeding
|
26 (49.1%)
|
8 (11.9%)
|
|
Fulfilling
|
27 (50.9%)
|
59 (88.1%)
|
|
|
|
|
|
AFP: Alpha-feto protein in ng/ml; D: Diameter of the largest tumor in mm; MELD: Model of end-stage liver disease; N: Number of tumors; MC: Milan Criteria; UTS: Up-to-seven Criteria. Data are shown as the average and standard deviation (round brackets) for normally distributed data and as the median and quantiles (square brackets) for nonnormally distributed data.