Characteristics of included patients
Finally, 2163 metastatic HCC patients were identified between 2010 and 2015 from the SEER database. A total of 274 patients were classified as the LTS group, and 1889 patients were classified as the STS group. The demographic and clinicopathological characteristics of the patients in the STS group and LTS group are listed in Table 1. A total of 1515 patients were divided into the training group, and 648 patients were divided into the validation group. The demographic and clinicopathological characteristics of the patients in the training group and validation group are listed in Table 2. All patients were divided into three age groups according to their age (19–59, 60–69, and over 70 years old). Race was classified into white, black and other (American Indian/AK Native, Asian/Pacific Islander). Marital status was classified as married or unmarried. The patients were divided into three groups according to their tumor sizes (less than 3 cm, 3 cm-5 cm and over 5 cm). The median age of the patients was 73 years (ranging from 19 to 85). The median follow-up time of the patients was 90 days (ranging from 1 to 2460). Of all patients, 1403 patients were white, 356 patients were black, and 404 patients were other (American Indian/AK Native, Asian/Pacific Islander).
Table 1
Demographic and clinicopathologic characteristics of the LTS group and the STS group
Characteristic
|
LTS group
|
STS group
|
P value
|
(n = 274)
|
(n = 1889)
|
Age
|
|
|
0.747
|
≤ 59
|
105 (38.3)
|
763 (40.4)
|
|
60–69
|
100 (36.5)
|
684 (36.2)
|
|
≥ 70
|
69 (25.2)
|
442 (23.4)
|
|
Race
|
|
|
0.091
|
White
|
189 (69.0)
|
1214 (64.3)
|
|
Black
|
47 (17.2)
|
309 (16.4)
|
|
Other
|
38 (13.9)
|
366 (19.4)
|
|
Gender
|
|
|
0.505
|
Male
|
220 (80.3)
|
1552 (82.2)
|
|
Female
|
54 (19.7)
|
337 (17.8)
|
|
Marital status
|
|
|
0.584
|
Unmarried
|
136 (49.6)
|
975 (51.6)
|
|
Married
|
138 (50.4)
|
914 (48.4)
|
|
T
|
|
|
< 0.001###
|
T1
|
85 (31.0)
|
381 (20.2)
|
|
T2
|
43 (15.7)
|
269 (14.2)
|
|
T3
|
114 (41.6)
|
962 (50.9)
|
|
T4
|
22 (8.0)
|
205 (10.9)
|
|
TX
|
10 (3.6)
|
72 (3.8)
|
|
N
|
|
|
< 0.001###
|
N0
|
1997 (71.9)
|
1150 (60.9)
|
|
N1
|
52 (19.0)
|
544 (28.8)
|
|
NX
|
25 (9.1)
|
195 (10.3)
|
|
Surgery
|
|
|
< 0.001###
|
Yes
|
41 (15.0)
|
51 (2.7)
|
|
No
|
233 (85.0)
|
1838 (97.3)
|
|
Radiation
|
|
|
< 0.001###
|
Yes
|
80 (29.2)
|
307 (16.3)
|
|
No/Unknown
|
194 (70.8)
|
1582 (83.7)
|
|
Chemotherapy
|
|
|
< 0.001###
|
Yes
|
191 (69.7)
|
737 (39.0)
|
|
No/Unknown
|
83 (30.3)
|
1152 (61.0)
|
|
Tumor size
|
|
|
< 0.001###
|
< 3 cm
|
44 (16.1)
|
188 (10.0)
|
|
3 cm-5 cm
|
56 (20.4)
|
296 (15.7)
|
|
> 5 cm
|
174 (63.5)
|
1405 (74.4)
|
|
DLN
|
|
|
0.404
|
Yes
|
83 (30.3)
|
624 (33.0)
|
|
No
|
191 (69.7)
|
1265 (67.0)
|
|
Bone Metastasis
|
|
|
0.817
|
Yes
|
79 (28.8)
|
528 (28.0)
|
|
No
|
195 (71.2)
|
1361 (72.0
|
|
Brain Metastasis
|
|
|
1.000
|
Yes
|
5 (1.8)
|
38 (2.0)
|
|
No
|
269 (98.2)
|
1851 (98)
|
|
Lung Metastasis
|
|
|
< 0.001###
|
Yes
|
76 (27.7)
|
791 (41.9)
|
|
No
|
198 (72.3)
|
1098(58.1)
|
|
AFP
|
|
|
< 0.001###
|
Positive
|
204 (74.5)
|
1641 (86.9)
|
|
Negative
|
70 (25.5)
|
248 (13.1)
|
|
DLN: Distal lymph node; AFP: Alpha fetoprotein; # P < 0.05; ## P < 0.01; ### P < 0.001
|
Table 2
Characteristics of cases in the training group and the validation group
Characteristics
|
Training group
|
Validation group
|
P value
|
(n = 1515)
|
(n = 648)
|
Age
|
|
|
0.818
|
≤ 59
|
608 (40.1)
|
260 (40.1)
|
|
60–69
|
544 (35.9)
|
240 (37.0)
|
|
≥ 70
|
363 (24.0)
|
148 (22.8)
|
|
Race
|
|
|
0.166
|
White
|
1000 (66.0)
|
403 (62.2)
|
|
Black
|
236 (15.6)
|
120 (18.5)
|
|
Other
|
279 (18.4)
|
125 (19.3)
|
|
Gender
|
|
|
0.240
|
Male
|
1231 (81.3)
|
541 (83.5)
|
|
Female
|
284 (18.7)
|
107 (16.5)
|
|
Marital status
|
|
|
1.000
|
Unmarried
|
778 (51.4)
|
333 (51.4)
|
|
Married
|
737 (48.6)
|
315 (48.6)
|
|
T
|
|
|
< 0.001###
|
T1
|
344 (22.7)
|
122 (18.8)
|
|
T2
|
207 (13.7)
|
105 (16.2)
|
|
T3
|
751 (49.6)
|
325 (50.2)
|
|
T4
|
165 (10.9)
|
62 (9.6)
|
|
TX
|
48 (5.2)
|
48 (3.2)
|
|
N
|
|
|
0.504
|
N0
|
955 (63.0)
|
392 (60.5)
|
|
N1
|
407 (26.9)
|
189 (29.2)
|
|
NX
|
153 (10.1)
|
67 (10.3)
|
|
Surgery
|
|
|
0.805
|
Yes
|
66 (4.4)
|
26 (4.0)
|
|
No
|
1449 (95.6)
|
622 (96.0)
|
|
Radiation
|
|
|
0.005##
|
Yes
|
283 (18.7)
|
104 (16.0)
|
|
No/Unknown
|
1232 (81.3)
|
644 (84.0)
|
|
Chemotherapy
|
|
|
0.539
|
Yes
|
643 (42.4)
|
285 (44.0)
|
|
No/Unknown
|
872 (57.6)
|
363 (56.0)
|
|
Tumor size
|
|
|
0.045#
|
< 3 cm
|
164 (10.8)
|
68 (10.5)
|
|
3 cm-5 cm
|
227 (15.0)
|
125 (19.3)
|
|
> 5 cm
|
1124 (74.2)
|
455 (70.2)
|
|
DLN
|
|
|
0.639
|
Yes
|
490 (32.3)
|
217 (33.5)
|
|
No
|
1025 (67.7)
|
431 (66.5)
|
|
Bone Metastasis
|
|
|
0.946
|
Yes
|
424 (28.0)
|
183 (28.2)
|
|
No
|
1091 (72.0)
|
465 (71.8)
|
|
Brain Metastasis
|
|
|
0.586
|
Yes
|
28 (1.8)
|
15 (2.3)
|
|
No
|
1487 (98.2)
|
633 (97.7)
|
|
Lung Metastasis
|
|
|
0.906
|
Yes
|
609 (40.2)
|
258 (39.8)
|
|
No
|
906 (59.8)
|
390 (60.2)
|
|
AFP
|
|
|
0.137
|
Positive
|
1304 (86.1)
|
541(83.5)
|
|
Negative
|
211 (13.9)
|
107 (16.5)
|
|
DLN: Distal lymph node; AFP: Alpha fetoprotein; # P < 0.05; ## P < 0.01; ### P < 0.001
|
Of all included HCC patients, 60.2% had T3-T4 tumors. Ninety-two (4.3%), 387 (17.9%) and 928 (42.9%) patients were treated with surgery, radiotherapy, and chemotherapy, respectively. In the SEER database, four extrahepatic metastasis sites were recorded, including bone, brain, lung, and distant lymph nodes. Therefore, we also analyzed metastasis at these four sites; among them, there were 867 (40.1%) patients with lung metastasis, which was the most reported metastatic site. The brain was the least reported metastatic site, with only 43 (2.0%) cases.
LTS and STS
In Table 1, the median age of the patients was 61 years and 62 years in the STS group and LTS group, respectively. There was no significant difference in age, race, gender, marital status, distant lymph node metastasis, bone metastasis or brain metastasis between the two groups. The LTS group had a higher proportion of patients at the T1-T2 stage (46.7% vs 33.4%, P < 0.001) and a lower proportion of patients at the N1 stage than the STS group (19.0% vs 28.8%, P < 0.001). For treatment modalities, fewer patients in the STS group underwent surgery (2.7% vs 15.0%, P < 0.001), radiation therapy (16.3% vs 29.2%, P < 0.001) and chemotherapy (39.0% vs 69.7%, P < 0.001). For AFP, the proportion of negative patients in the LTS group was significantly higher than that in the STS group (25.5% vs 13.1%, P < 0.001).
The distribution of site-specific metastasis was different in the two groups. There were 83 (30.3%) and 624 (33%) patients with distant lymph node metastasis, 79 (28.8%) and 528 (28.0%) patients with bone metastasis, 5 (1.8%) and 38 (2%) patients with brain metastasis, and 76 (27.7%) and 791 (41.9%) patients with lung metastasis in the LTS group and STS group, respectively. The results showed that patients in the STS group had higher lung metastasis (P < 0.001) rates than those in the LTS group. However, there was no significant difference in distant lymph node metastasis (P < 0.404), bone metastasis (P < 0.817) or brain metastasis (P < 1.000).
Prognostic analyses: development of nomograms to predict patients’ OS and CSS
In OS analysis, twelve variables, including gender, marital status, T stage, N stage, surgery, radiation, chemotherapy, tumor size, brain metastasis, bone metastasis, lung metastasis and AFP, were identified as potential predictors by univariate Cox regression analysis (P < 0.2). These variables were further included in multivariate Cox regression analysis to develop nomograms. Eight variables identified by univariate Cox regression analysis were potential predictors in CSS analysis, including gender, T stage, surgery, radiation, chemotherapy, tumor size, lung metastasis and AFP. Finally, 9 variables were identified as independent prognostic factors for OS, and 8 variables were identified as independent prognostic factors for CSS in the multivariable Cox regression analyses. Gender, T stage, surgery, radiation, chemotherapy, tumor size, lung metastasis and AFP were predictors in both the OS and CSS models, while N stage was a predictor only in the OS model (Table 3). These variables were selected to develop nomograms for predicting the 1-year and 2-year OS and CSS for all patients (Figs. 1 and 2).
Table 3. Univariate and multivariate analyses of OS and CSS in nomogram cohort
|
OS
|
CSS
|
Variables
|
Univariate Analysis
|
Multivariate Analysis
|
Univariate Analysis
|
Multivariate Analysis
|
|
HR (95%CI)
|
P value
|
HR (95%CI)
|
P value
|
HR (95%CI)
|
P value
|
HR (95%CI)
|
P value
|
Age
|
|
|
|
|
|
|
|
|
≤59
|
Reference
|
|
|
|
Reference
|
|
|
|
60-69
|
0.929(0.825-1.050)
|
0.22
|
|
|
0.924(0.817-1.046)
|
0.211
|
|
|
≥70
|
0.966(0.845-1.100)
|
0.61
|
|
|
0.970(0.845-1.113)
|
0.662
|
|
|
Race
|
|
|
|
|
|
|
|
|
White
|
Reference
|
|
|
|
Reference
|
|
|
|
Black
|
0.955(0.826-1.100)
|
0.53
|
|
|
1.016(0.914-1.129)
|
0.769
|
|
|
Other
|
1.094(0.954-1.250)
|
0.20
|
|
|
1.015(0.918-1.122)
|
0.774
|
|
|
Gender
|
|
0.16
|
|
0.0210#
|
|
0.082
|
|
0.007##
|
Male
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
Female
|
0.909(0.795-1.040)
|
|
0.851(0.742-0.976)
|
|
0.884(0.769-1.016)
|
|
0.822(0.713-0.947)
|
|
Marital status
|
|
<0.049#
|
|
0.984
|
|
0.246
|
|
|
Unmarried
|
Reference
|
|
Reference
|
|
Reference
|
|
|
|
Married
|
0.901(0.813-1.000)
|
|
1.001(0.900-1.113)
|
|
0.939(0.843-1.045)
|
|
|
|
T
|
|
|
|
|
|
|
|
|
T1
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
T2
|
1.059(0.886-1.270)
|
0.526
|
1.169(0.963-1.419)
|
0.115
|
1.093(0.893-1.338)
|
0.999
|
1.183(1.043-1.342)
|
0.388
|
T3
|
1.336(1.170-1.530)
|
<0.001###
|
1.267(1.098-1.462)
|
0.001###
|
1.241(1.071-1.437)
|
<0.001###
|
1.310(1.176-1.460)
|
0.004##
|
T4
|
1.356(1.119-1.640)
|
0.0019###
|
1.299(1.065-1.586)
|
0.001###
|
1.270(1.036-1.557)
|
0.003###
|
1.253(1.082-1.451)
|
0.0213
|
TX
|
1.265(0.925-1.730)
|
<0.1406
|
1.112(0.806-1.533)
|
0.518
|
1.099(0.788-1.532)
|
0.194
|
1.103(0.967-1.258)
|
0.5775
|
N
|
|
|
|
|
|
|
|
|
N0
|
Reference
|
|
Reference
|
|
Reference
|
|
|
|
N1
|
1.192(1.060-1.340)
|
0.004##
|
1.143(1.002-1.305)
|
0.047#
|
1.172(1.036-1.327)
|
0.012#
|
1.122(0.989-1.274)
|
0.0748
|
NX
|
1.110(0.999-1.234)
|
0.002##
|
1.136(0.947-1.363)
|
0.170
|
1.297(1.081-1.556)
|
0.005##
|
1.120(0.928-1.352)
|
0.236
|
Surgery
|
|
<0.001###
|
|
<0.001###
|
|
<0.001###
|
|
<0.001###
|
No
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
Yes
|
0.407(0.310-0.533)
|
|
0.423(0.321-0.558)
|
|
0.407(0.307-0.540)
|
|
0.423(0.318-0.563)
|
|
Radiation
|
|
<0.001###
|
|
<0.001###
|
|
<0.001###
|
|
<0.001###
|
No/Unknown
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
Yes
|
0.664(0.581-0.760)
|
|
0.763(0.655-0.888)
|
|
0.696(0.607-0.798)
|
|
0.834(0.725-0.960)
|
|
Chemotherapy
|
|
<0.001###
|
|
<0.001###
|
|
<0.001###
|
|
<0.001###
|
No/Unknown
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
Yes
|
0.465(0.418-0.517)
|
|
0.436(0.390-0.487)
|
|
0.488(0.438-0.545)
|
|
0.453(0.405-0.507)
|
|
Tumor size
|
|
|
|
|
|
|
|
|
< 3cm
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
3cm-5cm
|
1.022(0.829-1.260)
|
0.839
|
1.180(0.954-1.459)
|
0.127
|
1.012(0.814-1.259)
|
0.913
|
1.147(0.921-1.428)
|
0.220
|
> 5cm
|
1.346(1.133-1.600)
|
0.0007###
|
1.363(1.117-1.663)
|
0.002##
|
1.358(1.136-1.623)
|
<0.001###
|
1.322(1.079-1.621)
|
0.007##
|
DLN
|
|
0.690
|
|
0.968
|
|
0.610
|
|
|
No
|
Reference
|
|
Reference
|
|
Reference
|
|
|
|
Yes
|
0.978(0.876-1.090)
|
|
1.003(0.880-1.143)
|
|
0.971(0.866-1.088)
|
|
|
|
Bone Metastasis
|
|
0.065
|
|
0.161
|
|
0.249
|
|
|
No
|
Reference
|
|
Reference
|
|
Reference
|
|
|
|
Yes
|
0.897(0.799-1.010)
|
|
1.104(0.962-1.267)
|
|
0.933(0.829-1.050)
|
|
|
|
Brain Metastasis
|
|
0.15
|
|
0.326
|
|
0.287
|
|
|
No
|
Reference
|
|
Reference
|
|
Reference
|
|
|
|
Yes
|
1.323(0.904-1.940)
|
|
1.217(0.823-1.799)
|
|
1.246(0.832-1.866)
|
|
|
|
Lung Metastasis
|
|
<0.001###
|
|
<0.001###
|
|
<0.001###
|
|
<0.001###
|
No
|
Reference
|
|
Reference
|
|
Reference
|
|
Reference
|
|
Yes
|
1.411(1.270-1.570)
|
|
1.382(1.229-1.553)
|
|
1.436(1.287-1.602)
|
|
1.384(1.234-1.553)
|
|
AFP
|
|
<0.001###
|
|
<0.001###
|
|
<0.001###
|
|
<0.001###
|
Positive
|
Reference
|
|
Reference
|
|
Reference
|
|
|
|
Negative
|
1.451(1.240-1.690)
|
|
1.375(1.176-1.608)
|
|
1.529(1.301-1.799)
|
|
1.450(1.230-1.701)
|
|
DLN: Distal lymph node; AFP: Alpha fetoprotein; # P <0.05; ## P <0.01; ### P <0.001
|
Nomogram validation
The nomograms were validated using the calibration plot and ROC curve methods. Internal validation via the training cohort showed that the nomograms predicting OS and CSS were in good agreement with actual OS and CSS, with concordance indexes (C-indices) of 0.72 and 0.71, respectively. The internal OS and CSS nomogram calibration plots showed good agreement between the calibration curves and the 45-degree perfect match straight lines (Figs. 3 and 4). The AUCs to predict the 1-year and 2-year OS rates were 0.756 and 0.770, and those for the CSS rates were 0.738 and 0.757, respectively (Fig. 5).
Risk stratifications
The risk scores for every patient were calculated by using the corresponding nomogram. The patients were then divided into high- and low-risk groups accordingly. The Kaplan-Meier method was used to plot the survival curves of OS and CSS in the training and validation groups. The low-risk group showed a better prognosis than the high-risk group (Fig. 6).