Patient characteristics of the pooled and matched cohorts
Between June, 2015 and July, 2021, 4563 patients were diagnosed with HCC. Among them, 3991 patients did not meet the eligibility criteria and were excluded. We included in this study 207 patients who received GKR and 365 patients who received TACE (Supplementary Fig. 1). Before matching, the median follow-up period was 25.5 months (95% CI 19.1–31.9) for the GKR group and 20.8 months (95% CI 17.8–23.8) for the TACE group. Patients who underwent TACE had more multiple tumors (P = 0.012), larger tumors (P = 0.007), higher AFP levels (P = 0.001), more lymph node metastases (P = 0.010), worse PVTT type (P = 0.016) than did those patients who underwent GKR. Patients in the GKR group had experienced a higher number of previous therapies (P < 0.001) than patients in the TACE group (Table 1).
Table 1
Baseline characteristics of the patients before and after PSM
|
Before PSM
|
After PSM
|
Variable
|
GKR
|
TACE
|
P
|
GKR
|
TACE
|
P
|
patients
|
207
|
365
|
|
188
|
188
|
|
Male sex
|
183(88.4)
|
320(87.7)
|
0.795
|
164(87.2)
|
170(90.4)
|
0.405
|
Age ≥ 60 years
|
77(37.2)
|
117(32.1)
|
0.212
|
65(34.6)
|
70(37.2)
|
0.630
|
Child–Pugh B
|
59(28.5)
|
116(31.8)
|
0.414
|
56(29.8)
|
60(31.9)
|
0.724
|
Number of tumors ≥ 2
|
155(74.9)
|
305(83.6)
|
0.012
|
147(78.2)
|
157(83.5)
|
0.220
|
Tumor size ≥ 5 cm
|
151(72.9)
|
301(82.5)
|
0.007
|
142(75.5)
|
155(82.4)
|
0.085
|
Serum AFP ≥ 400 ng/ml
|
97(46.9)
|
223(61.1)
|
0.001
|
95(50.5)
|
108(57.4)
|
0.154
|
ALP levels ≥ 125 U/L
|
135(65.2)
|
270(74.0)
|
0.027
|
127(67.6)
|
133(70.7)
|
0.556
|
Platelet count ≥ 100 × 109/L
|
153(73.9)
|
267(73.2)
|
0.843
|
139(73.9)
|
133(70.7)
|
0.550
|
ALT levels ≥ 40 U/L
|
122(58.9)
|
227(62.2)
|
0.443
|
112(59.6)
|
112(59.6)
|
1.000
|
leukocyte ≥ 4 × 109/L
|
163(78.7)
|
292(80.0)
|
0.720
|
151(80.3)
|
151(80.3)
|
1.000
|
Number of TACE ≥ 2
|
-
|
80(21.9)
|
|
-
|
40(21.3)
|
|
Cheng’s type of PVTT
|
|
|
0.016
|
|
|
0.139
|
I
|
44(21.3)
|
45(12.3)
|
|
35(18.6)
|
29(15.4)
|
|
II
|
63(30.4)
|
147(40.3)
|
|
58(30.9)
|
78(41.5)
|
|
III
|
67(32.4)
|
118(32.3)
|
|
62(33.0)
|
55(29.3)
|
|
IV
|
33(15.9)
|
55(15.1)
|
|
33(17.6)
|
26(13.8)
|
|
Etiology
|
|
|
|
|
|
|
HBV
|
138(66.7)
|
221(60.5)
|
0.146
|
123(65.4)
|
118(62.8)
|
0.649
|
HCV
|
4(1.9)
|
9(2.5)
|
0.681
|
4(2.1)
|
4(2.1)
|
1.000
|
Alcohol
|
89(43)
|
147(40.3)
|
0.525
|
81(43.1)
|
76(40.4)
|
0.691
|
Lymph node metastasis
|
103(49.8)
|
222(60.8)
|
0.010
|
93(49.5)
|
104(55.3)
|
0.289
|
Extrahepatic metastases
|
58(28.0)
|
102(27.9)
|
0.985
|
48(25.5)
|
57(30.3)
|
0.368
|
Lung
|
29(14.0)
|
71(19.5)
|
|
25(13.3)
|
40(21.3)
|
|
Bone
|
24(11.6)
|
17(4.7)
|
|
16(8.5)
|
8(4.3)
|
|
other
|
19(9.2)
|
28(7.7)
|
|
17(9.0)
|
17(9.0)
|
|
Previous therapy
|
102(49.3)
|
74(20.3)
|
<0.001
|
85(45.2)
|
73(38.8)
|
0.210
|
Systemic therapy
|
45(21.7)
|
9(2.5)
|
|
40(21.3)
|
9(4.8)
|
|
Liver resection
|
44(21.3)
|
24(6.6)
|
|
34(18.1)
|
23(12.2)
|
|
radiotherapy
|
18(8.7)
|
0
|
|
14(7.4)
|
0
|
|
TACE
|
51(24.6)
|
51(14.0)
|
|
39(20.7)
|
51(27.1)
|
|
RFA
|
14(6.8)
|
4(1.1)
|
|
11(5.9)
|
4(2.1)
|
|
Abbreviations: PSM, propensity score matching; AFP, alpha fetoprotein; ALP, alkaline phosphatase; ALT, alanine aminotransferase; PVTT, portal vein tumor thrombus; HBV, hepatitis B virus; HCV, hepatitis C virus; GKR, gamma knife radiosurgery; TACE, transcatheter arterial chemoembolization; RFA, radiofrequency ablation.
|
After performing PSM, we identified 188 matched pairs of patients with comparable patient and tumor characteristics. In this matched cohort, patients in the GKR and TACE groups were not significantly different with regards to any patient or tumor covariates at baseline (Table 1). The median follow-up time was 25.9 months (95% CI 20.2-31.6) in the GKR group and 20.8 months (95% CI 13.7-27.9) in the TACE group.
Overall Survival Analyses in the pooled and matched Cohorts
At the cutoff date (September 1, 2021), In the pooled cohort, 105 patients (50.7%) in the GKR group and 253 (69.3%) in the TACE group had died. The mOS was 17.4 months (14.2-20.6) in the GKR group and 8.0 months (6.4-9.6) in the TACE group (p < 0.001, Fig. 1A). The cumulative OS rates at 12, 18, and 24 months were 62.9%, 46.1%, and 40.4% in the GKR group, and 39.3%, 30.7%, and 25.2% in the TACE group, respectively. The OS rates were significantly higher in patients in the GKR group than in those in the TACE group (p < 0.001). In subgroup analysis according to the type of PVTT, patients in the GKR group had a significantly longer OS than those patients with PVTT type II, III and IV in the TACE group (17.5 vs. 8.2 months, p < 0.001, Fig. 2C; 19.3 vs. 7.4 months, p < 0.001, Fig. 2E; 14.5 vs. 6.6 months, p = 0.008, Fig. 2G; respectively). However, there was no significant difference in the OS between the two groups of patients with PVTT type I (14.4 vs. 12.5 months, p = 0.396, Fig. 2A).
In the matched cohort, 102 (54.3%) patients in the GKR group patients and 126 (67.0%) in the TACE group patients died. The GKR group had a mOS of 15.8 (13.4–18.2) months, which was higher than that of 9.8 (6.1–13.5) months in the TACE group (p < 0.001, Fig. 1B). The cumulative OS rates at 12, 18, and 24 months were 59.7%, 41.9%, and 36.8 in the GKR group, and 45.1%, 34.8%, and 27.4% in the TACE group (p < 0.001), respectively. Patients with PVTT type II, III and IV in the GKR group had also a significantly longer OS than their counterparts the TACE group (17.5 vs. 9.8 months, p = 0.003, Fig. 2D; 17.2 vs. 7.8 months, p = 0.028, Fig. 2F; 14.5 vs. 5.5 months, p = 0.043, Fig. 2H; respectively). There was no significant difference in the OS between the two groups of patients with PVTT type I (11.2 vs. 14.4 months, p = 0.703, Fig. 2B).
Exploratory subgroup analysis of associated factors in the matched Cohorts
In exploratory subgroup analyses of OS after PSM (Supplementary Fig. 2), GKR seemed most beneficial in male patients (p = 0.002); those younger than 60 years (p = 0.001); tumor size ≥ 5 cm (p = 0.002),;ALP ≥ 125U/L (P < 0.001); ALT ≥ 40U/L (P < 0.001); leukocyte ≥ 4000/µL (p = 0.002); PVTT type II-IV (p = 0.003, p = 0.030, p = 0.048, respectively); non-HCV (p = 0.001); non-lymh node metastases (p < 0.001); and non-extrahepatic metastases (p < 0.001).
Factors Associated with Overall Survival in the matched Cohorts
We performed univariate and multivariate Cox regression analyses to confim prognostic independent factors after PSM. The child A, GKR, number of tumors < 2, tumor diameter < 5 cm, and ALP <125 U/L were all confirmed as independent positive prognostic factor for OS (all p < 0.005, Table 2).
Table 2
univariate and multivariate Cox regression analysis of overall survivalafter PSM
|
Univariable Cox regression
|
Multivariable Cox regression
|
Variable
|
HR
|
95%CI
|
P
|
HR
|
95%CI
|
P
|
Sex (male/female)
|
1.004
|
0.667-1.511
|
0.984
|
|
|
|
Age (≥60/<60 years)
|
0.813
|
0.617-1.072
|
0.143
|
|
|
|
Child-Pugh class (B/A)
|
1.657
|
1.256-2.184
|
<0.001
|
1.426
|
1.074-1.894
|
0.014
|
Number of tumor (≥2/<2)
|
1.780
|
1.235-2.566
|
0.002
|
1.497
|
1.035-2.164
|
0.032
|
Tumor diameter (≥5/<5 cm)
|
2.282
|
1.563-3.329
|
<0.001
|
1.896
|
1.292-2.781
|
0.001
|
AFP (≥400/<400 ng/ml)
|
1.266
|
0.973-1.646
|
0.079
|
|
|
|
ALP (≥125/<125 U/L)
|
1.95
|
1.439-2.644
|
<0.001
|
1.642
|
1.194-2.258
|
0.002
|
Platelet (<100000/≥100000/µL)
|
1.267
|
0.938-1.713
|
0.123
|
|
|
|
ALT (≥40/<40U/L)
|
1.223
|
0.936-1.597
|
0.14
|
|
|
|
leukocyte (<4000/≥4000/µL)
|
1.14
|
0.818-1.59
|
0.439
|
|
|
|
Cheng’s type of PVTT
|
|
|
0.641
|
|
|
|
I
|
1.000
|
|
|
|
|
|
II
|
1.045
|
0.710-1.538
|
0.825
|
|
|
|
III
|
1.149
|
0.776-1.703
|
0.488
|
|
|
|
IV
|
1.294
|
0.824-2.030
|
0.263
|
|
|
|
HBV (positive/negative)
|
1.199
|
0.911-1.578
|
0.195
|
|
|
|
HCV (positive/negative)
|
1.166
|
0.549-2.476
|
0.689
|
|
|
|
Alcoholism (positive/negative)
|
0.963
|
0.740-1.254
|
0.782
|
|
|
|
Lymph node metastasis (yes/no)
|
1.21
|
0.931-1.572
|
0.153
|
|
|
|
Extrahepatic metastases (yes/no)
|
1.264
|
0.954-1.675
|
0.103
|
|
|
|
Previous therapy (yes/no)
|
0.939
|
0.722-1.222
|
0.641
|
|
|
|
Treatment (GKR/TACE)
|
0.628
|
0.484-0.816
|
<0.001
|
0.664
|
0.510-0.864
|
0.002
|
Abbreviations: PSM, propensity score matching; HR, hazard ratio; PVTT, portal vein tumor thrombus; AFP, alpha fetoprotein; ALP, alkaline phosphatase; ALT, alanine transaminase; HBV, hepatitis B virus; HCV, hepatitis C virus; GKR, gamma knife radiosurgery; TACE, transcatheter arterial chemoembolization.
|