Pretreatment Non-Invasive Biomarkers as Predictors to Estimate Portal Vein Tumor Thrombosis (PVTT) Risk and Long-Term Survival in HBV-Related Hepatocellular Carcinoma Patients Without PVTT

Figures & data

Table 1 Baseline Characteristics of HBV-Related HCC Patients with and without PVTT

Characteristics	Entire Cohort (n=1026)	Non-PVTT (n=890)	PVTT (n=136)	p value
Gender, female / male	162 / 864 (15.8% / 84.2%)	151 / 739 (17% / 83%)	11/ 125 (8.1% / 91.9%)	0.008
Age, years	56 (48, 65)	56 (48, 65.75)	55 (48.75, 63)	0.269
≤60 / >60	646 / 380 (63% / 37%)	553 / 337 (62.1% / 37.9%)	93 / 43 (68.4% / 31.6%)	0.160
AAPR	0.41 (0.26, 0.57)	0.42 (0.27, 0.58)	0.35 (0.24, 0.46)	< 0.001
≤0.49 / >0.49	649 / 377 (63.3% / 36.7%)	540 / 350 (60.7% / 39.3%)	109 / 27 (80.1% / 19.9%)	< 0.001
AAR	1.16 (0.88, 1.54)	1.16 (0.88, 1.56)	1.13 (0.91, 1.41)	0.700
≤0.965 / >0.965	339 / 687 (33% / 67%)	295 / 595 (33.1% / 66.9%)	44 / 92 (32.4% / 67.6%)	0.855
APRI	0.67 (0.40, 1.41)	0.65 (0.39, 1.39)	0.87 (0.49, 1.68)	0.002
≤0.48 / >0.48	369 / 657 (36% / 64%)	338 / 552 (38% / 62%)	31 / 105 (22.8% / 77.2%)	< 0.001
FIB-4	2.44 (1.52, 4.73)	2.39 (1.47, 4.73)	2.80 (1.73, 4.68)	0.141
≤1.85 / >1.85	362 / 664 (35.3% / 64.7%)	322 / 568 (36.2% / 63.8%)	40 / 96 (29.4% / 70.6%)	0.124
AFP, ng/mL	49.79 (7.19, 987.03)	43.84 (7.01, 969.95)	96.51 (9.12, 1020)	0.179
<20 / ≥20	411 / 615 (40.1% / 59.9%)	365 /525 (41% / 59%)	46 / 90 (33.8% / 66.2%)	0.111
HBV-DNA, log IU/mL				0.118
Negative	419 (40.8%)	374 (42%)	45 (33.1%)
<5	324 (31.6%)	278 (31.2%)	46 (33.8%)
≥5	283 (27.6%)	238 (26.7%)	45 (33.1%)
ALBI score	−2.73 (−3.08, −2.24)	−2.75 (−3.09, −2.25)	−2.69 (−2.93, −2.22)	0.034
Grade 1	611 (59.6%)	537 (60.3%)	74 (54.4%)	0.072
Grade 2	374 (36.5%)	322 (36.2%)	52 (38.2%)
Grade 3	41 (4%)	31 (3.5%)	10 (7.4%)
Ascites				0.227
Negative	797 (77.7%)	689 (77.4%)	108 (79.4%)
Small	183 (17.8%)	164 (18.4%)	19 (14%)
Medium / large	46 (4.5%)	37 (4.2%)	9 (6.6%)
Extrahepatic metastasis, no / yes	894 / 132 (87.1% / 12.9%)	784 / 106 (88.1% / 11.9%)	110 / 26 (80.9% / 19.1%)	0.019
Tumor diameter, cm	5 (2.73, 8.70)	4.7 (2.7, 8.6)	5.95 (3.45, 9.43)	0.031
≤3	296 (28.8%)	268 (30.1%)	28 (20.6%)	0.073
3 to 10	536 (52.2%)	456 (51.2%)	80 (58.8%)
>10	194 (18.9%)	166 (18.7%)	28 (20.6%)
Tumor number, single / multiple	542 / 484 (52.8% / 47.2%)	481 / 409 (54% / 46%)	61 / 75 (44.9% / 55.1%)	0.046
BCLC stage				0.072
0	108 (10.5%)	97 (10.9%)	11 (8.1%)
A	416 (40.5%)	373 (41.9%)	43 (31.6%)
B	296 (28.8%)	245 (27.5%)	51 (37.5%)
C	173 (16.9%)	147 (16.5%)	26 (19.1%)
D	33 (3.2%)	28 (3.1%)	5 (3.7%)
OS event, alive / death	404 /622 (39.4% / 60.6%)	394 / 496 (44.3% / 55.7%)	10 / 126 (7.4% / 92.6%)	< 0.001
Median OS time, days	1052 (927–1139)	1164 (1036–1314)	637.5 (493–867)	< 0.001
PFS event, no / yes	206 / 820 (20.1% / 79.9%)	206 / 684 (23.1% / 76.9%)	0 / 136 (0% / 100%)	< 0.001
Median PFS time, days	336 (298–374)	374 (332–456)	171 (137–204)	< 0.001

Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; PVTT, portal vein tumor thrombosis; AAPR, albumin-to-alkaline phosphatase ratio; AAR, aspartate aminotransferase-to-alanine aminotransferase ratio; APRI, aspartate aminotransferase-to-platelet ratio index; FIB-4, fibrosis-4 index; AFP, alpha-fetoprotein; HBV-DNA, HBV deoxyribonucleic acid; ALBI, albumin-bilirubin; BCLC, Barcelona Clinic Liver Cancer; OS, overall survival; PFS, progression-free survival.

Table 2 Baseline Characteristics of the Three Cohorts

Characteristics	Training Cohort (n=515)	Internal Validation Cohort (n=216)	External Validation Cohort (n=295)	p value
Gender, female / male	83 / 432 (16.1%/83.9%)	31 / 185 (14.4% / 85.6%)	48 / 247 (16.3% / 83.7%)	0.807
Age, years	55.79 ± 12.07	56.12 ± 12.10	56.70 ± 12.24	0.592
≤60 / >60	330 /185 (64.1% / 35.9%)	133 / 83 (61.6% / 38.4%)	183 / 112 (62% / 38%)	0.755
AAPR	0.42 (0.27, 0.57)	0.41 (0.26, 0.58)	0.39 (0.25, 0.56)	0.522
≤0.49 / >0.49	320 / 195 (62.1% / 37.9%)	137 / 79 (63.4% / 36.6%)	192 /103 (65.1% / 34.9%)	0.703
AAR	1.16 (0.89, 1.54)	1.06 (0.84, 1.48)	1.18 (0.90, 1.62)	0.125
≤0.965 / >0.965	169 / 346 (32.8% / 67.2%)	82 / 134 (38% / 62%)	88 / 207 (29.8% / 70.2%)	0.153
APRI	0.67 (0.41, 1.39)	0.69 (0.38, 1.48)	0.67 (0.40, 1.33)	0.939
≤0.48 / >0.48	180 / 335 (35% / 65%)	83 / 133 (38.4% / 61.6%)	106 / 189 (35.9% / 64.1%)	0.671
FIB-4	2.43 (1.52, 4.71)	2.45 (1.49, 4.54)	2.44 (1.53, 4.89)	0.969
≤1.85 / >1.85	183 / 332 (35.5% / 64.5%)	78 / 138 (36.1% / 63.9%)	101 /194 (34.2% / 65.8%)	0.896
AFP, ng/mL	52.70 (7.55, 1095)	43.06 (7.08, 674.60)	46.56 (6.36, 790.65)	0.760
<20 / ≥20	202 / 313 (39.2% / 60.8%)	90 / 126 (41.7% / 58.3%)	119 / 176 (40.3% / 59.7%)	0.822
HBV-DNA, log IU/mL				0.967
Negative	212 (41.2%)	88 (40.7%)	119 (40.3%)
<5	165 (32%)	69 (31.9%)	90 (30.5%)
≥5	138 (26.8%)	59 (27.3%)	86 (29.2%)
ALBI score	−2.71 (−3.06, −2.28)	−2.76 (−3.10, −2.21)	−2.77 (−3.09, −2.22)	0.842
Grade 1	302 (58.6%)	129 (59.7%)	180 (61%)	0.675
Grade 2	194 (37.7%)	75 (34.7%)	105 (35.6%)
Grade 3	19 (3.7%)	12 (5.6%)	10 (3.4%)
Ascites				0.723
Negative	400 (77.7%)	172 (79.6%)	225 (76.3%)
Small	90 (17.5%)	34 (15.7%)	59 (20%)
Medium / large	25 (4.9%)	10 (4.6%)	11 (3.7%)
Extrahepatic metastasis, no / yes	448 / 67 (87% / 13%)	193 / 23 (89.4% / 10.6%)	253 / 42 (85.8% / 14.2%)	0.484
PVTT event, no / yes	449 / 66 (87.2% / 12.8%)	184 / 32 (85.2% / 14.8%)	257 / 38 (87.1% / 12.9%)	0.748
Tumor diameter, cm	5.1 (2.75, 9.05)	4.6 (2.6, 8)	5.2 (2.8, 8.8)	0.327
≤3	149 (28.9%)	65 (30.1%)	82 (27.8%)	0.836
3 to 10	266 (51.7%)	116 (53.7%)	154 (52.2%)
>10	100 (19.4%)	35 (16.2%)	59 (20%)
Tumor number, single / multiple	273 / 242 (53% / 47%)	122 / 94 (56.5% / 43.5%)	147 / 148 (49.8% / 50.2%)	0.328
BCLC stage				0.489
0	57 (11.1%)	23 (10.6%)	28 (9.5%)
A	203 (39.4%)	99 (45.8%)	114 (38.6%)
B	145 (28.2%)	60 (27.8%)	91 (30.8%)
C	89 (17.3%)	29 (13.4%)	55 (18.6%)
D	21 (4.1%)	5 (2.3%)	7 (2.4%)

Abbreviations: AAPR, albumin-to-alkaline phosphatase ratio; AAR, aspartate aminotransferase-to-alanine aminotransferase ratio; APRI, aspartate aminotransferase-to-platelet ratio index; FIB-4, fibrosis-4 index; AFP, alpha-fetoprotein; HBV-DNA, hepatitis B virus deoxyribonucleic acid; ALBI, albumin-bilirubin; PVTT, portal vein tumor thrombosis; BCLC, Barcelona Clinic Liver Cancer.

Figure 1 Comparison of clinical characteristics and prognosis between PVTT group and non-PVTT group. The values of AAPR (A), APRI (B), ALBI score (C), and tumor diameter (D) were marked differences between the PVTT group and the non-PVTT group. KM survival curves revealed that patients occurred PVTT events had poorer OS (E) and PFS (F) than patients without PVTT.

Abbreviations: AAPR, albumin-to-alkaline phosphatase ratio; APRI, aspartate aminotransferase-to-platelet ratio index; ALBI, albumin-bilirubin; PVTT, portal vein tumor thrombosis; HR, hazard ratio.

Figure 2 Cox regression analysis and forest plot of PVTT in the entire cohort.

Abbreviations: PVTT, portal vein tumor thrombosis; HR, hazard ratio; AAPR, albumin-to-alkaline phosphatase ratio; AAR, aspartate aminotransferase-to-alanine aminotransferase ratio; APRI, aspartate aminotransferase-to-platelet ratio index; FIB-4, fibrosis-4 index; AFP, alpha-fetoprotein; HBV-DNA, hepatitis B virus DNA; ALBI, albumin-bilirubin.

Figure 3 Cox regression analysis and forest plots of OS (A) and PFS (B) in the training cohort.

Abbreviations: OS, overall survival; PFS, progression-free survival; HR, hazard ratio; AAPR, albumin-to-alkaline phosphatase ratio; AAR, aspartate aminotransferase-to-alanine aminotransferase ratio; APRI, aspartate aminotransferase-to-platelet ratio index; FIB-4, fibrosis-4 index; AFP, alpha-fetoprotein; HBV-DNA, hepatitis B virus DNA; ALBI, albumin-bilirubin; PVTT, portal vein tumor thrombosis.

Figure 4 Construction and validation of the OS nomogram model. Nomogram predicting the OS for HBV-related HCC patients without PVTT (A). The calibration curves of the OS model for predicting 1‐, 3‐, and 5‐year OS in the training cohort (B), internal validation cohort (C), and external validation cohort (D). The time-dependent ROC curves of the OS model were used to evaluate the predictive ability of 1‐, 3‐, and 5‐year OS in the training cohort (E), internal validation cohort (F), and external validation cohort (G). The DCA curves of the OS model were performed to assess the clinical utility of 5‐year OS in the training cohort (H), internal validation cohort (I), and external validation cohort (J). KM survival analysis of OS among different risk groups based on the score of the OS nomogram model in the training cohort (K), internal validation cohort (L), and external validation cohort (M).

Abbreviations: AAR, aspartate aminotransferase-to-alanine aminotransferase ratio; APRI, aspartate aminotransferase-to-platelet ratio index; AFP, alpha-fetoprotein; ALBI, albumin-bilirubin; PVTT, portal vein tumor thrombosis; OS, overall survival; AUC, the area under the curve; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program.

Figure 5 Construction and validation of the PFS nomogram model. Nomogram predicting the PFS for HBV-related HCC patients without PVTT (A). The calibration curves of the PFS model for predicting 1‐, 3‐, and 5‐year PFS in the training cohort (B), internal validation cohort (C), and external validation cohort (D). The time-dependent ROC curves of the PFS model were used to evaluate the predictive ability of 1‐, 3‐, and 5‐year PFS in the training cohort (E), internal validation cohort (F), and external validation cohort (G). The DCA curves of the PFS model were performed to assess the clinical utility of 5‐year PFS in the training cohort (H), internal validation cohort (I), and external validation cohort (J). KM survival analysis of PFS among different risk groups based on the score of the PFS nomogram model in the training cohort (K), internal validation cohort (L), and external validation cohort (M).

Abbreviations: AAR, aspartate aminotransferase-to-alanine aminotransferase ratio; APRI, aspartate aminotransferase-to-platelet ratio index; AFP, alpha-fetoprotein; PVTT, portal vein tumor thrombosis; PFS, progression-free survival; AUC, the area under the curve; BCLC, Barcelona Clinic Liver Cancer; CLIP, Cancer of the Liver Italian Program.

Figure 6 Subgroup survival analysis for the entire cohort stratified by the BCLC staging system. KM survival analysis of OS and PFS among different risk groups based on the score of the OS nomogram model and PFS nomogram model in BCLC stage 0/A patients (A and D), BCLC stage B patients (B and E), and BCLC stage C/D patients (C and F), respectively.

Abbreviation: BCLC, Barcelona Clinic Liver Cancer.