World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://wjon.elmerpub.com

Original Article

Volume 16, Number 6, December 2025, pages 565-573

Utility of Alpha-Fetoprotein and Protein Induced by Vitamin K Absence or Antagonist-II Kinetics in Predicting Radiologic Response and Survival in Unresectable Hepatocellular Carcinoma Undergoing Immunotherapy

↓ Figure 1. Flow chart of patient selection. AFP: alpha-fetoprotein; HCC: hepatocellular carcinoma; N: number of patients; OR: objective response.

↓ Figure 3. Kaplan-Meier analysis of overall survival in patients with AFP decline ≥ 30% or without. AFP: alpha-fetoprotein; CI: confidence interval.

↓ Figure 4. Kaplan-Meier analysis of overall survival in patients with AFP decline ≥ 30% + PIVKA-II decline ≥ 15% or without. AFP: alpha-fetoprotein; CI: confidence interval.

↓ **Table 1.** Baseline Characteristics in Patients at the Initiation of Immunotherapy
Variables, mean ± SD or n (%)	Total, n = 33 (100%)	OR, n = 10 (30.3%)	Non-OR, n = 23 (69.7%)	P value
AFP; alpha-fetoprotein; ALBI: Albumin-Bilirubin; EHS: extrahepatic spread; HBV: hepatitis B; HCV: hepatitis C; LRT: locoregional therapy; MVI: macrovascular invasion; OR: objective response; SD: standard deviation; TKI: tyrosine kinase inhibitor.
Age (years)	66.4 ± 12.4	64.7 ± 11.3	68.5 ± 12.9	0.425
> 65	14 (42.4%)	4 (40%)	10 (43.5%)	0.581
Gender
Male	26 (78.8%)	9 (90.0%)	17 (73.9%)	0.294
Female	7 (21.2%)	1 (10.0%)	6 (26.1%)
Viral hepatitis
HBV	19 (57.6%)	5 (50.0%)	14 (60.9%)	0.419
HCV	8 (22.2%)	4 (40.0%)	4 (17.4%)	0.170
ALBI grade
1	15 (45.5%)	5 (50.0%)	10 (43.5%)	0.512
2/3	18 (54.5%)	5 (50.0%)	13 (56.5%)
BCLC stage
B	4 (12.1%)	2 (20.0%)	2 (8.7%)	0.351
C	29 (87.9%)	8 (80.0%)	21 (91.3%)
MVI	24 (72.7%)	7 (70.0%)	17 (73.9%)	0.566
EHS	13 (39.4%)	3 (30.0%)	10 (43.5%)	0.371
Concurrent
TKI	19 (57.6%)	8 (80.0%)	11 (47.8%)	0.131
LRT	9 (27.3%)	2 (20.0%)	7 (30.4%)	0.434
AFP (ng/mL)	26,911.3 ± 56,182.9	38,036.6 ± 57,340.2	22,074.2 ± 56,263.2	0.470
AFP > 100 ng/mL	22 (66.7%)	9 (90.0%)	13 (56.5%)	0.066
PIVKA-II (mAU/mL)	3,754.6 ± 7,912.7	2,629.1 ± 4,505.5	4,243.9 ± 9,052.1	0.598

↓ Table 1. Baseline Characteristics in Patients at the Initiation of Immunotherapy

Variables, mean ± SD or n (%)

Total, n = 33 (100%)

OR, n = 10 (30.3%)

Non-OR, n = 23 (69.7%)

P value

AFP; alpha-fetoprotein; ALBI: Albumin-Bilirubin; EHS: extrahepatic spread; HBV: hepatitis B; HCV: hepatitis C; LRT: locoregional therapy; MVI: macrovascular invasion; OR: objective response; SD: standard deviation; TKI: tyrosine kinase inhibitor.

Age (years)

66.4 ± 12.4

64.7 ± 11.3

68.5 ± 12.9

0.425

> 65

14 (42.4%)

4 (40%)

10 (43.5%)

0.581

Gender

Male

26 (78.8%)

9 (90.0%)

17 (73.9%)

0.294

Female

7 (21.2%)

1 (10.0%)

6 (26.1%)

Viral hepatitis

HBV

19 (57.6%)

5 (50.0%)

14 (60.9%)

0.419

HCV

8 (22.2%)

4 (40.0%)

4 (17.4%)

0.170

ALBI grade

15 (45.5%)

5 (50.0%)

10 (43.5%)

0.512

2/3

18 (54.5%)

5 (50.0%)

13 (56.5%)

BCLC stage

4 (12.1%)

2 (20.0%)

2 (8.7%)

0.351

29 (87.9%)

8 (80.0%)

21 (91.3%)

MVI

24 (72.7%)

7 (70.0%)

17 (73.9%)

0.566

EHS

13 (39.4%)

3 (30.0%)

10 (43.5%)

0.371

Concurrent

TKI

19 (57.6%)

8 (80.0%)

11 (47.8%)

0.131

LRT

9 (27.3%)

2 (20.0%)

7 (30.4%)

0.434

AFP (ng/mL)

26,911.3 ± 56,182.9

38,036.6 ± 57,340.2

22,074.2 ± 56,263.2

0.470

AFP > 100 ng/mL

22 (66.7%)

9 (90.0%)

13 (56.5%)

0.066

PIVKA-II (mAU/mL)

3,754.6 ± 7,912.7

2,629.1 ± 4,505.5

4,243.9 ± 9,052.1

0.598

↓ **Table 2.** The Best Radiological Tumor Responses of Patients Receiving Immunotherapy
RECIST	All (n = 33)
Complete response	1	3.0%
Partial response	9	27.3%
Stable disease	6	18.2%
Progressive disease	17	51.5%
Objective response rate	10	30.3%
Disease control rate	16	48.5%

↓ Table 2. The Best Radiological Tumor Responses of Patients Receiving Immunotherapy

RECIST

All (n = 33)

Complete response

3.0%

Partial response

27.3%

Stable disease

18.2%

Progressive disease

51.5%

Objective response rate

30.3%

Disease control rate

48.5%

↓ **Table 3.** Diagnostic Efficacy of Biomarker Kinetics at 4 Weeks to Objective Response (OR) of Tumor
	To OR
AFP: alpha-fetoprotein; PIVKA-II: protein induced by vitamin K absence or antagonist-II; AUC: area under the curve; OR: objective response; ROC: receiver operating characteristic.
AFP decline from baseline
≥ 5%	1.0	0.70	1.70	0.79	0.70
≥ 10%	0.90	0.70	1.60	0.76	0.60
≥ 15%	0.90	0.74	1.64	0.79	0.64
≥ 20%	0.90	0.78	1.68	0.82	0.68
≥ 25%	0.90	0.78	1.68	0.82	0.68
≥ 30%	0.90	0.91	1.81	0.91	0.81	0.907
≥ 35%	0.90	0.91	1.81	0.91	0.81
≥ 40%	0.90	0.91	1.81	0.91	0.81
≥ 45%	0.80	0.91	1.71	0.88	0.71
≥ 50%	0.80	0.91	1.71	0.88	0.71
PIVKA-II decline from baseline
≥ 5%	1.00	0.65	1.65	0.76	0.65
≥ 10%	1.00	0.65	1.65	0.76	0.65
≥ 15%	1.00	0.70	1.70	0.77	0.70	0.848
≥ 20%	0.90	0.74	1.64	0.77	0.64
≥ 25%	0.80	0.74	1.54	0.76	0.54
≥ 30%	0.80	0.74	1.54	0.76	0.54
≥ 35%	0.80	0.74	1.54	0.76	0.54
≥ 40%	0.70	0.74	1.44	0.73	0.44
≥ 45%	0.70	0.78	1.48	0.76	0.48
AFP and/or PIVKA-II decline from baseline
AFP ≥ 30%	0.90	0.91	1.81	0.91	0.81	0.907
PIVKA-II ≥ 15%	1.00	0.70	1.70	0.77	0.70	0.848
AFP ≥ 30% and PIVKA-II ≥ 15%	0.90	0.91	1.81	0.91	0.81	0.907
AFP ≥ 30% or PIVKA-II ≥ 15%	1.00	0.70	1.70	0.79	0.70	0.848

↓ Table 3. Diagnostic Efficacy of Biomarker Kinetics at 4 Weeks to Objective Response (OR) of Tumor

To OR

Sensitivity (SEN)

Specificity (SPE)

SEN + SPE

Diagnostic efficacy

Youden index

ROC AUC

AFP: alpha-fetoprotein; PIVKA-II: protein induced by vitamin K absence or antagonist-II; AUC: area under the curve; OR: objective response; ROC: receiver operating characteristic.

AFP decline from baseline

≥ 5%

1.0

0.70

1.70

0.79

0.70

≥ 10%

0.90

0.70

1.60

0.76

0.60

≥ 15%

0.90

0.74

1.64

0.79

0.64

≥ 20%

0.90

0.78

1.68

0.82

0.68

≥ 25%

0.90

0.78

1.68

0.82

0.68

≥ 30%

0.90

0.91

1.81

0.91

0.81

0.907

≥ 35%

0.90

0.91

1.81

0.91

0.81

≥ 40%

0.90

0.91

1.81

0.91

0.81

≥ 45%

0.80

0.91

1.71

0.88

0.71

≥ 50%

0.80

0.91

1.71

0.88

0.71

PIVKA-II decline from baseline

≥ 5%

1.00

0.65

1.65

0.76

0.65

≥ 10%

1.00

0.65

1.65

0.76

0.65

≥ 15%

1.00

0.70

1.70

0.77

0.70

0.848

≥ 20%

0.90

0.74

1.64

0.77

0.64

≥ 25%

0.80

0.74

1.54

0.76

0.54

≥ 30%

0.80

0.74

1.54

0.76

0.54

≥ 35%

0.80

0.74

1.54

0.76

0.54

≥ 40%

0.70

0.74

1.44

0.73

0.44

≥ 45%

0.70

0.78

1.48

0.76

0.48

AFP and/or PIVKA-II decline from baseline

AFP ≥ 30%

0.90

0.91

1.81

0.91

0.81

0.907

PIVKA-II ≥ 15%

1.00

0.70

1.70

0.77

0.70

0.848

AFP ≥ 30% and PIVKA-II ≥ 15%

0.90

0.91

1.81

0.91

0.81

0.907

AFP ≥ 30% or PIVKA-II ≥ 15%

1.00

0.70

1.70

0.79

0.70

0.848

↓ **Table 4.** The Strength of Association Between Clinical Parameters and Overall Survival Following Immunotherapy Usage
Variables	Univariate analysis
ALBI: Albumin-Bilirubin; AFP: alpha-fetoprotein; HBsAg: hepatitis B surface antigen; BCLC: Barcelona Clinic Liver Cancer; CI: confidence interval; EHS: extrahepatic spread; HBV: hepatitis B; HCV: hepatitis C; HR: hazard ratio; LRT: locoregional therapy; MVI: macrovascular invasion; OR: objective response; OS: overall survival; PIVKA-II: protein induced by vitamin K absence or antagonist-II; TKI: tyrosine kinase inhibitor.
Age (≤ 65 vs. > 65 years)	0.57 (0.23 - 1.42)	0.230
Gender (male vs. female)	1.29 (0.47 - 3.57)	0.624
HBV (HBsAg + vs. -)	1.09 (0.46 - 2.59)	0.845
HCV (anti-HCV + vs. -)	0.72 (0.28 - 1.87)	0.501
ALBI grade (1 vs. 2/3)	0.66 (0.27 - 1.58)	0.348
BCLC stage (B vs. C)	0.21 (0.03 - 1.60)	0.133
MVI (yes vs. no)	1.40 (0.53 - 3.66)	0.494
EHS (yes vs. no)	1.25 (0.52 - 3.00)	0.612
Concurrent TKI (yes vs. no)	0.42 (0.18 - 1.01)	0.053
Concurrent LRT (yes vs. no)	0.89 (0.34 - 2.30)	0.807
Baseline AFP (≤ 100 vs. > 100 ng/mL)	0.56 (0.23 - 1.35)	0.195
AFP decline ≥ 30% (yes vs. no)	0.32 (0.11 - 0.95)	0.041
PIVKA-II decline ≥ 15% (yes vs. no)	0.41 (0.16 - 1.03)	0.057
AFP ≥ 30% and PIVKA-II decline ≥ 15% (yes vs. no)	0.21 (0.06 - 0.73)	0.014

↓ Table 4. The Strength of Association Between Clinical Parameters and Overall Survival Following Immunotherapy Usage

Variables

Univariate analysis

HR (95% CI)

P value

ALBI: Albumin-Bilirubin; AFP: alpha-fetoprotein; HBsAg: hepatitis B surface antigen; BCLC: Barcelona Clinic Liver Cancer; CI: confidence interval; EHS: extrahepatic spread; HBV: hepatitis B; HCV: hepatitis C; HR: hazard ratio; LRT: locoregional therapy; MVI: macrovascular invasion; OR: objective response; OS: overall survival; PIVKA-II: protein induced by vitamin K absence or antagonist-II; TKI: tyrosine kinase inhibitor.

Age (≤ 65 vs. > 65 years)

0.57 (0.23 - 1.42)

0.230

Gender (male vs. female)

1.29 (0.47 - 3.57)

0.624

HBV (HBsAg + vs. -)

1.09 (0.46 - 2.59)

0.845

HCV (anti-HCV + vs. -)

0.72 (0.28 - 1.87)

0.501

ALBI grade (1 vs. 2/3)

0.66 (0.27 - 1.58)

0.348

BCLC stage (B vs. C)

0.21 (0.03 - 1.60)

0.133

MVI (yes vs. no)

1.40 (0.53 - 3.66)

0.494

EHS (yes vs. no)

1.25 (0.52 - 3.00)

0.612

Concurrent TKI (yes vs. no)

0.42 (0.18 - 1.01)

0.053

Concurrent LRT (yes vs. no)

0.89 (0.34 - 2.30)

0.807

Baseline AFP (≤ 100 vs. > 100 ng/mL)

0.56 (0.23 - 1.35)

0.195

AFP decline ≥ 30% (yes vs. no)

0.32 (0.11 - 0.95)

0.041

PIVKA-II decline ≥ 15% (yes vs. no)

0.41 (0.16 - 1.03)

0.057

AFP ≥ 30% and PIVKA-II decline ≥ 15% (yes vs. no)

0.21 (0.06 - 0.73)

0.014