Hepatic immune prognostic index as a prognostic biomarker in hepatocellular carcinoma patients treated with transarterial chemoembolization

Abstract

Background:

Due to hepatocellular carcinoma (HCC) heterogeneity, the prognosis of patients who receive transarterial chemoembolization (TACE) treatment varies greatly. A thorough pre-treatment assessment is necessary to identify suitable candidates for TACE.

Objective:

To develop a hepatic immune prognostic index (HIPI) using neutrophil-to-lymphocyte ratio (NLR) and alpha-fetoprotein (AFP), and evaluate its prognostic value in patients with unresectable HCC undergoing TACE.

Design:

This retrospective study reviewed 663 patients with unresectable HCC who received TACE. Based on biomarkers, patients were categorized into two cohorts: HIPI-low (n = 125) and HIPI-high (n = 538) groups.

Methods:

Baseline clinical characteristics and specific biomarkers were collected and analyzed to develop the HIPI. HIPI was defined as high if NLR ⩾3 or AFP ⩾20 ng/mL, and low if both were below these cutoffs. Survival curves were compared using the Kaplan–Meier method and the log-rank test. Cox proportional hazards regression models and 1:1 propensity score matching (PSM) analysis were applied to assess the independent prognostic value of the HIPI and to adjust for baseline confounding factors. Prognostic factors affecting treatment efficacy were also analyzed.

Results:

Before PSM, the HIPI-low group had significantly longer median overall survival (OS; 26.0 vs 12.4 months, p < 0.001) and median progression-free survival (PFS; 9.4 vs 5.5 months, p < 0.001) than the HIPI-high group. After PSM (113 pairs), the survival advantage for the HIPI-low group remained significant (median OS: 26.7 vs 17.6 months, p < 0.001; median PFS: 8.5 vs 8.1 months, p = 0.0004). The HIPI-low group also achieved a significantly higher objective response rate and disease control rate, both before and after PSM. Univariate and multivariate analyses identified high HIPI as an independent risk factor for worse OS (hazard ratio (HR), 1.812; p < 0.001) and PFS (HR, 1.548; p < 0.001).

Conclusion:

The pretreatment HIPI, derived from NLR and AFP, is a potent and independent prognostic biomarker for patients with unresectable HCC treated with TACE. It effectively facilitates risk stratification and treatment decision-making.

Keywords

alpha-fetoprotein hepatic immune prognostic index hepatocellular carcinoma neutrophil-to-lymphocyte ratio transarterial chemoembolization

Introduction

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which is the third leading cause of cancer-related deaths worldwide, with its incidence and mortality rates continuing to rise.^1,2 The 5-year survival rate for HCC remains poor, and only a small number of patients are eligible for curative treatments (such as ablation, surgical resection, and liver transplantation),² as the majority of HCC patients are diagnosed at an unresectable stage. To date, the treatment of unresectable HCC remains a significant challenge.

Transarterial chemoembolization (TACE) is an important and widely used treatment for unresectable HCC.^2,3 HCC exhibits strong arterial neovascularization during its progression. The principle of TACE is as follows: infusion of cytotoxic drugs into the artery followed by embolization of the tumor-supplying vessels produces a strong cytotoxic and ischemic effect that is accurately targeted to the tumor tissue.⁴ This is because tumors usually rely entirely on arterial blood supply, while the surrounding parenchymal tissue mainly obtains blood flow through the portal vein system. However, because of the high heterogeneity of HCC, the prognosis of patients who receive TACE treatment varies greatly.^5,6 Among patients receiving TACE treatment, 70%–80% die because of tumor progression rather than liver failure.^7,8 Therefore, a thorough assessment of efficacy and prognosis is necessary before TACE to identify suitable candidates for the procedure.

Serum components are promising biomarkers for HCC monitoring, as they allow easy implementation and rapid measurement. While various immune scores exist, we selected the neutrophil-to-lymphocyte ratio (NLR) and alpha-fetoprotein (AFP) because they are routinely tested, cost-effective, and reflect two critical aspects of HCC: systemic host immunity and local tumor biology. Neutrophils are strongly associated with tumor cell proliferation and survival, and are also linked to tumor angiogenesis, metastasis, and the disruption of the adaptive immune system.⁹ Meanwhile, lymphocytes serve as the essential mediators of cancer immunosurveillance, consequently suppressing tumor progression.¹⁰ As a marker of systemic inflammation, the NLR is associated with tumor progression, metastasis, and prognosis across various cancers, and a high NLR is associated with poorer survival in HCC patients who receive TACE treatment.^11–13 However, there is currently no unified standard for the critical value of NLR that predicts the recurrence of HCC. Serum-based tumor biomarkers are widely used for prediction of tumor prognosis, with AFP being the most common one in HCC.¹⁴ AFP has been included in several prognostic scoring systems for HCC patients who receive TACE treatment.^15–17 However, as with NLR, there is still no universally accepted AFP standard for the assessment of TACE treatment for unresectable HCC. Biologically, AFP reflects the intrinsic malignancy and aggressive biology of the tumor itself, whereas NLR serves as a surrogate for the host’s systemic inflammatory and immune response. Therefore, integrating these two parameters could theoretically provide a more comprehensive reflection of the dynamic interplay between the tumor and the host microenvironment. The main purpose of this study is to determine the clinical utility of NLR and AFP as prognostic indicators of treatment efficacy in patients with unresectable HCC undergoing TACE.

Materials and methods

Patients

From April 2019 to August 2023, 713 HCC patients who received TACE in our hospital were reviewed retrospectively. The main inclusion criteria were as follows: (1) patients over the age of 18 years; (2) patients diagnosed with HCC according to pathological examination or non-invasive criteria in accordance with European Association for the Study of Liver; (3) Barcelona Clinic Liver Cancer (BCLC) tumor stage B or C; (4) Eastern Cooperative Oncology Group performance status ⩽2; (5) at least one measurable target lesion; (6) Child–Pugh class A or B; (7) at least one TACE session. Patients were excluded according to the following criteria: (1) complete obstruction of the main portal vein; (2) prior receipt of other treatments, such as ablation, immunotherapy, targeted therapy, or hepatic arterial infusion chemotherapy; (3) presence of other malignant tumors; (4) incomplete data. Baseline absolute neutrophil and lymphocyte counts, along with other hematological parameters obtained within 30 days before the first TACE session, were extracted from electronic medical records. Liver cirrhosis was diagnosed based on definitive radiological findings from contrast-enhanced CT or MRI (e.g., nodular liver surface, parenchymal heterogeneity, splenomegaly, or portosystemic collaterals), combined with consistent laboratory data (e.g., thrombocytopenia, hypoalbuminemia) and clinical manifestations of portal hypertension (e.g., ascites or variceal bleeding), in accordance with standard clinical practice guidelines. All hematological and biochemical tests were performed at our hospital’s central laboratory using standardized automated analyzers, ensuring consistent reference ranges and measurement units. This study was approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (No: UHCT20250813) and was conducted in accordance with the ethical principles of the 1975 Helsinki Declaration. The requirement for informed consent was waived due to the retrospective nature of this study.

Hepatic immune prognostic index (HIPI) status (high or low) was determined by NLR and AFP levels. According to prior studies,^18,19 the cutoff value for NLR was 3. The AFP cutoff was 20 ng/mL, which was based on previous studies.^20,21 These cutoffs were chosen based on established clinical relevance and broad acceptance in hepatology guidelines. An NLR of 3 is a widely accepted threshold indicating a systemic shift toward a pro-tumor inflammatory state.²² An AFP of 20 ng/mL is the most widely used diagnostic and risk-stratification cutoff in clinical practice, such as in the AASLD guidelines.²⁰ While statistical methods such as median values were also explored, these established clinical thresholds were chosen to ensure the index’s practical applicability in real-world clinical settings. NLR < 3 and AFP < 20 ng/mL were defined as HIPI-low, and NLR ⩾3 or AFP ⩾20 ng/mL as HIPI-high.

Treatment protocol

TACE was performed by interventional physicians with more than 10 years of experience. Following local anesthesia at the patient’s femoral artery puncture site, a 5-F Yashiro catheter (Terumo, Tokyo, Japan) was inserted into the celiac trunk and superior mesenteric artery under digital subtraction angiography guidance for arteriography to identify the tumor-feeding arteries. Subsequently, a 2.7-F microcatheter (Terumo) was superselectively inserted into the tumor-feeding artery for embolization. The choice of TACE modality (C-TACE or DEB-TACE) was made jointly by the physician and the patient. For C-TACE, a mixture of lipiodol and doxorubicin emulsion was injected into the tumor-feeding artery via the microcatheter. The lipiodol dosage was primarily determined by tumor size, number of lesions, and the degree of arterial vascularity, typically not exceeding 20 mL per session. This was followed by embolization using gelatin sponge particles (350–560 μm; Hangzhou Alicon Pharmaceutical Sci. & Tech. Co., Ltd, Zhejiang, China) until near stasis of blood flow was achieved in the target vessel. For DEB-TACE, drug-eluting beads (CalliSpheres; Jiangsu Hengrui Pharmaceuticals Co., Ltd, Jiangsu, China) loaded with epirubicin (60 mg; Hangzhou Honour Co., Ltd, Zhejiang, China) were injected through the microcatheter into the tumor-feeding artery. The bead size and dose were determined based on tumor vascularity, the presence of arteriovenous shunting, and tumor size. Embolization was stopped when blood flow stasis occurred. A post-embolization angiography was then performed to confirm the absence of tumor staining. All patients received TACE as their sole initial treatment prior to progression; subsequent systemic therapies (e.g., targeted therapy or immunotherapy) were only initiated after documented disease progression.

Follow-up and assessment

The first follow-up imaging was conducted 4–6 weeks after the initial TACE treatment to evaluate early tumor response and the need for additional on-demand TACE sessions. For patients with stable disease (SD), subsequent regular follow-ups were recommended every 8–12 weeks. Each follow-up included a contrast-enhanced CT scan or contrast-enhanced liver MRI, chest CT, blood biochemistry analyses, and other examinations as clinically indicated. Tumor response was evaluated using contrast‑enhanced CT or MRI according to the modified Response Evaluation Criteria in Solid Tumors. The best objective tumor response was evaluated by two independent, experienced radiologists who were blinded to the patients’ HIPI status and clinical outcomes. The disease control rate (DCR) was defined as the percentage of patients with a complete response (CR), partial response (PR), and SD; the objective response rate (ORR) was the percentage of patients with CR and PR. The overall survival (OS) was calculated from the initial treatment date until the occurrence of death or last follow-up. The progression-free survival (PFS) was defined as the time from initial treatment to tumor progression or death.

Statistical analysis

All statistical analyses were performed using SPSS (version 26.0; IBM, Armonk, NY, USA) and GraphPad Prism (version 8.0.0; GraphPad Software, Inc., San Diego, CA, USA). Continuous variables were presented as mean ± standard deviation (sd) or median (interquartile range, IQR) and compared using the Student’s t test or the Wilcoxon rank sum test. Categorical variables were summarized as numbers (percentages) and compared using the Chi-squared test. The OS and PFS curves were estimated by the Kaplan–Meier method, and differences between curves were compared with a log-rank test. Variables showing a significance level of p < 0.10 in univariate analysis were included in a multivariate Cox proportional hazards regression model to identify independent risk factors affecting OS and PFS. A two-tailed p value of less than 0.05 was considered statistically significant. Propensity score matching (PSM) analysis was conducted to reduce selection bias and balance variables between the HIPI-low and HIPI-high groups. Covariates included in the PSM model were age, gender, body weight, Child–Pugh class, hepatitis B virus (HBV), BCLC grade, liver cirrhosis, ascites, tumor size, tumor distribution, macrovascular invasion, and distant metastasis. One-to-one matching without replacement was applied, with a caliper value of 0.05.

The specific guideline

This study was reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies²³ (STROBE table, Supplemental File 1).

Results

Baseline characteristics of the study patients

A total of 663 HCC patients who received TACE treatment were included in this study. Among the 663 patients, 538 were classified into the HIPI-high group and 125 into the HIPI-low group (Supplemental Figure 1). The baseline demographic and clinical characteristics of the patients before and after PSM are summarized in Table 1. Prior to matching, significant imbalances were observed between the two groups in several key prognostic factors, including Child–Pugh class (p < 0.001), BCLC grade (p < 0.001), tumor size (p < 0.001), macrovascular invasion (p < 0.001), white blood cell count (p < 0.001), alanine aminotransferase (ALT; p = 0.002), total bilirubin (TBIL; p = 0.015), and albumin (ALB; p < 0.001). To reduce these differences and achieve balance, PSM was performed, resulting in 113 well-matched pairs.

Table 1.

Baseline characteristics of patients before and after PSM analysis.

Characteristics	Before PSM			After PSM
Characteristics	HIPI-low	HIPI-high	p Value	HIPI-low	HIPI-high	p Value
N	125	538		113	113
Age, mean ± sd	58.712 ± 11.37	56.978 ± 11.562	0.130	58.142 ± 10.769	57.434 ± 11.992	0.641
Gender, n (%)			0.710			0.572
Male	104 (83.2%)	440 (81.8%)		95 (84.1%)	98 (86.7%)
Female	21 (16.8%)	98 (18.2%)		18 (15.9%)	15 (13.3%)
Body weight, median (IQR)	65 (58.375, 71)	63 (57, 70)	0.254	64.673 ± 8.4784	64.416 ± 10.926	0.844
Child–Pugh class, n (%)			<0.001			0.646
A	97 (77.6%)	332 (61.7%)		86 (76.1%)	83 (73.5%)
B	28 (22.4%)	206 (38.3%)		27 (23.9%)	30 (26.5%)
HBV, n (%)			0.330			0.874
Yes	95 (76%)	430 (79.9%)		87 (77%)	88 (77.9%)
No	30 (24%)	108 (20.1%)		26 (23%)	25 (22.1%)
BCLC grade, n (%)			<0.001			0.286
B	72 (57.6%)	176 (32.7%)		64 (56.6%)	56 (49.6%)
C	53 (42.4%)	362 (67.3%)		49 (43.4%)	57 (50.4%)
Liver cirrhosis, n (%)			0.033			0.633
Yes	97 (77.6%)	365 (67.8%)		89 (78.8%)	86 (76.1%)
No	28 (22.4%)	173 (32.2%)		24 (21.2%)	27 (23.9%)
Ascites, n (%)			0.131			0.195
Yes	9 (7.2%)	64 (11.9%)		9 (8%)	15 (13.3%)
No	116 (92.8%)	474 (88.1%)		104 (92%)	98 (86.7%)
Tumor size, n (%)			<0.001			0.258
>10 cm	26 (20.8%)	217 (40.3%)		21 (18.6%)	28 (24.8%)
⩽10 cm	99 (79.2%)	321 (59.7%)		92 (81.4%)	85 (75.2%)
Tumor distribution, n (%)			0.879			0.689
⩾3	66 (52.8%)	280 (52%)		58 (51.3%)	61 (54%)
<3	59 (47.2%)	258 (48%)		55 (48.7%)	52 (46%)
Macrovascular invasion, n (%)			<0.001			0.366
Yes	28 (22.4%)	250 (46.5%)		27 (23.9%)	33 (29.2%)
No	97 (77.6%)	288 (53.5%)		86 (76.1%)	80 (70.8%)
Distant metastasis, n (%)			0.447			0.851
Yes	17 (13.6%)	88 (16.4%)		16 (14.2%)	17 (15%)
No	108 (86.4%)	450 (83.6%)		97 (85.8%)	96 (85%)
NLR, n (%)			<0.001			<0.001
⩾3	0 (0.0%)	344 (63.9%)		0 (0.0%)	52 (46.0%)
<3	125 (100.0%)	194 (36.1%)		113 (100.0%)	61 (54.0%)
AFP, n (%)			<0.001			<0.001
⩾20 ng/mL	0 (0.0%)	437 (81.2%)		0 (0.0%)	97 (85.8%)
<20 ng/mL	125 (100.0%)	101 (18.8%)		113 (100.0%)	16 (14.2%)
Hb, median (IQR)	125 (113, 139)	123 (109, 135)	0.221	124.2 ± 20.852	123.73 ± 19.916	0.863
Platelet, median (IQR)	128 (85, 168)	140 (88, 209.75)	0.053	128 (83, 171)	108 (70, 173)	0.260
PT, median (IQR)	13.9 (13.2, 14.6)	13.9 (13.3, 14.7)	0.762	13.9 (13.2, 14.7)	14 (13.5, 14.8)	0.144
WBC, median (IQR)	4.42 (3.26, 5.41)	5.53 (4.07, 7.74)	<0.001	4.42 (3.29, 5.41)	4.47 (3.57, 6.29)	0.240
ALT, median (IQR)	35 (21, 55)	43 (27, 76.75)	0.002	34 (21, 55)	37 (26, 56)	0.359
TBIL, median (IQR)	15.9 (12.1, 23.9)	18.8 (13.4, 26.8)	0.015	15.8 (12.1, 24.4)	18.8 (13.2, 26.7)	0.155
ALB, median (IQR)	38.3 (33.9, 41.6)	35.6 (31.9, 39.175)	<0.001	38.1 (33.9, 41.6)	36.1 (33.1, 40.4)	0.169

AFP, alpha-fetoprotein; ALB, albumin; ALT, alanine aminotransferase; BCLC, Barcelona Clinic Liver Cancer; Hb, hemoglobin; HBV, hepatitis B virus; HIPI, hepatic immune prognostic index; IQR, interquartile range; NLR, neutrophil to lymphocyte ratio; PSM, propensity score matching; PT, prothrombin time; sd, standard deviation; TBIL, total bilirubin; WBC, white blood cell.

Tumor response

Based on the tumor response evaluation following TACE treatment, significant differences were observed between the HIPI-low and HIPI-high groups both before and after PSM (Table 2). Prior to matching, the ORR and DCR were significantly higher in the HIPI-low group than in the HIPI-high group (ORR: 64.0% vs 31.6%, p < 0.001; DCR: 86.4% vs 68.4%, p < 0.001). After PSM, the ORR and DCR in the HIPI-low group were significantly higher than those in the HIPI-high group (ORR: 63.7% vs 41.6%, p = 0.001; DCR: 86.7% vs 71.7%, p = 0.005).

Table 2.

Tumor response of patients before and after PSM analysis.

Characteristics	Before PSM			After PSM
Characteristics	HIPI-low	HIPI-high	p Value	HIPI-low	HIPI-high	p Value
CR	14 (11.2%)	14 (2.6%)	<0.001	14 (12.4%)	3 (2.7%)	0.002
PR	66 (52.8%)	156 (29%)		58 (51.3%)	44 (38.9%)
SD	28 (22.4%)	186 (34.6%)		26 (23%)	34 (30.1%)
PD	17 (13.6%)	182 (33.8%)		15 (13.3%)	32 (28.3%)
ORR	80 (64%)	170 (31.6%)	<0.001	72 (63.7%)	47 (41.6%)	0.001
DCR	108 (86.4%)	356 (68.4%)	<0.001	98 (86.7%)	81 (71.7%)	0.005

CR, complete response; DCR, disease control rate; HIPI, hepatic immune prognostic index; ORR, objective response rate; PD, progressive disease; PR, partial response; PSM, propensity score matching; SD, stable disease.

Survival analysis

The median follow-up time was 22.0 months (IQR, 17.0–29.0 months). Kaplan–Meier survival curves demonstrated significantly worse survival outcomes in HIPI-high patients than in HIPI-low patients, both before and after PSM (Figure 1). Before PSM, the median OS in the HIPI-low group was significantly longer than that in the HIPI-high group (26.0 vs 12.4 months, p < 0.001; Figure 1(a)), and the median PFS was also significantly longer in the HIPI-low group (9.4 vs 5.5 months, p < 0.001; Figure 1(b)). Likewise, after PSM, the HIPI-low group continued to show a significantly longer median OS (26.7 vs 17.6 months, p < 0.001; Figure 1(c)) and PFS (8.5 vs 8.1 months, p = 0.0004; Figure 1(d)) than the HIPI-high group.

Figure 1.

Kaplan–Meier curves between the two groups for median OS and median PFS before (a and b) and after (c and d) PSM analysis.

Cox regression analysis

Before PSM, univariable analysis identified the following potential predictors for OS: HIPI group, body weight, Child–Pugh class, BCLC grade, ascites, tumor size, macrovascular invasion, distant metastasis, platelet count, white blood cell count, ALT, TBIL, and ALB. For PFS, potential predictors included HIPI group, Child–Pugh class, BCLC grade, tumor size, macrovascular invasion, distant metastasis, platelet count, white blood cell count, and ALT. These variables were subsequently included in the multivariable regression analysis. Multivariable Cox regression confirmed that HIPI-high group (hazard ratio (HR), 1.812 (95% confidence interval (CI), 1.429–2.299); p < 0.001), Child–Pugh class B (HR, 1.415 (95% CI, 1.162–1.722); p < 0.001), BCLC grade C (HR, 1.817 (95% CI, 1.397–2.364); p < 0.001), and tumor size >10 cm (HR, 1.569 (95% CI, 1.293–1.904); p < 0.001) were independently associated with worse OS (Table 3). Meanwhile, the HIPI-high group (HR, 1.548 (95% CI, 1.244–1.927); p < 0.001), Child–Pugh class B (HR, 1.286 (95% CI, 1.092–1.516); p = 0.003), BCLC grade C (HR, 2.331 (95% CI, 1.818–2.989); p < 0.001), tumor size >10 cm (HR, 1.358 (95% CI, 1.139–1.621); p < 0.001), and distant metastasis (HR, 1.404 (95% CI, 1.103–1.789); p = 0.006) were significantly associated with shorter PFS (Table 4). After PSM, the HIPI-high group (HR, 1.730 (95% CI, 1.298–2.306); p < 0.001) remained significantly associated with worse OS (Table 5). In addition, HIPI-high group (HR, 1.503 (95% CI, 1.123–2.011); p = 0.006), BCLC grade C (HR, 1.765 (95% CI, 1.156–2.695); p = 0.009), and tumor size >10 cm (HR, 1.544 (95% CI, 1.085–2.198); p = 0.016) were significantly associated with poorer PFS (Table 6).

Table 3.

Univariate and multivariate analysis for the OS before PSM analysis.

Characteristics	Total (N)	Univariate analysis		Multivariate analysis
Characteristics	Total (N)	Hazard ratio (95% CI)	p Value	Hazard ratio (95% CI)	p Value
Group	663
HIPI-low	125	Reference		Reference
HIPI-high	538	2.155 (1.736–2.680)	<0.001	1.812 (1.429–2.299)	<0.001
Age	663	0.998 (0.992–1.005)	0.653
Gender	663
Male	544	Reference
Female	119	0.985 (0.803–1.210)	0.888
Body weight	579	0.992 (0.984–1.000)	0.046	0.993 (0.985–1.001)	0.099
Child–Pugh class	663
A	429	Reference		Reference
B	234	1.398 (1.186–1.648)	<0.001	1.415 (1.162–1.722)	<0.001
HBV	663
Yes	525	Reference
No	138	0.893 (0.734–1.086)	0.255
BCLC grade	663
B	248	Reference		Reference
C	415	2.270 (1.917–2.687)	<0.001	1.817 (1.397–2.364)	<0.001
Liver cirrhosis	663
Yes	462	Reference
No	201	0.938 (0.790–1.114)	0.467
Ascites	663
No	590	Reference		Reference
Yes	73	1.378 (1.070–1.774)	0.013	1.052 (0.783–1.414)	0.738
Tumor size	663
⩽10 cm	420	Reference		Reference
>10 cm	243	1.785 (1.514–2.104)	<0.001	1.569 (1.293–1.904)	<0.001
Tumor distribution	663
⩾3	346	Reference
<3	317	1.033 (0.882–1.210)	0.683
Macrovascular invasion	663
No	385	Reference		Reference
Yes	278	1.956 (1.662–2.302)	<0.001	1.074 (0.843–1.367)	0.565
Distant metastasis	663
No	558	Reference		Reference
Yes	105	1.326 (1.070–1.644)	0.010	0.870 (0.671–1.127)	0.292
Hb	663	0.999 (0.995–1.002)	0.479
Platelet	663	1.001 (1.000–1.002)	0.005	1.000 (0.999–1.001)	0.881
PT	663	1.014 (0.970–1.060)	0.536
WBC	663	1.043 (1.016–1.072)	0.002	1.004 (0.970–1.039)	0.834
ALT	663	1.000 (1.000–1.001)	0.092	1.000 (0.999–1.001)	0.938
TBIL	663	1.002 (1.000–1.003)	0.053	0.999 (0.997–1.002)	0.632
ALB	663	0.991 (0.979–1.003)	0.127

ALB, albumin; ALT, alanine aminotransferase; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; Hb, hemoglobin; HBV, hepatitis B virus; HIPI, hepatic immune prognostic index; OS, overall survival; PSM, propensity score matching; PT, prothrombin time; TBIL, total bilirubin; WBC, white blood cell.

Table 4.

Univariate and multivariate analysis for the PFS before PSM analysis.

Characteristics	Total (N)	Univariate analysis		Multivariate analysis
Characteristics	Total (N)	Hazard ratio (95% CI)	p Value	Hazard ratio (95% CI)	p Value
Group	663
HIPI-low	125	Reference		Reference
HIPI-high	538	1.930 (1.565–2.381)	<0.001	1.548 (1.244–1.927)	<0.001
Age	663	0.994 (0.988–1.001)	0.109
Gender	663
Male	544	Reference
Female	119	0.947 (0.774–1.159)	0.598
Body weight	579	0.994 (0.987–1.002)	0.157
Child–Pugh class	663
A	429	Reference		Reference
B	234	1.309 (1.113–1.540)	0.001	1.286 (1.092–1.516)	0.003
HBV	663
Yes	525	Reference
No	138	0.917 (0.756–1.113)	0.383
BCLC grade	663
B	248	Reference		Reference
C	415	2.366 (2.003–2.796)	<0.001	2.331 (1.818–2.989)	<0.001
Liver cirrhosis	663
Yes	462	Reference
No	201	0.993 (0.839–1.175)	0.934
Ascites	663
No	590	Reference
Yes	73	1.110 (0.863–1.427)	0.418
Tumor size	663
⩽10 cm	420	Reference		Reference
>10 cm	243	1.736 (1.476–2.043)	<0.001	1.358 (1.139–1.621)	<0.001
Tumor distribution	663
⩾3	346	Reference
<3	317	1.009 (0.864–1.179)	0.909
Macrovascular invasion	663
No	385	Reference		Reference
Yes	278	1.992 (1.695–2.343)	<0.001	0.948 (0.755–1.189)	0.641
Distant metastasis	663
No	558	Reference		Reference
Yes	105	1.231 (0.996–1.522)	0.054	1.404 (1.103–1.789)	0.006
Hb	663	1.000 (0.997–1.004)	0.809
Platelet	663	1.002 (1.001–1.003)	<0.001	1.000 (0.999–1.001)	0.367
PT	663	0.981 (0.941–1.023)	0.369
WBC	663	1.051 (1.024–1.079)	<0.001	1.012 (0.982–1.043)	0.441
ALT	663	1.001 (1.000–1.002)	0.008	1.000 (1.000–1.001)	0.168
TBIL	663	1.001 (0.999–1.003)	0.329
ALB	663	0.993 (0.982–1.005)	0.274

ALB, albumin; ALT, alanine aminotransferase; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; Hb, hemoglobin; HBV, hepatitis B virus; HIPI, hepatic immune prognostic index; PFS, progression-free survival; PSM, propensity score matching; PT, prothrombin time; TBIL, total bilirubin; WBC, white blood cell.

Table 5.

Univariate and multivariate analysis for the OS after PSM analysis.

Characteristics	Total (N)	Univariate analysis		Multivariate analysis
Characteristics	Total (N)	Hazard ratio (95% CI)	p Value	Hazard ratio (95% CI)	p Value
Group	226
HIPI-low	113	Reference		Reference
HIPI-high	113	1.862 (1.401–2.474)	<0.001	1.730 (1.298–2.306)	<0.001
Age	226	1.009 (0.996–1.021)	0.173
Gender	226
Male	193	Reference
Female	33	1.155 (0.778–1.715)	0.474
Body weight	226	0.989 (0.974–1.004)	0.140
Child–Pugh class	226
A	169	Reference
B	57	1.194 (0.866–1.646)	0.280
HBV	226
Yes	175	Reference
No	51	1.022 (0.732–1.426)	0.898
BCLC grade	226
B	120	Reference		Reference
C	106	2.021 (1.526–2.676)	<0.001	1.343 (0.883–2.043)	0.168
Liver cirrhosis	226
Yes	175	Reference
No	51	0.926 (0.669–1.282)	0.645
Ascites	226
No	202	Reference
Yes	24	1.224 (0.762–1.967)	0.403
Tumor size	226
⩽10 cm	177	Reference		Reference
>10 cm	49	1.892 (1.356–2.639)	<0.001	1.347 (0.944–1.920)	0.100
Tumor distribution	226
⩾3	119	Reference
<3	107	1.113 (0.842–1.472)	0.452
Macrovascular invasion	226
No	166	Reference		Reference
Yes	60	2.023 (1.478–2.768)	<0.001	1.471 (0.966–2.240)	0.072
Distant metastasis	226
No	193	Reference		Reference
Yes	33	1.709 (1.161–2.516)	0.007	1.190 (0.766–1.848)	0.439
Hb	226	0.994 (0.987–1.001)	0.078	0.993 (0.986–1.000)	0.056
Platelet	226	1.000 (0.999–1.002)	0.626
PT	226	1.012 (0.940–1.088)	0.758
WBC	226	1.035 (0.971–1.103)	0.295
ALT	226	1.000 (0.998–1.002)	0.974
TBIL	226	1.001 (0.994–1.008)	0.751
ALB	226	1.002 (0.983–1.021)	0.860

Table 6.

Univariate and multivariate analysis for the PFS after PSM analysis.

Characteristics	Total (N)	Univariate analysis		Multivariate analysis
Characteristics	Total (N)	Hazard ratio (95% CI)	p Value	Hazard ratio (95% CI)	p Value
Group	226
HIPI-low	113	Reference		Reference
HIPI-high	113	1.652 (1.250–2.183)	<0.001	1.503 (1.123–2.011)	0.006
Age	226	1.003 (0.990–1.015)	0.666
Gender	226
Male	193	Reference
Female	33	0.935 (0.634–1.379)	0.733
Body weight	226	1.002 (0.987–1.016)	0.836
Child–Pugh class	226
A	169	Reference
B	57	0.988 (0.720–1.356)	0.941
HBV	226
Yes	175	Reference
No	51	0.992 (0.716–1.374)	0.960
BCLC grade	226
B	120	Reference		Reference
C	106	2.105 (1.596–2.777)	<0.001	1.765 (1.156–2.695)	0.009
Liver cirrhosis	226
Yes	175	Reference
No	51	0.952 (0.691–1.312)	0.764
Ascites	226
No	202	Reference
Yes	24	0.801 (0.499–1.285)	0.358
Tumor size	226
⩽10 cm	177	Reference		Reference
>10 cm	49	2.025 (1.457–2.815)	<0.001	1.544 (1.085–2.198)	0.016
Tumor distribution	226
⩾3	119	Reference
<3	107	1.057 (0.805–1.387)	0.689
Macrovascular invasion	226
No	166	Reference		Reference
Yes	60	2.146 (1.572–2.929)	<0.001	1.260 (0.808–1.963)	0.308
Distant metastasis	226
No	193	Reference		Reference
Yes	33	1.403 (0.957–2.058)	0.083	0.772 (0.486–1.225)	0.272
Hb	226	0.999 (0.993–1.005)	0.763
Platelet	226	1.001 (1.000–1.003)	0.130
PT	226	0.961 (0.894–1.033)	0.282
WBC	226	1.073 (1.010–1.140)	0.023	0.998 (0.933–1.068)	0.953
ALT	226	1.000 (0.998–1.002)	0.846
TBIL	226	0.999 (0.992–1.005)	0.663
ALB	226	1.002 (0.983–1.021)	0.845

ALB, albumin; ALT, alanine aminotransferase; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; Hb, hemoglobin; HBV, hepatitis B virus; HIPI, hepatic immune prognostic index; PFS, progression-free survival; PSM, propensity score matching; PT, prothrombin time; TBIL, total bilirubin; WBC, white blood cell.

Subgroup analysis

Subgroup analyses based on baseline characteristics in the PSM cohort revealed consistent trends for OS and PFS. In the OS analysis (Figure 2), a significant interaction was identified between ascites status and HIPI group (p for interaction = 0.023). The HIPI-high status was associated with inferior OS regardless of ascites status; however, this effect was more pronounced in patients with ascites (HR, 4.20; 95% CI, 1.34–13.20). Although the difference did not reach statistical significance in some subgroups, high HIPI status was consistently correlated with worse OS across other subgroups. For PFS (Figure 3), a significant interaction was observed between tumor size and HIPI group (p for interaction = 0.019), with a more substantial increase in PFS risk for tumors >10 cm (HR, 3.98; 95% CI, 1.27–12.46). In addition, among patients with ascites or distant metastasis, those in the HIPI-high group showed a nonsignificant trend toward lower PFS risk than those in the HIPI-low group. In all other subgroups, high HIPI status was uniformly associated with poorer PFS outcomes, even when statistical significance was not reached in certain subsets.

Figure 2.

Forest plot for subgroup analysis of overall survival.

Figure 3.

Forest plot for subgroup analysis of progression‑free survival.

Discussion

In this study, we developed and evaluated a novel HIPI based on the combination of pretreatment NLR and AFP levels. Our findings demonstrated that HIPI is a significant and independent prognostic biomarker for patients with unresectable HCC who receive TACE treatment. Patients in the HIPI-low group had significantly longer OS and PFS, as well as higher ORR and DCR, than those in the HIPI-high group, both before and after PSM.

The prognostic value of systemic inflammation and serum tumor biomarkers in HCC has been well-established. NLR, as a marker reflecting the balance between pro-tumor neutrophilia and anti-tumor lymphocytes, has been associated with tumor progression, metastasis, and poorer survival in HCC patients undergoing TACE treatment.^11
–13 Similarly, AFP is a widely used serological marker for HCC, and its elevated level has been incorporated into several prognostic models for TACE in the treatment of HCC.^15
–17 Our study built upon these concepts by integrating these two accessible parameters into a composite index. The rationale for this combination was that it could simultaneously capture the host’s systemic inflammatory state and the tumor’s secretory activity, providing a more comprehensive prognostic assessment than either marker alone. Conceptually, the biological rationale of the HIPI reflects the “seed and soil” hypothesis in cancer progression. Elevated AFP represents the aggressive “seed” (rapid intrinsic tumor proliferation and macrovascular invasion), while a high NLR represents the “fertile soil” (a pro-tumor inflammatory and immunosuppressive microenvironment driven by neutrophilia and lymphopenia). Combining both provides a holistic evaluation of the tumor-host interaction, which explains its superior prognostic accuracy.

The results of our multivariate Cox regression analyses further underscored the robustness of HIPI as an independent prognostic factor. Before PSM, a high HIPI, Child–Pugh class B, BCLC stage C, and tumor size >10 cm were identified as independent risk factors for both OS and PFS. After PSM, a high HIPI remained significantly associated with worse OS and PFS. Although the absolute difference in median PFS after PSM was modest (8.5 vs 8.1 months), the Kaplan–Meier curves demonstrated a sustained separation over the entire follow-up period, and the HR indicated a persistent and significant increase in progression risk for HIPI-high patients. This consistency confirmed that the prognostic value of HIPI was not merely a reflection of underlying liver function or tumor stage.

The subgroup analyses provided further insights into the potential utility of HIPI. A significant interaction was observed between HIPI and ascites status for OS, and between HIPI and tumor size for PFS. The negative impact of high HIPI was more pronounced in patients with ascites or larger tumors (>10 cm), suggesting that HIPI may be particularly useful for identifying patients with advanced disease or poor liver reserve who are at the highest risk for poor clinical outcomes.

The biological mechanisms underlying the association between HIPI and poor prognosis after TACE are likely multifactorial. An elevated NLR reflects a systemic inflammatory state that promotes tumor proliferation, angiogenesis, and metastasis, while simultaneously suppressing adaptive anti-tumor immunity.^9,10 TACE-induced hypoxia and inflammation may worsen the tumor microenvironment.^22,24,25 A high AFP level indicates active tumor growth and has been implicated in immune suppression.¹⁴ Therefore, the HIPI likely identifies a subgroup of patients with both a pro-tumor inflammatory milieu and aggressive tumor biology, which makes them less responsive to TACE and more prone to rapid progression. The ultimate goal of HIPI is to enable simple bedside risk stratification. For patients identified as HIPI-high, TACE monotherapy may be insufficient, and these patients might benefit from shortened surveillance intervals and early intervention with combination therapies, such as TACE combined with systemic targeted therapy and immunotherapy.

Our study had several limitations. First, the inclusion of a heterogeneous population, encompassing both BCLC B and C stages with the presence of macrovascular invasion and extrahepatic metastasis, may introduce baseline confounding. Furthermore, the choice of TACE modality (C-TACE vs DEB-TACE) was non-randomized and based on real-world clinical practice, which may have introduced additional confounding despite PSM. Our study lacked internal resampling validation (e.g., bootstrapping) or an external independent validation cohort, which may limit the generalizability of the index. Second, consistent with the epidemiology of HCC in China, our cohort was predominantly composed of patients with HBV infection. The sample size of HCV-positive patients was too small for meaningful statistical analysis; thus, the prognostic value of HIPI in HCV-related HCC populations requires further validation. Finally, whether the prognostic value of HIPI can be extrapolated to other liver-directed therapies, such as ablation or transarterial radioembolization, remains unknown and requires further investigation.

In conclusion, the HIPI, a simple composite score based on pretreatment NLR and AFP, served as a robust and independent prognostic biomarker for patients with unresectable HCC undergoing TACE. HIPI-low status was associated with significantly better survival outcomes and TACE treatment response. This readily available index could aid in risk stratification and patient counseling in clinical practice.

Conclusion

The HIPI is a novel, noninvasive, and robust prognostic biomarker for patients with unresectable HCC undergoing TACE. By integrating systemic inflammation (NLR) and tumor biology (AFP) using routine clinical parameters, the HIPI effectively stratifies survival risk to guide personalized treatment.

Supplemental Material

sj-docx-1-tam-10.1177_17588359261447986 – Supplemental material for Hepatic immune prognostic index as a prognostic biomarker in hepatocellular carcinoma patients treated with transarterial chemoembolization

Supplemental material, sj-docx-1-tam-10.1177_17588359261447986 for Hepatic immune prognostic index as a prognostic biomarker in hepatocellular carcinoma patients treated with transarterial chemoembolization by Jing Li, Yi Ren, Guilin Zhang, Yusheng Guo, Suyue Wu, Weimin Zhao, Chuansheng Zheng, Lian Yang and Xuefeng Kan in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-jpg-2-tam-10.1177_17588359261447986 – Supplemental material for Hepatic immune prognostic index as a prognostic biomarker in hepatocellular carcinoma patients treated with transarterial chemoembolization

Supplemental material, sj-jpg-2-tam-10.1177_17588359261447986 for Hepatic immune prognostic index as a prognostic biomarker in hepatocellular carcinoma patients treated with transarterial chemoembolization by Jing Li, Yi Ren, Guilin Zhang, Yusheng Guo, Suyue Wu, Weimin Zhao, Chuansheng Zheng, Lian Yang and Xuefeng Kan in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

We would like to express our sincere gratitude to all the patients and their families for their valuable contribution to this study. We would like to thank Dr Xiaoming Yang (Image-Guided Bio-Molecular Intervention Research and Section of Vascular and Interventional Radiology, Department of Radiology, University of Washington School of Medicine, Seattle, WA, USA), a native English speaker, for his professional English language editing and revision of this manuscript.

Declarations

ORCID iDs

Chuansheng Zheng

Lian Yang

Xuefeng Kan

Supplemental material

Supplemental material for this article is available online.

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