Next Article in Journal
JAK Inhibitors and Risk of Cancer in IBD Patients
Previous Article in Journal
Sociodemographic and Health-Service Precursors of Local-Stage Lung Cancer Diagnosis: A Population-Based Study in New South Wales, Australia
Previous Article in Special Issue
The Definition of the Best Margin Cutoff and Related Oncological Outcomes After Liver Resection for Hepatocellular Carcinoma: A Systematic Review
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 17
Issue 11
10.3390/cancers17111794
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Clinical Comparison Between Curative and Non-Curative Treatment for Hepatocellular Carcinoma with Hepatic Vein Invasion: A Nationwide Cohort Study

by
Sehyeon Yu
,
Hye-Sung Jo
*,
Young-Dong Yu
,
Yoo-Jin Choi
,
Su-Min Jeon
and
Dong-Sik Kim
Division of Hepato-Biliary-Pancreatic Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul 02841, Republic of Korea
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(11), 1794; https://doi.org/10.3390/cancers17111794
Submission received: 26 April 2025 / Revised: 16 May 2025 / Accepted: 23 May 2025 / Published: 27 May 2025
(This article belongs to the Special Issue Advances in the Multidisciplinary Management of Hepatocellular Carcinoma)
Browse Figures
Review Reports Versions Notes

Simple Summary

Hepatocellular carcinoma (HCC) with hepatic vein invasion (HVI) is typically treated with palliative approaches due to its advanced stage. However, this study shows that curative-intent treatments such as surgical resection or local ablation can significantly improve long-term survival in selected patients. Using data from a large Korean national registry, we compared outcomes between patients receiving curative versus non-curative treatment after adjusting for key clinical factors. Despite similar tumor burden, those in the curative group showed markedly better overall and cancer-specific survival. These findings suggest that curative approaches may offer a meaningful survival benefit for HCC even in the presence of HVI in patients with preserved liver function and good performance status.

Abstract

Background: Hepatocellular carcinoma (HCC) with hepatic vein invasion (HVI) is classified as advanced stage and palliative management is the primary treatment option. This study compared the long-term outcomes of curative and non-curative treatments in patients of HCC with HVI. Methods: Data were obtained from a retrospective multicenter cohort of the Korean Primary Liver Cancer Registry. We reviewed 18,315 patients newly diagnosed with HCC between 2008 and 2019. After propensity score matching based on the albumin-bilirubin (ALBI) score; tumor number, and tumor size, clinical outcomes were compared between the curative group (n = 42, 29.0%) undergoing surgical resection or local ablation and the non-curative group (n = 103, 71.0%) receiving other treatments. Results: Tumor burdens such as tumor number, maximum tumor size, levels of alpha-fetoprotein (AFP), and protein induced by absence of vitamin K or antagonist-II did not differ significantly between the groups (p = 0.672, p = 0.143, p = 0.153 and p = 0.651, respectively). In long-term outcomes, the overall survival (OS) and cancer-specific survival (CSS) were significantly better in the curative group compared to the non-curative group (p < 0.001, both). Multivariate analysis indicated that non-curative treatment, ALBI grade ≥ 2, and AFP ≥ 400 ng/mL were common risk factors for OS and CSS. Conclusions: Curative-intent treatment has the potential to significantly enhance long-term outcomes in selected patients of HCC with HVI who preserved liver function and performance status.

1. Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and one of the leading causes of cancer-related mortality worldwide [1,2,3]. Vascular invasion, observed in approximately 25–50% of HCC cases, is a well-established factor associated with poor prognosis [4]. The most commonly observed vascular invasion in HCC is portal vein invasion (PVI). Due to the biological feature for portal dissemination of HCC, PVI has been widely discussed. Hepatic vein invasion (HVI), although present in only about 5% of HCC patients [5], can cause direct dissemination of tumor cells into the systemic circulation [1,6]. Despite this concern, its prognostic relevance and therapeutic implications remain less well-defined than those of PVI.
The 8th edition of the American Joint Committee on Cancer (AJCC) staging system classifies HCC with major branch invasion of the hepatic vein as the T4 stage, whereas in previous editions, such major vascular involvement was categorized as T3b [7]. This reclassification reflected a poor prognosis associated with extensive vascular invasion. However, subsequent validation studies have not examined HVI independent of other T4 factors, such as direct invasion into adjacent organs [8,9,10]. Furthermore, few studies have specifically evaluated the prognostic impact or treatment strategies for HVI separately from PVI [11]. The Barcelona Clinic Liver Cancer (BCLC) staging system classifies HCC with PVI as advanced stage and recommends palliative treatment; however, specific guidelines for HCC with HVI remain insufficient [12]. A national practice guideline for the management of HCC states that in patients with well-preserved liver function, surgical resection may be selectively considered even in the presence of HVI. However, the level of evidence and strength of recommendation for this approach remains low [13].
Thus, clear guidelines regarding optimal treatment strategies for HCC with HVI are yet to be established. Considering the potential role of curative treatment for HCC with HVI, it is crucial to investigate the clinical impact of HVI and treatment-related outcomes using large-scale HCC registry data. Therefore, this study aimed to compare the clinical outcomes of curative and non-curative treatment in patients of HCC with HVI and to identify prognostic factors affecting long-term outcomes.

2. Materials and Methods

2.1. Data

We used the database of patients with HCC newly diagnosed in Korea between 2008 and 2019, provided by the Korean Primary Liver Cancer Registry (KPLCR). This study utilized a retrospective multicenter observational cohort comprising randomly extracted and registered HCC data from the Korean Central Cancer Registry (KCCR), based on the International Classification of Disease (ICD) code C22.0, collected since 2008. Information on patient survival status and censoring was obtained through the national death registry as of 31 December 2022.

2.2. Study Population and Matching

All patients diagnosed with HCC registered in the KPLCR from 54 hospitals between 2008 and 2019 were enrolled in this study (Figure 1). Among a total of 18,315 cases, patients who met the following criteria were excluded: (I) the presence of extrahepatic metastasis, (II) a Child-Turcotte-Pugh (CTP) score ≥ 7, (III) Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2, and (IV) who underwent liver transplantation as 1st treatment for HCC. Of the remaining 12,211 patients, 350 had HVI at diagnosis, and 293 underwent treatment. After excluding 51 patients with insufficient medical records, a final analysis was conducted on 242 patients divided into two groups: a curative group (n = 42, 17.4%) comprising patients who were treated with surgical resection or local ablation therapy, and a non-curative group (n = 200, 82.6%), comprising patients who had received trans-arterial therapy, chemotherapy or radiation therapy.
However, patients of HCC with HVI receiving non-curative treatment are more likely to have a higher tumor burden and poor liver function, making them unsuitable candidates for curative-intent treatment. In addition, there was a substantial difference in patient numbers between the curative and non-curative groups. To minimize differences in baseline characteristics and sample size between the two groups, it was necessary to match critical factors related to liver function and morphologic tumor burden to ensure comparability. Therefore, we performed propensity score matching based on the albumin-bilirubin (ALBI) grade (grade 1: ≤ −2.60; grade 2: > −2.60 and ≤ −1.39; grade 3: > −1.39), the number and the maximum size of tumors for the curative and non-curative group. Finally, we compared and analyzed treatment outcomes of 42 (29.0%) and 103 (71.0%) patients in the curative and non-curative groups, respectively.

2.3. Diagnosis and Definition

All the patients included in the study were newly diagnosed with HCC. HCC was diagnosed if the histological and immunological findings were positive or if a tumor (or tumors) ≥ 1 cm in size was identified on multi-phase computed tomography (CT) or magnetic resonance imaging (MRI) with imaging features consistent with HCC: i.e., hyperenhancement in the arterial phase, and washout at the portal venous or delayed phase. HVI was assessed using imaging studies, and the provided dataset did not include information on the HVI grade.
Overall survival (OS) and cancer-specific survival (CSS) were analyzed in each group. OS was defined as the time from diagnosis to death or the last follow-up date, whereas CSS was defined as the time from diagnosis to death due to HCC, using the Korean Standard Classification of Diseases version 7 system or the last follow-up date.

2.4. Statistical Analysis

Categorical variables are presented as numbers with percentages compared using the chi-square test or Fisher’s exact test as appropriate. Continuous variables are presented as medians and interquartile ranges and compared using the Student’s t-test and Mann-Whitney test. Propensity score matching (PSM) was conducted using the ALBI score and the number and maximum size of tumors. After propensity score matching, the standard mean difference suggested an appropriate balance between the two groups. (Figure S1 and Table S1). Kaplan-Meier analysis and log-rank tests were used to calculate OS and CSS. Cox proportional hazards regression analysis was used to evaluate the prognostic factors for survival and was conducted in two stages: univariate and multivariate analyses. For the multivariate analysis, factors with a p-value of 0.150 or less in the univariate analysis were included, and factors with a p-value less than 0.050 were considered significant. Regarding time-dependent effects of risk factors on OS and CSS, the cumulative regression coefficients for each covariate were plotted with 95% confidence intervals to visualize the temporal contribution of each variable to the hazard function. Statistical analyses were performed using IBM Statistics for Windows (version 20.0; IBM Corp., Armonk, NY, USA) and R software (version 3.6.1; Vienna, Austria; “rms”, “survival” and “survminer” packages).

3. Results

3.1. Descriptive Analysis and Pre-Matched Cohort

The incidence of HCC with HVI was 5.4%, corresponding to 988 cases in the total cohort before applying the exclusion criteria and propensity score matching. The distribution of treatments administered to these patients is shown in Figure S2. Among them, only 58 (5.9%) patients received curative-intent treatment, whereas 541 (54.8%) received non-curative treatment. On the other hand, 360 (36.4%) patients who were diagnosed with HCC accompanied by HVI did not receive any treatment. Among them, 33 patients had CTP grade A and ECOG scores between 0 to 1 without extrahepatic metastasis. The median tumor number and size of those patients were 1 (1–5) and 12 (8.5–15.4) cm, respectively. The median alpha-fetoprotein (AFP) level was 201.5 (10.4–10,500.0) ng/mL (Table S2).
Before PSM, the curative group comprised 42 (17.4%) patients, whereas the non-curative group comprised 200 (82.6%) patients. The number of tumors was significantly higher in the non-curative group compared to the curative group (1 [1–1] vs. 2 [1–5], p < 0.001). Additionally, the maximum tumor size was significantly larger in the non-curative group (5.1 [3.1–10.7] vs. 8.3 [5.3–12.0] cm, p = 0.010) and albumin levels were significantly higher in the curative group (4.3 [3.9–4.5] vs. 4.0 [3.6–4.2] g/dL, p < 0.001). These variables are related to tumor burden and underlying liver function and are considered potential factors that may significantly impact long-term survival. Therefore, we performed propensity score matching using tumor number, tumor size, and ALBI grade.

3.2. Baseline Characteristics of Matched Cohort

The baseline characteristics of the curative and non-curative groups after PSM are presented in Table 1. No statistically significant differences between the two groups in terms of age, sex, or major underlying conditions, including liver disease (p > 0.050) were observed. Serum albumin levels remained significantly higher in the curative group than in the non-curative group (4.3 [3.9–4.5] vs. 4.1 [3.8–4.3] g/dL, p = 0.035); however, there was no significant difference in ALBI grade between the two groups (p = 0.403). None of the patients had a history of hepatic encephalopathy, and there were no significant differences in laboratory tests between the two groups except for serum albumin levels. In addition, there were no cases of hepatic encephalopathy (HEP) in either group, and there were no significant differences between the two groups in portal hypertension parameters such as platelet count and ascites.
Regarding tumor burden-related factors, the number and size of tumors used for matching showed no differences between the curative and non-curative groups (1 [1–1] vs. 1 [1–2], p = 0.672 and 5.1 [3.1–10.7] vs. 7.3 [4.9–10.0] cm, p = 0.143, respectively) (Table 2). Additionally, there were no significant differences between the two groups in terms of tumor markers (alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II), vascular or bile duct invasion as shown in Table 2 (p > 0.050).

3.3. Overall and Cancer-Specific Survival and Risk Factors

Survival rates according to treatment modality in the entire cohort before applying the exclusion criteria and propensity score matching are presented in Figure S3. The 5-year OS and CSS rates in no HVI group were 49% and 53%, respectively. In the curative-intent treatment group, the 5-year OS and CSS rates were 44% and 49%, respectively. This contrasts with each non-curative treatment group, in which the 5-year OS and CSS rates were 4–9% and 6–13%, respectively (p < 0.001).
After applying exclusion criteria and PSM, the median follow-up period for OS and CSS was 18 months. The 1-, 3-, and 5-year OS rates in the curative group were significantly higher than those in the non-curative group (83%, 64%, and 48% vs. 59%, 24% and 15%, respectively; p < 0.001) (Figure 2a). The 1-, 3-, and 5-year CSS rates in the curative group were also significantly higher than those in the non-curative group (83%, 64%, and 55% vs. 59%, 25%, and 17%, respectively; p < 0.001) (Figure 2b).
In the multivariate Cox regression analysis (Table 3), the non-curative treatment was identified as a strong risk factor for both OS and CSS (hazard ratio and 95% confidence interval, 2.43 [1.50–3.92], p < 0.001 and 2.45 [1.49–4.01], p < 0.001, respectively). ALBI grade 2 or higher was also found to be a significant risk factor for both OS and CSS (2.00 [1.31–3.14], p = 0.001 and 2.07 [1.33–3.22], p < 0.001, respectively). Additionally, AFP ≥ 400 ng/mL was also identified as a significant risk factor for both OS and CSS (1.70 [1.13–2.56], p = 0.011 and 1.70 [1.12–2.59], p = 0.013, respectively). On the other hand, the number of tumors, tumor size, and portal vein invasion were not significant risk factors for survival. The forest plot showed the results of the multivariate Cox regression analyses for OS and CSS (Figure 3).
Figure 4 illustrates the time-dependent effects of the risk factors identified from the multivariate Cox proportional hazards regression analysis for OS and CSS. The cumulative effects of selected covariates over time were evaluated using Aalen’s additive regression model. Solid lines represent the estimated cumulative effects and shaded areas indicate the corresponding confidence intervals. It is noteworthy that the initial treatment decision (curative vs. non-curative) for HCC with HVI exhibited an increasing cumulative impact on survival risk over time.

4. Discussion

Clinically evident HVI in HCC can cause extrahepatic spread through systemic circulation. Furthermore, with respect to higher-grade HVI, hepatic congestion due to outflow obstruction can lead to impaired liver function and promotion of intrahepatic metastases [1,14]. Therefore, HCC with HVI is considered an advanced stage, which causes hesitation in pursuing curative-intent treatment. Currently, curative-intent treatment for HCC with HVI is rarely performed in real clinical practice, and there has been a prevailing atmosphere of prioritizing the non-curative treatment, including transcatheter arterial chemoembolization (TACE), chemotherapy, or radiation therapy without a clear treatment guideline [15,16,17].
The incidence of HCC with HVI was low; only 5.9% of the HCC with HVI cases underwent curative treatment, while 54.8% of the patients received non-curative treatment in the entire cohort. Only a few studies have reported the efficacy of surgical resection or ablation therapy on HCC with vascular invasion, including portal vein, hepatic vein, and inferior vena cava [18,19,20,21]. One study compared the median OS for hepatectomy and TACE in cases of HCC with HVI and the median OS was 4.47 and 1.58 years, respectively [11]. Moreover, based on a nationwide Japanese study, the Japan Society of Hepatology recently (5th JSH-HCC Guidelines) recommends that surgical resection is prioritized if feasible in cases of vessel invasion [22]. In several studies using non-curative treatment such as trans-arterial therapy, chemotherapy, or radiation therapy, either alone or in combination, the median OS was reported to be between 7.9 and 17.4 months [23,24,25,26]. Although we could not evaluate the preoperative images of the patients, which made treatment decisions difficult, considering the relatively poor long-term survival rate of patients undergoing non-curative treatment for HCC with HVI raises concern regarding the potential role of curative-intent treatment in these patients.
In this study, the curative group showed better long-term survival than the non-curative group. The clearly different survival outcomes between the two groups highlight the need to reexamine the role of curative-intent treatment for HCC with HVI. In the entire cohort before applying the exclusion criteria and propensity score matching, the curative-intent treatment group demonstrated a slightly lower but comparable survival curve compared to patients without HVI (Figure S3). These findings suggest that curative-intent treatment could potentially mitigate the adverse prognostic impact of HVI, achieving survival outcomes comparable to patients without HVI. Furthermore, considering that the 5-year CSS rates of the curative group exceed 50% after PSM, curative-intent treatment could have a potential role in achieving better long-term outcomes in selected patients of HCC with HVI. As imaging techniques for HCC, surgical strategies, and perioperative management continue to progress, it is important to enhance our understanding of HCC with HVI and move away from a passive approach to treatment based on systematic research.
In multivariate Cox proportional hazards regression analysis, non-curative treatment, male sex, ALBI grade ≥ 2, and AFP ≥ 400 ng/mL were independent risk factors increasing HR for OS and CSS. Figure 4 illustrates the time-dependent HR for independent risk factors, demonstrating that the risk associated with the initial choice between curative and non-curative treatment continued to increase over time, similar to other well-known risk factors for HCC. This finding emphasizes the importance of initial treatment selection in patients of HCC with HVI who are eligible for curative-intent treatment.
In this study, a higher-grade ALBI was the strongest independent risk factor for long-term survival following non-curative treatment. The ALBI score provides a simplified yet robust assessment of liver function using only two parameters—serum albumin and total bilirubin—while being a continuous variable that allows for a more precise evaluation than the CTP score. It has been extensively validated in previous studies, with established grade cut-off values demonstrating a significant clinical impact on liver function [27,28,29,30]. Additionally, it does not include subjective factors such as ascites or hepatic encephalopathy, making it a more objective indicator for evaluating liver function. Our results underscore the clinical importance of the ALBI score in HCC, where—unlike other malignancies—both tumor factors and individual patient liver function serve as crucial prognostic indicators.
The strength of this study lies in utilizing large-scale HCC registry data to investigate the incidence, treatment trends, and clinical outcomes in patients of HCC with HVI. Establishing the criteria for applying curative-intent treatment to patients of HCC with HVI will require a more systematic research process. The results do not suggest that all patients of HCC with HVI should undergo curative-intent treatments. However, unless there are specific contraindications—such as poor liver function, complicated underlying conditions, old age, poor ECOG status, or insufficient future remnant liver volume—it is important to consider the potential for curative-intent treatment in patients of HCC with HVI.
This retrospective study has several limitations. First, the final cohort size was small due to the low incidence of HCC with HVI; however, the low incidence of HVI observed in large-scale HCC cohorts is a meaningful result in itself. Second, there were differences in both the number of cases and the baseline characteristics between the two groups; To minimize these differences, we performed PSM focusing on liver function and tumor burden, which were considered the most critical confounding factors. Including more variables in the PSM could have enhanced the reliability of the study results; however, this was limited by the relatively small sample size of the HVI group that received curative treatment. Nevertheless, most baseline characteristics were well-balanced between the groups following PSM. Moreover, one of the limitations of this study using a nationwide registry is the absence of detailed operative and pathological variables, including the grade of HVI. Nevertheless, because lower-grade HVI is often difficult to diagnose both radiologically and pathologically in clinical practice, a substantial proportion of patients in this study likely had high-grade HVI. In addition, as the data in this study were collected from patients treated between 2008 and 2019, a key limitation is that it does not reflect recent advances in systemic treatment strategies or their therapeutic outcomes [31]. Finally, due to the low incidence of HCC with HVI and retrospective study design, it is difficult to provide a detailed description of surgical indications for HCC with HVI. However, through PSM, we compared treatment outcomes between the two groups with similar liver function, tumor size, and tumor number, and found a statistically significant survival benefit in those receiving curative-intent treatment. These findings could serve as a foundation for more precise studies in the future.

5. Conclusions

This large-scale registry-based study demonstrated the significant potential of curative-intent treatment for HCC in patients accompanied by HVI with preserved liver function and performance status. Based on this study, well-designed prospective trials are warranted to establish precise selection criteria for identifying patients who are most likely to benefit from curative strategies and achieve improved survival outcomes.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers17111794/s1, Table S1: Means, standard deviations, and standardized mean differences on covariates and propensity scores post-matching; Figure S1: Standardized mean differences before and after matching; Figure S2: Distribution of treatment methods in hepatocellular carcinoma with hepatic vein invasion in the entire cohort before applying exclusion criteria and propensity score matching; Table S2: The baseline characteristics of the 33 patients of HCC with HVI who did not receive any treatment despite having Child-Pugh class A, PST 0–1, and no distant metastasis; Figure S3: Overall and cancer-specific survival according to treatment methods in the entire cohort before applying exclusion criteria and propensity score matching. A survival curve of hepatocellular carcinoma with no hepatic vein invasion is presented regardless of treatment modality. The survival curves of hepatocellular carcinoma with hepatic vein invasion are shown in different colors according to treatment modality.

Author Contributions

Conceptualization, H.-S.J. and S.Y.; methodology, H.-S.J. and S.Y.; software, H.-S.J. and S.Y.; validation, H.-S.J., S.Y., Y.-J.C., S.-M.J. and Y.-D.Y.; formal analysis, H.-S.J. and S.Y.; investigation, H.-S.J., S.Y., Y.-J.C., S.-M.J., Y.-D.Y. and D.-S.K.; resources, H.-S.J., S.Y., Y.-J.C., S.-M.J., Y.-D.Y. and D.-S.K.; data curation, H.-S.J., S.Y. and S.-M.J.; writing—original draft preparation, S.Y.; writing—review and editing, H.-S.J.; visualization, H.-S.J. and S.Y.; supervision, H.-S.J.; project administration, H.-S.J. and D.-S.K.; funding acquisition, H.-S.J. and D.-S.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

This study was approved by the ethics review board of Korea University Anam Hospital (No. 2023AN0006, approved 13 February 2024) and was conducted in accordance with the tenets of the Declaration of Helsinki (revised in 2013) and the Declaration of Istanbul.

Informed Consent Statement

Informed consent was not obtained because of the retrospective nature of the study and anonymous data collection.

Data Availability Statement

The data is unavailable due to privacy and ethical restrictions.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
AFPAlpha-fetoprotein
AJCCAmerican Joint Committee on Cancer
ALBIAlbumin-bilirubin
BCLCBarcelona Clinic Liver Cancer
BMIbody mass index
CIConfidence interval
CrCreatinine
CSSCancer-specific survival
CTComputed tomography
CTPChild-Turcotte-Pugh
ECOGEastern Cooperative Oncology Group
HBVHepatitis B virus
HCCHepatocellular carcinoma
HCVHepatitis C virus
HRHazard ratio
HVIHepatic vein invasion
ICDInternational Classification of Disease
IQRInterquartile ranges
JSHJapan Society of Hepatology
KCCRKorean Central Cancer Registry
KPLCRKorean Primary Liver Cancer Registry
MELDModel for end-stage liver disease
MRIMagnetic resonance imaging
OSOverall survival
PIVKA-IIProtein induced by vitamin K absence or antagonist-II
PSperformance status
PSMPropensity score matching
PSTPerformance status test
PT-INRProthrombin time-international normalized ratio
PVIPortal vein invasion
TACETranscatheter arterial chemoembolization

References

  1. Shukla, A.; Jain, A. Hepatocellular Carcinoma with Hepatic Vein and Inferior Vena Cava Invasion. J. Clin. Exp. Hepatol. 2023, 13, 813–819. [Google Scholar] [CrossRef] [PubMed]
  2. Forner, A.; Reig, M.; Bruix, J. Hepatocellular carcinoma. Lancet 2018, 391, 1301–1314. [Google Scholar] [CrossRef]
  3. Llovet, J.M.; Kelley, R.K.; Villanueva, A.; Singal, A.G.; Pikarsky, E.; Roayaie, S.; Lencioni, R.; Koike, K.; Zucman-Rossi, J.; Finn, R.S. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 2021, 7, 6. [Google Scholar] [CrossRef] [PubMed]
  4. Krishnan, M.S.; Rajan Kd, A.; Park, J.; Arjunan, V.; Garcia Marques, F.J.; Bermudez, A.; Girvan, O.A.; Hoang, N.S.; Yin, J.; Nguyen, M.H.; et al. Genomic Analysis of Vascular Invasion in HCC Reveals Molecular Drivers and Predictive Biomarkers. Hepatology 2021, 73, 2342–2360. [Google Scholar] [CrossRef]
  5. Kokudo, T.; Hasegawa, K.; Matsuyama, Y.; Takayama, T.; Izumi, N.; Kadoya, M.; Kudo, M.; Kubo, S.; Sakamoto, M.; Nakashima, O.; et al. Liver resection for hepatocellular carcinoma associated with hepatic vein invasion: A Japanese nationwide survey. Hepatology 2017, 66, 510–517. [Google Scholar] [CrossRef]
  6. Sakamoto, K.; Nagano, H. Outcomes of surgery for hepatocellular carcinoma with tumor thrombus in the inferior vena cava or right atrium. Surg. Today 2018, 48, 819–824. [Google Scholar] [CrossRef]
  7. Liao, X.; Zhang, D. The 8th Edition American Joint Committee on Cancer Staging for Hepato-pancreato-biliary Cancer: A Review and Update. Arch. Pathol. Lab. Med. 2021, 145, 543–553. [Google Scholar] [CrossRef]
  8. Chan, A.C.; Fan, S.T.; Poon, R.T.; Cheung, T.T.; Chok, K.S.; Chan, S.C.; Lo, C.M. Evaluation of the seventh edition of the American Joint Committee on Cancer tumour-node-metastasis (TNM) staging system for patients undergoing curative resection of hepatocellular carcinoma: Implications for the development of a refined staging system. HPB 2013, 15, 439–448. [Google Scholar] [CrossRef]
  9. Park, S.; Choi, S.; Cho, Y.A.; Sinn, D.H.; Kim, J.M.; Park, C.K.; Ha, S.Y. Evaluation of the American Joint Committee on Cancer (AJCC) 8th Edition Staging System for Hepatocellular Carcinoma in 1,008 Patients with Curative Resection. Cancer Res. Treat. 2020, 52, 1145–1152. [Google Scholar] [CrossRef]
  10. Anwanwan, D.; Singh, S.K.; Singh, S.; Saikam, V.; Singh, R. Challenges in liver cancer and possible treatment approaches. Biochim. Biophys. Acta Rev. Cancer 2020, 1873, 188314. [Google Scholar] [CrossRef]
  11. Zhang, Z.Y.; Zhang, E.L.; Zhang, B.X.; Chen, X.P.; Zhang, W. Treatment for hepatocellular carcinoma with tumor thrombosis in the hepatic vein or inferior vena cava: A comprehensive review. World J. Gastrointest. Surg. 2021, 13, 796–805. [Google Scholar] [CrossRef] [PubMed]
  12. Reig, M.; Forner, A.; Rimola, J.; Ferrer-Fàbrega, J.; Burrel, M.; Garcia-Criado, Á.; Kelley, R.K.; Galle, P.R.; Mazzaferro, V.; Salem, R.; et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J. Hepatol. 2022, 76, 681–693. [Google Scholar] [CrossRef] [PubMed]
  13. Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. J. Liver Cancer 2023, 23, 1–120. [Google Scholar] [CrossRef] [PubMed]
  14. Sessa, A.; Allaire, M.; Lebray, P.; Medmoun, M.; Tiritilli, A.; Iaria, P.; Cadranel, J.F. From congestive hepatopathy to hepatocellular carcinoma, how can we improve patient management? JHEP Rep. 2021, 3, 100249. [Google Scholar] [CrossRef]
  15. Kumari, R.; Sahu, M.K.; Tripathy, A.; Uthansingh, K.; Behera, M. Hepatocellular carcinoma treatment: Hurdles, advances and prospects. Hepat. Oncol. 2018, 5, Hep08. [Google Scholar] [CrossRef]
  16. Wege, H.; Li, J.; Ittrich, H. Treatment Lines in Hepatocellular Carcinoma. Visc. Med. 2019, 35, 266–272. [Google Scholar] [CrossRef]
  17. Angeli-Pahim, I.; Chambers, A.; Duarte, S.; Zarrinpar, A.; Hayashi, H.; Midorikawa, Y. Current Trends in Surgical Management of Hepatocellular Carcinoma. Cancers 2023, 15, 5378. [Google Scholar] [CrossRef]
  18. Jo, H.S.; Park, P.J.; Yu, Y.D.; Choi, Y.J.; Yu, S.H.; Kim, D.S. Clinical significance of surgical resection for hepatocellular carcinoma with portal vein invasion: A nationwide cohort study. Hepatobiliary Surg. Nutr. 2024, 13, 814–823. [Google Scholar] [CrossRef]
  19. Kokudo, T.; Hasegawa, K.; Yamamoto, S.; Shindoh, J.; Takemura, N.; Aoki, T.; Sakamoto, Y.; Makuuchi, M.; Sugawara, Y.; Kokudo, N. Surgical treatment of hepatocellular carcinoma associated with hepatic vein tumor thrombosis. J. Hepatol. 2014, 61, 583–588. [Google Scholar] [CrossRef]
  20. Wang, Y.; Ma, L.; Yuan, Z.; Zheng, J.; Li, W. Percutaneous thermal ablation combined with TACE versus TACE monotherapy in the treatment for liver cancer with hepatic vein tumor thrombus: A retrospective study. PLoS ONE 2018, 13, e0201525. [Google Scholar] [CrossRef]
  21. Yoshidome, H.; Takeuchi, D.; Kimura, F.; Shimizu, H.; Ohtsuka, M.; Kato, A.; Furukawa, K.; Yoshitomi, H.; Miyazaki, M. Treatment strategy for hepatocellular carcinoma with major portal vein or inferior vena cava invasion: A single institution experience. J. Am. Coll. Surg. 2011, 212, 796–803. [Google Scholar] [CrossRef] [PubMed]
  22. Hasegawa, K.; Takemura, N.; Yamashita, T.; Watadani, T.; Kaibori, M.; Kubo, S.; Shimada, M.; Nagano, H.; Hatano, E.; Aikata, H.; et al. Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2021 version (5th JSH-HCC Guidelines). Hepatol. Res. 2023, 53, 383–390. [Google Scholar] [CrossRef] [PubMed]
  23. Chung, S.M.; Yoon, C.J.; Lee, S.S.; Hong, S.; Chung, J.W.; Yang, S.W.; Seong, N.J.; Jang, E.S.; Kim, J.W.; Jeong, S.H. Treatment outcomes of transcatheter arterial chemoembolization for hepatocellular carcinoma that invades hepatic vein or inferior vena cava. Cardiovasc. Intervent. Radiol. 2014, 37, 1507–1515. [Google Scholar] [CrossRef]
  24. Bae, B.K.; Kim, J.C. The response of thrombosis in the portal vein or hepatic vein in hepatocellular carcinoma to radiation therapy. Radiat. Oncol. J. 2016, 34, 168–176. [Google Scholar] [CrossRef]
  25. Hou, J.Z.; Zeng, Z.C.; Zhang, J.Y.; Fan, J.; Zhou, J.; Zeng, M.S. Influence of tumor thrombus location on the outcome of external-beam radiation therapy in advanced hepatocellular carcinoma with macrovascular invasion. Int. J. Radiat. Oncol. Biol. Phys. 2012, 84, 362–368. [Google Scholar] [CrossRef]
  26. Murakami, E.; Aikata, H.; Miyaki, D.; Nagaoki, Y.; Katamura, Y.; Kawaoka, T.; Takaki, S.; Hiramatsu, A.; Waki, K.; Takahashi, S.; et al. Hepatic arterial infusion chemotherapy using 5-fluorouracil and systemic interferon-α for advanced hepatocellular carcinoma in combination with or without three-dimensional conformal radiotherapy to venous tumor thrombosis in hepatic vein or inferior vena cava. Hepatol. Res. 2012, 42, 442–453. [Google Scholar] [CrossRef]
  27. Toyoda, H.; Johnson, P.J. The ALBI score: From liver function in patients with HCC to a general measure of liver function. JHEP Rep. 2022, 4, 100557. [Google Scholar] [CrossRef]
  28. Demirtas, C.O.; D’Alessio, A.; Rimassa, L.; Sharma, R.; Pinato, D.J. ALBI grade: Evidence for an improved model for liver functional estimation in patients with hepatocellular carcinoma. JHEP Rep. 2021, 3, 100347. [Google Scholar] [CrossRef]
  29. Feng, D.; Wang, M.; Hu, J.; Li, S.; Zhao, S.; Li, H.; Liu, L. Prognostic value of the albumin-bilirubin grade in patients with hepatocellular carcinoma and other liver diseases. Ann. Transl. Med. 2020, 8, 553. [Google Scholar] [CrossRef]
  30. Marasco, G.; Alemanni, L.V.; Colecchia, A.; Festi, D.; Bazzoli, F.; Mazzella, G.; Montagnani, M.; Azzaroli, F. Prognostic Value of the Albumin-Bilirubin Grade for the Prediction of Post-Hepatectomy Liver Failure: A Systematic Review and Meta-Analysis. J. Clin. Med. 2021, 10, 2011. [Google Scholar] [CrossRef]
  31. Facciorusso, A.; Abd El Aziz, M.A.; Sacco, R. Efficacy of Regorafenib in Hepatocellular Carcinoma Patients: A Systematic Review and Meta-Analysis. Cancers 2019, 12, 36. [Google Scholar] [CrossRef]
Cancers 17 01794 g001
Figure 1. Study population. CTP, Child-Turcotte-Pugh; PS, performance status; HVI, hepatic vein invasion; HCC, hepatocellular carcinoma; ALBI, albumin-bilirubin.
Figure 1. Study population. CTP, Child-Turcotte-Pugh; PS, performance status; HVI, hepatic vein invasion; HCC, hepatocellular carcinoma; ALBI, albumin-bilirubin.
Cancers 17 01794 g001
Cancers 17 01794 g002
Figure 2. Survival curves for long-term outcomes in the curative group and the non-curative group. (a) OS; (b) CSS. Abbreviations: OS, overall survival; CSS, cancer-specific survival.
Figure 2. Survival curves for long-term outcomes in the curative group and the non-curative group. (a) OS; (b) CSS. Abbreviations: OS, overall survival; CSS, cancer-specific survival.
Cancers 17 01794 g002
Cancers 17 01794 g003aCancers 17 01794 g003b
Figure 3. Forest plot (Cox-multivariate) for (a) OS and (b) CSS. Abbreviations: ALBI, albumin-bilirubin grade; AFP, alpha-fetoprotein; OS, overall survival; CSS, cancer-specific survival.
Figure 3. Forest plot (Cox-multivariate) for (a) OS and (b) CSS. Abbreviations: ALBI, albumin-bilirubin grade; AFP, alpha-fetoprotein; OS, overall survival; CSS, cancer-specific survival.
Cancers 17 01794 g003aCancers 17 01794 g003b
Cancers 17 01794 g004aCancers 17 01794 g004b
Figure 4. Time-varying effects of risk factors on OS and CSS. (a) Time-varying effects of covariates on OS; (b) Time-varying effects of covariates on CSS. The figure shows the cumulative effects of selected covariates over time based on Aalen’s additive regression model. Solid lines represent the estimated cumulative effects, and shaded areas indicate the confidence intervals. Abbreviations: AFP, alpha-fetoprotein; ALBI, albumin-bilirubin grade; MELD, a model for end-stage liver disease; OS, overall survival; CSS, cancer-specific survival.
Figure 4. Time-varying effects of risk factors on OS and CSS. (a) Time-varying effects of covariates on OS; (b) Time-varying effects of covariates on CSS. The figure shows the cumulative effects of selected covariates over time based on Aalen’s additive regression model. Solid lines represent the estimated cumulative effects, and shaded areas indicate the confidence intervals. Abbreviations: AFP, alpha-fetoprotein; ALBI, albumin-bilirubin grade; MELD, a model for end-stage liver disease; OS, overall survival; CSS, cancer-specific survival.
Cancers 17 01794 g004aCancers 17 01794 g004b
Table 1. Baseline characteristics of curative and non-curative groups.
Table 1. Baseline characteristics of curative and non-curative groups.
Curative Group
(n = 42)		Non-Curative Group
(n = 103)		Total
(n = 145)		p-Value
  Age63 (54–66)60 (51–69)61 (52–68)0.827
  Sex (female)11 (26.2%)18 (17.5%)29 (20.0%)0.257
  BMI (kg/m2)23.8 (21.7–26.0)23.5 (20.9–25.5)23.7 (21.4–25.7)0.553
  Smoking24 (57.1%)51 (50.5%)75 (52.4%)0.468
  PST (grade 1)8 (26.7%)23 (28.7%)31 (28.2%)0.829
  Hypertension16 (38.1%)43 (41.7%)59 (40.7%)0.685
Diabetes mellitus9 (22.0%)27 (26.7%)36 (25.4%)0.553
Underlying liver disease (multiple)
   HBV28 (66.7%)64 (64.6%)92 (65.2%)0.818
   HCV4 (10.5%)18 (19.6%)22 (16.9%)0.211
   Alcoholic liver disease14 (33.3%)37 (35.9%)51 (35.2%)0.767
Underlying liver function
   Ascites ‡3 (7.1%)12 (11.7%)15 (10.3%)0.555
   Hepatic encephalopathy0 (0%)0 (0%)0 (0%)—
   MELD score †7 (7–9)8 (7–9)8 (7–9)0.200
   ALBI grade † 0.403
      1; ≤−2.6033 (78.6%)74 (71.8%)107 (73.8%)
      2; <−2.60 and ≤−1.399 (21.4%)29 (28.2%)38 (26.2%)
      3; >−1.39–––
Laboratory findings
   Albumin (g/dL)4.3 (3.9–4.5)4.1 (3.8–4.3)4.1 (3.8–4.4)0.035
    Total bilirubin (mg/dL)0.80 (0.50–1.11)0.74 (0.52–1.10)0.80 (0.52–1.10)0.867
   PT-INR1.04 (1.00–1.12)1.08 (1.01–1.13)1.07 (1.01–1.13)0.223
   Platelet (×103)177 (141–218)171 (124–222)173 (128–219)0.793
   Cr (mg/dL) †0.80 (0.71–0.95)0.87 (0.72–1.03)0.84 (0.72–1.00)0.171
Values are presented as median (IQR) for continuous data and n (%) for categorical data. † Mann–Whitney, ‡ Fisher’s exact. Abbreviations: BMI, body mass index; PST, performance status test; HBV, hepatitis B virus; HCV, hepatitis C virus; CTP, Child-Turcotte-Pugh; MELD, model for end-stage liver disease; ALBI, albumin-bilirubin; PT-INR, prothrombin time-international normalized ratio; Cr, creatinine.
Table 2. Characteristics of HCC between curative and non-curative groups.
Table 2. Characteristics of HCC between curative and non-curative groups.
Curative Group
(n = 42)		Non-Curative Group
(n = 103)		Total
(n = 145)		p-Value
Tumor number1 (1–1)1 (1–2)1 (1–1)0.672
Tumor size (cm, maxinum)5.1 (3.1–10.7)7.3 (4.9–10.0)6.8 (3.8–10.6)0.143
Portal vein invasion18 (42.9%)55 (53.4%)73 (50.3%)0.250
Hepatic artery invasion ‡1 (2.4%)1 (1.0%)2 91.4%)0.497
Bile duct invasion ‡0 (0%)5 (4.9%)5 (3.4%)0.322
AFP (ng/mL) †183.4 (15.6–2528.0)496.0 (31.8–6501.3)417.2 (29.0–4628.8)0.153
PIVKA-II (mAU/mL)290.0 (57.0–2324.0)1709.5 (180.5–10,215.5)861.0 (127.0–7289.0)0.651
Values are presented as median (IQR) for continuous data and n (%) for categorical data. † Mann–Whitney, ‡ Fisher’s exact. Abbreviations: HCC, hepatocellular carcinoma; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence or antagonist-II.
Table 3. Univariate and multivariate analysis for overall and cancer-specific survival in the matched cohort.
Table 3. Univariate and multivariate analysis for overall and cancer-specific survival in the matched cohort.
Overall SurvivalCancer-Specific Survival
Univariate AnalysisMultivariate AnalysisUnivariate AnalysisMultivariate Analysis
HR
(95% CI)		p-ValueHR
(95% CI)		p-ValueHR
(95% CI)		p-ValueHR
(95% CI)		p-Value
Non-curative treatment2.19 (1.39–3.44)0.0012.43 (1.50–3.92)<0.0012.36 (1.47–3.81)<0.0012.45 (1.49–4.01)<0.001
Age (≥65 years)0.99 (0.68–1.46)0.977 0.89 (0.60–1.33)0.574
Sex (male)1.69 (1.03–2.77)0.0391.91 (1.10–3.33)0.0221.68 (1.01–2.80)0.0452.04 (1.17–3.58)0.012
BMI (<18.5 kg/m2)1.94 (0.78–4.77)0.152 1.91 (0.77–4.71)0.161
Smoking1.07 (0.73–1.56)0.732 1.09 (0.74–1.61)0.648
PST (≥1)1.13 (0.71–1.82)0.603 1.17 (0.73–1.88)0.523
HBV0.84 (0.57–1.24)0.385 1.00 (0.67–1.50)0.999
HCV1.21 (0.71–2.07)0.483 1.27 (0.74–2.18)0.383
Alcoholic liver disease0.92 (0.62–1.37)0.678 0.90 (0.60–1.36)0.625
Ascites (positive)1.25 (0.68–2.27)0.473 1.33 (0.73–2.42)0.359
ALBI grade (≥2)1.92 (1.28–2.88)0.0022.00 (1.31–3.14)0.0011.91 (1.26–2.89)0.0022.07 (1.33–3.22)<0.001
MELD score (≥10)1.48 (0.93–2.36)0.095 1.33 (0.82–2.18)0.252
Multiple tumors (≥2)0.97 (0.62–1.50)0.880 1.03 (0.66–1.61)0.892
Tumor size (≥5 cm)1.88 (1.23–2.90)0.0041.39 (0.87–2.23)0.1681.91 (1.22–2.96)0.0041.46 (0.90–2.36)0.124
Portal vein invasion1.21 (0.83–1.75)0.327 1.30 (0.88–1.91)0.183
Hepatic artery invasion0.60 (0.08–4.28)0.607 0.66 (0.09–4.71)0.675
Bile duct invasion1.05 (0.39–2.85)0.929 1.08 (0.40–2.94)0.880
AFP (≥400 ng/mL)1.35 (0.91–2.00)0.1311.70 (1.13–2.56)0.0111.44 (0.97–2.16)0.0731.70 (1.12–2.59)0.013
PIVKA-II (≥500 mAU/mL)1.35 (0.85–2.13)0.199 1.43 (0.89–2.28)0.136
Abbreviations: BMI, body mass index; PST, performance status test; HBV, hepatitis B virus; HCV, hepatitis C virus; ALBI, albumin-bilirubin; MELD, model for end-stage liver disease; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence or antagonist-II; HR, hazard ratio, CI, confidence interval.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Yu, S.; Jo, H.-S.; Yu, Y.-D.; Choi, Y.-J.; Jeon, S.-M.; Kim, D.-S. Clinical Comparison Between Curative and Non-Curative Treatment for Hepatocellular Carcinoma with Hepatic Vein Invasion: A Nationwide Cohort Study. Cancers 2025, 17, 1794. https://doi.org/10.3390/cancers17111794

AMA Style

Yu S, Jo H-S, Yu Y-D, Choi Y-J, Jeon S-M, Kim D-S. Clinical Comparison Between Curative and Non-Curative Treatment for Hepatocellular Carcinoma with Hepatic Vein Invasion: A Nationwide Cohort Study. Cancers. 2025; 17(11):1794. https://doi.org/10.3390/cancers17111794

Chicago/Turabian Style

Yu, Sehyeon, Hye-Sung Jo, Young-Dong Yu, Yoo-Jin Choi, Su-Min Jeon, and Dong-Sik Kim. 2025. "Clinical Comparison Between Curative and Non-Curative Treatment for Hepatocellular Carcinoma with Hepatic Vein Invasion: A Nationwide Cohort Study" Cancers 17, no. 11: 1794. https://doi.org/10.3390/cancers17111794

APA Style

Yu, S., Jo, H.-S., Yu, Y.-D., Choi, Y.-J., Jeon, S.-M., & Kim, D.-S. (2025). Clinical Comparison Between Curative and Non-Curative Treatment for Hepatocellular Carcinoma with Hepatic Vein Invasion: A Nationwide Cohort Study. Cancers, 17(11), 1794. https://doi.org/10.3390/cancers17111794

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop