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Hypohepatia limits the feasibility of therapeutic options for hepatocellular carcinoma (HCC), negatively affecting patient prognosis. Established guidelines for the treatment strategies of HCC patients with hypohepatia are lacking. This study was performed to evaluate therapeutic benefits between liver resection (LR) and interventional treatments using ablation or transarterial chemoembolization (TACE) in such population.
Methods
Survival analyses were performed using the Kaplan–Meier method and log-rank test. The Cox proportional hazards regression models were used to analyze potential risk factors associated with prognosis. Multivariate regression and propensity score regression adjustment analyses were applied to adjust for baseline confounding variables. Restricted cubic spline curves were used to assess the association between prognostic index and risk of death or progression on a continuous scale.
Results
Of the enrolled 5774 HCC patients with hypohepatia, 506 (8.8%), 2326 (40.3%) and 2942 (51.0%) underwent ablation, LR and TACE, respectively. A tentative analysis of the overall cohort demonstrated that a high degree of heterogeneity existed in this population, while LR rendered a possible tendency to survival benefit over ablation and TACE through adjustment for baseline confounding variables. After categorizing the patients according to the indication of ablation treatment, the indisputable superiority of LR over ablation and TACE in terms of OS and DFS before and after adjustments were evident and the survival advantages of LR were consistent across all pre-specified subgroups. Individualized treatment decision analyses based on restricted cubic spline curves demonstrated that LR group presented the lowest risk of death and disease progression.
Conclusions
HCC patients with hypohepatia could obtain survival benefits through surgical and non-surgical treatment approaches. LR appears to confer a significant survival benefit compared with interventional treatments using ablation or TACE, even for selected intermediate and advanced populations.
Shoujie Zhao, Yejing Zhu and Jinming Zhu have contributed equally to this work.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Hepatocellular carcinoma (HCC) represents the most common primary liver tumor which ranks as the third leading cause of cancer-related death worldwide [1, 2]. HCC is generally deem to be highly aggressive and heterogeneous which developed from a background of hepatocellular damage, inflammatory infiltrate, fibrosis and cirrhosis originated from various etiopathogenesis [3‐5]. During insidious and asymptomatic disease progression, repressed hepatocyte regeneration and increased hepatocyte death lead to hypohepatia, which increase the complexity of treatment selection and reduce the opportunity to receive additional treatments, negatively affecting the survival outcomes of HCC patients [6‐8].
Liver transplantation is the optimal and definitive treatment for HCC patients, as it eliminates malignancy while restoring normal liver function [9, 10]. However, the limited availability of donor organs, immunological side effects, and economic reasons constrains its widespread application. Ablation, liver resection (LR) and transarterial chemoembolization (TACE) represents effective treatment modalities in HCC patients with preserved liver function and selected tumor characteristics, identifying as the optimal candidates according to the current Barcelona Clinic Liver Cancer (BCLC) strategy [2]. However, no clear recommendations are provided for HCC patients with hypohepatia, as this population presents with an intermediate, partially compromised situation between well-preserved and terminal liver function. With recent improvements in minimally invasive surgical and interventional treatment concepts and techniques, ablation, LR and TACE has been reported as alternative treatment approaches rather than an absolute contraindication for HCC patients with hypohepatia [11‐14]. However, most previous studies concentrated on this issue either enrolled limited number of patients in a single center or established non-standard control group, which resulted in inherent selection and information biases [11‐14]. The clinical treatment of HCC patients with hypohepatia is still controversial, while a further investigation of effective treatment approaches is essential for personalizing care of HCC patients with hypohepatia.
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This large multicenter exploratory study aimed to investigate prognostic factors and evaluate the short- and long-term survival outcomes of HCC patients with hypohepatia who underwent LR versus interventional treatments using ablation or TACE.
Materials and methods
Patients’ eligibility
Study data were extracted from a nationwide database of consecutive HCC patients treated at sixteen Chinese tertiary hospitals between January 2013 and December 2023. We included patients who were diagnosed with HCC according to the American Association for the Study of the Liver Disease/European Association for the Study of the Liver Guidelines and received ablation, LR or TACE [2, 15]. After applying the exclusion criteria, 5774 patients (ablation group, n = 506; LR group, n = 2326; TACE group, n = 2942) were included in the current study cohort. A detailed flowchart showing the inclusion and exclusion criteria for the study participants was presented in Fig. 1. In addition, this work has been reported in line with the STROCSS criteria.
Fig. 1
Flowchart of the patient selection process. ALBI albumin-bilirubin, ECOG-PS Eastern Cooperative Oncology Group performance status, EHS extrahepatic spread, HCC hepatocellular carcinoma, LR liver resection, PVTT portal vein tumor thrombosis, TACE transarterial chemoembolization
Treatment and assessment methods for the enrolled patients
The therapeutic regimens for all patients were determined based on the results of a stringent preoperative evaluation implemented by a multidisciplinary treatment group to ensure safety and potential survival benefit. The Child–Pugh (CP) classification has been proposed and widely adopted for liver function assessment. However, subjective components and dichotomous variables compromise its accuracy. The most recent version of the Barcelona Clinic Liver Cancer (BCLC) noted that liver function should be evaluated beyond conventional CP staging [2]. The albumin-bilirubin (ALBI) grade has been established as a more objective prognostic factor for HCC patients than the Child–Pugh classification, which would be more conducive to discovering patients with potentially hypohepatia in clinical practice [16‐18]. Therefore, the ALBI grade was used and subsequently stratified into three categories (ALBI grade 1–3). The ALBI grade 2 category represents a middle stage, which were defined as hypohepatia in the present study. Considering the wide range of ALBI grade 2, we adopted the modified ALBI grade (mALBI grade) by dividing ALBI grade 2 into subgrades (2a and 2b) [19]. Specifically, the newly discovered and statistics-based cut-off points were: more than − 2.60 to ≤ − 2.29 (mALBI grade 2a) and more than − 2.29 to ≤ − 1.39 (mALBI grade 2b). Furthermore, portal vein tumor thrombus (PVTT) was graded according to the Cheng’s classification of the extent of PVTT in the portal vein [20].
Statistical analysis
Categorical variables are described in terms of frequencies and percentages, while continuous data are represented as either mean with standard deviation (SD) or median with interquartile range (IQR) depending on the analysis results regarding normal distribution and homogeneity of variances. Differences in baseline characteristics among enrolled patients underwent different treatments were compared using the χ2 test or Fisher exact test for categorical variables, while continuous variables were compared using the two-sample t-test, Mann–Whitney U test, or Kruskal–wallis H test. Overall survival (OS) was defined as the time from the initiation of ablation, LR or TACE to the date of death from any cause or the last follow-up. Disease-free survival (DFS) was defined as the time from the initiation of ablation, LR or TACE to the date of local or metastatic recurrence, the last follow-up, or death from any cause, whichever occurred first. Kaplan–Meier curves were generated and compared using the log-rank test. The Cox proportional hazards regression models was employed to identify independent prognostic factors and adjust other confounding variables correlated with observation endpoints, while treatment modalities (ablation, LR and TACE) served as stratifying covariates. Considering the impact of baseline characteristics on treatment assignments and outcomes, propensity scores (PS) were calculated using logistic regression incorporating a set of covariates that exhibited significant imbalance across different treatment groups, and then adjusted survival curves were estimated using the multivariable regression model while the estimated PS was used as a covariate to mitigate the impact of sample size reduction on the statistical results. Patient stratification analyses based on various baseline backgrounds were conducted to further minimize the potential influence of confounding variables and validate the effectiveness across different characteristics of the population. Restricted cubic spline curve was used to assess the association between prognostic index and risk of death or progression on a continuous scale. Statistical significance was established at P < 0.05. Statistical analyses were carried out using R version 4.0.1 (R Foundation for Statistical Computing, Vienna, Austria) and IBM SPSS software (version 26.0; SPSS Inc., Chicago, IL, USA).
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Results
Baseline characteristics
During the median follow-up period of 48.2 months (95% confidence interval, CI: 47.1–49.4 months), the median OS time was 42.4 months (95%CI 38.9–45.9 months) and the median DFS time was 19.7 months (95%CI 18.5–20.9 months). The predominant patients had hepatitis B virus (HBV) infection (90.2%). There was no statistically significant differences in etiology, gender, serum alpha-fetoprotein (AFP) level and serum creatinine (Cr) level among the three treatment groups. However, a higher percentage of enrolled HCC patients had worse liver function and greater tumor burden in the TACE group compared to those in the ablation and LR groups. The distribution of other baseline characteristics across the three groups is illustrated in Table 1.
Exploratory survival analyses among the whole cohort
Preliminary findings indicated the LR group did not experience a better OS benefit when compared to the ablation group (P = 0.095) but showed a OS advantage over TACE group (P < 0.001) (Fig. 2a). It is important to note that during the first half of the follow-up period (pre—48 months), the ablation group even showed a higher survival rate. Next, univariate and multivariate Cox regression analyses were conducted to identify independent risk factors associated with prognosis. According to the univariate Cox regression analyses for OS, treatment method, ALBI grade, Eastern Cooperative Oncology Group performance status (ECOG-PS), hemoglobin (HGB) concentration, blood urea nitrogen (BUN), aspartate aminotransferase (AST), serum AFP level, presence of portal vein tumor thrombus (PVTT), tumor size, tumor number and gender were factors influencing the survival of HCC patients with hypohepatia (P < 0.05) (Table 2).Subsequently, the multivariate Cox regression analysis revealed that tumor size (hazard ratio [HR]: 1.074, 95% CI, 1.065–1.083, P < 0.001), tumor number (2–3 nodules vs 1 nodule: HR, 1.312; 95% CI, 1.200–1.435; P < 0.001; more than 3 nodules vs 1 nodule: HR, 1.594; 95% CI, 1.448–1.756; P < 0.001), presence of PVTT (HR: 1.590, 95% CI, 1.449–1.744, P < 0.001), serum AFP level (HR: 1.341, 95% CI, 1.243–1.447, P < 0.001), ECOG-PS (HR: 1.343, 95% CI, 1.240–1.454, P < 0.001) and ALBI grade (HR: 1.399, 95% CI, 1.267–1.545, P < 0.001) were independently associated with OS. (Table 2). In consideration of the potential impact of underlying liver disease on survival prognosis, interactions between etiology and treatment methods on the risk of death were further assessed. However, no statistically significant multiplicative interaction of etiology and treatment methods on OS was found (OS: P for multiplicative interaction = 0.794, interaction hazard risk = 1.039 (95% CI: 0.781–1.382)). Furthermore, results from the additive interaction analysis also showed that there is no evidence for interaction of etiology and treatment method on the additive scale for OS (The 95%CI of RERI and AP include 0 while the 95%CI of S include 1) (Supplementary Table 1). Additionally, the multivariate Cox regression analysis showed that LR conferred a survival benefit over interventional treatments (Ablation vs LR: HR, 1.343; 95% CI, 1.111–1.623; P = 0.002; TACE vs LR: HR, 2.788; 95% CI, 2.515–3.090; P < 0.001) (Table 2 and Fig. 2b). Additionally, by constructing adjusted estimated survival curves using covariates of PS in Cox regression model, ablation exhibited the highest survival benefit compared to both LR and TACE (Ablation vs LR: HR, 0.727; 95% CI, 0.603–0.887; P = 0.001; TACE vs LR: HR, 2.915; 95% CI, 2.623–3.239; P < 0.001) (Fig. 2c).
Fig. 2
Probability of OS and DFS in the ablation group, LR group and TACE group in the entire cohort using Kaplan–Meier method, multivariate Cox regression model and PS-based multivariate adjustment method. a–c Comparison of OS according to treatment modalities. d–f Comparison of DFS according to treatment modalities. CI confidence interval, DFS disease-free survival, HR hazard ratio, LR liver resection, OS overall survival, PS propensity score, TACE transarterial chemoembolization
Univariate and multivariate analyses for OS and DFS in the entire cohort
Baseline characteristics
OS
DFS
Univariate analyses
Multivariate analyses
Univariate analyses
Multivariate analyses
HR (95% CI)
P value
HR (95% CI)
P value
HR (95% CI)
P value
HR (95% CI)
P value
Gender (Ref: Female)
1.133 (1.017–1.262)
0.023
1.050 (0.941–1.171)
0.384
1.129 (1.028–1.240)
0.012
1.062 (0.966–1.168)
0.211
Age, per year increase
1.003 (1.000–1.006)
0.055
0.997 (0.994–1.000)
0.049
0.998 (0.995–1.001)
0.131
Etiology (Ref: HBV)
1.028 (0.910–1.162)
0.654
1.069 (0.960–1.191)
0.222
Tumor size, per 1 cm increase
1.094 (1.089–1.099)
< 0.001
1.074 (1.065–1.083)
< 0.001
1.077 (1.072–1.082)
< 0.001
1.061 (1.054–1.069)
< 0.001
Tumor number (Ref: 1 nodule)
< 0.001
< 0.001
< 0.001
< 0.001
2–3 nodules
1.795 (1.645–1.958)
< 0.001
1.312 (1.200–1.435)
< 0.001
1.324 (1.226–1.429)
< 0.001
1.131 (1.045–1.225)
0.002
> 3 nodules
2.858 (2.604–3.136)
< 0.001
1.594 (1.448–1.756)
< 0.001
1.711 (1.571–1.864)
< 0.001
1.259 (1.150–1.379)
< 0.001
PVTT (Ref: Negative)
2.781 (2.558–3.024)
< 0.001
1.590 (1.449–1.744)
< 0.001
2.286 (2.116–2.471)
< 0.001
1.455 (1.335–1.586)
< 0.001
AFP (Ref: ≥ 400 ng/mL)
1.794 (1.668–1.930)
< 0.001
1.341 (1.243–1.447)
< 0.001
1.495 (1.402–1.594)
< 0.001
1.222 (1.142–1.307)
< 0.001
PLT, per 1 × 109/L increase
1.000 (1.000–1.001)
0.230
1.000 (1.000–1.001)
0.157
AST, per 1U/L increase
0.999 (0.999–1.000)
0.024
1.000 (0.999–1.000)
0.661
0.999 (0.999–1.000)
0.010
1.000 (0.999–1.000)
0.191
Cr, per 1 µmol/l increase
1.000 (1.000–1.001)
0.222
0.999 (0.999–1.000)
0.078
BUN, per 1 mmol/l increase
1.021 (1.008–1.034)
0.001
0.991 (0.976–1.006)
0.218
0.992 (0.979–1.005)
0.239
HGB, per 1 µmol/l increase
0.994 (0.993–0.995)
< 0.001
1.000 (0.999–1.000)
0.341
0.997 (0.997–0.998)
< 0.001
1.000 (1.000–1.001)
0.358
ECOG-PS (Ref: 0 score)
2.118 (1.967–2.281)
< 0.001
1.343 (1.240–1.454)
< 0.001
1.740 (1.629–1.859)
< 0.001
1.302 (1.213–1.398)
< 0.001
ALBI score, per 1 score increase
2.595 (2.410–2.794)
< 0.001
1.399 (1.267–1.545)
< 0.001
1.641 (1.534–1.756)
< 0.001
1.154 (1.060–1.255)
0.001
Treatment method (Ref: LR)
< 0.001
< 0.001
< 0.001
< 0.001
Ablation
0.850 (0.707–1.023)
0.086
1.343 (1.111–1.623)
0.002
1.244 (1.100–1.407)
< 0.001
1.746 (1.538–1.983)
< 0.001
TACE
4.325 (3.962–4.722)
< 0.001
2.788 (2.515–3.090)
< 0.001
2.116 (1.972–2.271)
< 0.001
1.556 (1.438–1.696)
< 0.001
AFP alpha-fetoprotein, ALBI albumin-bilirubin, AST aspartate aminotransferase, BUN blood urea nitrogen, CI confidence interval, Cr creatinine, ECOG-PS Eastern Cooperative Oncology Group performance status, HGB hemoglobin, HBV hepatitis B virus, HR hazard ratio, LR liver resection, PLT platelets, PVTT portal vein tumor thrombus, Ref: reference, TACE transarterial chemoembolization
Given a high possibility of the patients experiencing tumor relapse after the initial treatment and necessitating subsequent treatment regimens, which significantly impacts OS and greatly increases the risk of result bias, DFS was utilized as an additional primary endpoint. Prior to adjusting for potential confounding factors, Kaplan–Meier survival analysis demonstrated that the LR group rendered a survival advantage over the ablation group (Fig. 2d), while the survival curves of the two groups showed a largely overlap incipiently and presented a tendency to diverge during the second half of follow-up (12 months post). Univariate and multivariate Cox regression analyses for DFS were also performed. The univariate Cox regression analyses indicated that gender, age, treatment method, ALBI grade, ECOG-PS, HGB concentration, serum AST level, serum AFP level, presence of PVTT, tumor size and tumor number were significant factors influencing the survival of HCC patients with hypohepatia (P < 0.05) (Table 2). The multivariate Cox regression analysis revealed that tumor size (HR: 1.061, 95% CI, 1.054–1.069, P < 0.001), tumor number (2–3 nodules vs 1 nodule: HR, 1.131; 95% CI, 1.045–1.225; P = 0.002; more than 3 nodules vs 1 nodule: HR, 1.259; 95% CI, 1.150–1.379; P < 0.001), presence of PVTT (HR: 1.455, 95% CI, 1.335–1.586, P < 0.001), serum AFP level (HR: 1.222, 95% CI, 1.142–1.307, P < 0.001), ECOG-PS (HR: 1.302, 95% CI, 1.213–1.398, P < 0.001) and ALBI grade (HR: 1.154, 95% CI, 1.060–1.255, P = 0.001) were independently associated with OS (Table 2). Similarly, the above univariate analysis did not reveal that etiology has an impact on survival. Multiplicative and additive interactions between etiology and treatment methods on the risk of progression were evaluated. The results indicate that no statistically significant multiplicative and additive interaction of etiology and treatment methods on OS and DFS was found (P for multiplicative interaction = 0.346, interaction hazard risk = 0.895 (95% CI: 0.710, 1.128); The 95%CI of RERI and AP include 0 while the 95%CI of S include 1) (Supplementary Table 1). Additionally, the multivariate Cox regression analysis showed that LR provided a statistically significant benefit in DFS over interventional treatments (Ablation vs LR: HR, 1.746; 95% CI, 1.538–1.983; P < 0.001; TACE vs LR: HR, 1.556; 95% CI, 1.438–1.696; P < 0.001) (Table 2 and Fig. 2e). After background correction using PS, LR significantly prolonged DFS compared to ablation and TACE (Ablation vs LR: HR, 1.161; 95% CI, 1.025–1.315; P = 0.019; TACE vs LR: HR, 1.784; 95% CI, 1.635–1.948; P < 0.001) (Fig. 2f). Meanwhile, major changes have take place in terms of the hazard ratios (HRs) among the three treatment groups especially the HRs of ablation. The detailed baseline characteristics used for calculating the propensity score and adjusting during multivariate Cox regression analysis in the whole cohort are listed in Supplementary Tables 2 and 3.
The above results revealed that HCC patients with hypohepatia exhibit considerable heterogeneity, while tumor-related baseline characteristics and treatment modalities significantly influence prognosis. LR might provide more survival benefits than interventional treatments and careful candidate selection and suitable treatment allocation for this population are essential.
In-depth survival analyses in accordance with tumor burden
Clinical practice guidelines and previous studies proposed that ablation should be considered as the first-line treatment strategy for selected HCC patients when tumor number is fewer than three and tumor size is less than three cm even extending to five cm. Consequently, the included patients were categorized into two predominant subsets in this study: within ablation criteria (no more than three tumors and tumor size not exceed five cm) and without ablation criteria (more than three tumors and/or tumor size more than five cm).
For the subset composed of patients meeting the criteria for ablation, statistically significant differences were noted between ablation and LR (P < 0.001) and between TACE and LR (P < 0.001), as illustrated in Fig. 3a. Multivariable Cox survival analysis showed LR was independently associated with a reduced risk of death compared to ablation and TACE, while ablation exhibited a HR of 1.887 (95% CI, 1.492–2.386; P < 0.001), and TACE demonstrated a HR of 3.065 (95% CI, 2.453–3.829; P < 0.001) (Fig. 3b). After adjusting for potential selection biases using PS, LR still exhibited the highest survival benefit compared to both ablation and TACE (P < 0.001, Fig. 3c). The Kaplan–Meier DFS rates at 1, 3, and 5 years were as follows: LR (84.3%, 64.1%, and 52.3%), ablation (72.1%, 42.9%, 31.3%), and TACE (76.0%, 42.1%, 27.3%) (Ablation vs. LR, P < 0.001; TACE vs. LR, P < 0.001, Fig. 3d). After adjustment for potential covariates using a multivariable Cox model, patients treated with LR exhibited significantly higher DFS compared to those receiving ablation and TACE (HR, 2.049; 95% CI, 1.759–2.386; P < 0.001) and TACE (HR, 1.567; 95% CI, 1.323–1.855; P < 0.001) (Fig. 3e). Furthermore, after adjustment for potential covariates using a PS-adjusted Cox model, patients treated with LR exhibited significantly higher DFS compared to those receiving ablation (HR, 1.849; 95% CI, 1.595–2.145; P < 0.001) and TACE (HR, 1.787; 95% CI, 1.509–2.115; P < 0.001), the Kaplan–Meier survival curves are illustrated in Fig. 3f. In terms of short-term endpoint incident rates, the 1-year mortality rate was significantly higher in the TACE group (13.9%) compared to the LR group (4.3%) and the ablation group (6.7%). Additionally, the 6-month recurrence rate in the LR group (9.1%) was slightly lower than that in the ablation group (11.9%) and significantly lower than that in the TACE group (17.4%) (Fig. S1a). The baseline characteristics of HCC patients with hypohepatia relevant to mortality or recurrence were explored. Patients with different etiology presented similar 1-year mortality rate and 6-month recurrence rate (Fig. S1b). Patients with ECOG-PS greater than 0, liver function ALBI grade worsen than 1, and serum AFP level exceeding 400 ng/mL demonstrated an increased risk of death at 1 year and a heightened risk of recurrence at 6 months (Fig. S1c). Subgroup analyses were conducted based on indicators of liver function, tumor burden, tumor markers, and physical condition. Consistent findings were observed in the analyses of OS and DFS across different subsets (all HR > 1.0, Fig. S2). The detailed adjustment covariates in different statistical models were listed in Supplementary Tables 2 and 3.
Fig. 3
Probability of OS and DFS in the ablation group, LR group and TACE group in the HCC patients with hypohepatia within ablation criteria using Kaplan–Meier method, multivariate Cox regression model and PS-based multivariate adjustment method. a–c Comparison of OS according to treatment modalities. d–f Comparison of DFS according to treatment modalities. CI confidence interval, DFS disease-free survival, HR hazard ratio, LR liver resection, OS overall survival, PS propensity score, TACE transarterial chemoembolization
For patients beyond ablation criteria, during the median follow-up period of 47.3 months (95%CI: 45.6–49.0 months), 525 (42.3%) and 784 (63.2%) patients experienced death and disease progression in the LR group, respectively, while 1762 (74.2%) and 1873 (78.9%) patients died and exhibited disease progression in the TACE group, respectively. According to the Kaplan–Meier analyses, the median OS of patients treated with LR was 81.4 months compared to 13.1 months for those treated with TACE (P < 0.001, Fig. 4a). Within the LR group, the OS rates were 81.2% at 1 year, 63.2% at 3 years, and 54.0% at 5 years. For the TACE group, the OS rates was 52.9% at 1 year, 22.9% at 3 years, and 14.0% at 5 years. Multivariate Cox regression analysis demonstrated that the OS of patients who underwent LR was significantly longer than that of patients treated with TACE (HR 2.556, 95%CI, 2.278–2.869; P < 0.001; Fig. 4b). Similarly, the PS-adjusted survival curves were also estimated to compare OS between treatment groups (HR 2.246, 95%CI, 1.992–2.531, P < 0.001, Fig. 4c). According to the Kaplan–Meier analyses, the median DFS of patients treated with LR was 20.8 months, compared to 10.4 months for those treated with TACE (P < 0.001, Fig. 4d). Adjusted survival curves based on multivariate Cox regression and PS-adjusted analysis revealed that TACE remained less effective than LR in terms of DFS benefit (HR 1.533, 95%CI, 1.385–1.697, P < 0.001, Fig. 4e; HR 1.474, 95%CI, 1.327–1.637, P < 0.001, Fig. 4f). Regarding the short-term endpoint incident rates, the 1-year mortality rate was significantly higher in the TACE group (46.1%) compared to the LR group (18.6%), while the 6-month disease progression rate in the LR group (27.0%) was significantly lower than that in the TACE group (34.2%) (Fig. S3a). HBV patients presented a higher incidence of predefined endpoints, especially for 6-month recurrence rate, compared to non-HBV patients (Fig. S3b). Additionally, patients with ECOG-PS greater than 0, liver function ALBI grade worsen than 1, serum AFP level exceeding 400 ng/mL and presence of PVTT exhibited a higher risk of death at 1 year and disease progression at 6 months (Fig. S3c). Consistent results were observed in the survival analyses for OS and DFS across different subsets, including patients with selected intermediate or advanced stages (all HR > 1.0, Fig. S4). The detailed adjustment covariates in different statistical models were listed in Supplementary Tables 2 and 3.
Fig. 4
Probability of OS and DFS in the ablation, LR and TACE groups in the HCC patients with hypohepatia beyond ablation criteria using Kaplan–Meier method, multivariate Cox regression model and PS-based multivariate adjustment method. a–c Comparison of OS according to treatment modalities. d–f Comparison of DFS according to treatment modalities. CI confidence interval, DFS disease-free survival, HR hazard ratio, LR liver resection, OS overall survival, PS propensity score, TACE transarterial chemoembolization
Individualized treatment decision analyses for HCC patients with hypohepatia
Although the above analyses demonstrated prognostic effects of the proposed three treatment methods (ablation, LR and TACE), personalized treatment and decision-making is indispensable due to the exist of significant heterogeneity among HCC patients with hypohepatia, which could offers potential prognostic benefits for clinical management. To conduct further in-depth research on the interrelationships among these therapies and the influence of the characteristics of the disease on the survival prognosis, the restricted cubic spline (RCS) curve was used to assess the association between prognostic index (PI) and risk of death or disease progression on a continuous scale divided by treatment methods based on the Cox proportional hazard models for OS and DFS (Table 2). Specifically, the PI for OS is given by the following formula = (0.295 × ECOG-PS (ECOG-PS 0 = 0; ECOG-PS 1 = 1)) + (0 × Tumor number (if single nodule), 0.272 × Tumor number (if 2–3 nodules) or 0.466 × Tumor number (if more than three nodules)) + (0.071 × Tumor size in cm) + (0.464 × PVTT (Positive of PVTT = 0; Negative of PVTT = 1) + (0.293 × AFP (the serum concentration of AFP < 400 ng/mL = 0; the serum concentration of AFP ≥ 400 ng/mL = 1) + (0.366 × ALBI score). The PI for DFS is given by the following formula = (0.264 × ECOG-PS (ECOG-PS 0 = 0; ECOG-PS 1 = 1)) + (0 × Tumor number (if single nodule), 0.123 × Tumor number (if 2–3 nodules) or 0.231 × Tumor number (if more than three nodules)) + (0.059 × Tumor size in cm) + (0.375 × PVTT (Positive of PVTT = 0; Negative of PVTT = 1) + (0.200 × AFP (the serum concentration of AFP < 400 ng/mL = 0; the serum concentration of AFP ≥ 400 ng/mL = 1) + (0.143 × ALBI score). Based on the prognostic indexes, risk of death or disease progression plotted divided by treatment modalities were constructed (Fig. 5). The PIs and HRs of death and progression exhibited nonlinear relationships (P for nonlinear < 0.001). Importantly, the HRs of death and progression increased in all patients regardless of treatment received as the PIs for OS and DFS rose, while LR group presented the lowest risk of death and disease progression compared to ablation and TACE.
Fig. 5
Risk of death or disease progression plotted of prognostic index according to the different treatment modalities. a Comparison of risk of death according to treatment modalities. b Comparison of risk of disease progression according to treatment modalities. CI confidence interval, DFS disease-free survival, HR hazard ratio, LR liver resection, OS overall survival, PS propensity score, TACE transarterial chemoembolization
In view of disease-specific progression, the presence of hypohepatia is considered as a vital clinical feature of HCC patients and induces poor survival outcomes [11]. A high prevalence of hypohepatia in HCC patients exists, as it represents 23% of all HCC cases recorded in the BRIDGE global cohort [21]. However, HCC patients with hypohepatia are often excluded from research studies and clinical trials, which lead to no clear evidence-based recommendations for this population at present [2, 11]. Based on this controversial topic, this multicenter clinical study explored the survival benefits of LR compared to interventional treatments using ablation or TACE were evaluated in HCC patients with hypohepatia, which demonstrated that the indisputable superiority of LR over ablation and TACE regarding OS and DFS, even among selected patients classified as intermediate or advanced stage. The individualized treatment decision analyses based on restricted cubic spline curves demonstrated that LR group presented the lowest risk of death and disease progression, irrespective of the high-risk or low-risk classification of the patients.
The borderline category represents a middle stage, gathering very different degrees of hepatic impairment that can fall into various tumor stages [2]. Liver transplantation is the only treatment strategy to cure both tumor and underlying liver cirrhosis [9]. However, strict inclusion criteria and limited resources restrict the option of transplantation to a minority of patients [10]. Recently, strong evidence have been provided that hypohepatia is a negative risk factor for survival of HCC patients treated with hepatectomy [12‐14]. However, a negative prognostic factor should not be simply regarded as an absolute contraindication and should be challenged with the perspectives that different individual patients receive other possible treatment options. It was worth noting that the current BCLC algorithm underscores the indicative function of “stage hierarchy”, indicating that the HCC stage dictates treatment choice [2]. In this context, LR was discouraged for patients with multinodular HCC presenting with 2 or 3 nodules that each measures 3 cm or smaller, while TACE was recognized as a proven treatment option for intermediate HCC. Moreover, HCC patients with ECOG-PS of 1 and PVTT are considered as advanced diseases, for whom system therapies should be employed. Although a systematic review and meta-analysis showed that immunotherapies in advanced HCC patients with hypohepatia appears to be safe and associated with a significant number of radiologic response, the survival benefit remains limited, with a median OS and DFS time less than 12.0 and 6.0 months, respectively [22]. Notably, several previous studies have reappraised these notions and provided substantial evidence that HCC patients with not only hypohepatia but also beyond early tumor stage could undergo LR with acceptable mortality and liver decompensation rates [11‐14, 23, 24]. Unfortunately, exploratory analyses comparing resection with other treatments in this population were scarce, and the tiny sample size remarkably reduced the statistical power of the few subsistent studies, while external validation is required.
Based on the analyses of OS and DFS for the entire population, significant changes have occurred in survival benefits among diverse treatment modalities which implied the existence of huge heterogeneity and the vital impact of baseline information. To better align with the clinical practice, the overall population was divided into two primary cohorts based on patients’ tumor burden in the current study [25, 26]. The clear superiority of LR over non-surgical therapies for this population in terms of short- and long-term OS and DFS, while the survival benefits persists across each subgroup, even for selected intermediate and advanced populations. The analyses of treatment decisions tailored to individual patients, utilizing restricted cubic spline curves, revealed that the LR group exhibited the least risk of mortality and disease progression, regardless of whether the patients were classified as high-risk or low-risk. Additionally, in view of the prognosis of HCC is also significantly associated with underlying liver diseases, we have discovered that HBV patients presented a higher incidence of predefined endpoints, especially for 6-month recurrence rate, compared to non-HBV patients in patients with higher tumor burden. The above results suggested to us that special attention must be given to patients’ liver function during various therapies to patients with higher tumor burden in order to achieve favorable survival prognosis. These results are robustly supported by a sufficiently large sample size and the application of multiple baseline covariates adjustment techniques, which reduced confounding factors while maintaining the population size in the comparison of treatment groups, indicating internal validity. Current treatment indications elucidate the harm of LR and routinely excluded LR for the treatment of HCC patients with hypohepatia from early to late stage, while the results of this study would suggest the potential risk of incurring under treatment if the BCLC indications are strictly adhered [2]. In general, the current study validated the concept of treatment stage migration and treatment hierarchy, which means that treatment is an ordinal variable statistically independent from HCC stages [27]. Given these observations and acknowledging therapeutic algorithms typically do not incorporate factors that significantly influence therapeutic decisions in real-world scenarios, such as patient frailty, comorbidities and critical tumor features, a multiparametric model has been recently proposed [27]. Importantly, the ultimate decision-making should always be taken in a multidisciplinary setting after an integrated assessment of harmful effects and potential benefits for anticancer treatments, thereby switching the strategy from stage-centered to patient-customized therapy, as envisioned by precision medicine.
Compared to previous studies, the strength of the current study lies in (1) its multicenter consecutive dataset with a larger sample size and broader population characteristics; (2) internationally recognized standards for patient evaluation and stratification; and (3) well-designed confounding factor controlling methods employing multiple evidence-based multivariate regression models used for controlling potential bias. However, this study may harbor some potential flaws deserving further attention. Firstly, its retrospective nature renders it susceptible to confounding effects stemming from both unintended selection and information bias. To minimize potential bias, HCC patients from various tertiary hospitals were included, and multiple follow-up visits were attempted. Secondly, the reduction in sample size within each risk stratification diminished the statistical power during subgroup analyses. Given the baseline characteristics on the impact of treatment allocation and patient prognosis, multiple multivariate adjustment methods were employed to control for confounding factors. Thirdly, the predominant population included in this study comprised individuals with HBV-associated HCC, while hepatitis C infection and metabolic-associated fatty liver disease were also represent significant pathogenic factors for HCC [28‐30]. Generalization of our findings should be approached with caution, and future prospective studies are necessary. Fourthly, the indocyanine green retention test and indocyanine green clearance test with makuuchi algoritm is more accurate compared to the techniques described by the present study, however, its widespread application is currently still limited by its great differences among individuals, high operational requirements and increased healthcare costs [31]. Consequently, the present study chose the commonly used biochemical evaluation of functional liver reserve since both serum bilirubin and albumin are readily available.
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In conclusion, HCC patients with hypohepatia could obtain survival benefits through surgical and non-surgical treatment approaches, while LR appears to confer a significant survival benefit compared with ablation or TACE, even for selected intermediate and advanced populations. This study offers new evidence and bridges a gap between traditional clinical guidelines and emerging understanding of treatment allocation for HCC patients with hypohepatia.
Declarations
Disclosures
Shoujie Zhao, Yejing Zhu, Jinming Zhu, Bo Wang, Enxin Wang, Jun Zhu, Liangzhi Wen, Yan Zhao, Man Yang, Luo Zuo, Jiahao Fan, Jia Jia, Wenbing Wu, Weirong Ren, Xing Chen, Jing Li, Xingshun Qi, Xilin Du and Lei Lie have no conflict of interest or financial ties to disclose.
Ethical approval
The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of the corresponding author’s institution (Assigned No. TDLL-202401-02) and was registered with Research Registry (identifier research registry9898). The datasets are available from the corresponding author upon reasonable request which would be shared in anonymized format.
Informed consent
Written informed consent was obtained from all patients before treatment initiation, consisting of consent for treatment and the potential use of clinical data in future investigations.
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Liver resection versus interventional treatments for hepatocellular carcinoma patients with hypohepatia: a multicenter study
Verfasst von
Shoujie Zhao
Yejing Zhu
Jinming Zhu
Bo Wang
Enxin Wang
Jun Zhu
Liangzhi Wen
Yan Zhao
Man Yang
Luo Zuo
Jiahao Fan
Jia Jia
Wenbing Wu
Weirong Ren
Xing Chen
Jing Li
Xingshun Qi
Xilin Du
Lei Liu
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Eine 31-jährige, ansonsten gesunde Frau stellte sich in der Kopf- und Halschirurgie mit einer progredient zunehmenden Raumforderung im linken Unterkieferbereich vor. In der Vorgeschichte war ein pleomorphes Adenom reseziert worden. Worum könnte es sich dieses Mal handeln?
Ob der Nachweis von positiven Schnitträndern nach radikaler Prostatektomie mittelfristig mit einem erhöhten Risiko für biochemische Rezidive und für Metastasen einhergeht, hängt auch von der Ausdehnung des Randbefalls ab.
Für die Therapie von Patientinnen – betroffen sind fast ausschließlich Frauen – mit Lipödem existiert eine Reihe von Optionen, mit einem eindeutigen Favoriten in puncto Effektivität. Ein großes Problem ist jedoch die korrekte Diagnose.
Wenn sich in der Medizin verhängnisvolle Komplikationen oder Fehler ereignen, gibt es neben den betroffenen Patienten oft ein zweites Opfer: die behandelnden Ärztinnen oder Ärzte. Eine dafür besonders anfällige Disziplin ist die Chirurgie.
