Abstract
Objective
To evaluate the incidence of and factors associated with frailty in hepatocellular carcinoma (HCC) patients after transarterial chemoembolization (TACE), with the objective to inform future personalized managements.
Methods
In this cross-sectional study conducted from January to October 2025, HCC patients undergoing TACE at a tertiary hospital in Suzhou were selected by convenience sampling and completed a general information questionnaire. The Fried frailty phenotype, Nutritional Risk Screening 2002 tool, and Barthel Index for activities of daily living were comprehensively evaluated between postoperative days 1 and 4 following TACE. Factors associated with frailty after TACE were identified via univariate and multivariate logistic regression analyses.
Results
Among the 312 included patients, 87 (27.9%) patients and 225 (72.1%) patients were in the frailty and non-frailty groups, respectively. Univariate analysis revealed statistically significant differences in age, sex, nutritional risk, Barthel Index, systemic immune-inflammatory index (SII), and hemoglobin level between the two groups (P<0.05). Multivariate logistic regression analysis identified that age, sex, nutritional risk, Barthel Index, SII, and hemoglobin level were associated with frailty after TACE, with odds ratios of 1.060, 4.199, 6.870, 0.954, 1.001, and 0.980, respectively (all P<0.05).
Conclusion
A significant number of HCC patients could have frailty after TACE. Advanced age, female sex, poor nutrition, low Barthel Index, high SII, and low hemoglobin level were associated with frailty in these patients. Further prospective trials are required to identify modifiable variables and evaluate interventions to prevent or reduce frailty in HCC patients undergoing TACE.
Keywords: hepatocellular carcinoma, transarterial chemoembolization, frailty, nursing care
Introduction
Hepatocellular carcinoma (HCC) is the fourth most common malignant tumor and the second leading cause of cancer-related deaths in China.1–3 Due to the insidious nature of the disease, most cases are diagnosed at an advanced stage when surgical treatment is no longer an option, and thus, only interventional therapy is appropriate.4,5 Although recent studies have identified several promising molecular targets, novel anticancer proteins, and potential therapeutic strategies, as well as ultrasound-based therapies, such as sonodynamic therapy and histotripsy, for HCC, most remain in the investigational, preclinical, or early translational stages.6–10 Transarterial chemoembolization (TACE) is still the most effective interventional treatment currently for unresectable advanced HCC,11 based on effective inhibition of tumor progression and improved patient survival rates. However, TACE can induce a systemic inflammatory response that promotes skeletal muscle catabolism through activation of inflammatory pathways and suppression of anabolic signaling.12,13 Concurrent mitochondrial dysfunction, hyperammonemia, and metabolic disturbances further accelerate sarcopenia, creating a vicious cycle of progressive muscle loss.14 These changes ultimately contribute to the development of frailty.
Frailty refers to a non-specific state characterized by diminished physiological functions and reserve capacity of various systems, resulting in reduced stress resistance and increased vulnerability.15–17 Previous research identified frailty as an independent prognostic factor after TACE, with good predictive ability for overall survival and progression-free survival, and higher predictive value in the early postoperative period compared with later periods.18 To date, most frailty studies in patients with liver diseases were primarily focused on the identification of factors influencing frailty in patients with liver cirrhosis.19–21 In contrast, relatively few studies have examined the development of frailty among HCC patients after TACE or other liver-directly therapy.18,22 The limited available evidence suggests that the incidence of frailty in HCC patients after TACE ranged from 32% to 49%,18,22 underscoring the substantial burden of frailty after TACE and the requirement for further investigation to address our knowledge gap regarding frailty and its associated factors following TACE.
Therefore, the present study aimed to explore the incidence of and factors associated with frailty in HCC patients after TACE, with the objective to provide a reference for future interventions to improve postoperative frailty status and quality of life of these HCC patients undergoing TACE.
Materials and Methods
Study Participants
Patients with HCC who underwent TACE at a tertiary grade A hospital in Suzhou, China, between January 2025 and October 2025 were selected via convenience sampling. The inclusion criteria were as follows: (1) age ≥18 years; (2) meeting the diagnostic criteria for HCC based on the “Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2024 Edition)”;23 and (3) treatment with TACE as determined by their primary treating physicians. Patients were excluded if they met any of the following exclusion criteria: (1) impaired consciousness or mental disorder that made communication difficult; or (2) inability to walk or cooperate with frailty assessment. According to the sample size calculation based on logistic regression, the sample size needed to be at least 5–10 times the number of independent variables. With 24 variables selected initially in this study and considering a 10% rate of sample loss and invalid questionnaire responses, the minimum sample size needed was 133. Ultimately, 312 cases were included. The study protocol was approved by the Ethics Committee of The First Affiliated Hospital of Soochow University (approval number: 2025–1077). Written informed consent was obtained from all participants prior to their enrollment.
Data Collection
Trained researchers used paper questionnaires to collect patients’ sociodemographic data and assess frailty, nutritional risk, and basic activities of daily living between postoperative days 1 and 4 (mean day 2) following TACE. All questionnaires were uniformly administered and completed by the researchers. Patients’ disease-related data and laboratory test results were obtained from the hospital information system (HIS). Patients were strictly screened according to the study standards. Responses from paper questionnaires were entered on the same day they were collected, and the researchers checked the authenticity and accuracy of the entered data. Any uncertainties were promptly verified with the patients. The data extracted from the HIS were organized and cleaned by the researchers themselves. Variables with ≥10% missing data were excluded.
General Information Questionnaire
The general information questionnaire included: (1) baseline information, including age, sex, marital status, smoking history, drinking history, educational level, living arrangement (alone or not), and body mass index (BMI); (2) disease-related data, including Barcelona Clinic Liver Cancer (BCLC) stage, duration of HCC, targeted therapy, immunotherapy, hypertension, diabetes; and (3) laboratory indicators, including hemoglobin, platelet count, alanine aminotransferase, aspartate aminotransferase, total bilirubin, interleukin-6 (IL-6), IL-8, and systemic immune-inflammatory index (SII).
Fried Frailty Phenotype
The Fried frailty phenotype was developed by Fried et al24 based on the cyclical frailty model and is currently the most widely used frailty assessment tool. It consists of five items: (1) weight loss of >4.5 kg or >5% in the previous year; (2) self-reported fatigue based on the number of days in the previous week when the respondent felt “a. I feel that I have difficulty doing everything”; or “b. I feel that I cannot walk”; (3) reduced physical activity based on the assessment of calories consumed during physical activity in the previous week, with reduced physical activity defined by consumption of <1602 kJ per week for men and <1130 kJ per week for women; (4) reduced walking speed calculated as the time required for the participance to walk 4.57 m compared with reference values for the participant’s sex and height; and (5) reduced grip strength measured using an electronic grip dynamometer compared with reference values for the participant’s sex and BMI. The total score for the Fried frailty phenotype ranges from 0 to 5, with 0 indicating a healthy state, 1–2 indicating pre-frailty status, and ≥3 indicating frailty status. This scale is suitable for assessing frailty among hospitalized patients, and its predictive validity has been widely verified.25,26
Nutritional Risk Screening 2002
The Nutritional Risk Screening 2002 (NRS2002), developed by Kondrup et al,27 is a nutritional risk screening tool recommended by the European Society for Clinical Nutrition and Metabolism and widely used in clinical practice with satisfactory universality.28 The NRS2002 assesses recent changes in weight, dietary habits, BMI, disease condition, and age, with a total score ranging from 0–7. A score of ≥3 represents malnutrition or elevated risk of malnutrition.
Barthel Index
The Barthel Index was developed by Mahoney and Barthel in 1965 and is the most widely used tool for assessing personal basic activities of daily living. The scale consists of 10 items covering: eating, dressing, bathing, grooming, toileting, bowel control, bladder control, bed-to-chair transfer, walking on level ground, and stair climbing. A lower score corresponds to a poorer ability to perform basic activities of daily living.
Statistical Methods
Continuous variables with <10% missing data were imputed as mean values. There were no missing data for categorical variables. Normally distributed continuous variables were described as mean ± standard deviation and compared between groups using the two independent samples t-test. Non-normally distributed continuous variables were described as median (interquartile range) and compared between groups using the rank sum test. Categorical variables were described by frequency and compared between groups using the χ2 test. Variables for which P<0.05 on the univariate analysis were included in the multivariate logistic regression analysis. The odds ratio (OR), 95% confidence interval, and Hosmer–Lemeshow test result were reported. All analyses were conducted in SPSS 26.0 (IBM, USA), with a P < 0.05 considered statistically significant.
Results
Baseline Characteristics and Frailty Status of Study Participants
A total of 312 HCC patients were included in this study. According to Fried frailty phenotype, 87 patients (27.9%) were included in the frailty group and 225 patients (72.1%) were assigned to the non-frailty group. The baseline and clinical characteristics of the patients in each group are presented in Table 1.
Table 1.
Baseline and Clinical Characteristics of Hepatocellular Carcinoma Patients with or Without Frailty After Transarterial Chemoembolization
| Characteristics | All Patients (n=312) | Non-Frailty Group (n=225) | Frailty Group (n=87) | Statistical Value | P |
|---|---|---|---|---|---|
| Age, years, median (IQR) | 61 (56,68) | 61 (55,66) | 66 (58,74) | −3.359a | 0.001 |
| Sex, n (%) | 44.696b | <0.001 | |||
| Male | 241 (77.2) | 196 (87.1) | 45 (51.7) | ||
| Female | 71 (22.8) | 29 (12.9) | 42 (48.3) | ||
| Marital status, n (%) | 2.033b | 0.154 | |||
| Married | 278 (89.1) | 204 (90.7) | 74 (85.1) | ||
| Other | 34 (10.9) | 21 (9.3) | 13 (14.9) | ||
| Smoking, n (%) | 97 (31.1) | 69 (30.7) | 28 (32.2) | 0.067b | 0.795 |
| Drinking alcohol, n (%) | 112 (35.9) | 88 (39.1) | 24 (27.6) | 3.621b | 0.057 |
| Educational attainment, n (%) | 7.136b | 0.068 | |||
| Primary school or below | 63 (20.2) | 38 (16.9) | 25 (28.7) | ||
| Junior high school | 153 (49.0) | 119 (52.9) | 34 (39.1) | ||
| Senior high school/technical secondary school | 65 (20.8) | 45 (20.0) | 20 (23.0) | ||
| Junior college or above | 31 (9.9) | 23 (10.2) | 8 (9.2) | ||
| Living alone, n (%) | 59 (18.9) | 39 (17.3) | 20 (23.0) | 1.309b | 0.253 |
| Body mass index, kg/m2, n (%) | 6.133b | 0.105 | |||
| <18.5 | 16 (5.1) | 12 (5.3) | 4 (4.6) | ||
| 18.5~24.0 | 205 (65.7) | 141 (62.7) | 64 (73.6) | ||
| 24.1~28.0 | 80 (25.6) | 61 (27.1) | 19 (21.8) | ||
| >28.0 | 11 (3.5) | 11 (4.9) | 0 (0.0) | ||
| Barcelona Clinic Liver Cancer stage, n (%) | 4.965b | 0.084 | |||
| A | 24 (7.7) | 22 (9.8) | 2 (2.3) | ||
| B | 36 (11.5) | 25 (11.1) | 11 (12.6) | ||
| C | 252 (80.8) | 178 (79.1) | 74 (85.1) | ||
| Duration of hepatocellular carcinoma, years, n (%) | 0.425b | 0.808 | |||
| <5 | 229 (73.4) | 167 (74.2) | 62 (71.3) | ||
| 5~9 | 62 (19.9) | 44 (19.6) | 18 (20.7) | ||
| ≥10 | 21 (6.7) | 14 (6.2) | 7 (8.0) | ||
| Targeted therapy, n (%) | 219 (70.2) | 155 (68.9) | 64 (73.6) | 0.655b | 0.418 |
| Immunotherapy, n (%) | 280 (89.7) | 201 (89.3) | 79 (90.8) | 0.148b | 0.701 |
| Hypertension, n (%) | 116 (37.2) | 79 (35.1) | 37 (42.5) | 1.478b | 0.224 |
| Diabetes, n (%) | 79 (25.3) | 26 (11.6) | 53 (60.9) | 1.329b | 0.249 |
| Hemoglobin, g/L, M±SD | 122.12±20.83 | 125.63±20.67 | 113.02±18.42 | 4.975c | <0.001 |
| Platelet count,109/L, M±SD | 128.67±74.81 | 127.53±72.72 | 131.60±80.33 | −0.430c | 0.668 |
| Alanine aminotransferase, U/L, M±SD | 44.64±45.20 | 42.53±43.47 | 50.11±49.26 | −1.259c | 0.210 |
| Aspartate aminotransferase, U/L, M±SD | 52.58±43.10 | 50.08±41.56 | 59.03±46.48 | −1.650c | 0.050 |
| Total bilirubin, μmmol/L, M±SD | 20.98±15.77 | 20.12±14.54 | 23.21±18.48 | −1.555c | 0.060 |
| Interleukin-6, pg/mL, M±SD | 28.56±69.86 | 30.91±80.44 | 22.50±27.29 | 1.377c | 0.170 |
| Interleukin-8, pg/mL, M±SD | 50.37±62.98 | 46.34±56.18 | 60.79±77.27 | −1.588c | 0.115 |
| Systemic immune-inflammatory index, M±SD | 509.95±526.19 | 431.74±425.18 | 712.21±687.76 | 3.550c | <0.001 |
| Nutrition Risk Screening 2002 | 71.374b | <0.001 | |||
| <3 | 189 | 169 | 20 | ||
| ≥3 | 123 | 56 | 67 | ||
| Barthel Index | 98.14±8.70 | 99.47±4.88 | 94.71±13.96 | 3.103c | 0.003 |
Notes: a: Z score; b: χ2 test; c: t test.
Abbreviations: IQR, interquartile range; M±SD, mean ± standard deviation.
Univariate Analysis of Factors of Associated with Frailty After TACE
Univariate analysis revealed statistically significant differences in age, sex, nutritional risk, Barthel index, SII, and hemoglobin level between the frailty and on-frailty groups (all P<0.05; Table 1).
Factors Associated with Frailty Among HCC Patients After TACE
Multivariate logistic regression analysis was conducted with the occurrence of frailty as the dependent variable (No=0, Yes=1) and the variables for which P<0.05 on the univariate analysis as independent variables. For continuous variables, the original values were used directly used. For non-continuous variables, the values assigned are listed in Table 2. This analysis identified age (odds ratio [OR]=1.060), sex (OR=4.199), nutritional risk (OR=6.870), Barthel Index (OR=0.954), SII (OR=1.001), and hemoglobin level (OR=0.980) as influencing factors for frailty after TACE among HCC patients (all P<0.05; Table 3). The goodness-of-fit test (Hosmer–Lemeshow test) returned P=0.384, indicating satisfactory agreement between predicted probabilities and observed outcomes.
Table 2.
Value Assignments for Non-Continuous Independent Variables
| Independent Variable | Value Assignment |
|---|---|
| Sex | Male=1, Female=2 |
| Nutritional risk | No nutritional risk=1, Nutritional risk=2 |
Table 3.
Multivariate Logistic Regression Analysis of Factors Associated with Frailty in Hepatocellular Carcinoma Patients After Transarterial Chemoembolization (n=312)
| Variables | β | SE | Wald χ2 | P | OR (95% CI) |
|---|---|---|---|---|---|
| Constant | 0.365 | 3.057 | 0.014 | 0.905 | 1.440 |
| Age | 0.059 | 0.020 | 8.999 | 0.003 | 1.060 (1.021,1.102) |
| Sexa | 1.435 | 0.357 | 16.124 | <0.001 | 4.199 (2.084,8.459) |
| Nutritional riskb | 1.927 | 0.342 | 31.803 | <0.001 | 6.870 (3.516,13.422) |
| Barthel Index | −0.047 | 0.024 | 3.960 | 0.047 | 0.954 (0.910,0.999) |
| Systemic immune-inflammatory index | 0.001 | 0.000 | 11.046 | <0.001 | 1.001 (1.000,1.002) |
| Hemoglobin | −0.020 | 0.008 | 5.594 | 0.018 | 0.980 (0.965,0.997) |
Notes: acompared with male patients, female patients had 4.199-fold higher odds of frailty. bcompared with patients without nutritional risk, patients with nutritional risk had 6.870-fold higher odds of frailty.
Abbreviations: CI, confidence interval; OR, odds ratio; SE, standard error.
Discussion
High Incidence of Frailty After TACE in HCC Patients
Among the HCC patients enrolled in the present study, the incidence of frailty in patients after TACE was 27.9%, which is lower than the rate of 32.2% reported by Shao et al18 in elderly patients with liver cancer after TACE. This difference could be related to the older age of patients in their study relative to ours. Additionally, the incidence of frailty after TACE in the present study was higher than the rates of 17.8% reported by Zhou et al29 and 19.9% reported by Li et al30 for hospitalized patients with hepatitis B-related cirrhosis. These differences could be related to differences in the severity and etiologies of liver disease. Additionally, the Fried frailty phenotype was used to evaluate frailty during postoperative days 1–4 after TACE in the present study, whereas the Shao et al mentioned above employed the modified 5-item frailty index and liver frailty index to assess frailty 6–8 weeks following TACE.18 The use of these different tools and observation periods might have influenced the different study results.
Factors Associated with Frailty After TACE in HCC Patients
The results of the present study showed that advanced age was associated with frailty in HCC patients after TACE. Consistently, previous research31 has demonstrated declining function of multiple tissues and organs such as the muscular and nervous systems with increasing age, as well as imbalance of the intestinal microbiota, leading to a decrease in overall body function. This suggests that healthcare providers should strengthen screening for frailty among older patients after TACE to support earlier implementation of exercise, nutritional, and multi-factor comprehensive interventions to improve clinical outcomes among these patients.
The present study found that female patients were more prone to frailty than male HCC patients after TACE. Compared with men, women in general are known to have lower physical strength and muscle strength and to be more prone to muscle synthesis disorders and significant bone loss.32 Moreover, with menopause, the rapid decline in estrogen levels in women leads to rapid decreases in bone density and muscle mass. Thus, compared with men of the same age, women are more likely to develop frailty. Accordingly, the results of the present study suggested that healthcare providers should closely assess frailty status in female patients after TACE and actively develop corresponding intervention measures to prevent or delay the occurrence of frailty.
Multivariate analysis in this study identified an increased risk of malnutrition as an influencing factor for frailty after TACE. Due to factors such as poor appetite and abnormal body metabolism, patients with HCC generally suffer from malnutrition, with energy and protein in a negative nitrogen balance state.33 Malnourishment further exacerbates the state of frailty via the lack of activity, elevated cytokine expression, and muscle catabolism. The clinical practice guidelines for nutrition in chronic liver disease of the European Association for the Study of the Liver recommend that non-obese patients consume 30–35 kcal/kg of energy and 1.2–1.5 g/kg of protein daily to improve nitrogen balance.34 For patients who are intolerant of albumin or whose daily protein intake does not reach the target level, daily treatment with branched-chain amino acids at a dose of 0.25 g/kg can be beneficial for improving the muscle status. Moreover, combined multi-form exercise interventions help to stimulate muscle protein synthesis from amino acids. In clinical practice, medical staff need to actively provide patients with scientific nutrition support plans to meet their metabolic needs.
The level of inflammation was significantly correlated with the degree of frailty in the present study. As an organ that maintains immune tolerance and the body’s immune response, healthy liver function is critical for immune balance. The long-term inflammatory state created by chronic liver disease can damage the liver’s immune system. Under such inflammatory conditions, overproduction of different cytokines leads to insulin resistance, which in turn promotes an increase in fat mass and reductions in muscle strength and mass, while the catabolism of muscle can activate the inflammatory pathway with subsequent protein degradation, likely accelerating the occurrence of frailty.35 The SII is an indicator of the systemic inflammatory and immune status that is based on platelet, neutrophil, and lymphocyte counts and is an important predictor of prognosis for liver cancer patients undergoing TACE.36 In clinical practice, regular assessment of inflammatory markers is necessary in patients undergoing TACE to inform the administration of drug or non-drug interventions, such as anti-inflammatory diets and exercise, to reduce the level of inflammation and prevent or delay the occurrence of frailty and its related adverse effects.
The present study identified the association between low Barthel index and frailty in patients after TACE. A low Barthel index reflects a decline in the patient’s physical activity and is an important predictor of frailty and disability in general.37 Impaired physical ability to perform various basic activities of daily living, such as moving, going up and down stairs, and walking, can lead to lower muscle mass, weakened muscle strength, and decreased enthusiasm for life, which in turn increase the risk of frailty and negatively affect patients’ quality of life. Secondly, patients with basic self-care deficiencies often have a lower sense of self-worth, worry more about disease progression and difficulty in recovery, and are prone to negative emotional conditions such as anxiety and depression. Therefore, in clinical practice, careful assessment of frailty is recommended for patients with a low ability to complete activities of daily living after TACE to support the timely implementation of intervention measures.
The results of the present study identified the association between a low hemoglobin level and frailty after TACE, which was consistent with the findings of previous research results.38 Hemoglobin functions to transport and store oxygen, regulate physiological metabolism, and modulate pH. A decrease in hemoglobin weakens the oxygen-carrying capacity of the blood, thereby reducing tissue oxygenation, which can lead to muscle damage and fatigue, further contributing to the occurrence of frailty.39 Hemoglobin also is an important indicator of nutritional status. Because HCC patients are prone to anemia, healthcare providers should aim to actively correct the anemic status of HCC patients undergoing TACE, ensuring adequate nutritional intake before surgery to help prevent or delay the occurrence of frailty.
Our study had several limitations, including its single-center and cross-sectional design, which could restrict the generalizability of the results and prevent causal relationship determination. Our study might also be susceptible to certain biases, such as selection bias from convenience sampling and information bias from self-reported answers in questionnaires. In addition, we did not consider many potential confounders, such as Child–Pugh classification, tumor burden, comorbidities, and treatment-related variables including the number of TACE sessions, which might impact the frailty assessment in the multivariate logistic regression analysis. We evaluated frailty during the early postoperative period (days 1–4 after TACE), without assessment of long-term frailty outcomes, which may be associated with different factors and underlying mechanisms.
Conclusion
Although further validation in future multi-center prospective studies is required, the results of the present study demonstrate that the incidence of frailty after TACE is relatively high and associated with multiple factors. Accordingly, in clinical practice, careful screening for frailty after TACE is recommended, especially for patients who are older or female, with a high inflammatory index, a high risk of malnutrition, a diminished ability to complete activities of daily living, or a low hemoglobin concentration. Our results highlight both the importance of frailty assessment in patients after TACE and identify possible corresponding intervention measures, such as nutrition support and anemia correction, which might prevent or delay the occurrence of frailty. In the future, multi-center, large-sample, long-term longitudinal studies are warranted to explore the changing trajectory and causal relationship of frailty in patients after TACE, as well as to test whether proposed interventions could impact frailty development following TACE. Such knowledge will facilitate the optimization of intervention timing and measures to combat frailty in patients after TACE for HCC.
Funding Statement
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data Sharing Statement
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
The study was approved by the Ethics Committee of The First Affiliated Hospital of Soochow University (approval number: 2025-1077) and adhered to the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all participants prior to their enrollment.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare that they have no competing interests.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.