Anxiety, depression, and quality of life in hepatocellular carcinoma treated with drug-eluting microspheres plus lenvatinib: A prospective study

Abstract

BACKGROUND

Patients with hepatocellular carcinoma (HCC) often experience considerable psychological distress that affects their quality of life (QoL).

AIM

To investigate the effects of drug-eluting microsphere - transcatheter arterial chemoembolization (DEM-TACE) combined with lenvatinib on anxiety, depression, and QoL.

METHODS

This prospective study enrolled 126 patients with primary HCC treated with DEM-TACE combined with lenvatinib from October 2022 to October 2025. Anxiety and depression assessment with the Hospital Anxiety and Depression Scale (HADS) and QoL evaluation with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and HCC-specific module were conducted at baseline and at 3-, 6-, and 12-month. Clinical outcomes, including overall survival, progression-free survival, and adverse events (AEs), were recorded.

RESULTS

Overall, 58.7% and 61.1% of patients exhibited anxiety and depression at baseline, respectively. After treatment, both psychological status and QoL significantly improved. At 12 months, the prevalence rates of anxiety and depression decreased to 31.0% and 28.6%, respectively (both P < 0.001). The EORTC QLQ-C30 global health status score increased from 52.3 ± 15.7 to 71.2 ± 14.3 (P < 0.001). Physical, role, and emotional functioning scores also significantly improved (all P < 0.001). Treatment-related AEs were generally manageable. Multivariate analysis showed that baseline HADS score, Barcelona Clinic Liver Cancer stage, and tumor response were independent predictors of QoL outcomes (P < 0.05).

CONCLUSION

DEM-TACE combined with lenvatinib shows an acceptable safety profile and favorable efficacy in improving anxiety, depression, and QoL in patients with HCC. Early psychological assessment and intervention may optimize outcomes.

Key Words: Anxiety; Depression; Drug-eluting microspheres; Hepatocellular carcinoma; Lenvatinib; Quality of life

Core Tip: This study investigated the impact of drug-eluting microsphere - transcatheter arterial chemoembolization (DEM-TACE) combined with lenvatinib on anxiety, depression, and quality of life (QoL) in patients with hepatocellular carcinoma (HCC). Among 126 enrolled patients, the prevalence of anxiety and depression significantly decreased over 12 months, accompanied by marked improvements in global health and functional scores on European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and Quality of Life Questionnaire-Hepatocellular Carcinoma 18. The combination therapy showed favorable tumor response and manageable toxicity. These findings highlight the dual benefits of DEM-TACE plus lenvatinib in improving both psychological well-being and overall QoL in HCC management.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer-related mortality worldwide, with particularly high incidence rates in Asia[1]. The diagnosis and treatment of HCC impose a substantial physical and psychological burden on patients, affecting their quality of life (QoL)[2]. Psychological factors prevalent in patients with HCC, particularly anxiety and depression, have been suggested to influence treatment outcomes and survival[3,4].

Transcatheter arterial chemoembolization (TACE) has been established as the standard treatment for intermediate-stage HCC, providing both local tumor control and palliative benefits[5]. Drug-eluting microspheres (DEMs) improve the therapeutic efficacy of TACE by enabling sustained tumor-selective drug delivery while minimizing systemic exposure[6,7]. DEM-TACE has several advantages over conventional TACE, including more predictable drug-release kinetics and reduced hepatotoxicity[8].

Lenvatinib, a multikinase inhibitor that targets vascular endothelial growth factor receptors, has been reported to be non-inferior to sorafenib as a first-line treatment for advanced HCC[9]. Additionally, lenvatinib has been demonstrated by the REFLECT trial to be an effective systemic therapy option, and its combination with locoregional therapies has been explored by subsequent studies[10]. Recent evidence suggests that TACE combined with lenvatinib may produce synergistic effects and improve both tumor response and survival outcomes compared with either modality alone[11,12]. Despite accumulative evidence supporting the clinical efficacy of DEM-TACE combined with lenvatinib, the psychological impact of this treatment regimen on patients with HCC has garnered limited attention[13]. Depression and anxiety are highly prevalent among patients with cancer, with reported rates ranging from 20% to 65% in HCC populations[14,15]. These psychological comorbidities are associated with reduced treatment compliance, poorer QoL, and potentially reduced survival[4,14].

This prospective study aimed to comprehensively investigate the effects of DEM-TACE combined with lenvatinib on anxiety, depression, and QoL in patients with primary HCC and to evaluate the safety and clinical efficacy of this combination therapy. Understanding these patient-reported outcomes is crucial for optimizing holistic cancer care and improving overall patient well-being.

MATERIALS AND METHODS

This single-center prospective study was initiated in October 2022 and completed in October 2025. Interim analysis results were reported based on a data cut-off date of October 2024, after which sufficient follow-up duration (minimum of 12 months) was achieved in 97 patients to allow for a meaningful assessment of the primary endpoints. The decision to report the interim analysis results was made because: (1) The primary endpoints of anxiety, depression, and QoL at 12 months had been reached in a substantial cohort; (2) The preliminary survival data have revealed encouraging trends that warrant early dissemination; and (3) The findings have important clinical implications for patient-centered care that merit timely communication to the medical community. This study continues to accrue longer-term follow-up data, and updated survival analysis results will be reported when the final cohort reaches maturity.

The patient inclusion criteria for this study were as follows: (1) Age of 18-75 years; (2) Histologically or radiologically confirmed diagnosis of HCC based on the European Association for the Study of the Liver criteria; (3) Barcelona Clinic Liver Cancer (BCLC) stage B or C disease deemed suitable for TACE; (4) Child-Pugh class A or B liver function; (5) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2; (6) Adequate hematologic function with platelet count ≥ 60 × 10⁹/L and hemoglobin level ≥ 80 g/L; (7) Adequate renal function with serum creatinine level ≤ 1.5 times the upper limit of normal; and (8) Ability to complete questionnaires in Chinese. The exclusion criteria were as follows: (1) Previous systemic therapy for HCC; (2) Extrahepatic metastases involving critical organs; (3) Portal vein tumor thrombus extending to the main portal vein; (4) Active gastrointestinal bleeding within 4 weeks; (5) Severe cardiovascular disease; (6) Concurrent malignancy; (7) Psychiatric disorders requiring medication; and (8) Inability to provide informed consent or complete follow-up assessments.

Out of 152 patients initially screened for eligibility, 18 did not meet the inclusion criteria, and eight declined to participate. Ultimately, a total of 126 enrolled patients were included in the final analysis.

This study was conducted in accordance with the Declaration of Helsinki and relevant national and institutional guidelines for research involving human participants. The study protocol was reviewed and approved by the Ethics Committee of the 980^th (Bethune International Peace) Hospital of the Joint Support Force of the Chinese People’s Liberation Army. All participants, or their legal guardians, provided written informed consent prior to enrollment.

Treatment protocol

DEM-TACE: Interventional radiologists with at least 10 years of experience in interventional radiology and HCC management performed all TACE procedures using standardized techniques. Femoral artery access was obtained under local anesthesia using the Seldinger technique. Angiography of the celiac and superior mesenteric arteries was performed to identify tumor-feeding arteries and assess vascular anatomy. A 2.7-Fr or 2.8-Fr microcatheter was advanced as selectively as possible into the tumor-feeding arteries under fluoroscopic guidance. Subsequently, 100- to 300-μm-diameter DEMs (CalliSpheres, Jiangsu Hengrui Medicine Co., Ltd., China) were loaded with doxorubicin (50 mg per vial) according to the manufacturer’s instructions. Loading involved mixing the microspheres with doxorubicin in a sterile syringe and allowing adequate time for drug uptake. Drug-loaded microspheres were then slowly injected through the microcatheter until near stasis of blood flow in the tumor-feeding vessels was achieved, as evidenced by delayed antegrade flow or reflux. The treating physician determined the embolization endpoint based on tumor vascularity and patient tolerance, aiming for complete tumor devascularization while preserving the non-tumoral liver parenchyma. For large or multifocal tumors, staged procedures were performed to minimize liver injury and reduce the risk of post-embolization syndrome. Additional embolization with bland microspheres or gelatin sponge particles was conducted as necessary to achieve sufficient hemostasis. Follow-up TACE was performed every 6-8 weeks if imaging findings revealed viable tumor tissues on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI), provided that liver function and performance status remained adequate.

Lenvatinib administration: Treatment with lenvatinib (Eisai Co., Ltd., Japan) was initiated at 3-7 days after the first TACE procedure. Its dose was determined based on patients’ body weight: 12 mg once daily for patients weighing ≥ 60 kg and 8 mg once daily for those weighing < 60 kg. Lenvatinib was administered orally at approximately the same time daily, preferably in the morning. Patients were instructed to take lenvatinib with or without food and to maintain consistency in administration relative to meals. Treatment was temporarily interrupted three days before TACE and resumed three days after each subsequent TACE procedure to minimize the risk of bleeding complications. Dose modifications were implemented according to established guidelines for managing adverse events (AEs). In particular, when intolerable grade 2 AEs or grade 3 AEs occurred, lenvatinib treatment was interrupted until resolution to grade 1 or baseline and was subsequently resumed at a reduced dose. The dose reduction schedule was 8 mg and 4 mg for patients initially receiving 12 mg and 8 mg, respectively. When grade 4 AEs or recurrent grade 3 AEs occurred despite dose reduction, lenvatinib treatment was permanently discontinued. Lenvatinib treatment was continued until disease progression, unacceptable toxicity, or patient withdrawal.

Psychological and QoL assessments

Hospital Anxiety and Depression Scale: Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS) at baseline and at 3-, 6-, and 12-month after treatment. The HADS is a well-validated 14-item self-reported questionnaire comprising two 7-item subscales for anxiety [HADS-Anxiety subscale (HADS-A)] and depression [HADS-Depression subscale (HADS-D)][16]. Each item is scored on a 4-point Likert scale (0-3), yielding subscale scores ranging from 0 to 21. Based on established cut-off values for patients with cancer, HADS scores of 0-7, 8-10, and 11-21 were interpreted as normal, borderline, and abnormal (indicative of clinically significant anxiety or depression), respectively[17]. Patients with HADS-A or HADS-D score of ≥ 8 were considered to have anxiety or depression. The Chinese version of the HADS, which has been confirmed to have good reliability and validity in cancer populations, was utilized in this study.

European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and HCC-specific module (Quality of Life Questionnaire-Hepatocellular Carcinoma 18): QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and Quality of Life Questionnaire-Hepatocellular Carcinoma 18 (QLQ-HCC18) at baseline and at 3-, 6-, and 12-month after treatment. The EORTC QLQ-C30 is a validated 30-item questionnaire that evaluates multiple dimensions of health-related QoL in patients with cancer[18]. The EORTC QLQ-C30 consists of: (1) A global health status/QoL scale; (2) Five functional scales that evaluate physical, role, emotional, cognitive, and social functioning; (3) Three symptom scales that assess fatigue, nausea/vomiting, and pain; and (4) Six items that evaluate dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Global health status items are rated on a 7-point scale (1 = very poor to 7 = excellent), whereas all other items are rated on a 4-point Likert scale (1 = not at all to 4 = very much). Scores were linearly transformed to a 0-100 scale according to the European Organization for Research and Treatment of Cancer scoring manual, with higher functional scale and global health status scores indicating better QoL and higher symptom scale scores denoting greater symptom burden.

The EORTC QLQ-HCC18 is an 18-item HCC-specific module that assesses disease-specific symptoms and concerns[19] and evaluates six domains: Fatigue (five items), body image (three items), jaundice (two items), nutrition (three items), pain (two items), and fever (one item), in addition to two items pertaining to abdominal swelling and sexual activity. Items are rated on the same 4-point Likert scale as the Quality of Life Questionnaire-Core 30, with scores ranging from 0 to 100; higher scores indicate greater symptom burden. Validated Chinese versions of both questionnaires, which have been demonstrated to be reliable and valid in Chinese HCC populations[20], were administered.

Clinical efficacy evaluation

Tumor response assessment: Tumor response was evaluated using contrast-enhanced CT or MRI at baseline and every 8-12 weeks after treatment initiation. Two radiologists with at least 10 years of experience in hepatobiliary imaging independently reviewed all imaging studies, and any discrepancy was resolved through consensus. Tumor response was classified according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria, which specifically account for viable tumor tissues based on arterial phase enhancement. Response categories included: (1) Complete response (CR), defined as the disappearance of intratumoral arterial enhancement in all target lesions; (2) Partial response (PR), defined as an at least 30% reduction in the sum of diameters of viable target lesions; (3) Progressive disease (PD), defined as an at least 20% increase in the sum of diameters of viable target lesions or the appearance of new lesions; and (4) Stable disease (SD), defined as any response not meeting the CR, PR, or PD criteria. The objective response rate was calculated as the proportion of patients who achieved CR or PR, whereas the disease control rate was calculated as the proportion of patients who achieved CR, PR, or SD.

Survival analysis: Overall survival (OS) was defined as the time from treatment initiation to death from any cause or the last follow-up. Progression-free survival (PFS) was defined as the time from treatment initiation to the first documented disease progression or death from any cause, whichever occurred first. Patients who were lost to follow-up or alive without progression on the data cut-off date were censored at the date of last contact or imaging assessment. Survival data were obtained via telephone interviews and reviews of hospital records and death certificates.

Safety assessment

AEs were monitored throughout the treatment period and graded according to Common Terminology Criteria for Adverse Events version 5.0. AEs were categorized into either TACE-related events (occurring within 30 days after TACE) or lenvatinib-related events (occurring during lenvatinib treatment). Post-embolization syndrome, characterized by fever, abdominal pain, and nausea/vomiting occurring within 72 hours after TACE, was documented separately. Laboratory parameters, including complete blood count, liver function (alanine aminotransferase, aspartate aminotransferase, total bilirubin, and albumin levels), renal function (creatinine and blood urea nitrogen levels), and coagulation, were measured at baseline, at 1 week after each TACE procedure, and monthly during lenvatinib treatment. Vital sign assessments and physical examinations were conducted at each follow-up visit. Serious AEs (SAEs), defined as life-threatening events or events requiring hospitalization or resulting in significant disability, were recorded and reported according to institutional protocols.

Statistical analysis

Statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, United States) and R version 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria). Continuous variables were tested for normality using the Shapiro-Wilk test and were expressed as means ± SD for normally distributed data or as medians with interquartile ranges for non-normally distributed data. Categorical variables were presented as n (%). Continuous variables were compared between time points using a paired t-test or Wilcoxon signed-rank test, as appropriate. Categorical variables were compared using the χ² test or Fisher's exact test. Changes in psychological scores and QoL metrics over time were examined using repeated-measures analysis of variance (ANOVA) with post-hoc Bonferroni correction for multiple comparisons. Survival curves were generated using the Kaplan-Meier method and compared using the log-rank test. Factors associated with OS and PFS were determined using univariate and multivariate Cox proportional hazards regression models. Variables with P < 0.10 in the univariate analysis were entered into the multivariate models. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with anxiety, depression, and QoL outcomes. Pearson’s or Spearman’s correlation coefficients were calculated to explore the relationship between psychological status and QoL scores. Out of 126 enrolled patients, 97 (77.0%) completed the 12-month QoL assessment, whereas 29 (23.0%) did not. Among those who did not complete the 12-month assessment, 16 (12.7%) patients died before 12 months, 8 (6.3%) experienced disease progression requiring hospice care or change in treatment strategy, 3 (2.4%) were lost to follow-up, and 2 (1.6%) withdrew their consent. To account for potential attrition bias, sensitivity analyses were conducted to compare baseline characteristics and early outcomes (3-month assessments) between completers and non-completers. No significant differences in baseline demographic and clinical characteristics or initial treatment responses were observed between these groups (all P > 0.05), indicating that the observed improvements in QoL were not substantially biased by the selective dropout of patients with poorer outcomes. For all analyses, statistical significance was set at a two-sided P value of < 0.05.

RESULTS

Patient characteristics

A total of 126 patients with primary HCC who were treated with DEM-TACE combined with lenvatinib were enrolled from October 2022 to October 2025. The baseline demographic and clinical characteristics of the study population are summarized in Table 1.

Table 1 Baseline characteristics of the study population (n = 126), n (%).

Characteristic	Value
Age (years), median (range)	56 (32-74)
Sex
Male	91 (72.2)
Female	35 (27.8)
Etiology
HBV	111 (88.1)
HCV	8 (6.3)
Non-viral	7 (5.6)
Child-Pugh class
A	102 (81.0)
B	24 (19.0)
ECOG PS
0	68 (54.0)
1	50 (39.7)
2	8 (6.3)
BCLC stage
B	47 (37.3)
C	79 (62.7)
Tumor diameter (cm), median (range)	7.2 (3.5-15.8)
Tumor number
Single	53 (42.1)
Multiple	73 (57.9)
Portal vein tumor thrombus	41 (32.5)
AFP (ng/mL), median (range)	386 (3.2-21450)
Number of TACE procedures, median (range)	2 (1-5)
Lenvatinib dose (mg/day)
12	78 (61.9)
8	48 (38.1)

HBV: Hepatitis B virus; HCV: Hepatitis C virus; ECOG PS: Eastern Cooperative Oncology Group performance status; BCLC: Barcelona Clinic Liver Cancer; AFP: Alpha-fetoprotein; TACE: Transcatheter arterial chemoembolization.

The median patient age was 56 years (range: 32-74 years), with male patients accounting for 72.2% (n = 91). Hepatitis B-related HCC (88.1%) was identified as the most frequent etiology, followed by hepatitis C-related HCC (6.3%) and non-viral etiologies (5.6%). Most patients had Child-Pugh class A liver function (81.0%). The ECOG performance status score was 0 and 1 in 54.0% and 39.7% of patients, respectively. Furthermore, 47 (37.3%) and 79 (62.7%) patients were classified to have BCLC stages B and C HCC, respectively. The median tumor diameter was 7.2 cm (range: 3.5-15.8 cm), and 73 (57.9%) patients had multifocal disease. Portal vein tumor thrombus was detected in 41 (32.5%) patients. The median alpha-fetoprotein level was 386 ng/mL (range: 3.2-21450 ng/mL). During the study period, patients underwent a median of two TACE procedures (range: 1-5), with a median interval of 7.3 weeks between procedures.

Changes in anxiety and depression

The prevalence and severity of anxiety and depression at baseline and follow-up are presented in Table 2. At baseline, 74 (58.7%) patients exhibited anxiety (HADS-A score ≥ 8), with a mean HADS-A score of 9.8 ± 4.2, and 77 (61.1%) patients met the criteria for depression (HADS-D score ≥ 8), with a mean HADS-D score of 10.3 ± 3.9. Following the initiation of DEM-TACE combined with lenvatinib, both anxiety and depression scores significantly improved over time (overall time effect, P < 0.001). At 3 months, the prevalence rates of anxiety and depression decreased to 42.9% (54 patients) and 45.2% (57 patients), respectively. Such improvements persisted at 6 months (35.7% for anxiety and 33.3% for depression) and 12 months (31.0% for anxiety and 28.6% for depression). The mean HADS-A score decreased progressively to 7.1 ± 3.8 at 3 months, 5.9 ± 3.2 at 6 months, and 5.2 ± 2.9 at 12 months (P < 0.001 for trend). Similarly, the mean HADS-D score decreased to 7.3 ± 3.5 at 3 months, 6.1 ± 3.0 at 6 months, and 5.4 ± 2.7 at 12 months (P < 0.001 for trend). Repeated-measures ANOVA confirmed significant time effects for both HADS-A and HADS-D scores (both P < 0.001), and post-hoc analyses indicated significant improvements at each time point compared with baseline (all P < 0.01).

Table 2 Changes in anxiety and depression over time (n = 126), mean ± SD/n (%).

Time point	Patients assessed	HADS-A score	Anxiety ≥ 8	HADS-D score	Depression ≥ 8
Baseline	126	9.8 ± 4.2	74 (58.7)	10.3 ± 3.9	77 (61.1)
3 months	126	7.1 ± 3.8a	54 (42.9)	7.3 ± 3.5a	57 (45.2)
6 months	119	5.9 ± 3.2a	42 (35.3)	6.1 ± 3.0a	39 (32.8)
12 months	97	5.2 ± 2.9a	30 (30.9)	5.4 ± 2.7a	28 (28.9)
P value1	-	< 0.001	< 0.001	< 0.001	< 0.001

^aP < 0.001 vs baseline (post-hoc analysis with Bonferroni correction).

¹P value from repeated-measures ANOVA for overall time effect.

HADS-A: Hospital Anxiety and Depression Scale-Anxiety subscale; HADS-D: Hospital Anxiety and Depression Scale-Depression subscale.

Changes in QoL

QoL assessments using the EORTC QLQ-C30 and QLQ-HCC18 revealed significant post-treatment improvements across multiple domains (Table 3). At baseline, the mean global health status/QoL score was 52.3 ± 15.7, which increased to 65.8 ± 14.5 at 3 months, 69.4 ± 13.8 at 6 months, and 71.2 ± 14.3 at 12 months (P < 0.001 for trend). With respect to the functional scales, physical functioning scores increased from 68.5 ± 18.3 at baseline to 81.2 ± 15.7 at 12 months (P < 0.001). Similarly, role, emotional, cognitive, and social functioning scores increased from 65.2 ± 21.4 to 78.9 ± 17.8 (P < 0.001), from 63.7 ± 19.5 to 79.6 ± 16.2 (P < 0.001), from 71.8 ± 17.2 to 82.4 ± 14.9 (P < 0.001), and from 64.9 ± 20.8 to 77.3 ± 18.5 (P < 0.001), respectively. Symptom scale scores correspondingly improved, with fatigue, pain, and nausea/vomiting scores at baseline decreasing from 58.3 ± 22.1 to 35.7 ± 19.4 at 12 months (P < 0.001), from 52.6 ± 24.3 to 28.9 ± 18.7 (P < 0.001), and from 28.4 ± 21.5 to 15.2 ± 14.8 (P < 0.001), respectively. The HCC-specific QLQ-HCC18 module also showed significant improvements in disease-specific symptoms. QLQ-HCC18 nutrition, fatigue, and body image scores improved from 54.7 ± 23.2 at baseline to 32.8 ± 19.5 at 12 months (P < 0.001), from 61.2 ± 21.8 to 38.4 ± 20.3 (P < 0.001), and from 48.9 ± 25.7 to 29.6 ± 21.4 (P < 0.001), respectively. QLQ-HCC18 jaundice and pain scores decreased from 35.2 ± 28.4 to 18.7 ± 22.3 (P < 0.001) and from 49.8 ± 26.1 to 27.5 ± 20.9 (P < 0.001), respectively.

Table 3 Changes in quality of life scores over time (n = 126), mean ± SD.

Scale/domain	At baseline	At 3 months	At 6 months	At 12 months	P value1
EORTC QLQ-C30
Global health status/QoL	52.3 ± 15.7	65.8 ± 14.5a	69.4 ± 13.8a	71.2 ± 14.3a	< 0.001
Physical functioning	68.5 ± 18.3	75.9 ± 16.8a	78.6 ± 16.1a	81.2 ± 15.7a	< 0.001
Role functioning	65.2 ± 21.4	72.4 ± 18.9a	76.1 ± 17.5a	78.9 ± 17.8a	< 0.001
Emotional functioning	63.7 ± 19.5	72.8 ± 17.2a	76.9 ± 16.4a	79.6 ± 16.2a	< 0.001
Cognitive functioning	71.8 ± 17.2	77.3 ± 15.8a	80.2 ± 15.1a	82.4 ± 14.9a	< 0.001
Social functioning	64.9 ± 20.8	71.5 ± 18.6a	74.8 ± 17.9a	77.3 ± 18.5a	< 0.001
Fatigue	58.3 ± 22.1	45.2 ± 20.3a	40.8 ± 19.7a	35.7 ± 19.4a	< 0.001
Nausea and vomiting	28.4 ± 21.5	22.7 ± 17.8a	19.3 ± 16.2a	15.2 ± 14.8a	< 0.001
Pain	52.6 ± 24.3	39.8 ± 21.6a	34.2 ± 20.1a	28.9 ± 18.7a	< 0.001
EORTC QLQ-HCC18
Fatigue	61.2 ± 21.8	48.7 ± 20.5a	43.9 ± 20.1a	38.4 ± 20.3a	< 0.001
Jaundice	35.2 ± 28.4	27.8 ± 24.7a	23.5 ± 23.1a	18.7 ± 22.3a	< 0.001
Nutrition	54.7 ± 23.2	42.3 ± 21.5a	37.8 ± 20.3a	32.8 ± 19.5a	< 0.001
Pain	49.8 ± 26.1	37.9 ± 23.4a	32.6 ± 21.8a	27.5 ± 20.9a	< 0.001
Body image	48.9 ± 25.7	38.2 ± 23.4a	33.7 ± 22.1a	29.6 ± 21.4a	< 0.001

^aP < 0.01 vs baseline (post-hoc analysis with Bonferroni correction).

¹P value from repeated-measures ANOVA for overall time effect.

EORTC: European Organization for Research and Treatment of Cancer; QLQ-C30: Quality of Life Questionnaire-Core 30; QLQ-HCC18: Quality of Life Questionnaire-Hepatocellular Carcinoma 18; QoL: Quality of life.

Correlation between psychological status and QoL

Correlation analysis revealed significant associations between psychological status and QoL outcomes at all time points (Table 4). At baseline, the HADS-A score was strongly negatively correlated with EORTC QLQ-C30 global health status (r = -0.68, P < 0.001), physical functioning (r = -0.61, P < 0.001), role functioning (r = -0.59, P < 0.001), and emotional functioning (r = -0.72, P < 0.001). Similarly, the HADS-D score showed negative correlations with global health status (r = -0.71, P < 0.001), physical functioning (r = -0.64, P < 0.001), role functioning (r = -0.62, P < 0.001), and emotional functioning (r = -0.75, P < 0.001). Both anxiety and depression scores were positively correlated with symptom scales, including fatigue (HADS-A: r = 0.58, HADS-D: r = 0.63, both P < 0.001), pain (HADS-A: r = 0.54, HADS-D: r = 0.57, both P < 0.001), and nausea/vomiting (HADS-A: r = 0.42, HADS-D: r = 0.45, both P < 0.001). The QLQ-HCC18 nutrition score showed strong correlations with both the HADS-A score (r = 0.56, P < 0.001) and HADS-D score (r = 0.61, P < 0.001). These correlation patterns persisted throughout the follow-up period; however, the correlation coefficients generally decreased in magnitude over time, consistent with the observed improvements in both psychological status and QoL.

Table 4 Correlation between the Hospital Anxiety and Depression Scale score and quality of life domains at baseline (n = 126).

QLQ-C30/QLQ-HCC18 domain	HADS-A score (r)	P value	HADS-D score (r)	P value
Global health status/QoL	-0.68	< 0.001	-0.71	< 0.001
Physical functioning	-0.61	< 0.001	-0.64	< 0.001
Role functioning	-0.59	< 0.001	-0.62	< 0.001
Emotional functioning	-0.72	< 0.001	-0.75	< 0.001
Social functioning	-0.57	< 0.001	-0.60	< 0.001
Fatigue	0.58	< 0.001	0.63	< 0.001
Pain	0.54	< 0.001	0.57	< 0.001
Nausea and vomiting	0.42	< 0.001	0.45	< 0.001
QLQ-HCC18 nutrition	0.56	< 0.001	0.61	< 0.001
QLQ-HCC18 fatigue	0.60	< 0.001	0.65	< 0.001
QLQ-HCC18 body image	0.52	< 0.001	0.55	< 0.001

HADS-A: Hospital Anxiety and Depression Scale-Anxiety subscale; HADS-D: Hospital Anxiety and Depression Scale-Depression subscale; QLQ-C30: Quality of Life Questionnaire-Core 30; QLQ-HCC18: Quality of Life Questionnaire-Hepatocellular Carcinoma 18; QoL: Quality of life.

Tumor response and survival outcomes

Tumor response was evaluated in all 126 patients. Based on the mRECIST criteria, the best overall response was observed in 18 (14.3%) patients achieving CR, 58 (46.0%) patients achieving PR, 38 (30.2%) patients with SD, and 12 (9.5%) patients with PD. The objective response rate was 60.3% (76/126), whereas the disease control rate was 90.5% (114/126). During a median follow-up period of 18.5 months (range: 6.2-36.0 months), 52 (41.3%) patients experienced disease progression, and 38 (30.2%) patients died. The median PFS was 14.3 months (95%CI: 11.8-16.9 months), and the median OS was not achieved at the time of data cut-off, with estimated 12-month and 24-month OS rates of 78.6% and 62.3%, respectively.

Factors associated with QoL outcomes

Multivariate logistic regression analysis was conducted to identify factors independently associated with good QoL (defined as global health status score ≥ 70) at 12 months. The factors included in the analysis were age, sex, ECOG performance status score, Child-Pugh class, BCLC stage, baseline HADS score, tumor response, and number of TACE procedures. Multivariate logistic regression analysis revealed that baseline HADS-A score ≥ 8 (OR = 0.28, 95%CI: 0.12-0.67, P = 0.004), baseline HADS-D score ≥ 8 (OR = 0.31, 95%CI: 0.13-0.74, P = 0.008), BCLC stage C (OR = 0.42, 95%CI: 0.19-0.93, P = 0.032), and objective tumor response (CR or PR; OR = 3.87, 95%CI: 1.52-9.85, P = 0.005) were independent predictors of QoL outcomes. In the multivariate model, age, sex, Child-Pugh class, and number of TACE procedures were not significantly associated with QoL at 12 months.

Safety and AEs

Treatment-related AEs are enumerated in Table 5. The most common AE was post-embolization syndrome (83.3%), followed by hypertension (47.6%), reduced appetite (42.9%), fatigue (38.1%), diarrhea (34.9%), and hand-foot skin reaction (31.7%). Most AEs were grade 1 or 2 in severity. Overall, 24.6% (n = 31) of patients experienced grade ≥ 3 AEs, including hypertension (9.5%), elevated transaminase levels (6.3%), proteinuria (4.0%), and thrombocytopenia (3.2%). No grade 4 AEs or treatment-related death occurred during the study period. Post-embolization syndrome was managed with a standardized supportive care protocol, including prophylactic antiemetics (8 mg of intravenous ondansetron), analgesics (50-100 mg of tramadol or non-steroidal anti-inflammatory drugs), antipyretics (acetaminophen), and intravenous fluid rehydration. All cases typically resolved within 5-7 days without long-term sequelae. Importantly, QoL assessments at 3 months and beyond revealed that the short-term effects of post-embolization syndrome did not impede any significant improvements in patient-reported outcomes, suggesting effective symptom management during the acute post-procedure period. Lenvatinib dose reduction was required in 28 (22.2%) patients because of AEs, with the most common reasons being hypertension (n = 10), fatigue (n = 8), and hand-foot skin reaction (n = 6). Notably, patients who required dose reduction maintained comparable tumor response rates to those who continued full-dose therapy (objective response rate: 57.1% vs 61.2%, P = 0.69), and the median PFS did not significantly differ between the two groups (13.8 months vs 14.6 months, P = 0.54), indicating that dose modifications for tolerability did not substantially compromise treatment efficacy. Lenvatinib treatment was permanently discontinued because of AEs in eight (6.3%) patients. SAEs occurred in 12 (9.5%) patients, including liver abscess (n = 3), upper gastrointestinal bleeding (n = 2), and hepatic encephalopathy (n = 2), all of which resolved with appropriate management.

Table 5 Treatment-related adverse events (n = 126), n (%).

AEs	Any grade	Grade 1 or 2	Grade ≥ 3
Post-embolization syndrome	105 (83.3)	105 (83.3)	0 (0)
Hypertension	60 (47.6)	48 (38.1)	12 (9.5)
Reduced appetite	54 (42.9)	52 (41.3)	2 (1.6)
Fatigue	48 (38.1)	45 (35.7)	3 (2.4)
Diarrhea	44 (34.9)	43 (34.1)	1 (0.8)
Hand-foot skin reaction	40 (31.7)	38 (30.2)	2 (1.6)
Elevated AST/ALT	38 (30.2)	30 (23.8)	8 (6.3)
Nausea	36 (28.6)	36 (28.6)	0 (0)
Proteinuria	28 (22.2)	23 (18.3)	5 (4.0)
Thrombocytopenia	24 (19.0)	20 (15.9)	4 (3.2)
Dysphonia	22 (17.5)	22 (17.5)	0 (0)
Abdominal pain	20 (15.9)	20 (15.9)	0 (0)
Weight loss	18 (14.3)	18 (14.3)	0 (0)
Hypothyroidism	14 (11.1)	14 (11.1)	0 (0)

AE: Adverse event; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

DISCUSSION

This prospective study demonstrated that DEM-TACE combined with lenvatinib significantly improved anxiety, depression, and QoL in patients with primary HCC while maintaining an acceptable safety profile. These findings offer important insights into the holistic impact of DEM-TACE combined with lenvatinib beyond traditional measures of tumor response and survival.

The high baseline prevalence rates of anxiety and depression observed in the present study are consistent with those previously reported in the literature. Recent systematic reviews and meta-analyses have reported pooled prevalence rates of 22%-24% for depression and anxiety in patients with HCC; nevertheless, these figures vary considerably depending on assessment methods and patient populations. Studies conducted in Asia, which has the highest incidence of HCC, have reported even higher rates, with some reports documenting prevalence rates of up to 64% and 65% for anxiety and depression, respectively[12]. Increased psychological distress among patients with HCC can be attributed to multiple factors, including the diagnosis of a life-threatening illness, concerns about treatment efficacy and adverse effects, financial burden, and impact on family dynamics[21].

The mechanisms underlying the improvements in psychological status observed after DEM-TACE combined with lenvatinib are likely multifactorial. First, effective tumor control through this combination therapy may directly alleviate disease-related symptoms such as pain, fatigue, and appetite loss, thereby reducing physical distress that often contributes to psychological symptoms[22]. Second, the achievement of tumor response offers hope and a sense of control over cancer among patients, which can positively influence their psychological well-being[23]. Third, the improvements in functional status and ability to perform daily activities may enhance self-esteem while reducing feelings of helplessness commonly associated with cancer[24]. Additionally, the Hawthorne effect, in which continuous attention, monitoring, and support from the multidisciplinary medical team throughout the treatment process contribute to improved psychological outcomes, cannot be discounted. Regular follow-up visits, detailed symptom assessments, and responsive clinical care may provide patients with reassurance and a sense of being cared for, which are important psychological factors that complement the direct effects of tumor control on psychological well-being.

Beyond statistical significance, the observed improvements in QoL in our study are clinically meaningful. The global health status score improved by 18.9 points from baseline to 12 months, considerably exceeding the established 10-point threshold for a clinically meaningful change in EORTC QLQ-C30 scores[25,26]. Similarly, the improvements in functional scale scores (physical functioning: 12.7 points, role functioning: 13.7 points, emotional functioning: 15.9 points) surpassed the 10-point threshold for a clinically significant difference. Such magnitude of changes implies that the combination therapy not only led to statistical improvements but also provided meaningful and perceptible benefits in patients’ daily lives and overall well-being. This distinction between statistical and clinical significance is important for clinicians and patients when making treatment decisions, as it demonstrates that the observed improvements represent real patient-perceivable enhancements in QoL rather than merely numerical changes.

The strong correlations between psychological status and QoL observed in our study are consistent with the findings of previous studies reporting that depression and anxiety are major determinants of health-related QoL in patients with cancer[27]. These bidirectional relationships suggest that interventions targeting psychological distress may yield benefits not only for mental health but also for overall QoL and potentially clinical outcomes. Psychological interventions, including cognitive-behavioral therapy, mindfulness-based stress reduction, and supportive counseling, can effectively reduce anxiety and depression while improving QoL in patients with cancer[28,29].

The tumor response rate and survival outcomes observed in our study are comparable to or better than those reported by recent studies on TACE-lenvatinib combination therapy. A multicenter retrospective study reported an objective response rate of 69.3% and median PFS of 10.4 months with lenvatinib combined with programmed death receptor-1 inhibitors plus TACE[30]. Another study evaluating TACE combined with lenvatinib vs TACE alone reported superior PFS (17.3 months vs 13.7 months) and OS (25.6 months vs 15.7 months) with combination therapy[31]. The synergistic mechanisms underlying the efficacy of TACE-lenvatinib combination therapy likely involve multiple pathways, including enhanced tumor ischemia through embolization, targeted inhibition of angiogenesis by lenvatinib, and potential immunomodulatory effects[32].

The combination of TACE and systemic therapy has recently been suggested to offer particular benefits in patients with intermediate-stage HCC with high tumor burden or those at risk of progression to advanced stage[33]. The LAUNCH trial showed that TACE combined with lenvatinib significantly improved OS and PFS compared with TACE alone in patients with advanced-stage HCC[34]. Furthermore, previous studies on triple therapy combining TACE, lenvatinib, and immune checkpoint inhibitors reported even more promising results, with an objective response rate exceeding 65% and median OS extending beyond 18 months[35,36].

The safety profile of DEM-TACE combined with lenvatinib in our study was generally manageable, with most AEs being grade 1 or 2 in severity. The incidence of grade ≥ 3 AEs was comparable to that reported in previous studies investigating lenvatinib monotherapy and combination regimens[37]. Post-embolization syndrome was the most common AE, occurring in 83.3% of patients, which is consistent with reported rates following TACE procedures. Importantly, the incidence of severe hepatotoxicity and biliary complications appeared lower than some earlier reports of DEM-TACE, potentially reflecting improvements in technique, patient selection, and supportive care[6]. The relatively low rate of treatment discontinuation due to AEs suggests that this combination therapy is generally well-tolerated when appropriately managed.

Several factors should be considered when interpreting our findings. First, the identification of baseline anxiety and depression as independent predictors of QoL outcomes underscores the importance of early psychological screening and intervention in patients with HCC. Implementing routine psychological assessment at diagnosis and throughout treatment may enable timely identification of patients who would benefit from psychological support services[28]. Second, the achievement of objective tumor response was strongly associated with improved QoL, highlighting the interconnected nature of physical and psychological well-being in patients with cancer. This finding supports the importance of optimizing treatment efficacy while simultaneously addressing psychological needs[29].

Third, the progressive improvements in QoL observed over the 12-month follow-up period suggest that the benefits of treatment extend beyond immediate tumor control. This may reflect recovery from baseline symptoms, adaptation to the diagnosis and treatment regimen, and potentially positive feedback effects between psychological improvement and physical functioning[30]. Fourth, the strong correlations between the HADS score and multiple QoL domains emphasize the pervasive impact of psychological distress on various aspects of patient well-being, including physical, emotional, and social functioning[31].

The treatment-related improvements in nutrition-related QoL metrics deserve particular attention. Malnutrition and cachexia are common complications in patients with HCC, contributing to decreased QoL and poorer outcomes[32]. The improvement in QLQ-HCC18 nutrition scores following treatment may reflect both direct effects of tumor control on appetite and metabolic function, as well as psychological benefits that enhance motivation to maintain adequate nutrition[33]. Nutritional interventions, when combined with effective cancer treatment and psychological support, may provide additive benefits for patients with HCC[34].

The identification of baseline anxiety and depression as independent predictors of poor QoL outcomes has important clinical implications. While our study did not implement formal psychological interventions as part of the treatment protocol, the findings suggest that patients with high baseline HADS score (≥ 8) may likely benefit from targeted psychological support. For patients with elevated anxiety or depression scores, future treatment protocols should incorporate routine psychological screening at diagnosis, followed by referral to psycho-oncology services. Evidence-based interventions such as cognitive-behavioral therapy, mindfulness-based stress reduction, and pharmacological treatment with selective serotonin reuptake inhibitors may provide additive benefits when combined with effective cancer treatment[28,29]. The integration of such interventions represents a clear direction for future treatment optimization strategies and requires investigations through randomized controlled trials.

From a clinical practice perspective, our findings support the integration of psychological screening and support into standard care for patients with HCC receiving DEM-TACE and lenvatinib therapy. The HADS has proven to be a practical and effective screening tool in this population, enabling efficient identification of patients requiring additional psychological interventions[35]. Multidisciplinary care teams that include psycho-oncology specialists, along with hepatologists, interventional radiologists, and oncologists, may optimize both physical and psychological outcomes for patients with HCC[36,37].

Our study has some limitations that warrant acknowledgment. First, as a single-center study, the generalizability of our findings to other populations and healthcare settings may be limited. Regional variations in HCC epidemiology, treatment practices, and psychosocial support systems may influence outcomes. Second, the lack of a control group receiving alternative treatment regimens limits our ability to attribute the observed improvements specifically to the DEM-TACE and lenvatinib combination. However, the magnitude and consistency of improvements across multiple psychological and QoL domains, along with favorable tumor response rates, suggest genuine treatment benefits. Third, the 12-month follow-up period, while adequate for assessing short to medium-term outcomes, may not fully capture long-term psychological trajectories and QoL. Longer-term studies are needed to determine whether the improvements observed are sustained over time. Fourth, we did not assess or control for potential confounding factors such as social support networks, financial resources, or receipt of psychological interventions outside the study protocol. These factors may have influenced both baseline psychological status and treatment responses. Fifth, survivorship bias may affect the interpretation of late follow-up data, as patients who died or progressed early were not included in later assessments. Finally, the study did not include detailed assessment of specific psychological interventions or coping strategies that patients may have employed during treatment, limiting our understanding of mechanisms underlying psychological improvements.

Future research directions should include randomized controlled trials comparing DEM-TACE combined with lenvatinib against alternative treatment strategies with comprehensive psychological and QoL assessments. Investigating the potential benefits of formal psychological interventions, such as cognitive-behavioral therapy or mindfulness-based approaches, as adjuncts to medical treatment would be valuable. Studies examining biomarkers of psychological distress and their relationship to inflammatory markers and tumor biology could provide insights into the mechanisms linking psychological status to clinical outcomes. Long-term follow-up studies tracking QoL trajectories and identifying factors associated with sustained psychological well-being would inform supportive care strategies. Finally, cost-effectiveness analyses incorporating quality-adjusted life years would help establish the value proposition of this combination therapy from both clinical and health economic perspectives.

CONCLUSION

DEM-TACE combined with lenvatinib demonstrates favorable efficacy in improving anxiety, depression, and QoL in patients with primary HCC while maintaining an acceptable safety profile. The strong associations between psychological status and QoL outcomes underscore the importance of holistic patient-centered care that addresses both physical and psychological needs. Early identification and management of psychological distress should be integrated into routine care for patients with HCC undergoing this treatment regimen to optimize overall outcomes and patient well-being.