Survival Analysis of TACE Monotherapy vs. Combination Therapy in BCLC B and C Stage Hepatocellular Carcinoma: A Retrospective Cohort Study

doi:10.21203/rs.3.rs-5011990/v1

Introduction

Standard treatments provide limited benefits for patients with intermediate or advanced hepatocellular carcinoma (HCC). This retrospective observational study aimed to assess potential improvements associated with systemic therapies in patients receiving transarterial chemoembolization (TACE) for initially unresectable HCC.

Methods

Between February 2019 to March 2023, we reviewed patients diagnosed with intermediate- to-advanced HCC, treated with either TACE or TACE combined with antiangiogenic and immunotherapy (combination group) as their initial treatment. To balance the impact of confounding biases, we further divided the entire study population into surgical and non-surgical cohorts and conducted separate assessments. The analysis focused on comparing the progression-free survival (PFS), overall survival (OS) and safety profile of the combination group with those of TACE monotherapy.

Results

Out of 279 patients with initially unresectable intermediate or advanced HCC, 156 successfully underwent subsequent curative intent liver resection after preoperative treatments (TACE group, n = 69, combination group, n = 87), while 123 patients continued non-surgical treatments (TACE group, n = 31, combination group, n = 92). After PSM, 26 matched patient pairs were generated in non-surgical cohort. The combination group exhibited a significantly extended PFS for non-surgical patients (9.4 vs. 7.2 months, p = 0.043). Cox analysis also suggested that this combination therapy regimen was associated with improved PFS in non-surgical cohort (HR = 0.476, 95% CI: 0.257–0.883, p = 0.019). In surgical patients exceeding up-to-seven criteria, the combination group demonstrated superior median PFS (18.0 vs. 14.6 months, p = 0.03) and OS (Not reached vs. 50.1 months, p = 0.049) compared to the TACE group. Adverse events were manageable and did not result in any treatment-related fatalities.

Conclusion

TACE in combination with systemic antitumor therapy demonstrated improved survival benefits in patients with intermediate to advanced HCC, particularly among surgical patients with higher tumor burden.

Transarterial chemoembolization

Combination therapy

Survival

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal malignancies worldwide, representing a relative 5-year survival rate of approximately 18% ^{[1, 2]}. The Barcelona Clinic Liver Cancer (BCLC) algorithm, which categorizes patients with HCC into five clinical stages, has been extensively employed on treatment allocation and prognosis prediction^{[3, 4]}. Although curative surgical therapies can confer survival benefits for early-stage cases (BCLC stage 0 or A), the majority of patients with HCC are diagnosed at an initially unresectable stage (BCLC Stage B or C). Transarterial chemoembolization (TACE) or systemic therapy play an important role in the management of intermediate or advanced HCC according to current practice^[5]. Nevertheless, efficacy of standard treatment alone remains unsatisfactory.

Recently, recommendations on multimodal treatment regimens for patients with locally advanced HCC have attracted much attention^{[6, 7]}. Much clinical research has been conducted to associate TACE with molecularly targeted or immune therapies, exhibiting promising results with tolerable toxicity for patients with advanced or unresectable HCC^[8–13]. As the encouraging improvement of survival in patients with technically and oncologically unresectable HCC after conversion therapy have been reported^[14], several studies also explored the perioperative effects and oncological outcomes of preoperative TACE combined with antiangiogenic therapy and/ or immune checkpoint inhibitors (ICIs)^[15–17]. However, it remains worth exploring whether more proactive combination strategies could reduce postoperative recurrence or achieve long-term tumor control, and identifying appropriate preoperative treatments from the perspective of survival benefits among patients with intermediate or advanced HCC.

Therefore, this retrospective research was designed to evaluate the clinical outcomes of TACE alone or in combination with immune and targeted therapy in the primary treatment for patients with intermediate to advanced stage HCC.

Study Design and Patients

This study was reviewed and approved by the research ethics committee of our hospital and performed in accordance with the principles of the Declaration of Helsinki and the STROCSS criteria^[18]. We retrospectively reviewed medical records for 598 consecutive patients with treatment-naive intermediate or advanced HCC who received with TACE alone or the combination therapy (TACE plus antiangiogenic agents with or without ICIs) at our institution from February 2019 to March 2023. These patients were considered ineligible for primary surgical resection by our multidisciplinary team (MDT) due to factors such as insufficient residual liver volume, uncontrolled comorbidities or technical reasons. All treatment decisions were reviewed by the attending physicians and consented by individual patients. Our study has been registered on ClinicalTrials.gov with the identifier NCT06261138.

Enrolled patients were also required to meet the following conditions: (1) age ranging from 18 to 75 years, (2) histologically or clinically confirmed HCC based on the American Association for the Study of Liver Diseases criteria^[19] and Chinese Guidelines for Diagnosis and Treatment of Primary Liver Cancer^[20], with no prior antitumor therapy, (3) at least one reproducibly measurable target lesion according to modified Response Evaluation Criteria in Solid Tumors (mRECIST)^[21], (4) BCLC stage B or C, and Child-Pugh liver function of A (score 5–6) to B (score 7), (5) anti-angiogenic therapy should be administrated for more than one month, and there were no restrictions regarding the types of systemic agents, (6) adequate organ and hematologic function.

Exclusion criteria included: (1) tumor recurrence after curative resection or ablation or diffuse unresectable HCC, (2) spontaneous rupture and bleeding of HCC, (3) pathologically confirmed cholangiocarcinoma or mixed HCC in cases involving surgical resection, (4) evidence of autoimmune disease or other concomitant malignancies or organ transplantation, (5) the interval between the initial administration of systemic medication and the first TACE procedure exceeded one month when patients received combination therapy, (6) discontinued treatment due to severe adverse reactions, (7) incomplete imaging or follow-up information.

TACE Procedure

Patients included in the study underwent either conventional TACE (cTACE) or drug-eluting beads TACE (DEB-TACE) procedures performed by experienced interventional radiologists, taking into account tumor burden, patient tolerance, and individual preferences. The femoral arteries were cannulated with an arterial catheter sheath by the Seldinger technique under local anesthesia. A 5-French RH catheter was then introduced to the celiac artery, superior mesenteric and artery common hepatic artery for angiography to determine tumor location, quantity, size, and vascularity. After confirmation by C-arm cone-beam computed tomography (CBCT), chemoembolization was administered by superselective catheterization of the branches of the tumor-feeding arteries using a 2.8-French coaxial microcatheter. For cTACE, oxaliplatin, raltitrexed and an emulsion containing idarubicin and ethiodized oil were infused for over 20 minutes, followed by combined embolization with blank embolic microspheres. For DEB-TACE, DC/LC Beads® (Biocompatibles, Farnham, Surrey, UK), as drug carriers and embolic materials, were loaded with doxorubicin hydrochloride and mixed with nonionic contrast medium. Real-time assessment of embolization was performed with the assistance of CBCT. The specific dosage of chemotherapy drugs and embolization agents were adjusted to achieve effective embolization based on the patient's tumor characteristics, body surface area, and specific condition. If necessary, additional embolization was conducted until slow-flowing blood or near stasis is observed in the artery directly feeding the tumor. Sheaths were removed and pressure bands and standard supportive care were provided after the procedure^[22].

Decisions regarding the need for repeated TACE procedures were guided by the MDT evaluation depending on objective tumor response.

Systemic Treatment

Systemic treatment commenced within one month after the initial TACE procedure, depending on the proper liver function. Anti-angiogenic agents involved in this study mainly comprised multikinase tyrosine kinase inhibitors (TKIs), such as sorafenib (Bayer HealthCare, Berlin, Germany), lenvatinib (Eisai, Tokyo, Japan), apatinib (Hengrui Pharmaceuticals, Lianyungang, China) and donafenib (Zelgen Biopharmaceuticals, Suzhou, China), while a minority of patients received bevacizumab (Innovent Biologics, Suzhou, China), a vascular endothelial growth factor inhibitor. ICIs included therapies targeting programmed cell death protein 1 and its ligands, such as sintilimab (Innovent Biologics, Suzhou, China), toripalimab (Junshi Biosciences, Suzhou, China), camrelizumab (Hengrui Pharmaceuticals, Lianyungang, China), tislelizumab (BeiGene, Shanghai, China), pembrolizumab (Merck Sharp & Dohme, NewJersey, USA), nivolumab (Bristol Myers Squibb, New York, USA), atezolizumab (Roche, Basel, Switzerland) and envafolimab (Alphamab Biopharmaceuticals, Suzhou, China).

The decision to combine systemic treatments was informed by guideline recommendations, reported efficacy and safety data and MDT discussions. The selection of medication type is made by the patient based on pros and cons, drug availability, as well as medical insurance and charity policies. The initial dosages, frequencies of systemic medications were administered in accordance with the drug's instructions. Dose reduction or treatment interruption was determined by the doctor's judgement and primarily influenced by treatment-related side effects or disease condition. Drugs were discontinued upon intolerable toxicity, disease progression or patient choice.

Surgical Resection

Patients could be candidates for subsequent curative resection if they met the following criteria on the basis of MDT evaluations: (1) imaging evidence of significant tumor shrinkage or necrosis or downstaging and capsule formation with a significant decline in serum tumor marker, (2) technically resectable with clear margins, and better predicted efficacy after surgery compared with non-surgical approaches, (3) intact or reconstructive vascular and bile-duct structures, and sufficient liver reserve function and remnant liver volume, (4) patients were generally good health, without contraindications for hepatic resection, and willing to undergo surgery, (5) hepatectomy may be superior to alternative treatment approaches following multidisciplinary discussions^[14]. Surgical resection should be scheduled within 8 weeks following the last TACE treatment, with a 2-week interruption in systemic therapy preceding the surgery. The hepatectomy procedure and postoperative management have been detailed in our previous study^[23]. Additional radiotherapy or intraoperative radiofrequency ablation was permitted whenever feasible. If necessary, thrombectomy was performed according to the location and extent of tumor thrombus for patients with macrovascular invasion^[24–26].

Following hepatectomy, pathological analysis consisted of histological differentiation, tumor size, number and location, surgical margin, the presence of satellite and microvascular invasion (mVI) and the percentage of residual viable tumor were reviewed and verified by experienced pathologists^[27]. Surgeons formulated personalized adjuvant therapy based on various factors, including tumor pathological characteristics, the effectiveness of preoperative treatments, overall health status, and economic considerations.

Assessments and Follow-up

At the initial diagnosis and within 4–8 weeks after each TACE treatment session, comprehensive laboratory tests and imaging examinations, including enhanced computed tomography (CT) or nuclear magnetic resonance imaging (MRI), were routinely conducted. Treatment response, categorized into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), was assessed and reviewed by experienced diagnostic radiologists as per the mRECIST^[21]. The best preoperative tumor response was also recorded as the final evaluation results for who underwent surgical resection.

The established treatment plan required modification if patients experienced PD or intolerable adverse effects through MDT discussion. Alternatively, it was recommended to either continue the current therapy or consider radical resection depending on the specific condition. For patients with progression or resection, regular follow-up assessments were carried out every 2–3 months thereafter to ascertain the patterns of recurrence (considering angiographic and/or radiologic findings) and survival status. And the choice of the subsequent treatments is also determined by MDT guidance and the patients’ requests.

Treatment-related adverse events (TRAEs) or postoperative complications were documented in the patients' medical records or ascertained through follow-up inquiries, and the degree of severity graded using National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0) or the Clavien-Dindo classification^[28]. For grade 1 to grade 2 TRAEs promptly managed with favorable recovery, treatment regimens remained unaltered. In the event of grade ≥ 3 or any persistent TRAEs, dose reduction or treatment suspension was required until symptoms alleviated to grade 1 or 2.

Progression-free survival (PFS) was the primary endpoint, which was referred to the time from the initiation of TACE treatment to the first documented disease progression (non-surgical patients) or tumor recurrence (surgical patients), death, whichever occurred first. Overall survival (OS) was the secondary endpoint of our study. For all patients, OS was defined as the duration from the start of treatment until all-cause death. Patients who remained alive without observed progression or recurrence were censored at their last follow-up date, which concluded on October 2023.

Statistical Analysis

Patient baseline information, treatment course, perioperative parameters and disease progress were collected and analyzed retrospectively. Qualitative and quantitative variables were compared using the Chi squared test and Student’s t test, respectively. We utilized Kaplan-Meier curves to illustrate the survival outcomes among different groups and assessed the significance of differences through the Log-rank test. All statistical analyses were conducted using SPSS statistical software (Version 23.0, IBM Corp., Armonk, NY, USA), and a two-side p value < 0.05 was considered statistically significant.

Recognizing the potential bias associated with surgical interventions, we stratified our study population into "non-surgical" and "surgical" groups. To mitigate the selection bias and minimize the impact of confounding factors within the surgical and non-surgical patients, we employed two distinct statistical approaches to comprehensively explore the association between treatment modalities (TACE monotherapy or combination therapy) and survival outcomes. For the non-surgical group, propensity score matching (PSM) analysis was conducted by incorporating the following covariates into the logistic regression model: age, AFP level, etiology, Child-Pugh class, tumor number and size, tumor distribution, presence or absence of macrovascular invasion and extrahepatic metastasis, BCLC stage, and concurrent treatment. The caliper width was set at 0.02, ensuring a one-to-one match through nearest-neighbor method without replacement between the two groups. For the surgical group, we strategically employed a stratified survival analysis method based on the up-to-seven criteria^[29] aiming to balance the variances in tumor burden, thereby control the potential influence of surgical intervention on our study results. Subsequently, Cox regression analysis was also performed to identify independent risk factors for the survival outcome, based on the coefficients and significance levels of each variable.

From February 2019 and March 2023, 598 consecutive patients with treatment-naive HCC who underwent TACE were retrospectively screened. After applying exclusion criteria, a total of 279 patients with initially unresectable intermediate-advanced HCC were enrolled in the analysis, including 100 patients received TACE monotherapy (TACE group) and 179 patients received TACE combined with anti-angiogenic therapy and ICIs (combination group). Out of these, 156 patients successfully underwent subsequent curative-intent liver resection after preoperative treatments, comprising 69 from the TACE group and 87 from the combination therapy group (p <0.01). Conversely, 31 patients in the TACE group and 92 patients in the combination group continued non-surgical treatments due to tumor-related factors or personal choice. (Shown in Fig. 1). We further divided the cohort into non-surgical and surgical segments for separate analyses.

Characteristics and treatments of non-surgical patients

In the TACE group, the median age was 63 years (range, 34-75), with 16.1% showing hepatic vein invasion—highlighting significant difference compared to the combination group. In the combination group, maximum tumor diameter (8.3cm vs. 8.1cm, p= 0.198), main portal vein invasion rate (66.3% vs. 54.8%, p= 0.252), and extrahepatic metastasis rate (28.3% vs. 16.1%, p= 0.178) were slightly higher than those in the TACE group, but without statistical significance. The two groups had comparable proportions of patients undergoing repeated TACE, with 67.7% in the TACE group and 66.3% in the combination group. After PSM, 26 non-surgical patients from the combination group were matched to 26 non-surgical patients from the TACE group, resulting in balanced baseline characteristics and staging between the two groups (All p > 0.05, Table 1).

The TACE group underwent a total of 73 cycles of TACE procedures, while the combination group received 195. There were no significant differences in the total number or types of TACE treatments between the two groups. However, a statistical difference was observed in the duration of treatments before disease progression (6.1 months vs. 8.4 months, p= 0.05). In the combination group, Lenvatinib (72, 78.3%) remained the primary choice among targeted therapies, whereas Tislelizumab (27, 29.3%), Sintilimab (23, 25%), and Envolizumab (19, 20.7%) were commonly used in immunotherapy. After PSM, treatment-related information became comparable between the two groups (Supplemental Table 1).

Survival analysis for non-surgical patients

The median follow-up duration for the non-surgical patients was 16.4 (range, 2.4-43.6) months. At the last follow-up date, a total of 30 (96.8%) patients in the TACE group and 77 (82.6%) patients in the combination group developed disease progression or metastasis or mortality.

In both the unmatched cohort (8.6 months [95% CI, 7.37-9.69] vs. 6.3 months, [95% CI, 4.25-8.35], hazard ratio [HR]= 0.74, p= 0.02) and the PSM-matched cohort (9.4 months [95% CI, 5.0-13.67] vs. 7.2 months, [95% CI, 2.89-11.06], HR=0.76, p= 0.043), patients in the combination group exhibited significantly longer PFS compared to those in the TACE group [Shown in Fig. 2. A and B]. The 1-year PFS rates before and after PSM were 37.0% and 42.3% in the combination therapy group, and 25.8% % and 30.8% in the TACE group, respectively. The median OS of the TACE group was 16.6 months (95% CI: 12.50-20.76), comparable to the combination group of 16.4 months (95% CI: 13.42-19.32), with an HR of 1.02 (p= 0.517). For PSM patients, the median OS of the combination group (22.9 months [95% CI, 15.63-30.23] vs. 22.0 months [95% CI, 12.37- 31.57], HR= 0.82, p=0.552) appeared slightly longer than that of TACE alone without statistical significance. [Shown in Fig. 2. C and D].

We also examined the progression pattern and post-progression treatments for all non-surgical patients. There still was no significant difference in the disease progression pattern between the two non-surgical groups. Among those who experienced disease progression in both groups, 17 patients (56.7%) in the TACE group and 26 patients (33.8%) in the combination group continued to receive TACE in combination with either first or second-line systemic drugs. Seven patients (9.1%) in the combination group chose to enroll in clinical trials. Supplemental Table 1 further detailed the treatment regimens provided to patients after tumor progression.

Univariate and multivariate Cox regression analyses conducted in the entire non-surgical patient cohort revealed that TACE treatment (HR= 1.915, 95% CI: 1.224-2.996, p= 0.004) and the largest tumor size (HR= 1.069, 95% CI: 1.019-1.122, p=0.006) were independent risk factors leading to a reduced PFS. Subsequent multivariate analysis within the PSM cohort demonstrated a similar result, identifying TACE monotherapy (HR= 2.101, 95% CI: 1.133-3.897, p=0.019) and a longer baseline tumor maximum diameter (HR= 1.120, 95% CI: 1.023-1.226, p=0.014) as prognostic factors associated with inferior PFS (Table 2).

Characteristics and treatments of surgical patients

All surgical patients were classified as Child-Pugh A, while the combination group had more patients with advanced HCC (62.1% vs. 40.6%, p= 0.008) and showed higher tumor burdens (Table 3). The median size of the largest nodule was 6.0cm in the TACE group and 8.9cm in the combination group (p= 0.007). Moreover, patients in the combination group presented elevated baseline AFP levels and a higher incidence of hepatic vein invasion. There were no significant differences in baseline tumor numbers and main portal vein invasion between the two groups. Similar proportions of patients in the TACE and combination groups underwent concomitant radiotherapy (17.2% vs. 10.1%, p= 0.206). However, a greater percentage of patients in the combination group received multiple preoperative TACE sessions (50.6% vs. 17.4%, p<0.001) and underwent postoperative adjuvant treatments (93.1% vs. 68.1%, p<0.001).

Regarding treatment details, the median numbers for TACE treatments were 1 (range, 1-4) and 2 (range, 1-4) in the TACE and combination groups, respectively (Supplemental Table 2). Lenvatinib (69, 79.3%) was the most frequently utilized anti-angiogenic agent, while Sintilimab (31, 35.6%) was the primary choice among immunotherapies. The median duration between the initial TACE treatment and surgical resection was 1.5 months (range, 0.8-10.4) for the TACE group and 3.2 months (range, 0.9-14.4) for the combination group (p< 0.001). The primary approach for hepatectomy in patients was open surgery, with 9 patients (10.4%) in the combination group underwent robot-assisted resection. The major hepatectomy rate (62.3% vs. 72.4%, p= 0.180) and postoperative hospital stay (9 days vs. 10 days, p= 0.831) showed no significant differences between the two groups. After preoperative therapy, 32 patients (46.4%) in the TACE group and 52 patients (59.8%) in the combination group achieved an objective response according to the mRECIST criteria. Postoperative pathological examination identified microvascular invasion in 19 patients (27.5%) and 17 (19.5%) patients, respectively. Furthermore, pathological evaluation indicated a higher rate of complete pathological response in the combination group, although the difference was not statistically significant (8.0% vs. 2.9%, p= 0.171).

Survival analysis for surgical patients

After a median post-surgery follow-up period of 24.0 months (range, 1.5-55.2), recurrence occurred in 101 patients (49 in the TACE group, 52 in the Combination group), and 42 patients (23 in the TACE group, 19 in the combination group) died.

A subgroup analysis was conducted in surgical patients (shown in Fig. 3). The preoperative combination therapy showed a survival benefit in these subgroups: absence of HBV infection (p= 0.027), largest tumor diameter> 5 cm (p= 0.032) and tumor number> 2 (p= 0.029). In order to clarify the beneficial population more accurately, we further analyzed up-to-seven criterion in the surgical cohort.

Among a total of 106 surgical patients whose baseline tumor burden outside the up-to-seven criteria, PFS was statistically significantly better in the combination group compared to the TACE group (18.0 vs. 14.6 months, p= 0.03, HR= 0.61, 95% CI: 0.37-0.96), with corresponding 1-year PFS rates of 59.7% and 56.8%. Also, there was a significant difference in the median OS for both groups (Not reached vs. 50.1 months, p= 0.049, HR= 0.48, 95% CI: 0.22-1.0), and the 1-year OS rates were 98.4% and 90.7%, respectively [shown in Fig. 4. A and B].

In contrast, among 50 patients who met the up-to-seven criteria, the median PFS was 29.4 months in the TACE group and 16.7 months in the combination group, yielding a HR of 1.57 (95% CI: 0.74-3.3; p= 0.23) that did not reach statistical significance. Correspondingly, the 1-year PFS rates were 52% and 79.3%, respectively. Similarly, although the median OS was not reached in either group, the TACE group showed a slightly better outcome than the combination group (Not reached vs. Not reached, p= 0.075, HR= 0.50, 95% CI: 0.18-1.40), with respective 1-year OS rates of 95.8% and 84.0% [shown in Fig. 4. C and D].

The primary recurrence pattern remains intrahepatic tumor. In both groups, 73.5% and 67.3% of patients, respectively, underwent a combination of locoregional therapy and systemic therapy. In the entire surgical patient cohort, Cox regression analysis for survival revealed an increased risk of worse PFS for individuals with positive chronic HBV infection (HR=1.736, 95% CI: 1.009-3.082, p=0.047), a greater baseline tumor number (HR=1.318, 95% CI: 1.080-1.609, p=0.007), a larger maximum diameter (HR=1.092, 95% CI: 1.034-1.153, p=0.002) and pathologically confirmed satellite nodule (HR=1.692, 95% CI: 1.038-2.758, p=0.035). Notably, this risk was found to be independent of the preoperative treatment modality (Table 4).

Safety

Each patient in both groups experienced at least one TRAE during the treatment period, which included adverse reactions resulting from both the TACE procedure and drug-related effects.

The primary adverse effect following TACE was post-embolization syndrome, characterized by abdominal pain, fever, nausea, and elevated liver function levels, with the majority being grade 1 or 2. The profile and severity of drug-related adverse events were comparable between surgical and non-surgical groups. Commonly observed adverse events included fatigue, gastrointestinal reactions, skin rash, hand-foot syndrome, as well as thyroid dysfunction, anemia, hypoalbuminemia, and thrombocytopenia. Moreover, combination therapy did not significantly increase the incidence of grade 3/4 TRAEs compared to TACE monotherapy. In the combination therapy group, 13 patients (14.1%) underwent a dose reduction of antiangiogenic drugs, and 5 patients (5.4%) experienced interruptions in systematic treatments due to intolerable toxicity, disease progression, or personal reasons.

Furthermore, among surgical patients, 21 (30.4%) in the TACE group and 31 (35.6%) in the combination group suffered from postoperative complications, such as pleural and abdominal effusion, hepatic failure, and bile leakage. Symptomatic interventions effectively managed the majority of these complications. The overall incidence of severe complications was slightly higher in the combination therapy group compared to the TACE group, but without statistical significance. Both groups had no perioperative deaths. Detailed TRAE profiles are summarized in the Table 5.

Patients with intermediate to advanced HCC continue to face challenges in achieving enhanced efficacy despite the widespread utilization of TACE. While TACE effectively alleviates the tumor burden, it introduces several unfavorable factors, including incomplete tumor necrosis, hypoxia, angiogenesis and immune suppression^{[30, 31]}. Simultaneously, systemic therapy has become an effective treatment for all stages of HCC. Multiple antiangiogenic agents have demonstrated potential in modifying tumor revascularization and enhancing drug delivery following TACE^[32]. Furthermore, inflammation and tumor-associated antigens induced by TACE or the inhibition of angiogenic factors may modulate the tumor immunosuppressive microenvironment, thereby improving the antitumor immune response, especially when combined immunotherapy^[33–36]. Recent data have reported improved outcomes with the combination of TACE, antiangiogenics and ICIs in unresectable or advanced HCC^[37–39].

In the present study, the combination group of the non-surgical cohort also showed a prolonged median PFS of 9.4 months, which seemed slightly shorter than previous studies. However, it was worth noting that our non-surgical population, even with a larger proportion of technically or oncologically unresectable disease owing to local tumor invasion, distant metastases, or compromised hepatic function following multidisciplinary assessments, achieved better PFS outcomes than those received TACE monotherapy. Importantly, this significant difference persisted even after PSM. Moreover, this combination therapy regimen was consistently identified as a strongly protective factor for PFS both before and after PSM, reducing the risk of disease progression by approximately 50%. This further confirmed that, for patients who cannot be cured by resection, the incorporation of systemic therapies to TACE could provide stronger synergistic anti-tumor effect and durable tumor inhibition.

The recommendations for conversion/ downstage therapy in patients with intermediate or advanced-stage HCC have also experienced significant changes due to the evolution of combined strategies^{[40, 41]}. Many studies have reported that the combination of systemic drugs with TACE therapy can also improve the limited overall conversion to resection compared to TACE monotherapy^{[16, 42, 43]}. Given the challenges posed by the complexity of tumor burden variations for effective matching between the two treatment groups, a subgroup analysis was conducted among surgical patients. The results revealed that patients with higher tumor burden experienced significant benefits from liver resection following preoperative combination therapy. Then we attempted stratified analyses based on the up-to-seven criteria. This allowed us to categorize patients into levels with similar characteristics, thereby better controlling for the potential impact of tumor burden on the survival outcomes of surgical patients.

Previous studies have shown that triple combination therapy may contribute to better disease control in intermediate or advanced stage patients with tumor diameters ≤ 10cm, more than three tumors or distant metastases^{[44, 45]}. Our analysis suggested that the preoperative addition of systemic regimen may confer a significant tumor-free survival advantage over TACE monotherapy when surgical resection was performed in patients beyond up-to-seven criteria. We also observed that a greater baseline tumor number or a larger maximum diameter was related to a notable adverse impact on the PFS outcomes among the entire surgical patients. This underscored the crucial role of baseline tumor characteristics in both surgical interventions and survival outcomes. Patients presented a heavier tumor burden at the initial diagnosis, probably leading to tumor recurrence due to intractable malignant biological behaviors, more potential intrahepatic lesions and insufficient remnant liver after liver resection. Combination strategy not only presented a feasible therapeutic approach for initially unresectable HCC patients with high tumor loads to pursue surgical opportunities, but created a more favorable environment for subsequent treatment implementation due to the decreased tumor burden. It should be noted that the complexity of surgical resection increases accordingly for patients with multiple or larger or metastatic tumors. This improvement has also, to some extent, experienced challenges in achieving favorable postoperative oncological outcomes. Therefore, whether combination treatments could optimize the long-term outcomes of surgical resection remains worthy of exploration.

Retrospective research has indicated that achieving a complete response to TACE followed by liver resection could lead to improved survival for intermediate-stage HCC patients^[46]. In our study, there was a more favorable improvement in PFS or OS with preoperative TACE therapy for patients within the up-to-seven criteria compared to combination therapy, although statistical significance was not reached. However, cautious interpretation of these findings is necessary for several reasons. First, as TACE has shown superior performance in controlling smaller intrahepatic lesions rather than extrahepatic metastases or vascular tumor thrombus^[47], patients with lower tumor burden were more likely to benefit from preoperative TACE, thus increasing the probability of subsequent surgical resection. For patients meeting up-to-seven criteria, TACE monotherapy may already be effective, and surgery further enhanced survival rates^[48]. Consequently, combination therapy failed to demonstrate additional survival benefits. Second, the surgical group may be more heterogeneous, possibly leading to varied responses to combination therapy compared to the overall trend. Third, systemic therapy takes effect relatively late, and its efficacy may be counteracted by the therapeutic benefits of sequential resection. As a result, both the timing of surgery and the choice of postoperative treatment may influence the effectiveness of combination therapy. Lastly, the efficacy to preoperative combined therapy was also influenced by the interactional effects among treatment duration, resection difficulty, surgical approach, and tolerance. Therefore, whether systemic therapy should be employed in patients within up-to-7 before curative resection is worthy to be explored.

In our study, subsequent treatment schedules following recurrence or disease progression in both groups were also recommended through multidisciplinary discussion and guided by expert consensus or guidelines. Our results revealed no apparent difference in OS between two treatment groups in non-surgical patients or in surgical patients within up-to-seven. This may be attributed to the subsequent treatment choices and effectiveness, as well as the overall health condition of the patients. In fact, although PFS of combination group in the surgical cohort did not improve among patients within up-to-seven criteria, the available one-year OS rate was comparable to previous studies^{[16, 42]}. This indicated that various aggressive treatments, such as repeat hepatectomy, combination with locoregional therapies and second-line systemic treatments, or participation in clinical trials, could still enhance the prognosis for such patients. For patients with the potential for successful conversion to resection, it is crucial to choose appropriate perioperative treatment modalities and adjust the treatment plan promptly.

The optimal timing for surgical resection following preoperative therapy remains undefined. In our study, the TACE group and combination group had median preoperative durations of 1.5 and 3.2 months, respectively. Early surgical resection not only prevents residual tumor progression or severe liver dysfunction but also facilitates the application of more appropriate postoperative treatment strategies guided by pathological findings. Moreover, in our study context, the diverse treatment responses and survival outcomes observed among patients highlighted the necessity for personalized therapeutic strategies involving a thorough consideration of tumor characteristics, liver function, and overall patient health. While these results only represented the experience of our center and required further validation, they might offer valuable guidance for the implementation of neoadjuvant/ convention surgical resection in patients with initially unresectable or technical resectable intermediate and advanced- stage HCC who experience improvement with effective preoperative therapy.

All TRAEs observed in this study were consistent with the established safety profile of the therapies employed and did not appear to induce any uncommon overlapping toxicity. Most adverse effects were mild to moderate and were alleviated by dose modifications and symptomatic treatment. No significant differences in adverse reactions were observed between the two treatment groups in this study. It should be noted that the incidence of gastrointestinal bleeding observed in the combination group was comparable to historical data from the IMbrave 150 trial^[49], especially in the non-surgical cohort. This suggested that the long-term use of targeted drugs or immunotherapy may lead to alterations in vascular permeability or inflammatory reactions, thereby increasing the risk of bleeding in patients with cirrhosis. Consequently, it is necessary to undertake appropriate monitoring or intervention for patients with esophageal varices.

We also observed that the introduction of systemic medications did not significantly worsen perioperative safety outcomes or prolong postoperative hospital stays. Post-hepatectomy liver failure is a major contributor to postoperative mortality, and its incidence may be elevated due to the administration of preoperative TACE or systemic treatments. In our study, the incidence of liver failure was maintained within an acceptable level in both groups, possibly attributed to comprehensive multidisciplinary discussions and advancements in surgical techniques. Nevertheless, given the high tumor burden and/or extensive tumor involvement in patients at intermediate and advanced stages, alongside potential impairment of liver function and general condition from preoperative therapy, meticulous attention to perioperative management remains crucial.

There were several limitations in our study. Firstly, after applying strict inclusion criteria and conducting appropriate statistical analyses, this retrospective study was still constrained by a limited sample size, subjective selection bias and insufficient follow-up time. Secondly, despite efforts to maintain standardization, the evolving landscape and complexity of TACE and surgical techniques, as well as the diversity of systemic drugs during the study period, may potentially affect the consistency of treatment regimens and result in biases on treatment outcomes. Additionally, our study did not assess the relationship between radiological or pathological tumor response and long-term outcomes, further exploration is warranted to identify potential biomarkers predictive of the antitumor response or prognosis to TACE-based therapy and evaluate the application, method, and duration of postoperative adjuvant therapy. Finally, the results from a single-center study may present limitations in terms of their applicability to wider populations or different healthcare settings. Therefore, further validation through extended follow-up periods and large-scale prospective studies is necessary. Additionally, considering economic benefits and quality of life, the study findings also emphasize the necessity for additional research into the comparative effectiveness of sequential therapy versus combination therapy, single-drug versus multi-drug approaches, and the appropriateness of preoperative versus postoperative usage, especially in cases where surgical resection is feasible.

The incorporation of anti-angiogenic therapy and immunotherapy did not significantly increase the incidence of adverse events compared to TACE alone. Instead, combination therapy was associated with favorable PFS in the non-surgical cohort among patients with BCLC B and C stage HCC. Additionally, in patients underwent surgical resection, preoperative combined therapy demonstrated long-term survival benefits for those exceeding the up-to-seven criteria. Future research should focus on refining personalized treatment strategies, considering factors like tumor burden and surgical criteria in HCC patient management.

Acknowledgement

The authors thank Ms. Chengcheng Li, Xin Huang, Meixiang Li and Boru Zhang for their assistance with information collection.

Statement of Ethics

As this study is a retrospective review, it did not involve any prospective data collection from human subjects. Therefore, formal ethics approval was not required for this research. The study design and data analysis adhered to ethical standards and guidelines. This exemption from ethics approval was determined by the research ethics committee of the First Affiliated Hospital of Zhejiang University.

Informed consent was waived for this retrospective study as it involves the analysis of existing data and does not compromise the welfare and rights of the patients. The utilization of non-identified information ensures the protection of patient confidentiality. This waiver was in accordance with the decision made by the research ethics committee of the First Affiliated Hospital of Zhejiang University and conforms to ethical standards for retrospective research.

Conflicts of interest

The authors declare no potential conflicts of interest.

Funding Sources

This study was financially supported by grants from National Key Research and Development Program of China (No.2019YFC1316000), the National High Technology Research and Development Program of China (No.2015AA020405), the Joint Fund for Regional Innovation and Development of National Natural Science Foundation of China (U23A20462), the National Natural Science Foundation of China (No. 82071867, 81871925) and “Ling Yan” Research and Development Program of Department of Zhejiang Province Science and Technology.

Author Contributions

Guo CX and Du WR: study concept and design, data analysis and interpretation, manuscript draft.

Guo CX, Du WR, Chen YW, Xue X: data collection and integration, data analysis.

Xiao WB, Sun K, Shen Y, Zhang M, Wu J, Gao SL, Yu J and Que RS: critical revision of the data collection, analysis and interpretation.

Liang TB and Bai XL: study design, discussion and critical manuscript revision and approval of the final draft.

All authors have approved the final draft submitted.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.

Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022 [J]. CA Cancer J Clin, 2022, 72(1): 7-33.
Vogel A, Meyer T, Sapisochin G, et al. Hepatocellular carcinoma [J]. Lancet, 2022, 400(10360): 1345-1362.
Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification [J]. Semin Liver Dis, 1999, 19(3): 329-338.
Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update [J]. J Hepatol, 2022, 76(3): 681-693.
Singal AG, Kudo M, Bruix J. Breakthroughs in Hepatocellular Carcinoma Therapies [J]. Clin Gastroenterol Hepatol, 2023, 21(8): 2135-2149.
Brown ZJ, Hewitt DB, Pawlik TM. Combination therapies plus transarterial chemoembolization in hepatocellular carcinoma: a snapshot of clinical trial progress [J]. Expert Opin Investig Drugs, 2022, 31(4): 379-391.
Young S, Hannallah J, Goldberg D, et al. Friend or Foe? Locoregional Therapies and Immunotherapies in the Current Hepatocellular Treatment Landscape [J]. Int J Mol Sci, 2023, 24(14).
Kudo M, Ueshima K, Ikeda M, et al. Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial [J]. Gut, 2020, 69(8): 1492-1501.
Peng Z, Fan W, Zhu B, et al. Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial (LAUNCH) [J]. J Clin Oncol, 2023, 41(1): 117-127.
Xia D, Bai W, Wang E, et al. Lenvatinib with or without Concurrent Drug-Eluting Beads Transarterial Chemoembolization in Patients with Unresectable, Advanced Hepatocellular Carcinoma: A Real-World, Multicenter, Retrospective Study [J]. Liver Cancer, 2022, 11(4): 368-382.
Marinelli B, Kim E, D'Alessio A, et al. Integrated use of PD-1 inhibition and transarterial chemoembolization for hepatocellular carcinoma: evaluation of safety and efficacy in a retrospective, propensity score-matched study [J]. J Immunother Cancer, 2022, 10(6).
Hu Y, Zhou M, Tang J, et al. Efficacy and safety of stereotactic body radiotherapy combined with Camrelizumab and Apatinib in hepatocellular carcinoma patients with portal vein tumor thrombus [J]. Clin Cancer Res, 2023.
Yuan Y, He W, Yang Z, et al. TACE-HAIC combined with targeted therapy and immunotherapy versus TACE alone for hepatocellular carcinoma with portal vein tumour thrombus: a propensity score matching study [J]. Int J Surg, 2023, 109(5): 1222-1230.
Sun HC, Zhou J, Wang Z, et al. Chinese expert consensus on conversion therapy for hepatocellular carcinoma (2021 edition) [J]. Hepatobiliary Surg Nutr, 2022, 11(2): 227-252.
Guo C, Zhang J, Huang X, et al. Preoperative sintilimab plus transarterial chemoembolization for hepatocellular carcinoma exceeding the Milan criteria: A phase II trial [J]. Hepatol Commun, 2023, 7(3): e0054.
Lin KY, Lin ZW, Chen QJ, et al. Perioperative safety, oncologic outcome, and risk factors of salvage liver resection for initially unresectable hepatocellular carcinoma converted by transarterial chemoembolization plus tyrosine kinase inhibitor and anti-PD-1 antibody: a retrospective multicenter study of 83 patients [J]. Hepatol Int, 2023.
Pan X, Wu SJ, Tang Y, et al. Safety and Efficacy of Transarterial Chemoembolization Combined with Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma: A Single Center Experience [J]. J Hepatocell Carcinoma, 2023, 10: 883-892.
Mathew G, Agha R, Albrecht J, et al. STROCSS 2021: Strengthening the reporting of cohort, cross-sectional and case-control studies in surgery [J]. Int J Surg, 2021, 96: 106165.
Bruix J, Sherman M, American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update [J]. Hepatology, 2011, 53(3): 1020-1022.
Zhou J, Sun H, Wang Z, et al. Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition) [J]. Liver Cancer, 2020, 9(6): 682-720.
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma [J]. Semin Liver Dis, 2010, 30(1): 52-60.
Clinical Guidelines Committee of Chinese College of I. [Chinese clinical practice guidelines for transarterial chemoembolization of hepatocellular carcinoma (2023 edition)] [J]. Zhonghua Yi Xue Za Zhi, 2023, 103(34): 2674-2694.
Guo C, Zou X, Hong Z, et al. Preoperative transarterial chemoembolization for barcelona clinic liver cancer stage A/B hepatocellular carcinoma beyond the milan criteria: a propensity score matching analysis [J]. HPB (Oxford), 2021, 23(9): 1427-1438.
Shi J, Lai EC, Li N, et al. Surgical treatment of hepatocellular carcinoma with portal vein tumor thrombus [J]. Ann Surg Oncol, 2010, 17(8): 2073-2080.
Kokudo T, Hasegawa K, Yamamoto S, et al. Surgical treatment of hepatocellular carcinoma associated with hepatic vein tumor thrombosis [J]. J Hepatol, 2014, 61(3): 583-588.
Minagawa M, Makuuchi M, Takayama T, et al. Selection criteria for hepatectomy in patients with hepatocellular carcinoma and portal vein tumor thrombus [J]. Ann Surg, 2001, 233(3): 379-384.
Stein JE, Lipson EJ, Cottrell TR, et al. Pan-Tumor Pathologic Scoring of Response to PD-(L)1 Blockade [J]. Clin Cancer Res, 2020, 26(3): 545-551.
Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience [J]. Ann Surg, 2009, 250(2): 187-196.
Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis [J]. Lancet Oncol, 2009, 10(1): 35-43.
Petrillo M, Patella F, Pesapane F, et al. Hypoxia and tumor angiogenesis in the era of hepatocellular carcinoma transarterial loco-regional treatments [J]. Future Oncol, 2018, 14(28): 2957-2967.
Han JW, Yoon SK. Immune Responses Following Locoregional Treatment for Hepatocellular Carcinoma: Possible Roles of Adjuvant Immunotherapy [J]. Pharmaceutics, 2021, 13(9).
Jiang H, Meng Q, Tan H, et al. Antiangiogenic therapy enhances the efficacy of transcatheter arterial embolization for hepatocellular carcinomas [J]. Int J Cancer, 2007, 121(2): 416-424.
Tischfield DJ, Gurevich A, Johnson O, et al. Transarterial Embolization Modulates the Immune Response within Target and Nontarget Hepatocellular Carcinomas in a Rat Model [J]. Radiology, 2022, 303(1): 215-225.
Pinato DJ, Murray SM, Forner A, et al. Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy [J]. J Immunother Cancer, 2021, 9(9).
Deng H, Kan A, Lyu N, et al. Dual Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Inhibition Elicits Antitumor Immunity and Enhances Programmed Cell Death-1 Checkpoint Blockade in Hepatocellular Carcinoma [J]. Liver Cancer, 2020, 9(3): 338-357.
Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa [J]. Nat Rev Clin Oncol, 2018, 15(5): 310-324.
Xin Y, Zhang X, Liu N, et al. Efficacy and safety of lenvatinib plus PD-1 inhibitor with or without transarterial chemoembolization in unresectable hepatocellular carcinoma [J]. Hepatol Int, 2023, 17(3): 753-764.
Duan X, Li H, Kuang D, et al. Transcatheter arterial chemoembolization plus apatinib with or without camrelizumab for unresectable hepatocellular carcinoma: a multicenter retrospective cohort study [J]. Hepatol Int, 2023, 17(4): 915-926.
Liu J, Wei S, Yang L, et al. Efficacy and safety of transarterial chemoembolization plus lenvatinib with or without programmed death-1 inhibitors in the treatment of unresectable hepatocellular carcinoma: a systematic review and meta-analysis [J]. J Cancer Res Clin Oncol, 2023, 149(15): 14451-14461.
Llovet JM, De Baere T, Kulik L, et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma [J]. Nat Rev Gastroenterol Hepatol, 2021, 18(5): 293-313.
Zhang W, Tong S, Hu B, et al. Lenvatinib plus anti-PD-1 antibodies as conversion therapy for patients with unresectable intermediate-advanced hepatocellular carcinoma: a single-arm, phase II trial [J]. J Immunother Cancer, 2023, 11(9).
Wu JY, Zhang ZB, Zhou JY, et al. Outcomes of Salvage Surgery for Initially Unresectable Hepatocellular Carcinoma Converted by Transcatheter Arterial Chemoembolization Combined with Lenvatinib plus Anti-PD-1 Antibodies: A Multicenter Retrospective Study [J]. Liver Cancer, 2023, 12(3): 229-237.
Huang J, Wang ZG, Tao QF, et al. Efficacy and safety of Lenvatinib-based combination therapies for patients with unresectable hepatocellular carcinoma: a single center retrospective study [J]. Front Immunol, 2023, 14: 1198562.
Lang M, Gan L, Ren S, et al. Lenvatinib plus sintilimab with or without transarterial chemoembolization for intermediate or advanced stage hepatocellular carcinoma: a propensity score-matching cohort study [J]. Am J Cancer Res, 2023, 13(6): 2540-2553.
Cai M, Huang W, Huang J, et al. Transarterial Chemoembolization Combined With Lenvatinib Plus PD-1 Inhibitor for Advanced Hepatocellular Carcinoma: A Retrospective Cohort Study [J]. Front Immunol, 2022, 13: 848387.
Hu Z, Wang X, Fu Y, et al. Survival benefit of liver resection following complete response to transarterial chemoembolization for intermediate-stage hepatocellular carcinoma: a retrospective, multicenter, cohort study [J]. Int J Surg, 2023.
Kishore SA, Bajwa R, Madoff DC. Embolotherapeutic Strategies for Hepatocellular Carcinoma: 2020 Update [J]. Cancers (Basel), 2020, 12(4).
Zhang W, Zhang K, Liu C, et al. Hepatic arterial infusion chemotherapy combined with anti-PD-1/PD-L1 immunotherapy and molecularly targeted agents for advanced hepatocellular carcinoma: a real world study [J]. Front Immunol, 2023, 14: 1127349.
Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma [J]. N Engl J Med, 2020, 382(20): 1894-1905.

Table 1 Clinical characteristics of non-surgical patients

	General cohort			PSM cohort
Characteristics	TACE (n=31)	Combination (n=92)	P	TACE (n=26)	Combination (n=26)	P
Age, years, median (IQR)	63 (51-68)	56 (50-62)	0.016	63.5 (52-68.3)	58 (50.8-64.0)	0.241
Gender n. (%)
Male	26 (83.9)	84 (91.3)	0.244	22 (84.6)	21 (80.8)	0.714
Female	5 (16.1)	8 (8.7)		4 (15.4)	5 (19.2)
Chronic HBV infection
Positive	26 (83.9)	76 (82.6)	0.872	21 (80.8)	23 (88.5)	0.442
Negative	5 (16.1)	16 (17.4)		5 (19.2)	3 (11.5)
Baseline AFP, ng/mL
≥400	11 (35.5)	47 (51.1)	0.132	9 (34.6)	11 (42.3)	0.569
<400	20 (64.5)	45 (48.9)		17 (65.4)	15 (57.7)
Child Pugh
A	26 (83.9)	79 (85.9)	0.785	24 (92.3)	22 (84.6)	0.385
B	5 (16.1)	13 (14.1)		2 (7.7)	4 (15.4)
Tumor number*
≤2	15 (48.4)	41 (44.6)	0.712	12 (42.6)	13 (50)	0.781
>2	16 (51.6)	51 (55.4)		14 (53.8)	13 (50)
Largest tumor size*, cm, median (IQR)	8.1 (4.3-9.7)	8.3 (5.5-11.8)	0.198	8 (4-9.8)	7.7 (4.5-9)	0.985
Main portal vein invasion
Present	17 (54.8)	61 (66.3)	0.252	13 (50)	16 (61.5)	0.402
Absent	14 (45.2)	31 (33.7)		13 (50)	10 (38.5)
Hepatic vein invasion
Present	5 (16.1)	37 (40.2)	0.014	4 (15.4)	9 (34.6)	0.109
Absent	26 (83.9)	55 (59.8)		22 (84.6)	17 (65.4)
Extrahepatic metastasis
Present	5 (16.1)	26 (28.3)	0.178	4 (15.4)	5 (19.2)	0.714
Absent	26 (83.9)	66 (71.7)		22 (84.6)	21 (80.8)
BCLC stage
B	10 (32.3)	22 (23.9)	0.360	9 (34.6)	8 (30.8)	0.768
C	21 (67.7)	70 (76.1)		17 (65.4)	18 (69.2)
TACE sessions
1	10 (32.3)	31 (33.7)	0.883	8 (30.8)	13 (50.0)	0.158
≥2	21 (67.7)	61 (66.3)		18 (69.2)	13 (50.0)
Concomitant radiotherapy
Yes	6 (19.4)	22 (23.9)	0.601	6 (23.1)	7 (26.9)	0.749
No	25 (80.6)	70 (76.1)		20 (76.9)	19 (73.1)

*Number or size of initially diagnosed tumors.

Table 2 Univariate and multivariate Cox regression analysis of PFS in the non-surgical cohort.

*Number or size of initially diagnosed tumors.

	General cohort			PSM cohort
Variables	Univariate analysis (p value)	Multivariate analysis		Univariate analysis (p value)	Multivariate analysis
Variables	Univariate analysis (p value)	Hazard ratio (95% CI)	p value	Univariate analysis (p value)	Hazard ratio (95% CI)	p value
Treatment, TACE/ combination	0.026	0.522 (0.334-0.817)	0.004	0.046	0.476 (0.257-0.883)	0.019
Age, years, ≤65/ >65	0.910			0.852
Gender, male/ female	0.322			0.375
Chronic HBV infection, positive/ negative	0.338			0.308
AFP, ng/mL, <400/ ≥400	0.337			0.643
Child–Pugh grade, A/B	0.459			0.438
Tumor number*, ≤2/ >2	0.829			0.311
Tumor distribution, uni-lobar/ bi-lobar	0.248			0.435
Largest tumor size*	0.034	1.069 (1.019-1.122)	0.006	0.037	1.120 (1.023-1.226)	0.014
Main portal vein invasion, present/ absent	0.467			0.911
Hepatic vein invasion, present/ absent	0.110			0.713
Extrahepatic metastasis, present/ absent	0.118			0.634
BCLC stage, B/ C	0.785			0.900
TACE sessions, 1/ ≥2	0.725			0.907
Concomitant radiotherapy, yes/ no	0.222			0.313

Table 3 Clinical characteristics of surgical patients

Characteristics	TACE (n=69)	Combination (n=87)	P
Age, years, median (IQR)	61 (54-67)	52 (45-59)	<0.001
Gender n. (%)
Male	61 (88.4)	78 (89.7)	0.804
Female	8 (11.6)	9 (10.3)
Chronic HBV infection
Positive	55 (79.7)	71 (81.6)	0.765
Negative	14 (20.3)	16 (18.4)
Baseline AFP, ng/mL			0.042
<400	43 (62.3)	40 (46.0)
≥400	26 (37.7)	47 (54.0)
Tumor number*, median (IQR)	2 (2-3)	2 (1-3)	0.289
Largest tumor size*, cm, median (IQR)	6 (4-9.2)	8.9 (5-11.8)	0.007
Main portal vein invasion			0.121
Present	21 (30.4)	37 (42.5)
Absent	48 (69.6)	50 (57.5)
Hepatic vein invasion			0.006
Present	15 (21.7)	37 (42.5)
Absent	54 (78.3)	50 (57.5)
BCLC stage
B	41 (59.4)	33 (37.9)	0.008
C	28 (40.6)	54 (62.1)
Preoperative TACE sessions			<0.001
1	57 (82.6)	43 (49.4)
≥2	12 (17.4)	44 (50.6)
Concomitant radiotherapy			0.206
Yes	7 (10.1)	15 (17.2)
No	62 (89.9)	72 (82.8)
Adjuvant therapy			<0.001
Present	47 (68.1)	81 (93.1)
Absent	22 (31.9)	6 (6.9)

*Number or size of preoperatively diagnosed tumors.

Table 4 Univariate and multivariate Cox regression analysis of PFS in the surgical cohort.

Variables	Univariate analysis (p value)	Multivariate analysis
Variables	Univariate analysis (p value)	Hazard ratio (95% CI)	p value
Treatment, TACE/ combination	0.329
Age, years, ≤65/ >65	0.851
Gender, male/ female	0.316
Chronic HBV infection, positive/ negative	0.045	1.736 (1.009-3.082)	0.047
Baseline AFP, ng/mL, <400/ ≥400	0.171
Tumor number*	0.032	1.318 (1.080-1.609)	0.007
Largest tumor size*	0.024	1.092 (1.034-1.153)	0.002
Main portal vein invasion, present/ absent	0.589
Hepatic vein invasion, present/ absent	0.808
BCLC stage, B/ C	0.344
TACE sessions, 1/ ≥2	0.738
Concomitant radiotherapy, yes/ no	0.715
Satellite nodule, present/ absent	0.004	1.692 (1.038-2.758)	0.035
Microvascular invasion, present/ absent	0.132
Adjuvant therapy, present/ absent	0.536

*Number or size of initially diagnosed tumors.

Table 5 is not available with this version.

No competing interests reported.

Survival Analysis of TACE Monotherapy vs. Combination Therapy in BCLC B and C Stage Hepatocellular Carcinoma: A Retrospective Cohort Study

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Abstract

Introduction

Methods

Results

Conclusion

Figures

Introduction

Methods

Study Design and Patients

TACE Procedure

Systemic Treatment

Surgical Resection

Assessments and Follow-up

Statistical Analysis

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

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