The data analysis in this study was based on the real world, conformed to the Declaration of Helsinki, and was approved by our Medical Ethics Committee (ethics number: 2019198). All patients were informed of the treatment details and signed a written informed consent form before treatment. Between January 2019 and June 2022, eight medical centers enrolled 423 patients with advanced HCC who received TACE-A treatment. A total of 389 patients were included in the study after 34 patients were excluded because of apatinib in less than a month (n=19) and incomplete follow-up data (n=15).

Moreover, HCC was diagnosed according to the American Association for the Study of Liver Diseases guidelines/European Association for the Study of Liver Diseases pathological examination or noninvasive criteria (19).

Inclusion criteria: (1) age ≥ 18 years old; (2) enhanced computed tomography (CT)/magnetic resonance imaging (MRI) examination displayed at least one measurable liver target lesion; (3) Barcelona Clinic Liver Cancer (BCLC) staging classification B/C; (4) liver function Child-Pugh score ≤ 7; (5) Eastern Cooperative Oncology Group (ECOG) score 0–1; (6) platelet count ≥ 50×10⁹/L, or can be corrected after treatment. The exclusion criteria were as follows: (1) diffuse HCC or tumor burden exceeding 70% of the whole liver; (2) complete occlusion of the main portal vein without compensation; (3) Child-Pugh score > 7; (4) previous TACE, radiotherapy, systemic therapy, or other anti-tumor therapies; and (5) severe comorbidities, including severe heart, lung, kidney, or coagulation dysfunction.

The TACE procedures and adverse event (AE) response strategies related to apatinib treatment at each medical center were consistent after unified training. Furthermore, TACE procedures were performed as described in our previous report on the technique (19). All TACE procedures were performed by two experienced interventional radiologists under local anesthesia using the traditional femoral approach. Conventional angiography was performed using a 5F RH catheter (Terumo, Tokyo, Japan), and a microcatheter (Terumo) was used for super-selective arterial cannulation of the tumor-feeding artery branch. Doxorubicin (China Hisun Pharmaceutical Co., Ltd.) and lipiodol (Garber, France) were thoroughly mixed and injected into the blood vessels of the tumor. Then 300–500um gelatin sponge particles (Ailikang Co., Ltd., Hangzhou, China) were given to supplement the embolism until the blood flow slowed down or nearly stagnated. The dosage of super-liquefied iodized oil was 5–20 milliliters, and the dosage of adriamycin was 30–50 mg. The actual dosage should be adjusted according to the patient’s liver function, the number and size of the tumors, whether the tumor is rich in blood supply, and the operator’s experience.

After obtaining informed consent from the patient and notifying them of the relevant precautions, the patient received oral apatinib (Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, China) at 250 mg/day, 3 days after the first TACE. If a grade 3 AE occurred related to apatinib, the administration of apatinib was adjusted every other day. Dosing is interrupted if AE (grade ≥ 3) or those related to drugs such as gastrointestinal bleeding continue to occur after dose adjustment. The dose was restored to 250 mg/day when the AEs were alleviated or eliminated. Apatinib was permanently discontinued if AE of grade ≥ 3 or above occurred again.

The last follow-up period was in June 2022. Each medical center adopted a consistent follow-up protocol. Patients were followed up every 4–6 weeks after TACE. Imaging examinations included plain chest CT, multiphase contrast-enhanced CT of the upper abdomen, and multiphase dynamic contrast-enhanced MRI. For patients with other discomforts, the doctor will provide corresponding imaging examinations according to the clinical symptoms. In case imaging examinations reveal tumor recurrence, new tumor, or residual tumor activity in the liver, and if the patient has no contraindications to TACE, repeat the procedure, that is, the principle of on-demand TACE. In case of the following conditions TACE was discontinued: liver function worsened to Child-Pugh class C (uncontrolled ascites, severe jaundice, overt hepatic encephalopathy, or hepatorenal syndrome), ECOG > 2, or if the target lesion continued to progress after two consecutive TACE treatments (20).

In terms of systemic treatment, patients continued to receive apatinib before on-demand TACE, and apatinib was discontinued on the day of TACE until 3 days after. All patients were administered apatinib regularly for 2 months after treatment initiation. When the patient was determined to have disease progression after two evaluations, or after TACE-A treatment, it no longer benefited. According to the patient’s wishes, TACE was combined with camrelizumab, sintilimab, and other immunotherapies, or changed to a second-line systemic treatment such as regorafenib.

The main objective of this study was to determine the median overall survival (mOS) of patients, defined as the time from the start of combination therapy to death from any cause, and median progression-free survival (mPFS), defined as the time from the start of TACE combination therapy to the first tumor progression or death from any cause. The prognostic factors affecting overall survival (OS) were also analyzed. The secondary objective was to determine the objective response rate (ORR) of patients at the first and second follow-ups. According to the modified response evaluation criteria for solid tumors (21), two senior radiologists (with more than 10 years of experience) evaluated the patients’ imaging data. The results were divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). If the two radiologists disagreed, they were evaluated by a radiologist with over 15 years of experience, and the evaluation result was considered the final result. Moreover, AEs were evaluated according to the National Cancer Institute’s “Common Terminology and Terminology Standards for Adverse Events, “ version 3.0.

Statistical analyses were performed using SPSS 22.0 statistical software (IBMCorp., Armonk, NY, USA) and R Language (version 4.1.2; R Foundation for Statistical Computing, Vienna, Austria; https://www.r-project.org/). The continuous variables conforming to the normal distribution are represented by mean ± standard deviation (x ± s), while those not conforming to the normal distribution are represented by the median and interquartile range [M (P25, P75)]. Survival curves were estimated using the Kaplan–Meier method, and mOS and mPFS were calculated. Univariate and multivariate Cox regression models were used to analyze prognostic factors associated with OS. Statistical significance was set at p < 0.05. significant.

Among the 389 patients included in this study, 75 (19.3%) were BCLC-B stage patients and 331 (80.7%) C-stage patients. The proportion of patients with single and multiple lesions was 197 (50.6%) and 192 (49.4%), respectively. Tumor size was defined as 50 mm in 147 cases (< 50 mm) (37.8%) and 242 cases (≥ 50 mm) (62.2%) ( Table 1 ). Among them, 124 patients (31.9%) had only portal vein tumor thrombus (PVTT), and three patients had both portal vein and hepatic vein tumor thrombi. 294 patients (75.6%) underwent two or fewer TACE procedures, while 95 patients (24.4%) required more than two on‐demand TACE treatments. Based on TACE-A treatment, 64 patients received ¹²⁵I seed implantation in PVTT, of which 53 (82.8%) with branched tumor thrombus and 11 patients with main and branch tumor thrombus received ¹²⁵I seed implantation of the branch tumor thrombus combined with camrelizumab. In addition, only 16 patients with a main PVTT were treated with camrelizumab. Eighty patients (63.0%) with vascular invasion underwent additional treatment. Of 109 patients with distant metastases, 21(19.3%) received additional immunotherapy (4 with sintilimab and 17 with camrelizumab). Moreover, among stage C patients, 35 patients received TACE-A combined with immunotherapy (toripalimab in 3 cases, sintilimab in 6 cases, and camrelizumab in 26 cases). A total of 136 patients received TACE-A treatment, including immunotherapy or ¹²⁵I seed implantation, accounting for 35.0%.

In our cohort, of the 188 patients who experienced progressive disease (PD) on first‐line TACE‐A, 76 (40.4%) went on to receive subsequent immune‐checkpoint inhibitor therapy. Specifically, 44 patients received camrelizumab and 32 received sintilimab, either immediately upon PD (direct combination) or following a short interval on apatinib alone (sequential strategy).

As of June 2022, 336 patients (86.4%) reached the study endpoint. The Kaplan–Meier curves of progression-free survival (PFS) and OS for all patients are displayed in Figure 1 . The mPFS was 7.0 months (95% confidence interval [CI]: 6.3–7.7), and the mOS was 18.9 months (95% CI: 17.5–20.3).

The median time for the first follow-up/efficacy evaluation was 1.2 months, and no patients were lost to follow-up; of these, SD and PD patients were 24 (6.1%), 107 (27.5%), 206 (52.9%), and 52 (13.3%) patients were lost to follow-up, respectively. Moreover, the ORR was 33.6%. The patients were divided into 4 groups, the mOS of patients in CR, PR, SD, and PD groups were 30.1 months (95% CI: 20.4–39.8), 20.9 months (95% CI: 18.5–23.3), 18.5 months (95% CI: 16.5–20.5), and 12.9 months (95% CI: 10.4–15.4), the difference was statistically significant (p < 0.05). The median time of the second follow-up/response evaluation was 2.1 months, of which 51 cases (13.1%) were CR, PR, SD, and PD; 94 cases (24.2%), 108 cases (27.8%), and 136 cases (35.0%), respectively, and the ORR was 37.3% ( Table 2 ). The two‐proportion z-test comparing ORR at the first (130/388 = 33.5%) versus second (145/389 = 37.3%) assessments yields a z-statistic of –1.099 with p = 0.272. This indicates no statistically significant difference in ORR between the two time points (p > 0.05).

Univariate analysis demonstrated that six characteristics correlated with OS, including BCLC stage, presence of distant metastasis, maximum tumor diameter, TACE times, and alpha-fetoprotein (AFP) level. The aforementioned covariates were included in the multivariate Cox regression analysis using the direct entry method. The final results exhibited distant metastasis (95% CI: 1.52 (1.18–1.96), p= 0.001), the largest tumor diameter > 50 mm (95% CI: 1.51 (1.20–1.89), p < 0.001), TACE times < 2 (95% CI: 0.66 (0.51–0.85), p= 0.001) and AFP level ≥ 400ng/ml (95% CI: 1.50 (1.20–1.87), p < 0.001) were independent risk factors affecting OS ( Table 3 ).

The variables with p < 0.05 in univariate Cox regression analysis included BCLC stage, presence or absence of distant metastasis, maximum tumor diameter, TACE times, and AFP level. The Kaplan–Meier curves of each variable grouping were plotted, and the mOS of each patient grouping was calculated. Among them, the mOS of BCLC-B and C patients were 21.7 months (95% CI: 17.73–25.67) and 18.5 months (95% CI: 17.16–19.84), respectively, and the B-stage patients were significantly better than C-stage patients (p= 0.001); the mOS of patients without distant metastasis and patients with distant metastasis were 20.0 months (95% CI: 18.41–21.59) and 15.0 (95% CI: 11.28–18.72), respectively, and the survival of patients with distant metastasis was worse (p < 0.001); the mOS of patients with APF levels < 400(ng/ml) and ≥ 400(ng/ml) were 20.8 months (95% CI: 18.53–23.07) and 16.3 months (95% CI: 13.58–19.02), respectively, and the difference was statistically significant (p < 0.001); the mOS of patients with maximum tumor diameter < 50 mm and ≥ 50 mm were 23.1 months (95% CI: 20.87–25.33) and 16.9 months (95% CI: 15.33–18.47), respectively, and patients with small maximum tumor diameter had a long survival period (p < 0.001); the mOS of patients who received more than two TACE treatments and those who only received two were 22.0 months (95% CI: 18.86–25.15) and 17.8 months (95% CI: 16.13–19.47), the difference was statistically significant (p = 0.001) ( Figure 2 ).

In a sensitivity analysis stratifying patients by apatinib adherence, the irregular-medication group (n = 245) had a median OS of 17.6 months and a median PFS of 6.1 months, while the regular-medication group (n = 144) had a median OS of 17.2 months and a median PFS of 6.7 months. Kaplan–Meier curves with log-rank tests showed no significant difference in OS (p = 0.924) or PFS (p = 0.995) between the two groups.

During the treatment and follow-up periods, the most frequent treatment-related AE (TRAE) in patients receiving TACE-A was post-embolism syndrome, which was mainly characterized by fever, pain, nausea, vomiting, and fatigue, all of which improved after symptomatic treatment.

The overall incidence of TRAEs of grade 3 and higher was 18.0% (70/389 patients). Among them, 45 cases of blood-related grade 3 AEs, 8 cases of decreased white blood cell count, 29 cases of decreased platelet count, and 8 cases of decreased neutrophil count were present. Moreover, 25 cases of non-blood-related grade 3 AEs, including 10 cases of hypertension, 6 cases of abnormal liver function, 8 cases of proteinuria, and 1 case of diarrhea were observed. After all, patients received symptomatic treatment and dose reduction or withdrawal, all TRAEs resolved ( Table 4 ).