Comparing the effectiveness and safety of Sorafenib plus TACE with Apatinib plus TACE for treating patients with unresectable hepatocellular carcinoma: a multicentre propensity score matching study

Study design

In this multi-center retrospective study, all patients who were diagnosed with HCC and were treated with TACE plus Sorafenib or TACE plus Apatinib at 5 Chinese medical centers in Anhui province (the First Affiliated Hospital of University of Science and Technology of China, the First Affiliated Hospital of Bengbu Medical College, the First Affiliated Hospital of Wannan Medical College, Anqing Municipal Hospital, and the Second Affiliated Hospital of Anhui Medical University) between January 2016 and December 2020 were included. This study was approved by the Ethics Committees of all the above-mentioned medical centers, and it was performed according to the Declaration of Helsinki. As this was a retrospective study, informed consent was waived by the Ethics Committees. All patients’ data were kept confidential. The inclusion criteria were as follows: 1) patients who were clinically diagnosed with primary HCC; 2) patients in Barcelona Clinic Liver Cancer (BCLC) stage B/C; 3) Child–Pugh class A/B; 4) the existence of complete imaging data (computed tomography (CT)/magnetic resonance imaging (MRI)) before surgery and during follow-up; 3) the East Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; 6) patients without contraindication to TACE, and those who received targeted therapy after TACE; and 7) the duration of undergoing targeted therapy and expected survival time would be > 3 months. The exclusion criteria were as follows: 1) patients who had been treated with other therapeutic methods, including systemic chemotherapy, immunotherapy, and radiofrequency ablation (RFA); 2) patients with other severe diseases (Combined with other tumors, or cardiovascular and cerebrovascular diseases, etc.); 3) patients with severe coagulation disorders (Patients with prothrombin time > 18 s or a tendency to bleed); and 4) patients who suspended the therapy for more than 1 month or changed the targeted therapeutic drugs within 1 month during follow-up.

Treatment

TACE was performed by experienced interventional radiologists who had at least 5 years of experience in TACE. The modified Seldinger technique was adopted to puncture the right femoral artery, and a 5F femoral artery sheath was placed. A 5F-RH catheter was delivered to the celiac trunk under the guiding of 0.032 in super-smooth guidewire for angiography, which clarified the tumor site and blood supply, as well as the existence of hepatic arterioportal fistulas and hepatic arteriovenous fistulas. Afterward, the coaxial microtube method was adopted for the delivery of the microcatheter, and chemotherapeutic drugs (e.g., 3–20 mg Lipiodol, 20–40 mg Epirubicin, and 150 mg Oxaliplatin) were injected into the tumor-feeding arteries according to the sizes of tumors. After the tumor vascular bed was saturated and the blood flow in portal vein branches adjacent to the tumor were slowed down, then, polyvinyl alcohol (PVA) particles (150–350 or 350–560 μm, and 560–710 μm) were infused slowly until the blood flow was completely blocked. The sizes of PVA particles were selected according to the superselective catheterization of hepatic artery and sizes of tumors.

Administration of Apatinib or Sorafenib

Regarding patients in the TACE-Apatinib group and TACE-Sorafenib group, Apatinib with the initial dose of 500 mg/d or Sorafenib with the initial dose of 400 mg/bid was orally administered at 3–5 days after TACE, respectively. If grade 3–4 drug-related AEs occurred, according to the Common Terminology Criteria for Adverse Events (ver. 4.0; CTCAE 4.0), the doses of oral Apatinib and Sorafenib were adjusted to 250 mg/d and 200 mg/bid, respectively, or the Apatinib and Sorafenib treatments could be discontinued for several days. When AEs improved, the patients were suggested to restore the previous doses until disease progression, death, or one of the following items requiring treatment to be discontinued: AEs requiring discontinuation of treatment, ECOG-PS score worsened to 4 points, deterioration of liver function, or a patient’s clinical requirements.

Follow-up

Follow-up was undertaken for all patients at 1 month after TACE, and repeated TACE could be performed according to the conditions of lesions, with the interval of 1.5–2 months. Patients with complete response (CR) were followed up every 3 months, in which evaluation of liver function, alpha-fetoprotein (AFP) screening, and contrast-enhanced CT or MRI were carried out. For patients who used Sorafenib or Apatinib, the liver and renal functions, blood circulation, and coagulation function were assessed every month. Patients were treated with continuous targeted therapy until intolerable AEs occurred, or tumor progressed, and patients could not benefit from the treatment according to clinical decisions. All patients were followed up until December 30, 2021.

Tumor responses and safety evaluation

Regarding patients in the two groups, the tumor responses were evaluated every 8 weeks, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) and contrast-enhanced CT(loversol) or MR(Primovist) images. A complete response (CR) was defined as the disappearance of any arterial enhancement in the target tumor, a partial response (PR) was defined as over 30% decrease in the sum of the diameters of viable lesions, progressive disease (PD) was defined as over 20% increase in the sum of the diameters of viable lesions, and a stable disease (SD) was defined as any cases with nonPR or nonPD. An objective response rate (ORR) was defined as the percentage of patients achieving either CR or PR, and disease control rate (DCR) as the percentage of patients achieving CR, PR, or SD. The tumor response of the target lesion was independently evaluated by two Senior radiologists (over 10 years of experience in radiology,) who were blinded to each other's conclusions.Disagreements were resolved by discussion until consensus could be achieved. The best overall response during the treatment was considered as the final response. The treatment-related AEs were classified according to the CTCAE 4.0. The vital signs and AEs were monitored throughout the study. The safety evaluation was mainly based on the occurrence, frequency, and severity of AEs. The safety was evaluated by the vital signs, results of physical examinations, data of clinical examinations, results of laboratorial examinations, and AEs. The safety of the two groups (TACE-Sorafenib and TACE-Apatinib groups) was evaluated, which included the proportion of patients who discontinued targeted therapy and patients who received a reduced dosage due to AEs.

Statistical analysis

The SPSS 22.0 software (IBM Corp., Armonk, NY, USA) was used to carry out statistical analysis. A logistic regression model was utilized to calculate the propensity scores of the patients, in which the propensity score matching (PSM) was accordingly performed. The covariates included in the analysis were gender, age, viral hepatitis, Child–Pugh score, serum AFP level, BCLC stage, ECOG-PS score, number of nodules, tumor size, liver function, vascular invasion, extrahepatic metastasis, frequency of undergoing TACE, and history of anti-tumor therapy. The 1:1 nearest neighbor matching was adopted. The Fisher’s exact test or χ2 test, as well as the Student’s t-test were utilized to compare differences in the above-mentioned characteristics between the two groups. The Kaplan–Meier method was adopted to estimate the rates of progression-free survival (PFS) and OS. P < 0.05 was considered statistically significant.

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