Comparison of the efficacy and safety of Transarterial chemoembolization with and without Apatinib for the treatment of BCLC stage C hepatocellular carcinoma

From March 2016 to October 2017, we retrospectively reviewed 80 consecutive patients with BCLC stage C HCC who underwent TACE-apatinib or TACE-alone as the initial treatment in our institution. Of these, 27 patients underwent TACE-apatinib treatment and 53 underwent TACE-alone treatment. Patients were diagnosed with BCLC stage C HCC on the basis of the criteria of the American Association for the Study of Liver Diseases (AASLD) guidelines [10].On confirmation of BCLC stage C HCC, the patient was informed of sorafenib administration as the recommended treatment. For those who refused to receive sorafenib, TACE-apatinib or TACE alone was recommended as an alternative treatment on the basis of previous phase II studies [8, 9, 11]. The most-common reason for rejection of sorafenib treatment was the high cost, as sorafenib is not on the list of drugs covered by medical insurance of China.

The diagnosis of HCC was established on the basis of suggestions from the AASLD [12] and the European Association for the Study of the Liver [13] by using clinical data, contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) findings, and serum levels of AFP. In 11 patients (13. 8%), the diagnosis was confirmed by ultrasound-guided fine-needle biopsy. The inclusion criteria were as follows: Eastern Cooperative Oncology Group performance score of 0–2, Child-Pugh liver function class A or B, adequate hematologic function (leukocyte count ≥3000/mm³, platelet count ≥50,000/mm³), and adequate liver function (serum total bilirubin level ≤ 2 mg/dL). The exclusion criteria were as follows: infiltrative or diffused HCC, incomplete course of apatinib (full course lasts for 4 weeks), previous systemic anticancer therapy, and loss to follow-up.

A week prior to treatment, we recorded a comprehensive medical history of all patients, measured their serum AFP levels, and determined their HBsAg status. No hepatitis C virus infection or alcohol addiction was noted in any patient. Abdominal contrast-enhanced CT or MRI and chest CT were included in the initial workup in all patients.

Each treatment was performed by an interventional radiologist with at least 5 years of TACE experience. In all patients who underwent TACE, the Seldinger technique was used for hepatic artery catheterization. Using digital subtraction angiography, the catheter or microcatheter was inserted from the right femoral artery and guided to the hepatic artery or its branches for angiography. Subsequently, tumor-feeding arteries were superselected on the basis of our understanding of the tumor blood supply indicated by hepatic arteriography. An emulsion of 3–20 mL Lipiodol (Guerbet Laboratories, Aulnay-Sous-Bois, France) and a chemotherapy agent such as 30 mg epirubicin and150 mg oxaliplatin was injected into the tumor-feeding arteries, which were then embolized using 25–130 mg gelatin sponge particles (GSP) (Ailikang Pharmaceutical Co., Ltd. Hangzhou, China). The GSP was available in three size ranges (150–350 μm, 350–560 μm, and 560–710 μm). The size of GSP depended on the superselected hepatic artery and tumor size, and the most-common size used was 350–560 μm. The aim of chemoembolization was to achieve complete arterial blockage in the arteries supplying the tumor. In some patients with serious portal thrombosis, wide tumor distribution, hepatic arterioportal fistula, or hepatic arterialvenous fistula, the full doses of embolic agents were not administered due to the high risk of failure to recover liver function after treatment.

The TACE treatment was repeated at least 40 days after the first treatment in patients with survival lesions according to the mRECIST [14]. TACE was not repeated until liver failure or tumor progression of the target lesions was observed.

Upon agreeing to participate in the study, all patients in the TACE-apatinib group were orally administered apatinib at an initial dose of 500 mg/day for the first time 2 days after TACE. When the patients encountered grade 3–4 drug-related AEs according to the Common Terminology Criteria for Adverse Events version 4.0, the drug dose was adjusted to 250 mg/day or stopped for several days. After the adverse events were relieved, the patients were recommended to resume daily intake of 500 mg/day apatinib. Treatment continued until patient death, significant disease progression, drug intolerance, or withdrawal of consent from the study.

Contrast-enhanced CT or MRI was performed 1 and 3 months after treatment, and the results were assessed according to the mRECIST to evaluate tumor response. Two radiologists compared the follow-up images with baseline images to evaluate tumor response to treatment. Based on the results, the patients were categorized into four groups: CR, partial response, stable disease, and progressive disease. The ORR was calculated as the rate of CR plus partial response. TTP was defined as the time between initiations of TACE treatment to the time of disease progression. OS referred to the time from initiation of the first TACE treatment to death or the date of the last follow-up for patients who were alive and censored.

All data analyses were performed using the SPSS software (version 18.0; SPSS, Chicago, IL, USA). Independent sample t-test, chi-square test, Kaplan–Meier survival analysis, and log–rank test were used to assess the differences between the two groups. In addition, multivariate Cox-regression was used to analyze overall survival. Values of P < 0.05 were considered statistically significant.

The mean age of patients in the TACE-apatinib group was 45. [8] ± 11.0 years and in the TACE-alone group was 54.4 ± 11.9 years. Although the TACE-apatinib group was younger than the TACE-alone group, there was no significant difference between the two groups. The sex distribution in both groups was as follows: TACE-apatinib group, 23 men and 4 women, and TACE-alone group, 43 men and 7 women. We did not observe any significant difference in the distribution of age, sex, hepatitis B surface antigen (HBsAg) expression, alpha-fetoprotein levels, Child-Pugh class, maximum HCC size, number of HCC foci, extrahepatic metastasis, vascular invasion, and number of TACE procedures between the two groups (Table 1). The date of the last follow-up was May 31, 2018, and the median follow-up period was 12 months. Six patients were lost to follow-up after 6–36 months.

During the follow-up, one patient received secondary surgical treatment in the TACE-apatinib group. A total of 19 patients were treated with additional radiofrequency ablation, including 8 patients in the TACE-alone group and 11 patients in the TACE-apatinib group. A total of 6 patients received additional radiotherapy, including 4 patients in the TACE-alone group and 2 patients in the TACE-apatinib group. There was no significant difference in supplementary therapy between the two groups.

Abdominal MRI scans before TACE and at 1 and 3 months after TACE showed changes in tumors in the two groups (Fig. 1 a–f). We evaluated tumor response in all 80 patients at 1 month after treatment and in 58 patients at 3 months after treatment in both groups using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) (Table 2). Complete response (CR) was not observed in any of the patients. The rate of overall response (ORR) was significantly higher in the TACE-apatinib group than in the TACE-alone group (18/27 [66.7%] vs 21/53 [39.6%], respectively, P = 0.020] at 1 month after treatment. The ORR was significantly higher in the TACE-apatinib group than in the TACE-alone group (11/24 [45.8%] vs 6/34 [17.6%], respectively, P = 0.021] at 3 months after treatment.

The median TTP was 6.3 months (95% confidence interval [CI]: 4.2–8.4 months) in the TACE-apatinib group and 3.5 months (95% CI:2.3–4.7 months) in the TACE-alone group. The median TTP in the TACE-apatinib group was significantly longer than that in the TACE-alone group (P = 0.002, Fig. 2).

The median survival period was 13.0 months (95% CI: 9. 8–16.2 months) in the TACE-apatinib group and 9.9 months (95% CI: 7.5–12.3 months) in the TACE-alone group. Survival rates at 1 and 2 years were 43.0 and 19.7%, respectively, in the TACE-apatinib group, and 33.3 and 11.3%, respectively, in the TACE-alone group (P = 0.041, Fig. 3). Multivariate Cox regression analyses revealed that overall response at 1 month after treatment was associated with OS. The length of the OS increased with an improvement in the overall response at 1 month after treatment (Table 3).

AEs associated with treatment in the two groups are listed in Table 4. There were no treatment-related deaths or grade 4 AEs. In the TACE-apatinib group, apatinib-related adverse reactions included hypertension (grade 1 in 6 patients, 22.2%; grade 2 in 13 patients, 48.1%), hand-foot syndrome (grade 1 in 4 patients, 14.8%; grade 2 in 9 patients, 33.3%; and grade 3 in 9 patients, 33.3%), oral ulcers (grade 2 in 1 patients, 3.7%; grade 3 in 4 patients, 14.8%), proteinuria (grade 1 in 2 patients, 7.4%; grade 2 in 3 patients, 11.1%; and grade 3 in 3 patients, 11.1%), and diarrhea (grade 1 in 2 patients, 7.4%; grade 2 in 5 patients, 15,5%); however, these AEs did not occur in the TACE-alone group. The difference in AEs was significant between the two groups (P < 0.05). All apatinib-related AEs were manageable by providing symptomatic treatment and/or adjusting the drug dose, which did not affect the treatment. The most-common AEs were hematologic toxicity, post-embolization syndrome (including fever, abdominal pain, nausea, and vomiting), and liver dysfunction in both groups, however, there was no significant difference between the two groups.