Comparison of CalliSpheres^® microspheres drug-eluting beads and conventional transarterial chemoembolization in hepatocellular carcinoma patients: a randomized controlled trial

This was a prospective, randomized, controlled study designed to compare the efficacy and safety of DEB-TACE with CSM and cTACE. All the subjects who participated in this study were randomized in a 1:1 ratio by a computerized system and enrolled by an investigator physician. The results of allocation were placed in a sealed envelope and delivered to the only assistant aware of DEB-TACE/cTACE progress. All the doctors in charge of surgery and data collection were blinded to the trial design and treatment. All participants were informed about the objective and experimental procedure and allowed to withdraw their consent or discontinue participation without restrictions at any time. Then those who voluntarily participated in the trial signed the written informed consent. All procedures in the trial were in accordance with the World Medical Association’s Helsinki Declaration. The study plan was approved by the Ethics Committee of the Second Hospital Affiliated Harbin Medical University (No. KY2020-267) and has been registered at Chictr.org.cn (No. ChiCTR2100044528).

From March 2020 to March 2021, 115 HCC patients from the Department of Interventional Radiography of the Second Hospital Affiliated Harbin Medical University were recruited in this study through advertisements or physicians. The inclusion criteria were as follows: (1) Patients diagnosed as primary HCC by pathological findings or clinical features and radiographic examinations according to American Association for the Study of the Liver Diseases (AASLD) guidelines; (2) Tumor location and extent not amenable to elective resection or ablation; (3) Patients undergoing treatment for the first time and were willing to accept CSM DEB-TACE or cTACE; (4) Digital substraction sngiography (DSA) showed that the tumor was abundant in blood supply with no hepatic/ portal vein invasion; (5) Patients > 18 years old; (6) Patients met Child-Pugh stage A or B and BCLC stage A or B and with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1; (7) Life expectancy > 6 months. The exclusion criteria were as follows: (1) Patients with a history of liver transplantation or other malignancies; (2) Patients with coagulation dysfunction or massive ascites; (3) Patients complicated with severe liver or renal dysfunction; (4) Patients with iodine allergy; (5) Patients with cognitive impairment or refusals.

Each patient had fasted for 6 h and water-deprived for 2 h. The patient was placed in a supine position, and a peripheral intravenous line was established before the procedure. The patient was given inhaled oxygen at 3 L/min with a nasal catheter. Vital signs, including ECG, blood pressure, and oxygen saturation, were monitored. Preoperatively, 3 mg granisetron was injected intravenously over 15 s to prevent nausea and vomiting.

The groin was prepared in a sterile fashion, and after local anesthesia, percutaneous right common femoral artery was punctured using the modified Seldinger method.

Then, a 5F (Terumo, Tokyo, Japan) /4F (Cordis, USA) RH catheter was introduced through a 5F vascular sheath (Merit Medical, USA), and placed into the celiac trunk under DSA guidance to perform celiac angiography to identify the tumor feeding artery. If the blood vessels in a certain area of the liver are sparse or the tumor is not fully displayed during celiac trunk angiography, look for the extrahepatic tumor blood supply artery, such as superior mesenteric artery, inferior phrenic artery, and right adrenal artery, right inferior intercostal artery, internal mammary artery, etc. After confirming the tumor-feeding artery, a superselective (segmental or sub-segmental) approach was used whenever possible using a 2.4 F microcatheter (Merit Medical, USA) for embolization. The tip of the catheter was advanced into the hepatic artery and feeding branch if the size, location, and blood supply were optimal.

The cTACE group was injected an emulsified mixture containing 10 mL lipiodol (Jiangsu Hengrui Medicine Co., Ltd, China) and 40 mg pirarubicin (Shenzhen Wanle Pharmaceutical Co., Ltd, China) into the tumor feeding artery through a microcatheter under fluoroscopic monitoring to avoid reflux of the emulsion. The volume of embolization emulsion was based on the size of the focus. Then according to the blood flow velocity of tumor blood vessels, gelatin sponge particles are appropriately selected to strengthen the embolization until the tumor staining was disappeared.

Patients in the DEB-TACE group received CSM (100-300 μm or 300-500 μm in diameter; Jiangsu Hengrui Medicine Co. Ltd, China) loaded with 40 mg pirarubicin.

TACE upon portal vein visualization achieved “near stasis,” with a further pause of 5 minutes to allow redistribution of the embolic agents within the lesion and their distal propulsion by the blood inflow. The second time angiography was conducted to detect the presence of the remaining blushed nodules. The endpoint of the treatment was complete satiation of the tumor vessels with drug and the disappearance of the tumor blush on subsequent angiographic imaging.

The puncture wound was bandaged with pressure, and all patients were told to rest in bed in the supine position for at least 6 h post-embolization. The blood supply and temperature of the affected leg should be under intensive focus. The patients were given routine treatment after the operation: (1) Reduced glutathione for liver protection; (2) Granisetron for postoperative nausea and vomiting; (3) Ibuprofen for fever; (4) Non-steroidal anti-inflammatory drugs (Flurbiprofen Axetil) or opioids (morphine) for analgesia; (5) Antibiotics to prevent infection.

All patients underwent blood test (liver function indexes and alpha-fetoprotein) and imaging examination in the first month after TACE. Patients, who showed tumor progression in the first month after TACE, would receive a second TACE according to the previous grouping. Patients with stables disease were followed with imaging every 3 months.

The treatment response was assessed by two experienced radiologists based on enhanced computed tomography (CT) or magnetic resonance imaging (MRI) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria¹¹ at 1 month, 3 months, 6 months post-treatment: complete response (CR), partial response (PR), stables disease (SD), and progressive disease (PD). In addition, the objective response rate (ORR) was calculated and defined as CR + PR / total × 100%, and the disease control rate (DCR) was calculated and defined as CR + PR + SD / total × 100%.

Although CT response evaluation differentiation between Lipiodol and contrast agent is limited, the tendency to overestimate treatment response was avoided in the cTACE group through comparison of tumor enhancement in the arterial phase and the extent of lipiodol accumulation in the unenhanced phase.

The survival status of the two groups was evaluated by overall survival (OS) and progression-free survival (PFS). The OS was defined as the interval between the date of the first TACE treatment and the date of patients’death from any cause or censored at the date of the last follow-up. The PFS was defined as the interval between the start of the first TACE treatment date and the first radiological progression date, patients’ death from any cause, or censored at the date of the last follow-up.¹²

The safety of the two groups was evaluated by the liver function indexes and post-embolization syndrome. The liver function indexes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), and total bilirubin (TBIL), were assessed before the procedure (baseline), at 1 week, and 1 month post-procedure. The post-embolization symptoms, including fatigue, fever, abdominal distension, abdominal pain, and nausea/emesis, were assessed during the procedure and within 1 month after the procedure. The degree of pain was evaluated by the numeric rating scale (NRS) (0-10), where a score of 0 means no pain and a score of 10 indicates the maximum level of intolerable pain.¹¹

According to the ORR at 3 months after TACE, as described previously (73.7% in the DEB-TACE group and 42.5% in the cTACE group (P = 0.005))¹¹, a sample size of at least 39 subjects in each group was required to provide 80% power to detect differences at an α level of 0.05, indicating significance. However, to prevent a 15% attrition rate, we eventually recruited 90 patients with 45 in each group.

GraphPad Prism 8.0.2 software (GraphPad Software Inc., San Diego, CA, USA) was used for statistical analysis and generating graphs. The normally distributed continuous data were presented as the means ± standard deviation, while skewed distributed continuous variables were presented as median (25th–75th quantiles) and compared using a t-test. The enumeration data were presented as frequencies and percentages and compared using the chi-squared test. Kaplan–Meier (K–M) method was applied for making the survival curves, and the comparison of OS and PFS between the two groups was estimated by Log-rank test. Statistical significance was set at P < 0.05.

A total of 115 HCC patients were recruited in this trial, 18 did not meet the inclusion criteria, and 7 declined to participate. Finally, 90 patients fulfilled the inclusion criteria and were randomly divided into DEB-TACE or cTACE group (n = 45). The study selection is illustrated in Figure 1. All patients for analysis did not undergo any other treatment previously, including surgery, radiofrequency ablation, TACE, and systematic chemotherapy. At 1 week, 1 month, 3 months, and 6 months all patients in each group were analyzed except 1 patient in the DEB-TACE group died in the 5^th month after the procedure.

Figure 1

The mean age of the cohort was 58.9 ± 7.1 years in the DEB-TACE group and 60.6 ± 6.5 years in the cTACE group (P = 0.229). In addition, the DEB-TACE group had 40, while the cTACE group consisted of 39 males (P = 0.747). The history of alcohol consumption and viral hepatitis, Child–Pugh stage, BCLC stage, ECOG performance status, liver function, tumor location and distribution, and diameter of the largest tumor in the two groups did not differ significantly. The detailed baseline characteristics of patients are listed in Table 1.

The treatment response is shown in Table 2. At 1 month after the procedure, the ORR in the DEB-TACE group was significantly higher than that in cTACE group (P = 0.031), while there was no significant difference of the CR and DCR between the two groups. At 3 months after the procedure, a significant difference was observed in the treatment response between the two groups. CR, ORR, and DCR in the DEB-TACE group were significantly higher than those in the cTACE group (P = 0.036, P = 0.003, P = 0.025), while PD in the DEB-TACE group was lower than that in the cTACE group (P = 0.025). At 6 months after the procedure, CR presented no difference between the two groups, but ORR and DCR were significantly elevated (P = 0.002, P = 0.031), and PD was significantly reduced in the DEB-TACE group compared to the cTACE group (P = 0.031).

The final date of survival analysis was March 2022. All patients were followed up until death, or the end of the study and the last follow-up time of the assessment with the median follow-up duration was 365 days (95% CI:150-730 days), which was estimated by reverse Kaplan-Meier method.

Log-rank test revealed that, the median OS of the DEB-TACE group (534 days, 95% CI: 458-634 days) was significantly longer than the cTACE group (367 days, 95% CI: 321-562 days, P = 0.027, Figure 2A). The median PFS of the DEB-TACE group (352 days, 95% CI: 301-467 days) was significantly longer than the cTACE group (278 days, 95% CI: 247-324 days, P = 0.004, Figure 2B).

Figure 2

No significant difference was noted in the baseline value of the liver function indexes (AST, ALT, ALB, and TBIL) between the two groups (Figure 3 A–D). At 1 week after the procedure, the AST, ALT, and TBIL indexes were significantly higher in both groups, while the ALB level was lower than the baseline (Table 3). The comparison at 1 week after the procedure between the two groups showed that, the AST, ALT, and TBIL content in the DEB-TACE group was higher than that in cTACE group (Figure 3 A, B, D). However, there was no significant difference of the ALB between the two groups (Figure 3 C). At 1 month after the procedure, all the liver function indexes in the two groups returned to the baseline values (Table 3) and had no difference between the two groups (Figure 3 A–D).

Figure 3

For post-embolizat ion syndrome, the incidence of fatigue, abdominal distension, abdominal pain, and nausea/emesis were similar in the two groups within 1 month after the operation; however, the incidence of fever was higher in the DEB-TACE group than the cTACE group (P = 0.031, Table 4). Notably, the NRS of abdominal pain in the DEB-TACE group (4.4 ± 1.9) was higher than that in cTA-CE group (3.6 ± 1.6, P = 0.037, Table 4). Strikingly, the fever alleviated by drinking excess water and taking ibuprofen, and abdominal pain alleviated by intravenous injection of flurbiprofen axetil or by taking in morphine in 2-3 days. In addition, no serious adverse events, such as liver abscess, acute liver function failure, severe infection, gastrointestinal/intratumoral bleeding, and hepatorenal syndrome, occurred in either group.