This study complies with the standards of the Declaration of Helsinki and current ethical guidelines, and approval was obtained from the institutional ethics committee (REC No. 64-257-7-1). The requirement for informed consent for this study was waived by the Institutional Review Board, and all the data were analyzed anonymously.
We followed the American Association for the Study of Liver Disease criteria for the diagnosis of HCC . Hepatic lesions larger than 1 cm were assessed by multiphasic contrast-enhanced computed tomography (CT) or dynamic magnetic resonance imaging (MRI). If the imaging characteristics were the typical appearance of HCC, no further diagnostic procedure was attempted.
The data of 337 HCC patients treated with selective TACE between January 2015 and December 2019 at our hospital were collected for this study. Eligible patients for inclusion included: (1) patients aged > 18 years, (2) HCC patients with tumor size ≤ 7 cm in diameter and the number of nodules ≤ 5, (3) patients ineligible for surgical resection or transplantation, (4) patients treated with selective conventional TACE, and (5) patients who underwent imaging examination by either dynamic MRI or 4-phase contrast-enhanced CT scan within one month after the initial procedure. The excluded patients were those with severe impaired hepatic function (Child-Pugh class C), extrahepatic metastasis, concomitant malignancy, severe arterioportal shunt, history of spontaneous tumor rupture, presence of vascular invasion, and cotreatment with any systemic or locoregional therapies during the TACE session.
Of the 337 HCC patients included in this study, 141 underwent TACE using DSA alone and 196 underwent TACE with CBCT (with or without AFD software) between January 2015 and December 2019. We assigned our patients to each technique on the basis of a discussion with interventional radiology staff. To minimize selection bias, patients treated by both techniques (i.e., first treated by TACE with DSA alone and subsequently underwent TACE by CBCT) were excluded from this study.
Selective conventional TACE protocols
All HCC patients underwent selective conventional TACE using an angiographic system (Allura Clarity FD20, Philips Healthcare, Eindhoven, the Netherlands) under the supervision of two interventional radiologists with more than 8 years of experience in body interventional radiology through the transfemoral route. Celiac and superior mesenteric arteries were selected at the beginning of the procedure using a 5-Fr diagnostic catheter and a 0.035-inch J-tip guidewire. We performed selective catheterization to the tumor feeding hepatic arteries or in extrahepatic collaterals as distal as possible in each tumor lesion using a 1.98-Fr to 2.4-Fr microcatheter. After the microcatheter was inserted into the target arterial feeder, we slowly administered a mixture of iodized oil (range, 2‒16 ml) (Lipiodol, Guerbet) and doxorubicin hydrochloride (range, 5 to 50 mg) (Adriamycin, Pfizer) or mitomycin (range, 10‒20 mg) (Vesimycin, Naprod Life Sciences) under real time monitoring with DSA. The amount of anticancer-in-oil-emulsion (1:2 or 1:4 ratio) was adjusted by total tumor size and the number of nodules. Subsequently, the feeding artery was embolized using gelatin sponge particles. We completed the procedure when the tumor feeding branch was completely obstructed and tumor staining from DSA completely disappeared.
Intraprocedural CBCT technique with AFD software
The CBCT data[GKS1] were acquired[GKS2] using an Allura Clarity FD20 which enabled CBCT acquisition and volumetric image reconstruction. A total of 242 projection images (60 frames/second) with X-ray parameters of 121 kV and 200‒300 mAs were obtained with the motorized C-arm covering a 220° clockwise rotation of the flat panel detectors. The patients were instructed to be at end-expiratory apnea during the CBCT scanning. All CBCT images of 5 mm thickness were interpreted using a workstation (Philips Healthcare, Eindhoven, the Netherlands). We performed CBCT with AFD software assisted TACE in three steps (Fig. 1).
Step 1: Identification of tumor nodules
We placed the catheter at the proper or common hepatic artery and performed CBCT during hepatic arteriography (CBCTHA). A total of 24 ml of non-diluted contrast media (Omnipaque 350 mgI/ml, Bayer, Bangkok, Thailand) was injected via a 5-Fr diagnostic catheter at the rate of 2 ml/second. The first phase of CBCTHA started after contrast material injection for 7 seconds and the second scan was achieved 30 seconds after finishing the first scan. The patients held their breath twice during the gantry rotation. All hepatic lesions with corona enhancement, which represented venous drainage through hypervascular HCC nodules  on the second scan of CBCTHA were targeted for treatment with conventional TACE.
Step 2: Detection of tumor feeding arteries
The automated tumor-feeder software (EmboGuide, Philips Healthcare, Best, the Netherlands) used the data from the first scan of CBCTHA to identify the tumor feeders in about 2 minutes at the workstation. We used AFD software to detect segmental tumor feeders in case they were not clearly seen on conventional DSA images. After the feeder branches were identified, embolization was performed without obtaining further DSA images.
Step 3: Evaluation of iodized oil accumulation:
We performed plain CBCT without contrast media injection just after the selective TACE procedure to monitor the distribution of iodized oil. The goal of chemoembolization is to completely embolize the entire target tumor with or without an adequate safety margin. If incomplete tumor stains occurred, further chemoembolization was performed.
Analysis of the prognostic factors for overall survival
Univariate and multivariate analyses were used to define the significant independent factors affecting overall survival (OS). Fourteen clinical factors were analyzed: age, gender, alcohol drinking, hepatitis B or C virus carrier, Child-Pugh class, albumin-bilirubin (ALBI) score, total bilirubin, albumin, international normalized ratio (INR), platelet count, serum alpha-fetoprotein (AFP) level, ascites, and BCLC staging. Also analyzed were four tumor factors: size of largest tumor, number of tumor nodules, lobar involvement, and the up-to-7 criteria plus two procedure-related factors: complete remission at 1 month and use of CBCT-assisted TACE.
Outcome and treatment evaluation
All eligible patients were followed up after selective TACE with a detailed clinical examination, blood chemistries, and an imaging study using 4-phase contrast-enhanced CT scan or dynamic MRI within one month after the initial procedure. If no definite evidence of residual or recurrent tumor presented, imaging investigation was performed subsequently at 3-month intervals. We used the modified Response Evaluation Criteria in Solid Tumors (mRECIST) to assess HCC after treatment . Complete response (CR) was defined as disappearance of any intratumoral arterial enhancement in all target lesions. Partial response (PR) was defined as at least 30% decrease in the sum of the diameters of the target lesions. Progressive disease (PD) was defined as at least 20% increase in the sum of the diameters of the target lesions, and stable disease (SD) was defined as not sufficient to qualify for either PR or PD. The decision to repeat the TACE procedure was based on tumor response by mRECIST, BCLC-staging of the disease, and the patient’s tolerance.
TACE-related complications were classified as major or minor following the standard Society of Interventional Radiology (SIR) guidelines . Major complications of conventional TACE were defined as admission to a hospital for therapy, an unplanned increase in the level of care, prolonged hospitalization, permanent adverse sequelae, or death after the procedures by SIR guidelines .
Data and statistical analysis
All data analyses were performed using R software (version 4.1.0). Numerical data are given descriptively using the central tendency (mean, median, and mode) and a measure of dispersion (standard deviation and range). We used chi-square or t-test to compare baseline characteristics between the HCC patients who underwent TACE with CBCT assistance and patients who received TACE with DSA. Local progression-free survival (PFS) was calculated from the date of selective TACE to the last date of local tumor progression or the date of patient death. Local tumor progression was diagnosed when an arterial enhancing lesion was depicted in or adjacent to the treated tumor on follow-up imaging. OS was calculated from the date of selective TACE to the date of patient death. Patient status at the end of the study (December 31, 2020) was defined as alive or dead using data from the Thailand civil registration database. The local PFS and OS rates for the two groups of HCC patients were compared using the Kaplan-Meier estimator. The probability of OS for the two groups was estimated using the Cox’s proportional hazards regression model. The OS rates at 1, 3, and 5 years were calculated and compared for each group.
Baseline clinical characteristics, tumor appearances, and procedure-related factors affecting survival were initially assessed by univariate analysis. Subsequently, all prognostic factors having p values ≤ 0.2 from the univariate analysis were entered into the initial multivariate Cox's proportional hazards regression. The model was refined by sequentially removing non-significant variables. P values < 0.05 were considered statistically significant.