Study population
This single-institution retrospective study was approved by the Institutional Ethics Committee of the Second Xiangya Hospital of Central South University in accordance with Declaration of Helsinki (approved number: 2018S230). Verbal informed consent was obtained from patients or their family members.
A total of 1341 patients with HCC underwent TACE between April 2013 and September 2017 were included in this retrospective study. Of 1341 patients, 117 patients were iHCC. The definition of iHCC was presence of an extensive permeative hepatic tumor with ill-defined margins on computed tomography (CT) or magnetic resonance (MR) (Fig. 1) [10]. The exclusion criteria were as follows (Fig. 2): (a) patients in whom we were unable to assess the tumor response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) for example the lesion was less than 1 cm, the lesion was unsuitable for repeat measurement, the lesion did not show intratumoral arterial enhancement on contrast-enhanced CT or MRI (n = 12); (b) patients who lost follow-up (n = 7); (c) patients received radiofrequency or microwave ablation prior to TACE (n = 9). Thus, the final study population consisted of 89 patients. Of these 89 patients, 56 patients were in the DEB-TACE group, and 33 patients were in the cTACE group. The data collected included patient age, patient gender, etiology of cirrhosis, Eastern Cooperative Oncology Group (ECOG) performance status, primary tumor size, Child-Pugh class, serum total bilirubin, creatinine and albumin levels, Barcelona Clinic Liver Cancer (BCLC) stage, model for end-stage liver disease (MELD) score, tumor burden, and presence or absence of portal venous tumor thrombus (PVTT), arterioportal shunt (APS), ascites, and distant metastasis. In the present study, patients with the situations that might have a poor outcome were defined as advanced disease including Child-Pugh class B, bilobar lesions, a tumor size greater than 10 cm, ECOG 1–2, a tumor burden of 50–70%, and the presence of ascites, arterioportal shunt (APS), and portal venous tumor thrombus (PVTT).
Interventions
The procedure was performed by three interventional radiologists with 17-year, 21-year and 13-year experience of liver interventions, respectively. The femoral artery was routinely catheterized. Celiac trunk arteriography and superior mesenteric arteriography, as well as indirect portography, were performed using a 4F catheter to demonstrate the variant hepatic arterial anatomy and evaluate the patency of the portal vein. Selective arteriography was performed to demonstrate the tumor blood supply, then a 2.7 F coaxial microcatheter (Progreat, Terumo Medical Corporation) was used to super-select the third- or fourth-order branch of the hepatic artery that supplied the target tumor. The chemoembolization was performed as selectively as possible. Lobar chemoembolization was performed only if the tumor feeding artery was difficult to super-select.
For the DEB-TACE group, the patients were treated with an intra-arterial injection of 1–2 g DEB (CalliSpheres Beads, Jiangsu Hengrui Medicine Co. Ltd). The size of DEB varied from 100 μm to 500 μm, and the amount of doxorubicin used ranged from 80 mg to 150 mg. The embolization endpoint was defined as stasis of blood flow in the tumor-feeding artery, which was often measured by the time it took to clear the contrast column (typically 4 heart beats). Repeated hepatic arteriography was performed to assess the devascularization after embolization. For the cTACE group, the patients were treated with an intra-arterial injection of 5–15 mL oil-doxorubicin emulsion. The oil-doxorubicin emulsion was created using the water-in-oil technique by mixing iodized oil (Lipiodol, Guerbet Group) with a distilled water solution containing a drug cocktail of dissolved doxorubicin at a ratio of 3:1. The doxorubicin dose used varied from 50 mg to 75 mg. After the oil-doxorubicin emulsion was injected, gelfoam slurry was used to embolize the tumor-feeding artery. The endpoint of embolization in the cTACE group was the same as that in the DEB-TACE group.
In both DEB-TACE and cTACE groups, follow-up imaging was performed 1–2 months intervals, repeat treatment was performed when there was viable tumor on the follow-up images. Patients received a maximum of three chemoembolizations (at baseline, 1 month, and 3 months) with a mean follow-up of 6 months.
Tumor response assessment
Tumor response was measured on contrast-enhanced CT or MR imaging based on the longest dimension of the viable tumor at 1 month and 3 months after the first TACE session according to mRECIST. Two liver radiologists with 18 years and 14 years of experience who were not involved in the treatment independently reviewed images and measured the longest dimension at before and 1 month as well as 3 months after the first TACE session. The diameter measured between two radiologists were averaged in each patient. The objective response rate (ORR) and disease control rate (DCR) of the two groups were calculated.
Progression-free survival (PFS) assessment
The PFS was defined as time between date of treatment and death whatever the cause, tumor progression or last clinical follow-up. The PFS was calculated and compared between DEB-TACE group and cTACE group.
Safety assessment
The safety assessment was evaluated based on a procedure related to toxicity grading. Toxicities were classified as clinical and laboratory toxicity, which was assessed within 1 month after the procedure. The grading of toxicity was defined as low (grades 1–2) or high (grades 3–4) according to Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0).
Statistical analysis
Continuous data were expressed as the mean ± SD. All statistical analyses were conducted using a statistics package (SPSS version 20, International Business Machines Corporation), and P < 0.05 was considered statistically significant. Continuous data, such as age, primary tumor size, serum total bilirubin, creatinine, and albumin, and MELD score were compared between the two groups using a 2-tailed independent samples t-test. Categorical data, such as the ORR, DCR, etiology of cirrhosis, ECOG ps, Child-Pugh class, BCLC stage, tumor burden, and presence or absence of PVTT, ascites, distant metastasis, and APS, were compared between the two groups using the Chi-square test or Fisher’s exact test (if appropriate). PFS curve was performed using the Kaplan-Meier method and compared between two groups using the log-rank test. The intraclass correlation coefficient (ICC) was performed to evaluate the inter-reader agreement of diameter measurement between two radiologists. Agreement was classified as poor (ICC, 0–0.40), fair to good (ICC, 0.40–0.75), and excellent (ICC, > 0.75).