In this retrospective, single-center study we analyzed the data of consecutive patients who underwent TACE. The first primary endpoint was overall survival; the second primary endpoint was time to progression in patients who achieved a favorable treatment response. Approval for the study was obtained from the local Institutional Ethical Committee of Human Experimentation and the study was performed in accordance with the current version of the Declaration of Helsinki.
Study population
A search of the internal database was performed for patients undergoing TACE between March 3, 2016 and January 26, 2018. Three radiologists reviewed the records and imaging via the picture archiving and communication system (PACS). Figure 1 shows a summary of the inclusion and exclusion criteria and the final study population.
The inclusion criteria were as follows: (1) patients had at least one index HCC lesion confirmed by imaging or pathology; (2) patients were undergoing TACE as HCC therapy; (3) patients had good liver function (i.e., Child-Pugh A or B), without the presence of vascular tumor thrombus or metastatic disease; (4) patients had an available dynamic contrast enhanced CT or MRI liver examination within 90 days after the first TACE cycle.
A total of 203 patients were excluded based on the following criteria: (1) other (non-TACE) HCC-specific treatment including ablation or resection; (2) liver transplantation before procedure or during follow-up period; (3) history of malignant neoplasm other than HCC; (4) uncontrolled functional or metabolic disease before the procedure or during the follow-up period (including portal vein thrombosis); (5) TACE complications (e.g. significant post-procedural liver decompensation); (6) incomplete clinical and follow-up data.
All patients underwent a series of laboratory examinations before the initial TACE session, including a liver function panel. The following variables were analyzed: age, sex, underlying etiology of chronic liver disease, serum total bilirubin, albumin, creatinine, international normalized ratio (INR), α-fetoprotein level, Barcelona-Clinic Liver Cancer (BCLC) stage, and Child-Pugh-Turcotte (CPT) score. The diagnosis of HCC was made using imaging criteria (LI-RADS).
TACE technique
All patients underwent standard conventional TACE procedures. After obtaining femoral access, angiographic runs were performed to confirm hepatic and tumoral blood supply. Vessels feeding target lesions were selectively catheterized with a microcatheter and 20–40 mL of a mixture of lipiodol and doxorubicin in a 1:1 ratio was slowly injected until arterial flow stasis was observed.
TACE was repeated after 4–6 weeks when indicated and feasible. A standard embolization cycle consisted of two (or three, if indicated) TACE sessions and subsequent CT/MRI work-up. One patient had only one TACE procedure before the first treatment response (LR-TR) assessment.
Postprocedural work-up and follow-up
All patients underwent a multiphasic CT (or optional MRI study) between 30 and 90 days after completion of the TACE cycle as recommended by the LR-TR guidelines (Chernyak et al. 2018). Image sections were acquired using a multi-slice CT scanner with non-ionic contrast medium during the precontrast phase, the late arterial phase, the portal venous phase and the equilibrium phase. All imaging examinations were compliant with LI-RADS 2018 technical recommendations. If a favorable treatment response with no viable tumor tissue was visualized after the TACE cycle, patients were followed up by serial imaging and measurements of serum α-fetoprotein concentration until HCC recurrence. If a viable tumor was present during follow-up, a multidisciplinary team meeting was held for consensus regarding management and further treatment options.
Imaging analysis
Two independent reviewers (with 5 years’ and 8 years’ experience in liver imaging, respectively) evaluated post-treatment images. Both observers were informed that study patients had undergone TACE for HCC but were blinded to the clinical, laboratory and survival data. All imaging features were analyzed according to the LR-TR (LI-RADS v. 2018) and recorded by the two radiologists. Another radiologist with 11 years’ experience of liver imaging re-evaluated any discordant results and drew the final conclusion.
All patients were divided into three subgroups according to the LR-TR, with response defined as follows:
- LR-TR non-viable — no arterial phase hyperenhancement (APHE) and/or presence of expected treatment-specific enhancement pattern.
- LR-TR equivocal — atypical enhancement pattern, not meeting criteria for non-viable or viable category.
- LR-TR viable — APHE or washout appearance or enhancement similar to pretreatment.
If a patient had more than one observation, each representing different responses, the final response category was reported in aggregate by choosing the one reflecting the less favorable response. In patients who did not achieve an initial non-viable response, the subsequent overall treatment response was defined using pre-existing radiology reports, with lack of tumoral enhancement as a criterion of favorable treatment response.
The date of the first TACE procedure was adopted as an index day. The end of the follow-up period was defined as the time of death or last clinical follow-up (September 24, 2020). In patients who achieved a favorable treatment response, time to progression was defined as the interval between achieving non-viable tumor status and the date of reported progression.
Statistical analysis and artwork
Statistical analyses were performed using SAS software (Statistical Analysis System version 9.4, SAS Institute Inc., Cary, NC, USA). Categorical variables are shown as counts and percentages. The kappa coefficient (κ) was used to assess the interobserver agreement for LR-TR responses. Fisher’s exact and Kruskal–Wallis tests were used to compare differences between study subgroups. In addition, we used the Kaplan-Meier method together with the log-rank and Peto-Peto-Prentice tests with Šidák correction to compare differences between survival curves. A Cox proportional hazard model was used for univariate and multivariate survival analyses.