Lipiodol

As has previously been reported (22 (link)), TACE was performed by administering doxorubicin mixed with 5–20 mL lipiodol (Lipiodol Ultrafluide, Laboratoire Guerbet, France) to both groups. The dose of doxorubicin was 50–75 mg/m² (Haizheng Pharmaceutical Co. Ltd., China) adjusted based on patient liver function, tumor size, vascularity, presence of an arterioportal shunt, and body surface area. All tumor-feeding arteries were superselected by a microcatheter (Terumo, Tokyo, Japan), and the mixture was injected at a rate of 1 mL/min until stagnation of blood flow was observed under fluoroscopic guidance. Gelatin sponge particles with a 500–700-um size was used to block feeding arteries of tumors. If an artery–portal vein shunt was performed, it was occluded before mixture embolization by big-size polyvinyl alcohol (Polyvinyl Alcohol Foam Embolization Particles; Cook Medical Inc., Bloomington, IN, USA) or a spiral steel ring based on angiography images and the doctor’s experience.

This analysis was reported according to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines.16As a prelude to the main study, the specificity of the HAP score for patients undergoing TACE was examined in 3,556 patients with early HCC who underwent resection and in 967 patients with advanced HCC who received sorafenib within clinical trials.17, 18In the main study, the reported TACE cohort19 was expanded by collecting further cases in which the response to TACE according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST)20, 21 was recorded. This analysis has involved only patients who were classified by the local investigator as undergoing TACE as their primary and first treatment. Patients whose TACE was used as a bridge to transplantation or other potentially curative treatment options were excluded, as were patients with extrahepatic metastasis. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the appropriate institutional review committee.
All participating centers had specific expertise in the management of HCC and the practice of TACE. There were 19 centers representing 11 different countries, including a reported multicenter cohort22, 23 that comprised patients from London (United Kingdom), Osaka (Japan), Seoul (Korea), and Novara (Italy) (Tables 1 and 2). Most centers used “conventional” TACE, although several moved to drug‐eluting bead (DEB)–based TACE after 2008. In all centers, patients were followed up by computed tomography (CT) or magnetic resonance imaging scans once every 3 months after stable disease (SD) had been attained.
Baseline variables available in all the centers were age, sex, cause (hepatitis C virus [HCV], hepatitis B virus [HBV], alcohol, or “other”), tumor number (solitary or multiple), tumor size (centimeters), VI, Child‐Pugh grade, albumin (grams per liter), bilirubin (micromoles per liter), and AFP (nanograms per milliliter). The approach to TACE (DEB‐based or lipiodol‐based methods) was not proscribed, although no case received transarterial radioembolization.
The “other” cause comprised mainly patients with nonalcoholic fatty liver disease (NAFLD), other types of chronic liver disease, and more than one cause. The first TACE procedure was undertaken within 6 weeks of diagnosis, and laboratory data were recorded during that period.
VI (including portal vein, hepatic vein, and inferior vena cava involvement) was assessed in the portal phase of CT and supplemented where appropriate by arterial portography and classified as “present” or “absent.” Response assessments according to mRECIST20, 21 were made within the 6 to 9 weeks following the first TACE treatment. mRECIST response was categorized as complete response (CR), partial response (PR), SD, and progressive disease (PD). mRECIST data were available in eight of the 17 cohorts (2,688 patients). This analysis did not take into account further TACE treatments undertaken after the first one. Liver function was assessed by the Child‐Pugh grade (as graded by the local investigator) and the albumin‐bilirubin (ALBI) score, the latter being graded according to the published cut‐off points.24 Grades 1, 2, and 3 refer to good, intermediate, and poor liver function, respectively. Data on treatment of hepatitis C with direct‐acting antivirals (DAAs) were not collected, but an estimate of the number who might have received this therapy was gained by assessing the date of TACE treatment, assuming there were only a very limited number who would receive DAAs before January 2012.
After generation of the models, as described below, they were externally validated in independent data sets from China and Germany, representing “Eastern” and “Western” cohorts respectively. External validation and calibration were undertaken using methods described by Royston and Altman.25, 26

All patients included were treated with TACE, including conventional TACE (cTACE) and drug-eluting bead TACE (DEB-TACE). Interventional physicians choose cTACE or DEB-TACE based on tumor burden and patient characteristics. The basic treatment process of DEB-TACE resembles that of cTACE except for the embolic agents. cTACE uses lipiodol (Guerbet), gelatin sponge particles, and polyvinyl alcohol as embolic agents. Selective or super-selective embolization of tumor-supplying vessels is performed whenever technically justified [23 (link)]. For DEB-TACE, 100–300 μm diameter CalliSpheres® Beads (CB; Jiangsu Hengrui Pharmaceutical Co., Ltd.) were used as carriers, loaded with 60–80 mg epirubicin, pirarubicin, or doxorubicin. All procedures were administered by interventional physicians with at least 10 years of experience. All patients were admitted for postoperative supportive care after TACE procedure and were managed routinely.
Study cohort judgment of TACE response was performed according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) [24 (link)] criterion. In brief, the therapeutic response of TACE was stratified into four grades: (a) complete response (CR): complete disappearance of the lesion; (b) partial response (PR): a minimum 30% reduction in the sum of diameters of viable target lesions (enhancement in the arterial phase); (c) progressive disease (PD): at least 20% extension in the sum of the diameters of viable (enhancing) target lesions; and (d) stable disease (SD): neither PR nor PD. Based on mRECIST, CR and PR patients were categorized as objective response (OR) cohort, and PD and SD patients as non-objective response (NOR) group. This assessment was determined by two professional abdominal radiologists based upon the follow-up MR images. Among the 144 patients enrolled, 75 were assigned to the NOR group and 69 to the OR group. In the independent external validation set, 14 patients were in the NOR group and 14 in the OR group.

The detailed procedure for TACE at our institution has been described previously [18 (link),19 (link)]. RT was performed for either curative or palliative aims according to the guidelines of the Korean Liver Cancer Association [20 (link),21 (link)] and applied after the general condition recovery of patients with a stabilized liver enzyme found in blood chemistry evaluation. All patients were educated on respiratory control. Respiratory gating or the breath-hold technique was utilized according to the radiation oncologist’s discretion. The gross tumor volume (GTV) included viable tumor areas, tumor areas filled by lipiodol, and tumor areas showing tissue necrosis after TACE. The internal target volume (ITV) was delineated based on the tumor movement during individual respiratory phases, and the planning target volume (PTV) was defined as the ITV with a 5-mm margin. RT doses were prescribed according to the physicians’ discretion to maximize the dose delivered to the tumor while satisfying the dose constraints for normal organs, such as the remnant liver and gastrointestinal tract.