Trial design
This study was an open-labeled, randomized, phase III trial conducted at the Sun Yat-sen University Cancer Center (Guangzhou, China), designed to evaluate the efficacy and safety of radical hepatectomy plus adjuvant TACE versus radical hepatectomy alone among HCC patients with solitary tumor ≥ 5 cm and MVI after curative resection. The protocol and all modifications were approved by the Institutional Review Board and Ethics Committee of our cancer center. This study complied with the Declaration of Helsinki and the Good Clinical Practice Guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Version E6) [22]. All patients provided written informed consents. This study was registered in ClinicalTrials.gov (http://ClinicalTrials.gov, trial number NCT02788526) on March 23, 2016.
Eligibility criteria
The eligibility criteria for inclusion were as follows: 18–75 years of age; histologically confirmed HCC with MVI (MVI was defined by the presence of tumor emboli within either the central hepatic vein, the portal, or the large capsular vessels [23]); Eastern Cooperative Oncology Group performance score (ECOG PS) ≤ 2; no previous treatment for HCC; solitary tumor ≥ 5 cm before surgery confirmed by 2 radiological examinations (ultrasonography with computer tomography or magnetic resonance imaging); R0 resection; no evidence of recurrence at radiological follow-up at 3–5 weeks after surgery; adequate hematologic, hepatic, and renal functions. The exclusion criteria included histologically positive resection margin (R1 resection); evidence of recurrence at radiological follow-up 3–5 weeks after surgery; history of organ transplantation; active uncontrolled infection; allergy to any TACE agent; other malignancies over the preceding 5 years before the HCC diagnosis, except for adequately treated carcinoma in situ of the cervix and squamous or basal cell carcinoma of the skin; pregnancy, breastfeeding, or lack of use of adequate contraception among women of childbearing potential; neurological or psychiatric disorders that may affect cognitive assessment and inform consent; concomitant antitumor therapy or participation in other interventional clinical trials.
Hepatectomy
All surgical resection procedures were performed following the techniques described in our previous study [10]. Briefly, routine abdominal exploration was carefully performed to evaluate the extent of the tumor and to exclude extrahepatic metastases. After adequate mobilization of the liver, we used intraoperative ultrasound (ALOKA SSD-5500, Tokyo, Japan) to assess the number of lesions and tumor size, the presence of MVI, and the extent of resection. During tumor removal, the liver parenchyma was separated using the Cavitron Ultrasonic Surgical Aspirator (Integra LifeSciences CUSA Excel, Plainsboro, NJ, USA), and the involved vessels were ligated. The Pringle maneuver was also applied to occlude blood inflow to the liver.
Randomization
All patients were screened for enrollment at the first follow-up (3–5 weeks after hepatectomy). Full patient assessment, including demographic characteristics, medical history, physical examination, routine blood analysis (hematology and biochemistry), and radiological examinations [computed tomography (CT) or magnetic resonance imaging (MRI)], were performed within 1 week of the study enrollment. The patients with evidence of recurrence during the screening for enrollment were excluded. Then the eligible patients were randomly assigned (at a 1:1 ratio) to receive either 1–2 cycles of adjuvant TACE (Hepatectomy-TACE group) or routine follow-up without adjuvant treatment (Hepatectomy Alone group). Randomization was performed using a sealed envelope system according to a predesigned random number.
Adjuvant TACE
The patients in the Hepatectomy-TACE group underwent TACE 4–6 weeks after hepatectomy according to liver function and performance status. TACE was performed using the techniques we have described previously [24]. In brief, a catheter was placed into the proper hepatic artery through the femoral artery using the Seldinger technique, hepatic arterial angiography was performed, and 200 mg/m2 carboplatin (Carboplatin, Bristol-Myers Squibb, New York, NY, USA) and 6 mg/m2 mitomycin (Mitomycin, Hisun, Taizhou, China) were infused followed by 4–5 mL of the emulsion of iodized oil (lipiodol, Andre Guerbet, Aulnay-sous-Bois, France) and 40 mg/m2 epirubicin (Epirubicin Hydrochloride, Pfizer, New York, NY, USA). After 4–6 weeks, these patients underwent a complete assessment consisting of physical examination, routine blood analysis, and CT scan. The second cycle of TACE was performed according to the decision of investigators based on the patients’ conditions and the assessment results.
Follow-up
All patients were followed-up at an interval of 2–3 months. To avoid the potential effect of hepatitis B virus (HBV) reactivation on recurrence, all patients with positive serum hepatitis B surface antigen (HBsAg) were administered with routine antiviral therapy with lamivudine (GlaxoSmithKline, Brentford, UK; 100 mg, once daily) or entecavir (Bristol-Myers Squibb, New York, USA; 0.5 mg, once daily). At each follow-up visit, physical examination, blood test (serum alpha-fetoprotein [AFP] and liver function), and enhanced abdominal CT or MRI scan were performed. Once suspicious recurrence/metastasis was detected, further examinations including hepatic angiography or biopsy were conducted. Recurrence/metastasis was confirmed based on the cytologic/histologic evidence or on the non-invasive diagnostic criteria for HCC by the European Association for the Study of Liver [7]. Patients with recurrence in both groups received subsequent treatment according to the decision of the multi-disciplinary team of our cancer center. Adverse events (AEs) were recorded from the day of randomization to the last day of follow-up. Toxicity was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). The study was censored on March 31, 2016.
Statistical analyses
The primary endpoint was DFS and was defined as from the time of randomization to the diagnosis of recurrence or death from any cause. The secondary endpoints included OS, which was defined as from the time of randomization to the date of the last follow-up or death, and AEs.
Assuming an increase in median DFS of 6 months between the Hepatectomy-TACE group (18.0 months) and Hepatectomy Alone group (12.0 months) [hazard ratio (HR) 0.66], it was estimated that 176 events and a total of 210 patients (105 in each group) were required for randomization to achieve a statistical power of 85% with a significance level of 0.05 for a one-sided error. All analyses were performed according to the per-protocol principle. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. The median survival with 95% confidence interval (CI) was calculated. Cox proportional analyses were performed to estimate HRs with 95% CIs. The t-test was used for group comparisons of AEs. We also performed subgroup analyses for sex (male vs. female), age (< 60 years vs. ≥ 60 years), ECOG PS (0 vs. 1–2), tumor size (5–10 cm vs. > 10 cm), cirrhosis (present vs. absent), and resection margin (< 2 cm vs. ≥ 2 cm). All statistical tests were performed with the Statistical Package for the Social Sciences (SPSS) (version 23, Chicago, IL, USA), Stata (version 13, College Station, TX, USA), and Medcalc (version 16.1, Acacialaan, Belgium) statistical software, and P values < 0.05 were considered significant.