Ethics statement
All examinations and treatments were conducted at the Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, in Shanghai, China and were in accordance with the Declaration of Helsinki. This study was approved by the Ethics Committee of the Eastern Hepatobiliary Surgery Hospital. Written informed consent was obtained from all patients included in this study.
Patients
Between January 2007 and July 2012, 7569 patients with HCC were admitted to the Department of Minimally Invasive Therapy. All very-early-stage HCC patients during the same period who met the following criteria were included in this retrospective study: (a) initial solitary HCC nodule of 2 cm or smaller in size; (b) liver cirrhosis class A or B (according to the Child–Pugh staging system), prothrombin activity greater than 50%, and platelet (PLT) count greater than 50 × 109/L; (c) absence of extrahepatic or vascular metastasis; and (d) thermal ablation as their first-choice treatment.
Tumor size was evaluated by computed tomography (CT) and magnetic resonance imaging (MRI). Because of possible complications arising from seeding cancer cells [18], a percutaneous liver biopsy is not suggested in the Eastern Hepatobiliary Surgery Hospital. The diagnosis of HCC followed the criteria established by the American Association for the Study of Liver Diseases: hepatic lesion mass of 2 cm or smaller as detected with four-phase CT and MRI with intense arterial uptake followed by “washout” of the contrast agent in the portal and delayed phases [3]. Unfavorable tumor locations were defined as nodules located 5 mm or closer to critical structures, including the gallbladder, gastrointestinal tract, hilum, pericardium, diaphragm, and major vessels [19]. Major vessels were defined as the first or second branch of the portal vein, the inferior vena cava, and the main hepatic veins [19]. The presence of “Heredity” refers to the status that any immediate relatives within three generations suffered from HCC.
Individual cases were examined and discussed by our multidisciplinary team, involving hepatologists, interventional radiologists, and surgeons. In this cohort, patients selected underwent either the MWA or RFA procedure if the tumors were not adjacent to major vessels. However, to lower susceptibility to the heat sink effect, MWA was recommended for tumors adjacent to major vessels.
Ablation procedure
MWA device
A FORSEATM MW delivery system (Qinghai Microwave Electronic Institute, Nanjing, Jiangsu, China) was used. This system is composed of an MTC-3 microwave generator with a frequency of 2450 MHz and a power output of 1–100 W, a flexible low-loss coaxial cable, and a 14-gauge cooled shaft antenna. The antenna consists of one 18-cm-long shaft coated with Teflon to prevent tissue adhesion and a 3-cm-long exposed antenna at its terminus with a 1.5-cm-long active tip coated with polytetrafluoroethylene.
RFA device
A Cool-tip™ RFA system (Valley Lab, Boulder, CO, USA) was used. This system is composed of a radiofrequency generator with a maximum power output of 200 W, as well as a 17-gauge and 18-cm-long internally cooled needle electrode. A 2-cm-long activating tip electrode was used.
After local anesthesia at the puncture site, under the guidance of real-time ultrasound, the antenna or electrode was percutaneously probed into the tumors, with the tip placed in the deepest part of the nodule. A RFA was applied for 10–12 min. For all patients, the application of MWA at 80–100 W was performed in automatic mode for 3–5 min. A safety margin of more than 1.0 cm was employed for all thermal ablation-treated tumors. At the end of ablation, the puncture tract was coagulated to prevent potential bleeding or tumor seeding.
Efficacy evaluation and follow-up
A contrast-enhanced CT scan was performed 48 h after ablation. The local efficacy was evaluated according to imaging manifestations [20] and our previous study [9]. Complete ablation was defined as that the ablated area completely covers the target tumor (Fig. 1). Incomplete ablation was defined as any enhancement within the ablation area or the target tumor. All patients with incomplete ablation were further treated by complementary ablations. A major complication was defined as an event that led to substantial morbidity or disability, upgrade of the level of care, or a substantially extended hospital stay [21].
All patients were regularly followed up every 2–3 months during the first 2 years and every 6 months in postoperative 3–5 years. Alpha-fetoprotein (AFP) detection and contrast-enhanced CT/MRI were regularly performed to monitor HCC recurrence. LTP was defined as any new lesion connected to the ablated zone. Distant recurrence (DR) was defined as a new intra-hepatic nodule [21]. Recurrence included LTP and DR. The strategy for managing recurrent HCC was based on simulation, but it was slightly different from the BCLC staging system: (1) for very-early-stage and early-stage HCC with a favorable location for local thermal ablation, repeated ablation was recommended; for very-early-stage and early-stage HCC with an unfavorable location, hepatic resection, if feasible, was recommended; (2) for intermediate- or advanced-stage HCC, transcatheter arterial chemoembolization (TACE) or sorafenib was recommended; (3) for terminal HCC with Child–Pugh A or B cirrhosis, TACE, conservative treatment, or sorafenib was recommended; and (4) for patients with extrahepatic metastasis, systemic chemotherapy was recommended. Treatment for a recurrent tumor was determined by the characteristics of the recurrent tumor and the recommendations of our multidisciplinary team.
The primary endpoint was the 5-year OS rate; the secondary endpoint was RFS rate. Additional points included complete ablation, complication occurrence rates, LTP, and DR. The OS was calculated from the date of ablation to the date of death or last follow-up; the RFS was calculated from the date of ablation to the date of LTP, DR, or last follow-up. The last follow-up date for this study was July 25, 2015.
Prognostic factor analysis
To identify the prognostic factors for OS, RFS, and LTP, 23 variables were used, including sex, age, etiology, heredity, tumor size, tumor location, Child–Pugh class, hepatitis B virus (HBV)-DNA level, antiviral therapy, alanine aminotransferase, total bilirubin, direct bilirubin (DBIL), albumin (ALB), gamma-glutamyl transpeptidase, PLT, prothrombin time, AFP level, carbohydrate antigen 19-9 (CA19-9), thermal ablation modality, initial local efficiency, LTP, DR, and treatment of recurrence. At the Eastern Hepatobiliary Surgery Hospital, HBV-DNA level of more than 50 copies/mL is considered HBV-DNA positive.
Statistical analysis
Continuous variables were reported as mean ± standard deviation. Differences in categorical variables and continuous variables between the groups were analyzed with the Chi square test or Fisher’s exact test and with Student’s t test, respectively, using the SPSS version 17.0 software (SPSS, Chicago, IL, USA). RFS and OS curves were evaluated using Kaplan–Meier curves and compared using the log-rank test. Variables with P values less than 0.05 in the univariate analysis were entered into a Cox proportional hazards model for multivariate analysis. Two-tailed P values less than 0.05 were considered statistically significant.