Surgical Resection is An Effective Therapy for Single Large Hepatocellular Carcinom

Background Identifying prognostic factors and therapeutic strategies for single large hepatocellular carcinoma (HCC) is crucial. This retrospective study investigated prognostic factors in patients with single large HCC ( ≥ 5 cm) and Child–Pugh (CP) class A liver disease and recommended therapeutic strategies. Methods In 305 Their and progression-free and were using and Cox regression resection vs. other treatments; HR: 0.37; 95% CI: 0.17–0.65, P = 0.016) were signicantly associated with OS. In addition, CP class A5/6 (A5 vs. A6; HR: 0.32; 95% CI: 0.18–0.56, P < 0.001) and initial treatment (resection vs. TACE; HR: 0.30; 95% CI: 0.16–0.51, P < 0.001; resection vs. other treatments; HR: 0.51; 95% CI: 0.26–0.81, P = 0.042) were signicantly


Introduction
Hepatocellular carcinoma (HCC) is the fth most common cancer and the second most common cause of cancer-related death worldwide [1][2][3][4][5]. Although HCC surveillance with alpha-fetoprotein (AFP) and ultrasound is recommended in patients at risk of HCC [3][4][5], the proportion of HCC that is large at diagnosis is still high [6]. Liver resection has been reported to promote overall survival (OS) in patients with HCC across various Barcelona Clinic Liver Cancer (BCLC) stages [7,8]. In 2012, the BCLC system designated a single large HCC (>5 cm) as BCLC stage A rather than stage B [9]. The revised BCLC classi cation schema has been endorsed by the American Association for the Study of Liver Diseases (AASLD) [3] and the European Association for the Study of the Liver [4]. Furthermore, the most recent version of the 2017 combined American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis staging system states that patients with multiple tumors, any of which are >5 cm, can be classi ed as T3 [10]. Recent studies have reported that approximately two-thirds of patients with tumor size >10 cm present microvascular invasion; more favorable outcomes have been reported after resection in these patients; thus, surgical resection should be considered for single large HCC [6,11]. Several studies have also demonstrated that liver resection is a safe and effective treatment for single large HCC [12][13][14][15][16][17]. However, these studies had limitations, such as limited data availability, lack of comparison with different treatments, and/or selection bias. The treatment for single large HCC (≥5 cm) still remains largely unknown and needs to be studied further. This study investigated prognostic factors and effective therapies for single large HCC.

Patients and follow-up
We retrospectively enrolled 4092 HCC patients from 2007 to 2018 at E-Da Hospital, I-Shou University, Kaohsiung, Taiwan. In total, we excluded 3787 patients due to multiple tumors, tumor size <5 cm, presence of macrovascular invasion and/or distal metastasis, or Child-Pugh (CP) classes B and C. Ultimately, 305 patients with HCC and CP class A liver disease, a single tumor ≥5 cm, and no macrovascular invasion and/or distal metastasis were included in this retrospective study (Fig. 1). This study was approved by the Institutional Review Board at E-Da Hospital.
HCC was diagnosed based on histology or typical imaging methods on the basis of the guideline of the AASLD [18]. Demographic characteristics, etiology, blood tests, CP class, cirrhotic of liver, tumor size, AFP, mortality, disease progression, and follow-up time, were recorded. Tumor size and number were determined according to pathological con rmation and radiologic ndings. Patients were treated with surgical resection, transarterial chemoembolization (TACE), hepatic artery infusion chemotherapy (HAIC), or liver transplantation. Our multidisciplinary team chose suitable therapies for each patient. Patients were followed up every 3 to 6 months by abdominal ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI), and AFP. OS and PFS was de ned as the time from the date of diagnosis to the date of death and disease progression or the last visit; the last follow-up date was December 2020.

Data analysis and statistics
Numerical data are shown using medians and ranges. Categorical data are shown as numbers and percentages. OS and PFS rates were used by the Kaplan-Meier method. OS and PFS rates was analyzed by Cox proportional hazards regression. A P value of <0.05 was considered statistically signi cant. All statistical analyses were performed using SPSS 23.0 (SPSS, Chicago, IL, USA).

Baseline characteristics
The demographic and clinical features of 305 patients with HCC and CP class A disease (77.8% male, median age 63 years) with single large tumors (≥5 cm) but without distant metastasis and/or macrovascular invasion are listed in Table 1. Regarding the etiology of HCC, 44.1% of the patients had hepatitis B virus (HBV) infection, 23.0% had hepatitis C virus (HCV) infection, and 30.9% had neither HBV nor HCV. Approximately 34.1% of patients had liver cirrhosis, and 89.6% had CP class A5 disease. The most common initial treatment modality was resection (49.5%), followed by TACE (48.2%), HAIC (1.3%), and liver transplantation (1%). The median follow-up time was 33 months.

OS in subgroup analysis
OS and PRS rates were signi cantly higher in patients with CP class A5 than in those with CP class A6 (P < 0.001, Figs. 4A-B). Of the 147 patients who underwent TACE as the initial treatment, 13 underwent resection as the secondary treatment. Their OS rates was similar to that of patients who underwent resection as the initial treatment (P = 0.241; Fig. 4C). In subgroup analysis in patients with CP class A5/6, no signi cant difference was observed in OS rates between resection and TACE as the initial treatment in patients with CP class A5 or A6 (all P > 0.05; Fig. 4D).

Discussion
Our study demonstrated that OS and PRS rates were signi cantly higher in patients receiving surgical resection than in those receiving TACE. The 10-year OS rates after surgical resection and TACE were 66.7% and 26.6%, respectively. The 10-year PFS rates after surgical resection and TACE were 51.0% and 22.7%, respectively. CP class A5/6 and initial treatment were signi cantly associated with OS and PFS in multivariate analysis. Surgical resection is a safe and effective treatment for single large HCC.
Surgical resection is widely used as the rst-line therapy in patients with HCC with favorable liver function and tumor factors [19,20]. Previous studies have reported that hepatic resection in patients with CP class A resulted in favorable outcomes, with a 5-year OS rate of over 60% and a 5-year PFS rate of over 40% [12,21,22]. Our study demonstrated that 151 patients (49.5%) underwent surgical resection and showed higher 5-year OS rates (76.7%) and PFS (55.7%) rates. This is consistent with previous ndings of a comparable prognosis in patients with large HCC, and hepatectomy can be considered regardless of tumor size [6,11]. Previous studies have reported that patients receiving surgical resection had higher OS rates than those receiving TACE among patients with BCLC stage B HCC [8,23]. Recently, several studies have reported a survival bene t for liver resection in patients with BCLC stage B HCC [16,17,[24][25][26][27]. Our study nding is also consistent with that of a previous study demonstrating that surgical resection is signi cantly associated with higher OS and PFS than TACE [12].
Thirteen patients received resection as secondary treatment after TACE. Their OS rates were similar to that of patients who underwent resection as the initial treatment, suggesting that hepatectomy after TACE may be another choice for patients with single large HCC. This nding is similar to that of studies reporting that resection after TACE may be considered an effective treatment in patients with BCLC stage B HCC [28, 29].
CP class was signi cantly associated with OS in patients with different BCLC stages of HCC [3][4][5]. Our study demonstrated that CP class A5 was signi cantly associated with higher OS and PFS rates in patients with single large HCC in multivariate analysis. Our results differed from those of previous studies reporting no signi cant difference in OS or PFS between CP class A5 and A6 patients with single large HCC in multivariate analysis [12]. To the best of our knowledge, our study is the rst to reveal that CP class A5 is signi cantly associated with OS and PFS in patients with single large HCC.
Limitations of the study include the following: First, the retrospective nature of the study might have resulted in unintended bias. Second, PFS may be biased, especially in patients receiving noncurative therapies.

Conclusions
Surgical resection was associated with signi cantly higher OS and PRS rates than TACE. CP class A5/6 and initial treatment were signi cantly associated with OS and PFS. Surgical resection is an effective and safe therapy for single large HCC. The study was conducted in accordance with the guidelines of the International Conference on Harmonization for Good Clinical Practice and was approved by the Ethics Committee of E-Da Hospital, I-Shou University (EMRP-107-130). The consent for study participation is informed and signed.

Consent for Publication
Not applicable.

Availability of data and material
Data is available from the corresponding author upon reasonable request. Authors' contributions PH, JHY and CMH: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; HYL, TQT, PNC, KCH, PMH, and YSC: study concept and design; critical revision of the manuscript for important intellectual content; administrative, technical, or material support; CWL: study concept and design; analysis and interpretation of data; critical revision of the manuscript for important intellectual content administrative, technical, or material support; study supervision. All authors approved the nal version of the manuscript.   Study owchart and participant inclusion criteria.

Figure 2
Overall survival and progression-free survival of the total cohort.