The Trends and Efficacy of Surgery in the Treatment of Hepatocellular Carcinoma

Background Surgery for the treatment of hepatocellular carcinoma (HCC) is limited. Recently, the possibility was advanced that surgical approach could be applied in HCC patients more widely. To address this issue, the trends in the use of surgery (including liver resection and ablation et, al) and liver resection for the treatment of HCC with time was analyzed. Additionally, whether patients gain a better survival benefit from surgery and liver resection than other treatments was evaluated. Methods Data from SEER registries was used to analyze the trends in the use surgery and liver resection for HCC and the survival benefits of these procedures. The study included patients between the ages of 35 and 84 years diagnosed as HCC between 1998 and 2015 (n = 80499). Propensity score matching (PSM) analysis was used to reduce selection bias.


Introduction
The incidence of hepatocellular carcinoma (HCC) becomes more frequent worldwide, with a 75% increase in the newly diagnosed cases from 1990 to 2015. It has been predicted that by 2030, HCC may become the third leading cause of cancer-related deaths in the USA [1]. The recommendations for the first-line treatment of early HCC include liver resection, transplantation or ablation. The first-line therapy for intermediate stages of HCC is transarterial chemoembolization (TACE), which can improve two-year survival outcomes. In advanced HCC with the tumor invading blood vessels and metastasizing to regional lymph nodes or distant organs, molecular-targeted drugs (sorafenib or lenvatinib) are recommended as the treatment of choice, which can extend the survival of the patients by up to 4 months [1,2].
The decision to treat the patient surgically or by chemotherapy is based on tumor staging, and patient's liver function and physical condition. The most common criteria used worldwide for HCC staging are defined by Barcelona Clinic Liver Cancer (BCLC) staging [3]. Previous studies have shown showed that the survival of patients with a single tumor larger than 5 cm can be extended by liver resection [4,5]. However, whether patients with a single tumor larger than 5 cm should be characterized as BCLC stage B is still a matter of controversy [6].
TACE is recommended as the first-line treatment for intermediate HCC and new embolic materials for this method, such as drug-eluting beads, have been developed. The drug-eluting beads may reduce complications of the TACE and prolong the progress-free survival but not overall survival (OS) [7,8].
However, some studies have documented that patients with intermediate HCC may have better survival after liver resection than TACE [9][10][11]. A prospective randomized controlled trial (RCT) showed that the 1-, 2-, and 3-year OS rates of patients with resectable multiple HCC outside of Milan Criteria who received liver resection were higher than that those of patients treated with TACE (P < 0.001) [9].
Another meta-analysis indicated that patients with intermediate-advanced HCC (BCLC B/C) who were treated by liver resection experienced greater survival benefit than those who received TACE therapy.
In fact, all patients in the liver resection group had longer OS than patients in the TACE group (P < 0.0001) [12]. However, these studies had certain limitations. An insufficient number of patients was included in both investigations, and the meta-analysis included one RCT only, which might have led to a low level of evidence. The surgery and liver resection rate of patients is still unclear.
In view of these uncertainties, the present population-based study aimed at the analysis of the trends of surgery (including liver resection and tumor destruction) and liver resection, and to identify the optimal type of treatment for patients with different HCC stages. Using SEER 18 registries database, patients, 35-84 years old, diagnosed with HCC (International   Classification of Diseases for Oncology, Third Edition (ICD-O-3), histology code 8170-8175, site code C220 (liver)) between 1998 and 2015 were included. The patients for which the information on whether they received surgical treatment was not available, were excluded. Finally, 78053 patients were included in the study: 18878 of them were treated surgically, and 59175 non-surgically.

Study Cohort
For the analysis of survival, patients with survival months code 0 (contact lost after diagnosis) and 9999 (unknown length of survival month) were excluded, leaving 66887 patients in this part of the study. After PSM, a total of 31120 patients were included into survival analysis. Among them, 15560 patients received surgery treatment and 15560 patients received non-surgery treatment. The baseline characteristics of patients before PSM and after PSM in the two group were compared (Table 1). To determine whether patients could gain an additional survival benefit from liver resection, the patients in localized group were divided into three groups (stage A-C) based on the BCLC stage A and B. Stage A included patients with a single tumor size smaller than 5 cm or 2-3 tumors with none larger than 3 cm. Stage B included patients with a single tumor larger than 5 cm, 2-3 tumors of which at least one was larger than 3 cm, or more than 3 tumors regardless of their size. Stage C included patients with a single tumor larger than 5 cm. For survival analysis of patients in the stage C group, the group was further divided into four groups: group 1 with tumor size 5-7 cm (n = 712), group 2 with tumor size 7-9 cm (n = 336), group 3 with tumor size 9-11 cm (n = 201), and group 4 with tumor size larger than 11 cm (n = 390).

Statistical analysis
The patients' information was extracted from the SEER database using the SEER*Stat software (version 8.3.5). Temporal trend of the rates of surgery and liver resection for the treatment of HCC was estimated using Cochran-Armitage test [13]. mOS was determined using Kaplan-Meier survival curves [14]. The prognostic factors for all patients and the liver resection group were assessed by Cox proportional hazards models [15].

Trends of surgery and liver resection on HCC
The number of patients and patients undergoing surgery increased with time from 1998 to 2015.
However, the number of patients undergoing liver resection remained essentially constant (Additional File Fig. 1). The trends of surgery rate increased in all patients (P = 0.016), and patients with localized tumor (P < 0.001) increased but declined in the regional (P < 0.001) and the distant group (P < 0.001).
The trends of surgery rate did not change with time in the unknown group (P = 0.360) (Fig. 1A). For liver resection, the frequencies and trends in localized (P < 0.001), regional (P = 0.004), distant (P = 0.014), and unknown groups (P = 0.007) declined with time ( Fig. 1B). In the localized group, for stage A, stage B, and stage C, the frequencies and trends of surgery and liver resection declined with time (P < 0.001 for stage A, B and C) ( Fig. 2A 36,42) and non-surgery (9 months, 95%CI: 8.4,9.6, P < 0.001) (Fig. 4C). To further evaluate the effect of surgery and liver resection in patients with tumor size larger than 5 cm, the stage C was divided into four groups: group 1 (tumor size 5-7cm), group 2 (7-9 cm), group 3 (9-11 cm) and group 4 (> 11 cm.   (Table 3). It has been previously shown that patients with single and small HCC who received radiofrequency ablation (RFA) had similar survival benefits from the therapy as patients undergoing liver resection [17][18][19][20]. With the development of microwave ablation and cryoablation, the surgery is better tolerated by the patients. In the past, the radiotherapy was not suitable for HCC treatment because the radiation could damage the normal liver tissue and vital organs located in the vicinity of the liver [21,22]. However, patients with early HCC treated with stereotactic body radiation therapy (SBRT) which allows precise targeting of the tumor have similar 1-and 2-years OS comparable to that achieved with RFA [23,24].
Alternatively, the tumor can be removed completely by liver resection, reducing tumor recurrence and metastasis. In the present analysis, patients with localized HCC were divided into three groups (stage A, stage B, and stage C) according to size and number of tumors. The mOS of patients with HCC stages A, B, and C undergoing liver resection group had the longest mOS. The classification of localized group was based on BCLC stage but did not include the liver function and physical condition of the patients. However, the analysis of all patients who were recommended to be treated surgically but did not consent indicated that the mOS of these patients ( It was suggested that patients with a single tumor larger than 5 cm should be classified as BCLC stage A and receive a better survival benefit from liver resection [32]. However, in the current analysis, the patients in the localized group with a single tumor larger than 5 cm were divided into four subgroups (group 1: 5-7 cm; group 2: 7-9 cm; group 3: 9-11 cm; group 4: >11 cm) and the efficacy of liver resection treatment was determined in each subgroup. Patients with a single tumor sized 5-7 cm had longer survival than patients with a single tumor larger than 11 cm. Although with increasing tumor diameter the possibility of vascular invasion and metastasis becomes higher, many patients with a single tumor larger than 5 cm do not exhibit vascular invasion or metastasis. Thus, simply dividing these patients into one category may not be justified. However, thus far no RCT was performed for patients with single tumor larger than 5 cm that would focus on the effect of tumor size on the therapeutic efficacy of liver resection or other types of surgery, such as TACE. Therefore, the outcome of various treatments in patients with different tumor size was worth exploring by a large cohort study.
Multivariate analysis of all patients included in this study also demonstrated that surgical treatment resulted in better mOS of the patients than non-surgical therapies. In agreement with earlier publications, older patients, male patients, black patients, patients with larger tumor size, patients with tumor metastasis, single patients and patients with an early diagnosis of HCC had a worse prognosis. Several studies have shown that a higher number of tumors is associated with a worse prognosis of the HCC patients with radical treatment [33][34][35]. However, the current work documented that the presence of multiple tumors was increased mOS of the patients. In multivariate analysis, we included patients with regional tumor invasion (n = 6363), distant metastasis (n = 958) and unknown stage patients (n = 829) who might influence the prognostic factors of all patients. So, we did multivariate analysis of OS for patients with liver resection in localized group and found that the patients with more tumor numbers might influent the prognosis of patients compared with patients with single tumor.
Although this study provided encouraging results for patients with treated surgically, in particular by liver resection, the surgery rate did not increase significantly with time, and the liver resection rate decreased in all patients and subgroups. These trends may be explained by the emergence of new surgical techniques. The recommendation by the BCLC criteria that patients with BCLC stage A and good liver function and physical condition should be treated by liver resection might be another reason for the decline in the treatment of HCC by liver resection. However, the results of the present analysis support the notion that patients can obtain a better survival benefit from liver resection than from other types of surgery. This conclusion was valid in all patients, in the localized group and its subgroups, and in the regional group. Patients with regional vascular and lymph invasion were considered to have advanced disease and to require a molecularly targeted drug treatment.
Recently, the concept of tumor oligometastasis was advanced and numerous studies have shown that patients with oligometastases who underwent the resection or radiotherapy of the primary tumor and metastatic lymph nodes could get better survival benefits than non-surgically treated patients [36,37] The retrospective design of the present study constitutes its limitation since it might have led to a selection bias. However, the analysis was based on a large number of patients, which could increase the reliability of the results. The efficacy of liver resection was compared only with other treatments, but comparisons with specific treatments were not performed. While this approach might not provide strong proof that liver resection is the best treatment for patients with a localized tumor or regional metastases, the evidence was obtained that patients can receive a better survival benefit from surgery, and liver resection might be the best treatment choice. This study did not answer the question of whether patients with poor liver function and physical status should be treated surgically, but from the side, these patients could get better survival after undergoing surgery. The conclusions reached here need to be confirmed by a large prospective cohort study.

Conclusions
In conclusion, this study provided a comprehensive analysis of the trends in the rate of surgery and liver resection for the treatment of HCC. Moreover, the efficacy of surgery was compared with the efficacy of non-surgery and liver resection in patients with different stages of HCC. The results indicated that surgery (especially for liver resection) might be used more widely in the treatment of HCC.

Declarations
Ethics approval and consent to participate: The research do not need to be reviewed by the ethics committee because the data were from SEER database and the written informed consent was exempted. However, the data used in the research was permitted by the SEER database management department.
ZCS, FY conceived the study, analyzed the data. CL and CS performed the data collection and conducted the statistical analysis. CL, CS and ST writed the manuscript. All authors read and approved the final manuscript.

Figure 1
The trends of surgery rate (A) and liver resection rate (B) in localized group, regional group, distant group and unknown/unstaged group from 1998 to 2015.

Supplementary Files
This is a list of supplementary files associated with this preprint. Click to download. AdditionalFileFigures.docx