The Efficacy of Surgery in Advanced Hepatocellular Carcinoma: A Propensity Score Analysis

Background There is still controversial that whether hepatocellular carcinoma (HCC) patients with lymph node invasion should receive surgery treatment. This study is to evaluate the efficacy of surgery in HCC patients with regional lymph node invasion. Methods The study utilized data from the Surveillance, Epidemiology, and End Results-18 (SEER-18) cancer registry. 1434 patients were included in the analysis. Among them, 168 patients were treated surgically and 1266 received non-surgery treatment. Propensity Score Matching (PSM) model was used to reduce selection bias. Results Before PSM, the median overall survival (mOS) and median cancer-specific survival (mCSS) of patients treated surgically were longer than in patients receiving non-surgery treatment (mOS: 20 months vs. 7 months, P<0.001; mCSS: 21 months vs. 6 months, P<0.001). Subgroup analysis did not detect a significant difference in mOS and mCSS between liver resection and non-liver resection surgery cohorts (P>0.05). Similar results were obtained in the PSM analysis. The mOS and mCSS in the surgery group were longer than in the non-surgery group (mOS: 20 months vs. 7 months, P<0.001; mCSS: 20 months vs. 6 months, P<0.001). The multivariate analysis documented that surgery was an independent predictor for OS and CSS before and after PSM. Conclusions HCC patients with invasion of regional lymph nodules may get more survival benefit from surgery than other types of treatment.

Introduction guideline and treatment with molecular target drugs is recommended [2]. The SHARP trial demonstrated that, in comparison with placebo, sorafenib prolongs the survival of advanced HCC patients by approximately four months [7]. However, only a small fraction of patients respond to the drug and many patients discontinue the therapy because they cannot bear the complications of the drugs, limiting the efficacy of pharmacologic treatment. Therefore, alternative therapeutic modalities that might prolong the survival of advanced HCC patients are worth considering.
The current guideline do not recommend surgery for the treatment of advanced HCC patients [2].
However, it has been proposed that patients with regional vascular, lymph nodes, or organs invasion, or limited distant metastases should not be defined as patients with advanced cancer. Conversely, they should be considered as the stage between intermediate and late stage since they could get a better survival benefit from surgery [8]. Recent data indicate that HCC patients with regional lymph node invasion or several metastasizes might receive the survival benefit from liver resection, ablation, radiotherapy, or transarterial chemoembolization (TACE) [9][10][11][12][13]. Although these studies presented encouraging results regarding the efficacy of surgery in patients with advanced HCC, the insufficient number of cases included in the analysis limits the strength of the conclusions reached.
The benefit of surgery in HCC patients with regional lymph nodules invasion remains unclear.
Moreover, no randomized controlled trial (RCT) was conducted to address this issue. Therefore, the goal of the present study was to analyze the efficacy of surgery on HCC patients with regional lymph nodules invasion based on record available in the Surveillance, Epidemiology, and End Results-18 (SEER-18) database.

Methods
The study utilized the information from a publicly-available cancer registry, SEER-18. This database includes approximately 28% of United States population (Connecticut, San Francisco, Iowa, Detroit, The analysis included patients aged 30-84 years, diagnosed with HCC (International Classification of Diseases for Oncology, Third Edition (ICD-O-3), histology code 8170-8175, site code C22.0 (liver)) from 2004 to 2015. Patients for whom the treatment type was not clear and those with distant metastasis or without regional lymph nodules invasion were excluded. For survival analysis, patients with the survival months coded as 0 and 999 were excluded. A total of 1434 patients were included in the study; 168 of them were treated surgically, and 1266 received non-surgical treatment (Supplementary Figure 1). The characteristics of patients before PSM are listed in Table 1.

Study outcomes
The endpoint of this study was patient death. The overall survival (OS) of patients was defined from the time of HCC diagnosis to death. Cancer-specific survival was defined as the time from HCC diagnosis to death caused by cancer.

Statistical analysis
The data were extracted using the SEER*Stat software ( Propensity score matching (PSM) was used to reduce potential confounding effects and selection bias.
The characteristics of gender, age, ethnicity, marital status, AJCC T stage, year of diagnosis, tumor size, number of tumors, and the type of treatment were included in PSM assessment. A total of 608 patients were generated by 1:4 ratio matching with an optimal caliper of 0.2. The characteristics of patients after PSM are listed in Table 3.
All tests were two-tailed, and the P value less than 0.05 was considered statistically significant. All statistical analyses were performed using GraphPad Prism 8.0 (GraphPad Software, San Diego, CA) and SPSS v24.0 (IBM, Chicago, IL, USA) software.
After PSM, the mOS and mCSS in the surgery group (mOS: 20 months, 95%CI: 15.1-24.9; mCSS: 20 months, 95%CI: 14.6-25.4) were longer than in the non-surgery group (mOS: 7 months, 95%CI: 5.9-8.1; mCSS: 6 months, 95%CI: 4.8-7.2) (P<0.001 for both mOS and mCSS) (Figure 3A-3B). were associated with worse outcome in all patients ( Table 2). For CSS, Similar results were obtained in the multivariate logistic regression analysis for CSS. Older age, higher AJCC stage, larger tumor size, and without receiving radiotherapy, chemotherapy and surgical treatment were all correlated with a shorter CSS of the patients.

Predictors for OS and CSS
After PSM, the multivariate logistic regression analysis showed that older patients, patients with high AJCC T stage, larger tumor size, and without receiving radiotherapy, chemotherapy and surgical treatment had worse OS and CSS (Table 4).

Discussion
The most widely adopted HCC staging system is based on Barcelona Clinical Liver Cancer (BCLC) criteria [14]. BCLC staging is endorsed by the guidelines of the American Association for the Study of Liver Diseases (AASLD) and The European Association for the Study of the Liver (EASL) due to its ability to account for liver function, tumor burden, and prognosis prediction [2,15] The current study demonstrated that the mOS and CSS of patients with surgical treatment was 20 months and 21 months before PSM, which was longer than in patients treated non-surgically included in previous studies presented 3−9 . Kokudo and collaborators compared the efficacy of portal vein tumor thrombosis in patients who received liver resection and patients who received other treatments, and found that patients with liver resection had longer mOS than patients not subjected to liver resection [28]. Similar results were obtained in the present study; patients with liver resection had longer mOS than patients with non-surgical treatment (P < 0.001). However, in the subgroup analysis, the mOS of patients with liver resection comparable to that of patients treated with other surgery (such as ablation) (P = 0.886), suggesting that liver resection might not be the preferred modality in patients with regional lymph nodes invasion. In the liver resection group, patients treated with liver resection combined with the removal of lymph nodes had no longer mOS than patients with liver resection alone, and there was no significant difference of mCSS between the two groups. This finding indicates that in patients treated with liver resection treatment, removal of regional lymph nodes should not be recommended as the mean to prolong the survival time and reduce the damage of surgery to patients. After PSM and reduction of the selection biases and confounding effects, the mOS and mCSS in the surgery group were still longer than in the non-surgery group (P < 0.001), supporting the conclusion that HCC patients with regional lymph nodes invasion could obtain a better survival benefit from surgery than from non-surgical approaches.
In multivariate logistic regression analysis, age at diagnosis, year of diagnosis, AJCC T stage, tumor size, radiotherapy treatment, chemoembolization treatment and utilization of surgery were included in the analysis to reduce mutual influence among the variables. This approach documented that nonsurgical treatment was an independent unfavorable factor for OS and CSS, regardless of whether PSM was performed or not. Patients not treated with surgery would have more than 2-fold higher risk of overall death and cancer-specific death than patients subjected to surgery.
Liver function and physical condition of patients were not included in the current analysis because these characteristics were not recorded in the SEER database. The BCLC criteria defines that patients with ECOG 1 should be classified advanced HCC and should receive molecular targeted drugs treatment or best support care. These patients were not included into this study, which might influence the accuracy of the results. However, patients with regional lymph nodes invasion were defined as having an advanced disease independently of liver function and physical condition. The patients included in the study might have good liver function and physical condition, but all of patients have lymph node invasion, which showed they had advanced HCC and they could get more survival benefits from surgery treatment. Thus, the study could still prove that surgery should be used in advanced HCC patients treatment if the patients had good liver function and physical condition.
Although this analysis provided encouraging results, some limitations resulting from the retrospective design of the study should be acknowledged. First, the analysis utilized the SEER database which does not include the laboratory and imaging results; these variables might represent more precise predictors for OS and CSS. Second, selection biases may persist despite the use of the PSM model. However, PSM might be the best option to reduce the selection biases since there are no RCTs or prospective studies focused on the issue presented in this analysis. Third, liver function and physical condition which might influence the OS of patients were not incorporated in the current work, which needed future high-quality studies to confirm the results of the study. Thus, patients with advanced HCC could get a better survival benefit from surgery than from other types of treatment.

Conclusions
In conclusion, although the guidelines recommend molecular targeted drugs as the first-line treatment for advanced HCC patients, among them, patients with regional lymph nodes invasion might get more survival benefit from surgery than from other treatments, and, therefore, surgery might be the better treatment option for these patients.   Consent for publication: All authors approved for publication of the manuscript for the journal.

Availability of data and materials:
The data could be found in SEER database (https://seer.cancer.gov/data/).

Competing interests:
The authors declare that they have no competing interests.
Fundinng: This study was supported by the National Natural Science Foundation of China (81873919).

Authors' Contributions: Chuansheng Zheng and Fan Yang designed the research; Lei Chen and Tao
Sun extracted the data from SEER database; Lei Chen, Tao Sun and Shi Chen made statistical analysis; Lei Chen, Tao Sun, Shi Chen and YanQiao Ren written the manuscript; Chuansheng Zheng and Fan Yang reviewed the manuscript.