Efficacy and Safety of Lobaplatin-TACE in the Treatment of Primary Hepatocellular Carcinoma: A Retrospective Study

Purpose To investigate the safety and efficacy of lobaplatin-TACE in treating primary hepatocellular carcinoma. Methods The data of 536 patients who underwent TACE in the interventional department from January 2016 to January 2020 were collected. Patients were divided into two groups according to the chemotherapeutic drugs used in TACE.: the epirubicin-TACE group (N = 260) and the lobaplatin-TACE group (N = 276). Primary study endpoint: (1) The tumor response after TACE; (2) The survival rates; Secondary study endpoints:(1) Changes in liver function and blood routine before and after TACE; (2) Occurrence of the post-embolization syndrome and infection after TACE. Results The ORR was 35.0% in the epirubicin-TACE group and 51.1% in the lobaplatin-TACE group (p=0.001). The DCR was 73.1% in the epirubicin-TACE group and 82.2% in the lobaplatin-TACE group (p=0.011). The 6-month, 9-month, 12-month, and 15-month survival rates were higher in the lobaplatin-TACE group than in the epirubicin-TACE group (p=0.029, p=0.001, p=0.005, p=0.002). mOS: Epirubicin-TACE group,14.8 months; Lobaplatin-TACE group,18.6 months (p=0.007). mPFS: Epirubicin-TACE group,9.5 months; Lobaplatin-TACE group,12.8 months (P =0.000). There was no statistical difference in ALT, AST, total bilirubin and Leucocyte after TACE between the two groups (p=0.343, p=0.368, p=0.288, p=0.359). The platelet decrease after TACE was more significant in the lobaplatin-TACE group than in the epirubicin-TACE group (p=0.046). There was no statistical difference in the incidence rate of abdominal pain, fever and infection after TACE between the two groups (p=0.502, p=0.602, p=0.726). The incidence of vomiting after TACE in the lobaplatin-TACE group was higher than that in the epirubicin-TACE group (p=0.003). Conclusion Lobaplatin-TACE has a higher tumor response rate and survival rate. Lobaplatin-TACE is a safe and effective treatment strategy; it is worthy of clinical application.


INTRODUCTION
Primary hepatocellular carcinoma is a malignant tumor with high morbidity and mortality [1,2,3], and it seriously threatens people's lives. Because there are no obvious symptoms and signs in the early stage of the disease, most patients are found in the middle and advanced stages and lose the chance of surgery. Transarterial chemoembolization (TACE) has been performed since the late1970s [4,5]. The European Association for the Study of the Liver (EASL) guidelines recommend TACE for unresectable, Child-Pugh A or B multiple HCC with no vascular invasion [BCLC-B stage (intermediate-stage) HCC]. TACE can significantly prolong the overall survival(OS) and progression-free survival(PFS) of patients and benefit more and more patients with hepatocellular carcinoma [6,7]. TACE includes Conventional transarterial chemoembolization (C-TACE) and Drug-eluting beads transarterial chemoembolization (DEB-TACE). In both C-TACE and DEB-TACE, we need to use chemotherapeutic agents. The types of chemotherapeutic drugs used in TACE may affect the efficacy of *Address correspondence to this author at the Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China; Tel: +86-18995639281; +86-027-85350850; E-mail: 1354039648@qq.com patients. The most commonly used and classical chemotherapeutic agents in TACE are anthracycline antineoplastic agents, such as epirubicin. Platinum is also a commonly used drug for hepatocellular carcinoma chemotherapy [8,9]. Lobaplatin is a third-generation anti-tumor drug with good water solubility, strong anti-tumor activity, no cross-resistance with other platinum, and low toxicity. This study aimed to investigate the safety and efficacy of using lobaplatin-lipiodol emulsion in TACE for primary hepatocellular carcinoma.

General Information
The data of 536 patients who underwent TACE in the Department of Interventional Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology were collected from January 2016 to January 2020. This is a retrospective study. Inclusion criteria:(1) Clinical or pathological diagnosis of primary hepatocellular carcinoma; (2) Child-Pugh classification of liver function [10] A or B, performance score (ECOG) 0-2 points; (3) Aged 18-70 years old; (4) No use of molecular targeted drugs or immunotherapy during treatment. Exclusion criteria: (1) Child-Pugh classification of liver function C, performance score (ECOG) > 2 points; (2) severe coagulation dysfunction and can not be corrected; (3) cachexia or distant tumor metastasis; (4) complete portal vein occlusion and collateral vessels; (5) renal insufficiency;(6) total bilirubin>51.3 umol/L. The patients were reexamined every three months, and TACE was performed as needed according to the reexamination results. The number of TACE treatments for patients was 2-5 times. The patients were divided into two groups according to the chemotherapeutic drugs used in TACE: the group using lipiodol + epirubicin emulsion for TACE (epirubicin-TACE group, N = 260) and the group using lipiodol + lobaplatin emulsion for TACE (lobaplatin-TACE group, N = 276). All patients had liver cirrhosis on imaging examination. The baseline data collected before TACE included gender, age, etiology of liver cirrhosis, WBC, platelet, ALT, AST, total bilirubin, preoperative Child-Pugh classification of liver function, BCLC staging and ECOG score. The chemotherapeutic drugs and the amount of lipiodol used in TACE were recorded.

Methods
After disinfection, draping, and local anesthesia of the puncture site with 2% lidocaine, the right femoral artery was punctured using the Seldinger technique and a 5F vascular sheath (TERUMO5F-10CM, Terumo, Japan) was placed. The feeding artery of the tumor was identified by catheterization with a 5F Yashino catheter (Terumo, Japan) to the celiac trunk and superior mesenteric artery for angiography. A 2.7 F microcatheter (Terumo, Japan) was then used to super selectively cannulate into the tumor feeding artery. Embolization was performed by slowly injecting an appropriate amount of iodized oil emulsion and supplementing embolization with 300-500 um gel foam particles (CFDA 20193131657, Hangzhou ALICON Pharmaceutical Technology Co., Ltd, China), and the embolization endpoint was a stagnation of forwarding blood flow in the tumor feeding artery. Chemotherapeutic drugs used during TACE are divided into two types: (1) lobaplatin 50 mg; (GYZZ H20050308, Hainan Chang'an International Pharmaceutical Co., Ltd., China) (2) epirubicin 30 mg. (GYZZ H19990280, Zhejiang Hisun Pharmaceutical Co., Ltd., China) The dose setting of these chemotherapeutic drugs was based on the results of previous studies in our center, which found that increasing the dosage of chemotherapeutic drugs in TACE did not increase the efficacy of TACE but increased the side effects. The amount of lipiodol (GYZZ H20163348, Jiangsu Hengrui Pharmaceutical Co., Ltd, China) was 5-20ml. Composition of epirubicin-TACE group lipiodol emulsion: lipiodol+epirubicin; Composition of lobaplatin-TACE group lipiodol emulsion: lipiodol+lobaplatin.

Outcome Measures
Primary study endpoints: (1) The efficacy evaluation of tumor response after TACE in the two groups [complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD)]; (2) Objective response rate (ORR) and Disease control rate (DCR) after TACE in the two groups; (3) The survival rates at 3 months, 6 months, 9 months, 12 months and 15 months in the two groups;(4) Overall survival (OS), Progression-Free Survival (PFS).
The efficacy of tumor response after TACE was evaluated in both groups, using the imaging data before and after the last TACE for efficacy evaluation, and the mRECIST criteria were used as the evaluation criteria [11,12].
Secondary study endpoints: (1) Changes in liver function (ALT, AST, total bilirubin) before and after TACE in the two groups; (2) Changes in blood routine examination (WBC and PLT count) before and after TACE in the two groups; (3) Incidence of post-TACE embolism syndrome (including abdominal pain, fever, vomiting) in the two groups; (4) Incidence of infection after TACE in the two groups; The liver function changes and blood routine examination before and after TACE in the two groups were compared with the results before and after the first TACE. Blood routine and liver function were reexamined one week after TACE.

Statistical Methods
Statistical analysis was performed using SPSS software (Version 24.0, IBM, Armonk, New York). Enumeration data were described by the number of cases (expressed as a percentage), and the difference between the two groups was analyzed by the Chi-square test, including Pearson Chi-Square and Fisher's Exact Test. Measurement data were expressed as mean ± standard deviation, and differences between two groups were analyzed by two independent samples or paired sample t-test. p<0.05 was considered to indicate a statistically significant difference.

Basic Information
There were no statistical differences in the gender, Child-Pugh classification of liver function, etiology of liver cirrhosis, tumor BCLC stage and ECOG score before TACE between the Epirubicin-TACE group and Lobaplatin-TACE group (Chi-square test was used with p-value > 0.05, Table 1). The average age was 46.9±12.3 years in the epirubicin-TACE group and 47.8±13.0 years in the lobaplatin-TACE group; The ALT was 42.8 ± 18.6 U/L in epirubicin-TACE group and 41.8 ± 19.2 U/L in the lobaplatin-TACE group; The AST was 40.4 ± 20.9 U/L in epirubicin-TACE group and 42.6 ± 18.9 U/L in the lobaplatin-TACE group; The total bilirubin was 17.6 ± 9.0 umol/L in epirubicin-TACE group and 18.4 ± 9.6 umol/L in the lobaplatin-TACE group; The white blood cells were 3.96 ± 1.24 G/L in epirubicin-TACE group and 3.86 ± 1.88 G/L in the lobaplatin-TACE group; The platelets was 111.7 ± 52.3G/L in epirubicin-TACE group and 110.3 ± 56.2G/L in the lobaplatin-TACE group. Comparisons between the two groups were performed using the t-test with P-value > 0.05 and no statistical difference. ( Table 2) There was no statistical difference in the dosage of lipiodol in TACE between the epirubicin-TACE group and the lobaplatin-TACE group. (Chi-square test was used with p-value > 0.05, Table 3).
A paired sample t-test was used, and a p-value < 0.05 indicated a statistical difference.

DISCUSSION
TACE is one of the mainstays of treatment for hepatocellular carcinoma.TACE was shown to improve median survival from 16 to 20 months. Its main principle is to intubate the catheter into the feeding artery of the tumor super selectively after establishing vascular access through femoral artery puncture and injecting chemotherapeutic drugs and embolic agents [13]. On the one hand, chemotherapeutic drugs induce apoptosis and inhibit tumor cell proliferation; on the other hand, after tumor supply artery embolization, it leads to tumor cell ischemia, hypoxia and necrosis.TACE is effective in treating HCC and plays a very important role in the treatment of HCC. It is one of the main means for the treatment of advanced HCC. There is no uniform standard for the chemotherapeutic agents used in TACE, and there are various chemotherapeutic agents used in TACE in clinical practice [14]. The most commonly used chemotherapeutic agents are anthracycline antineoplastic agents, such as epirubicin, which are even regimens in the control group of many clinical studies. Different chemotherapeutic agents in TACE may affect the efficacy after TACE [15]. As seen from chemotherapy regimens for hepatocellular carcinoma, platinum is also one of the recommended chemotherapeutic agents [16]. Lobaplatin is a third-generation platinum anti-tumor drug [17],     which can hinder the replication and transcription of DNA by generating platinum-GG and platinum-AG intra-chain cross-links, thereby interfering with the tumor cell cycle and is characterized by good water solubility, wide anti-tumor spectrum, strong anti-tumor activity, no cross-resistance with other platinum and low toxic side effects. Lobaplatin is mainly used for the treatment of breast cancer [18], small cell lung cancer [19] and chronic myelogenous leukemia, and it has also been confirmed that lobaplatin also has a good effect on nasopharyngeal carcinoma [20], colorectal cancer [21,22], gastric cancer [23], and hepatocellular carcinoma [24,25]. It has also been reported in the literature of different centers that lobaplatin has also achieved good efficacy in TACE for hepatocellular carcinoma [26]. Chen et al. showed [27] that lobaplatin, the 3rd generation of anti-tumor platinum-based drugs, is less toxic and more effective than cisplatin in TACE. Sheng Peng et al. reported [28] that Lobaplatin-TACE combined with 125I seed implantation is favorable and safe for treating primary HCC.
In this study, we found a statistically significant difference in the response rate between the lobaplatin-TACE group and the epirubicin-TACE group. The ORR and DCR in the lobaplatin-TACE group were significantly higher than those in the epirubicin-TACE group (ORR: 51.1% vs. 35.0%; DCR: 82.2% vs. 73.1%), which reported [29] that Triple-drug(50 mg epirubicin, 50 mg lobaplatin, 6 mg mitomycin C) TACE seems to benefit patients with HCC larger than 10 cm in particular compared with single-drug(50 mg epirubicin) TACE. This study found that the survival rate at 6 months, 9 months, 12 months and 15 months of the lobaplatin-TACE group was superior to that of the epirubicin-TACE group, with a statistical difference, which was also related to the strong anti-tumor effect, low toxicity and high safety of lobaplatin. TACE has been reported to affect patients' liver function in a short time due to hepatic artery embolization and simultaneous use of chemotherapeutic drugs. Wang et al. found [30] that lobaplatin has better efficiency in the aspects of patient's mean survival time and therapeutic response in TACE. This is consistent with the results of this study. A study by Zhou et al. reported [31] that Lobaplatin-based chemoembolization may elicit effective tumor response for recurrent HCCs and improve the overall survival of patients with unresectable HCC recurrence following orthotopic liver transplantation.
In this study, there was a statistically significant increase in postoperative AST and total bilirubin in both the lobaplatin-TACE group and the epirubicin-TACE group, which was consistent with the results of other studies. However, this study found that there was no significant difference in postoperative ALT, AST, and total bilirubin between the lobaplatin-TACE group and the epirubicin-TACE group, indicating that lobaplatin-TACE was as safe as the standard regimen of C-TACE (lipiodol+epirubicin) and did not cause uncontrollable damage to the patient's liver function. The most common side effects after TACE are post-embolization syndrome [32], including abdominal pain, fever, nausea and vomiting. More and more attention has been paid to post-embolization syndrome after TACE by doctors and patients [33]. According to the existing studies on the efficacy and safety of TACE, the incidence rate of the post-embolization syndrome after TACE was about 47.7% [7]. This study found that the incidence of postoperative fever was 44.9% vs. 42.7%, and postoperative abdominal pain was 31.9% vs. 34.6% in the lobaplatin-TACE group versus the epirubicin-TACE group, with no statistically significant difference. However, the incidence of postoperative vomiting was 33.7% vs. 22.3%, a statistically significant difference. The incidence of postoperative vomiting was higher in the lobaplatin-TACE group, which may be related to the higher emetogenic risk of platinum than epirubicin. Still, with the advent of new antiemetics and the update of antiemetic regimens, the occurrence of postoperative vomiting in TACE patients can be effectively reduced by using drugs. Zhao et al. showed [34] that Lobaplatin-based TACE is an effective and safe treatment for primary liver cancer, adverse reactions (III-IV grade) were not common, with only 4 cases of vomiting and 2 cases of thrombocytopenia (III grade). A rare side effect after TACE is an infection, which will seriously affect the recovery of patients once it occurs [35]. This study's data showed no significant statistical difference in the incidence of postoperative infection between the lobaplatin-TACE group and the epirubicin-TACE group (3.6% vs. 3.1%). A study by Muhammet Arslan et al. reported [36] that the formation of liver abscesses after TACE is a rare but serious complication. In their research, liver abscesses were formed after treatment in four of the 163 (2.4%) patients and four (1.3%) of the 313 chemoembolization procedures. It is similar to the incidence in this study. The most common adverse effects of chemotherapeutic drugs are liver function damage, gastrointestinal reactions, and hematologic toxicity. Platinum chemotherapeutic agents are prone to myelosuppression [37]. A study by Wu et al. reported [38] that the main side effects of lobaplatin were myelosuppression. Twenty-five patients (21.9%) had grade 3/4 neutrophil suppression, and 18 patients (15.8%) had grade 3/4 thrombocytopenia. The results of this study showed that platelets after TACE in the lobaplatin-TACE group and epirubicin-TACE group were significantly reduced compared with those before TACE (110.3 ± 56.2 vs. 79.5 ± 38.5; 111.7 ± 52.3 vs. 86.2 ± 39.1), with a statistically significant difference. Meanwhile, the postoperative platelet decrease was more significant in the lobaplatin-TACE group than in the epirubicin-TACE group (79.5 ± 38.5 vs. 86.2 ± 39.1), with a statistically significant difference, which may be consistent with the fact that platinum-based chemotherapy drugs are prone to adverse reactions of myelosuppression, which is consistent with other results, but the postoperative platelet value was > 50.0 G/L in the lobaplatin-TACE group, which is in a relatively safe range. Lv et al. reported [39] that for HCC patients with normal pre-intervention platelet levels, the incidences of mild decrease, moderate decrease and severe decrease after intervention were 16.50%, 10.47% and 4.88%, respectively, and the incidences of long-term platelet reduction after intervention were 13.25%, 4.73% and 1.65% respectively. The long-term incidence of thrombocytopenia after interventional therapy was not high in TACE patients with HCC treated with lobaplatin alone, which was relatively safe. Thrombocytopenia due to lobaplatin has also been reported in treating other tumors. Lv et al. [40] reported that patients with advanced lung cancer developed thrombocytopenia using lobaplatin. Leukocytes increased significantly after TACE in both the lobaplatin-TACE group and the epirubicin-TACE group (3.86 ± 1.88 vs. 4.58 ± 2.55; 3.96 ± 1.24 vs. 4.75 ± 2.03), with a statistical difference. However, there was no statistically significant difference in leukocytes after TACE between the lobaplatin-TACE group and the epirubicin-TACE group (4.58 ± 2.55 vs. 4.75 ± 2.03). Patients in both groups had postoperative leukocytosis, which correlated with tumor necrosis absorption and aseptic inflammation after TACE [41,42].

CONCLUSION
There are various chemotherapeutic drugs used in TACE in clinical practice, and the choice of different chemotherapeutic drugs will affect the efficacy of TACE. Lobaplatin-TACE has a higher tumor response rate and survival rate. Lobaplatin-TACE is safe and has controllable postoperative side effects. Lobaplatin-TACE is a good therapeutic strategy and is worthy of clinical application.
The shortcomings of this study are that the sample size is limited, and it is a retrospective study. A multicenter, large-sample, prospective study can be conducted later to provide more help for clinical work.

AUTHORS' CONTRIBUTIONS
Haohao Lu has contributed substantially to the conception and design of the work, the acquisition of analysis of data, and manuscript writing. Chuansheng Zheng has made contributions to the design of the work. Bin Liang has made contributions to the acquisition and analysis of data. Bin Xiong has contributed to the analysis, data interpretation, and manuscript writing. All authors have agreed to be personally accountable for the author's contributions and to ensure that questions related to the accuracy or integrity of any part of the work. Haohao Lu is the first author. Chuansheng Zheng is the corresponding author and is responsible for ensuring that all listed authors have approved the manuscript before submission.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The medical ethics committee of our college (Wuhan Union Hospital, Tongji Medical College, Huazhong University of science and technology, Wuhan, Hubei Province) approved the retrospective study. As the study was retrospective, it did not affect the diagnosis and treatment of patients. The medical ethics committee of our college gave up the written informed consent. Although the ethics committee gave up the written consent, for the safety and rationality of the research.

HUMAN AND ANIMAL RIGHTS
No animals were used in this research. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or research committee and with the 1975 Declaration of Helsinki, as revised in 2013.

CONSENT FOR PUBLICATION
All participants signed informed consent for the study.

STANDARDS OF REPORTING
STROBE guidelines were followed.

AVAILABILITY OF DATA AND MATERIALS
Not applicable.

FUNDING
None.

CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.