Application of Lobaplatin in Trans-catheter Arterial Chemoembolization for Primary Hepatic Carcinoma

Hepatocellular carcinoma (HCC) ranks the fifth in global tumors. About 0.5-1.0 million people are diagnosed as newly-increased HCC patients every year, most of which are Chinese (El-Serag et al., 2007; Gomes et al., 2013). At present, HCC has been topped the second place in tumor-caused deaths (Huang et al., 2007). Transcatheter arterial chemoembolization (TACE) has been considered as the optimal method for unresectable hepatic carcinoma, and its selection for chemotherapy regimens during operation is closely associated with efficiency. As the third generation of platinum anti-tumor drug, lobaplatin (LBP) exerts definite effects in the treatment of various tumors (Yang et al., 2009; Ali et al., 2013). In this study, single LBP was selected as the chemotherapy drug in TACE, and its influence on the efficiency of primary hepatic carcinoma in TACE was evaluated by survival time and therapeutic response under the precondition of other chemotherapy drugs as a control.


Introduction
Hepatocellular carcinoma (HCC) ranks the fifth in global tumors.About 0.5-1.0 million people are diagnosed as newly-increased HCC patients every year, most of which are Chinese (El-Serag et al., 2007;Gomes et al., 2013).At present, HCC has been topped the second place in tumor-caused deaths (Huang et al., 2007).Transcatheter arterial chemoembolization (TACE) has been considered as the optimal method for unresectable hepatic carcinoma, and its selection for chemotherapy regimens during operation is closely associated with efficiency.As the third generation of platinum anti-tumor drug, lobaplatin (LBP) exerts definite effects in the treatment of various tumors (Yang et al., 2009;Ali et al., 2013).In this study, single LBP was selected as the chemotherapy drug in TACE, and its influence on the efficiency of primary hepatic carcinoma in TACE was evaluated by survival time and therapeutic response under the precondition of other chemotherapy drugs as a control.

General data
173 patients with primary hepatic carcinoma undergoing TACE were selected in Radiology Department

Application of Lobaplatin in Trans-catheter Arterial Chemoembolization for Primary Hepatic Carcinoma
Nan Wang 1 , Yin-Zhang Lv 1 , An-Hui Xu 1 , Yan-Rong Huang 1 , Ling Peng 1 , Jia-Rui Li 2 * of our hospital from Mar., 2011 to Jul., 2012, in which males and females were respectively 153 and 20 cases, with mean age of 49.8 years old.All the patients with primary hepatic carcinoma diagnosed by imaging or pathology were unable or unwilling to undergo the operation, but got the informed consent form and operation consent form before enrollment and were approved by Ethics Committee of our hospital; those with severe liver dysfunction, arteriovenous fistula, tumor embolus in portal veins and distal metastasis were excluded.The patients were randomly divided into experimental group given 131 times of TACE with LBP as the chemotherapy drug and control group given 119 times of TACE with pirarubicin hydrochloride as the chemotherapy drug.There was no significant difference regarding the general data of patients between two groups (P>0.05)(Table 1).

TACE method
Under local anesthesia, 5F Yashrio, Cobra or HR catheter was placed for super-selection to tumor feeding arteries after Seldinger method was used to conduct the femoral arterial puncture intubation.SP microtubules were applied if necessary.After that, the emulgator mixed with lipiodol and chemotherapy drugs was injected.The chemotherapy drug in experimental group was LBP (specification: 50 mg/bottle, Hainan Changan International Pharmaceutical Co., Ltd.), and its dose was regulated by the operator according to the pathological condition of patients, usually being 20-50 mg.The chemotherapy drug in control group was pirarubicin hydrochloride (specification: 10 mg/bottle, Shenzhen Main Luck Pharmaceuticals Inc.), and its dose was also regulated by the operator according to the pathological condition of patients, usually being 5-10 mg, while that of lipiodol was decided by the manipulator, being 1.0-1.5 mL/cm in general, and the maximum was no more than 25 mL.There still was tumor stain if the scheduled dose was injected, then gelatin sponge or PVA particles could be used for embolism.

Comparison on survival time and therapeutic response
Imageological examination was performed 1 month after operation every time to confirm the changes of tumor size.Response evaluation criteria in solid tumors were adopted to evaluate the response of tumors to the drugs.Complete response (CR): all lesions disappeared in the targeted area; partial response (PR): the maximum diameter was decreased to 30%-99% in the targeted area; stable disease (SD): it was between PR and progressive disease (PD); PD: the maximum diameter was increased over 20% in the targeted area.Clinical response rate (RR) = (CR+PR) / total number of cases×100%.For the patients undergoing TACE many times, the therapeutic response was assessed according to the final efficiency of multiple treatments.

Statistical data analysis
SPSS16.0 statistical software was applied to analyze the data, and Kaplan-Meier survival curve to achieve 3, 6, 9 and 12-month survival rates of patients in two groups.
The mean survival time was calculated by Kaplan-Meier method and tested by Log-rank test.The therapeutic response was RXC table with unordered grouping variables but ordered index variables, and nonparametric test with rank conversion was used.All inspection levels of hypothesis testing were set α=0.05.

Clinical efficiency
The clinical efficiency of 10 and 9 cases respectively in experimental group and control group was unable to be evaluated due to the deaths, loss of visit, poor constitution and rejection to further consultation, therefore the final cases were 80 and 74 cases respectively in experimental group and control group.
In experimental group, there was no one being CR, but PR 23, SD 36 and PD 21; in control group, there was also no one being CR, but PR 11, SD 33 and PD 30.RR in experimental group was significantly higher than in control group (P<0.05)(Table 3).

Discussion
The incidence and mortality of HCC are relatively higher in our country.The causes of the latter lie in most patients are at the milled-advanced stage when diagnosed and miss the opportunities of receiving radical operation, or the postoperative recurrence rate is also higher even if they have opportunities to receive radical operation.TACE, the recognized optimal method for unresectable hepatic carcinoma at present (Giunchedi et al., 2013;Giunchedi et al., 2013;Hao et al., 2013), can not only reduce the intraoperative hemorrhage and postoperative complications before radical operation, but also has a certain effect on the patient waiting for the liver transplantation or those with recurrence after liver  (Zhou et al., 2010;Agnello et al., 2013;Cescon et al., 2013).There is no unified notion with regard to the variety and doses of chemotherapy drugs in TACE.In the variety of chemotherapy drugs, there are various kinds of drugs that can be selected, such as epirubicin hydrochloride, mitomycin, hydroxycamptothecine, 5-fluorouracil, platinum chemotherapy drugs and sapylin.
As the third generation of platinum anti-tumor drug, LBP can obstruct the process of DNA replication and transcription by forming Pt-GG and Pt-AG intrachain cross-linking so as to interfere the running of tumor cell cycles (Mckeage et al., 2001;Liu et al., 2013).Characterized by good water solubility, broad anti-tumor spectrum, strong anti-tumor activity, no achiasmate drug resistance with other platinum-based drugs and low toxicity, it exerts definite effects in the treatment of various tumors, such as breast cancer (Engel et al., 2012;Deng et al., 2013), lung cancer (Xie et al., 2012), esophageal carcinoma, gastrointestinal cancer (Li et al., 2013) and malignant pleural effusion and ascites.In terms of primary hepatic carcinoma, the in-vitro experimental studies have demonstrated that LBP has an inhibitory effect on hepatocellular carcinoma cells, and can be recommended to treat primary hepatic carcinoma in clinic (Qian et al., 2009;Wu et al., 2010;Wang et al., 2012).By applying LBP in TACE for hepatic carcinoma, the research results made by Shi et al. revealed that the efficiency of epirubicin hydrochloride combined with LBP and mitomycin was superior to that of single epirubicin hydrochloride in the treatment of unresectable hepatic carcinoma with good liver function (Shi et al., 2009;Shi et al., 2013).
By referring to the doses used in systemic chemotherapy, traditional TACE performs embolization after intra-arterial infusion plus chemotherapy drugs in terms of chemotherapy drug doses (Cui et al., 2012;Kong et al., 2012;Li et al., 2013;Minami et al., 2013;Murata et al., 2013;Wang et al., 2013).It is still controversial with regard to chemotherapy drug doses at present.There is a new method to reduce the variety and doses of chemotherapy drugs, namely small dose of TACE, which includes single-small dose of chemotherapy drugs only through the transarterial embolization and mixed lipiodol emulsion.In addition, gelatin sponge and PVA particles can be replenished if necessary.The previous research studies made by our department revealed that there was no significant difference between small and routine doses of TACE regarding the survival rates, and small dose of TACE had less damage on the liver function and postoperative adverse reactions were less (Hu et al., 2004).Thereby, it is more important to select proper chemotherapy drugs and apply appropriate doses when TACE is used in a small dose.In this study, 173 patients with primary hepatic carcinoma diagnosed by imaging or pathology were randomly divided into two groups, and respectively treated with single LBP and pirarubicin hydrochloride.Except for the used chemotherapy drugs, other therapeutic regimens were the same and the difference had no statistical significance about the patents' general data between two groups.The research results showed that single LBP as the chemotherapy drug was superior to pirarubicin hydrochloride during operation in the aspects of survival time and therapeutic response, with statistical significance, suggesting that single LBP can be as a chemotherapy drug in TACE and has better efficiency in the aspects of mean survival time and therapeutic response, deserving to be popularized in clinic.
The disadvantages of this study lie in shorter follow-up time and deficiency of long-term statistical data.Besides, how to control LBP dose is also worthy of being studied further.