The Effect Observation of TACE Combinated with the Lobaplatin for Hepatocellular Carcinoma

WANG Xujie WANG song FENG Weihua SHI Lei YU Chunpeng

Abstract Objective To observe the effect and safety of lobaplatin combinated floxuridine/pirarubicin in transcatheter hepatic arterial chemoembolization（TACE） of unresectable primary liver cancer. Methods TACE combinated with the lobaplatin-based chemotherapy regimen was used to treat 34 unresectable primary liver cancer patients. The DSA/MRI/CT/blood routine examinations were used to evaluate the short term activity and toxicity after 4-5 weeks， the process was repeated if necessary. The results were observed. Results Among the 34 cases， 1 case （2.9%） showed a complete response， 21 cases （61.7%） showed a partial response， 8 cases （23.5%） showed stable disease， and 4 cases showed progressive disease， with a total effective rate of 67.6%. The content of AFP dropped by over 50% in 20 cases（58.8%）. The rate of recovery was hepatalgia（88.2%），ascites （47.1%），appetite（55.9%）， Performance Status（30.4%）. The median follow-up time（MFT）was 281 days（63-558 days），The median pro-gression-free survival was 118.5 days（95%，CI：88.8-148.2days）. Adverse reactions（III-IV grade）were less commom， Only 4 cases of vomiting and 2 cases of thrombocytopenia （III grade） were observed. Conclusion Lobaplatin-based TACE is an effective and safe treatment for primary liver cancer.

Key words Primary hepatic carcinoma；Chemoembolization；Platinum

Chinese Library Classification： R735.7 Document code： A

1 INTRODUCTION

Hepatocellular carcinoma （HCC） is a common malignant tumor. The majority of patients have reached the advanced or distant metastasis when diagnosed， and have lost the opportunities of surgical operation. Transcatheter arterial chemoembolization （TACE） is an important？nonsurgical treatment [1]. TACE combined with platinum？chemotherapy has been widely used in clinical and achieved good curative effects [2]. Because of its unique mechanism of action， good stability， wide antitumor spectrum， strong anti-tumor activity， low liver toxicity and without cross resistance ， Lobaplatin （LBP，an third generation platinum anticancer drugs） has got better curative effects on gastrointestinal tumors， Only a few published articles have addressed the use of LBP-based TACE in the treatment of unresectable HCC， This article aims to observe the feasibility and safety of LBP-based TACE in the treatment of unresectable HCC.

2 MATERIALS AND METHODS

2.1 Patient Population

Between January 2012 to June 2013，34 patients with HCC were enrolled to be treated with one or more cycles of LBP-based TACE ，male 29 cases， female 5 cases， average age for 57.2？0.7 years， 12 cases were biopsy-proven， 22 cases were in line with the China Cancer Association liver cancer Professional Committee amendment liver cancer clinical diagnosis standard， Patients were considered for TACE who were deemed to be unresectable but had white cell >4.0x109/l， platelet count >80x109/l， liver cirrhosis child-pugh A Level or B Level with 7 scores，the preoperative informed consent form. Patients were not enrolled who had a large number of ascites， portal vein embolization， liver metastasis， or less than 3 months expected survival time. More information of patients included HBsAg - positive in 25 cases， HCVAg positive in 2 cases，hepatitis cirrhosis in 29 cases， drug cirrhosis in 2 cases， unknown origin cirrhosis 1 cases.

2.2 Chemoembolization

Seldinger technique was used in TACE. After the introduction of a 5 French sheath into the femoral artery， the angiograms were performed in the hepatic artery， superior mesenteric artery， and inferior phrenic artery （when necessary） with the 4F catheter. Depending on the quantity ，size， location， and feeding arterials of tumors， the Microcatheter was advanced further into the segmental arteries， high concentration of chemotherapeutic drugs were infused selectively through the microcatheter， included 30-50mg lobaplatin for injection，0.5g-1.0g of floxuridine saline solution， and the mixture of 20-40mg pirarubicin hydrochloride for injection and 5-15ml imported lipiodol， PVA particles （100-500um） were selectively used for rich vascular hepatic tumors and arteriovenous fistula in embolization. Devascularization was confirmed with additional angiography of the hepatic artery. Pain， nausea， vomiting， fever， sensory and other adverse reactions were recorded， Liver function test， blood routine， AFP test and imaging studies （DSA angiography， CT， MRI） were performed in the 4-6 weeks after treatment. According to the examination results， the treatment was repeated with the same modality. The follow-up of living conditions was recorded for all patients.

2.3 Definitions and Data Analysis

2.3.1 Recent efficiency evaluation

Tumor response was retrospectively evaluated by Response Evaluation Criteria In Solid Tumors（RECIST），classified into four grades： complete response（CR）， partial response（PR）， stable disease（SD）， and progressive disease（PD）， Objective response rate（ORR）= CR+PR.

2.3.2 Toxicity evaluation

According to WHO anticancer drugs in acute and subacute toxicity grading standards ，Toxicities were classified into four grades（0-IV）.

2.3.3 Recording Progression-Free-Survival （PFS）

PFS was recorded from the day after first TACE to June 2013，.Statistical analysis was conducted with SPSS 17.0 software.

2.3.4 Clinical symptoms evaluation

Clinical symptoms evaluation included the abatement of hepatalgia （According to WHO pain classification standards， classified into 0-III grade， the postoperative pain degrade more than one level was recorded）， ascites disappearance （disappearance was recorded）， appetite （intake increasing more than 100g was recorded） and Performance status improvement（According to ECOG classification standards， the postoperative Physical situation degrade more than one point was recorded）.

3 Results

3.1 Efficiency evaluation

34 cases were successfully treated with at least one time TACE treatment， and totally 78 times treatments were successfully completed（ 2.3 times per person on average）. The curative effect was evaluated in the 4-6 weeks after treatment， Among the 34 cases， 1 case （2.9%） showed a complete response， 21 cases （61.7%） showed a partial response， 8 cases （23.5%） showed stable disease， and 4 cases showed progressive disease who were adviced to take sorafenib. The objective response rate was 67.6%. The content of AFP dropped by over 50% in 20 cases （58.8%）. The rate of recovery was separately hepatalgia （88.2%），ascites （47.1%），appetite（55.9%）， Performance Status （30.4%）in 4-6 weeks after treatment. The median follow-up time（MFT）was 281 days（63-558 days），The PFS was 118.5 days（95% ，CI：88.8-148.2days）.

3.2 Toxicity

After the treatments， 34 cases showed different degree of toxicity （mainly I-II level， table 2）， no IV grade toxicity. The III grade toxicity included： gastrointestinal reaction （nausea， ventosity） in 4 cases （11.8%）， bone marrow toxicity （thrombocytopenia） in 2 cases （5.9%）， no nervus and renal toxicity was recorded. 1 case showed Mallory-Weiss syndrome which was caused by vomiting after TACE， and the drugs of hemostasis， gastric acid inhibition and antiemetic have been used and got good effectiveness.18 cases showed different degree of thrombocytopenia， were only treated with Compound Zaofan Pills and Shengxuebao mixture， which had good recovery in 2 weeks after treatments.

4 Discussion

TACE， due to its Minimal invasive and good outcome， had become one of the important palliative treatments for the patients with advanced HCC. With the development of the high efficiency and low toxicity antitumor drugs， More kinds of chemotherapy regimens include LBP（a third generation platinum） were used with TACE and got the better effect.

Lobaplatin（D-19466；1，2-diammino-methyl-cyclobutaneplatium（II）-lactate） effects on the formation of DNA-drug adducts， mainly as GG and AG intra-strand cross-links， which could influence the proliferation of DNA[3]. LBP has been approved good inhibitory effect for the hepatocellular carcinoma cell lines（SMMC-27721， HepG2 and Bel2-7402） in the experiments in vitro[4]. The results of these studies proved the basic theory for that LBP-based TACE might be more useful for advanced HCC patients. In 2012 Zhang Peng [5] et al did a further study about the treatment with LBP for unresectable HCC patients， The thermochemotherapy and embolization via hepatic artery was used in the treatment for 20 cases of unresectable HCC patients. They finally got the result of a total effective rate of 55.0% and thought the use of thermochemotherapy and embolization via hepatic artery an effective and safe treatment for HCC. the our study， we firstly used the lobaplatin-based TACE in the treatment for unresectable HCC patients， and received the 67.6% of the total efficiency and 118.5 days median progression free survival time， postoperative AFP declined significantly， hepatalgia， ascites， appetite and other clinical symptoms improved significantly， the adverse reactions were minor and well tolerated， the quality of life of patients was significantly improved after treatments. Compared with the other studies， the information of this result is more detailed and exact ，and the short-term efficacy seems better.

The adverse reactions of LBP were mostly reported in the intravenous clinical application， the most common adverse reaction was the Dose-limiting toxicity of thrombocytopenia. The adverse reactions of digestive system （including nausea， vomiting and bloating） were milder than cisplatin， and also there were no significant renal toxicity and neurotoxicity. These results have been confirmed in the phase I， II phase clinical study and other clinical studies. In the phaseⅡclinical study performed by Jiang Wenqi et al about LBP monotherapy in the treatment of breast cancer [6]， 42 cases of recurrent or metastatic breast cancer patients were enrolled. The total efficiency was 45.2%， the thrombocytopenia （II-IV grade） was 14.5%， the kidney toxicity and neurotoxicity was low. In present study， the adverse reactions were similar to that reported in the literatures， mainly including the gastrointestinal toxicity and thrombocytopenia， the rate of III grade was only 11.8%， 5.9% respectively， due to local perfusion application. Even though the thrombocytopenia was only in a few patients after the treatment， the low platelet count patients should be more cautious in using LBP. The patients who show I-II grade thrombocytopenia in this group were only treated with the drug therapy（Compound Zaofan Pills and Shengxuebao mixture）；The patients with III-IV grade thrombocytopenia without bleeding complications were treated with recombinant human interleukin-11 （subcutaneous injection of Juheli）. The patients with Platelet count <20x109/L or count <50x109/L with spontaneous hemorrhage should be monitored closely and treated timely with platelet transfusion， which usually could effectively controlle and cured those adverse reactions mentioned above. The kidney toxicity and neurotoxicity was not recorded in this study.

In conclusion， TACE with the lobaplatin-based Chemotherapy Regimen for HCC seems to have the better short-term efficacy and the lower toxicity.It is an effective and safe treatment for the unresectable HCC， which is worthy to be extended to clinical application. Because of the small number of cases enrolled in the group and the short follow-up time， the further effect still need further clinical studies.

*通訊作者：馮衛華

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