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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 12  |  Page : 1148-1151

Endostar continuous intravenous infusion combined with S-1 and oxaliplatin chemotherapy could be effective in treating liver metastasis from gastric cancer


Department of Oncology. Dongying People's Hospital, Dongying, Shandong, China

Date of Web Publication11-Dec-2018

Correspondence Address:
Minglin Wang
Dongying People's Hospital, Dongying 257091, Shandong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.204880

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 > Abstract 


Objective: Endostar is a new vascular epithelial inhibitor, which is reported to be effective in treating liver metastasis from gastric cancer. However, the optimal therapeutic regimen of Endostar remains unclear. Thus, our study aimed to examine the efficacy and safety of Endostar continuous intravenous infusion combined with S-1 and oxaliplatin (SOX) chemotherapy in treating such patients.
Patients and Methods: A total of sixty patients with liver metastasis from gastric cancer admitted in our department were enrolled. The experimental group (n = 30) was treated with Endostar continuous intravenous infusion combined with SOX regimen chemotherapy, and the control group (n = 30) received SOX regimen chemotherapy alone. All patients received at least two cycles of treatment. The objective effective rate (ORR), disease control rate (DCR), progression-free survival (PFS), and adverse reactions were recorded and compared.
Results: The ORR of the experimental group and control group was 63.3% and 43.3% (P = 0.046), respectively. The DCR of the experimental group and the control group was 86.7% and 73.3% (P = 0.034). The median PFS in the experimental group was longer than that in the control group (15.3 months vs. 12 months). There was no significant difference in the incidence of common adverse reactions such as gastrointestinal reaction, bone marrow suppression, and cardiac toxicity between the two groups. No death was observed in the study period.
Conclusion: Continuous infusion of Endostar combined with SOX chemotherapy could be recommended for the treatment of liver metastasis from gastric cancer due to its high effective rate, and Endostar did not increase the incidence of adverse reactions.

Keywords: Efficacy, Endostar, gastric cancer, liver hepatic metastasis, safety


How to cite this article:
Yang H, Sui Y, Guo X, Tan X, Li Y, Wang M. Endostar continuous intravenous infusion combined with S-1 and oxaliplatin chemotherapy could be effective in treating liver metastasis from gastric cancer. J Can Res Ther 2018;14, Suppl S5:1148-51

How to cite this URL:
Yang H, Sui Y, Guo X, Tan X, Li Y, Wang M. Endostar continuous intravenous infusion combined with S-1 and oxaliplatin chemotherapy could be effective in treating liver metastasis from gastric cancer. J Can Res Ther [serial online] 2018 [cited 2019 Oct 15];14:1148-51. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/1148/247190




 > Introduction Top


Gastric cancer is one of the most common gastrointestinal tumors, especially in Asian countries. Almost half of the patients with gastric cancer are diagnosed at advanced stage and lose the opportunity for radical resection.[1] These patients usually have liver metastasis, which greatly impairs the survival and life quality. However, there is still no effective treatment for liver metastasis in gastric cancer due to chemoresistance and severe adverse events caused by chemotherapy.[2] The development of anti-angiogenesis agents has optimized the current therapeutic regimen for treating multiple human cancers, which has attracted great attentions from clinicians and researchers all over the world.[3],[4]

Endostar is the first recombinant vascular epithelial inhibitor developed in China.[5] Endostar alone or combined therapy with chemotherapy and radiotherapy could be effective in treating malignant serous cavity effusion and nonsmall cell lung cancer.[6] Most of the previous studies introduced the regimen of 7.5 mg/m2 Endostar once a day combined with chemotherapy. In recent years, it has been proved that the antitumor activity of Endostar is time- and dose-dependent and be stable through intravenous infusion, which could guide the clinical application of Endostar. Microinfusion pump 24-h continuous infusion of Endostar has higher clinical efficacy in treating patients with malignant tumors,[7] but whether Endostar combined with S-1 and oxaliplatin (SOX) chemotherapy could achieve a synergistic effect in clinical practice has not been fully validated in gastric cancer. Thus, we conducted this study to investigate the safety and efficacy of Endostar plus SOX chemotherapy in treating Chinese patients with unresectable gastric cancer by comparing with those of SOX chemotherapy.


 > Patients and Methods Top


Patients

A total of sixty patients with liver metastasis from gastric cancer admitted in our department from January 2013 to December 2014 were included. All the patients underwent endoscopy, computed tomography (CT), and magnetic resonance imaging (MRI) examination, and the diagnosis of liver metastasis from gastric cancer was confirmed. Inclusion criteria were described as follows: (1) The histopathological diagnosis of gastric cancer; (2) unresectable or recurrent gastric cancer with liver metastasis shown by CT or MRI and the presence of over one liver metastatic lesion that could be measured; (3) without receiving antitumor therapy in the recent 3 months; (4) the age range of 20–80 years; (5) Karnofsky score ≥60 or Eastern Cooperative Oncology Group score ≤2; (6) good compliance; (7) expected survival ≥3 months; (8) hemoglobulin ≥80 g/L; (9) white blood cell count >3.5 × 109/L; (10) platelet count >75 × 109/L; (11) serum bilirubin ≤2 × upper limit of normal (ULN); (12) alanine aminotransferase and aspartate transaminase ≤5 × ULN; (13) serum creatinine < normal lower limit; (14) normal electrocardiogram and left ventricular ejection fraction. Patients who had advanced gastric cancer without liver metastasis, history of severe cardiopulmonary diseases (i.e., congestive heart failure, frequent angina pectoris, intractable hypertension, pulmonary infection or dysfunction, myocardial infarction within 1 month, etc.); uncontrolled psychiatric diseases; organ dysfunction (i.e., renal failure, uremia, brain metastasis, etc.); without measurable lesions; poor compliance; pregnancy and lactation. During the study period, patients who did not complete the examination or therapeutic course were not included in the final analysis. Our study was approved by the Ethics Committee in our hospital, and written informed consent was obtained from all the patients.

Treatment

The patients were randomly divided into two groups: experimental group (n = 30) and control group (n = 30) and blinded to the treatment. In experimental group, Endostar (Xiansheng Maidejin Biological Company, China) and SOX therapy were administrated. The doses were determined based on body surface area (BSA). 15 mg/m2 Endostar was given by 24-h continuous microinfusion pump infusion for day 1–7. S-1 (Lunan Pharmaceuticals, Shandong, China) at the dose of 40 mg/time if BSA was <1.25 m2, 50 mg/time if BSA was 1.25–1.5 m2, 60 mg/time if BSA was >1.5 m2 which was orally taken twice a day for 14 days, and oxaliplatin (Hengrui Pharmaceuticals, Shandong, China) at the dose of 130 mg/m2 was intravenously given for D1. In the control group, patients underwent SOX regimen chemotherapy at the same dose as experimental group. All the patients received at least two cycles of treatment and the period of 21 days was a cycle. A new cycle of chemotherapy was not given until the adverse effects were cured. The adverse events including nausea, vomit and the like were categorized as CTCAEV4.0. laboratory tests and radiological examinations were regularly conducted.

Safety and efficacy evaluation

Toxicity reaction was recorded following the criteria by the National Cancer Institute and classified into 0–4. The incidence was calculated. The therapeutic efficacy was evaluated as complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) using RECIST1.1 criteria every 2 weeks.[8] CR was defined as the CR of tumor for over 4 weeks, and PR was defined as reduced maximal diameter of the primary and metastatic tumors by 30% for 4 weeks. SD referred to the condition that the changes of the maximal diameter of the primary and metastatic tumors were stable within 20% and no new lesion was detected. PD referred to the condition that the maximal diameter of the primary and metastatic tumors increased by over 20% and new lesion was detected. The objective effective rate (ORR) and disease control rate (DCR) were calculated as ORR = CR + PR and DCR = CR + PR + SD. Patients were followed up at the 3-month interval, and the median progression-free survival (PFS) was collected.

Statistical analysis

All the statistical analyses were conducted using SPSS 17.0 software (SPSS, Inc., Chicago, IL, USA) for Windows. The categorical data were presented as percentage (%) and compared by Chi-square test. P < 0.05 was considered to be statistically significant.


 > Results Top


Demographic and clinical data

There were 35 male and 25 female patients. The mean age was 63.5 years, ranging 42-69. Patients in experimental and control group underwent an average of 3.85 and 3.56 cycles, and there was no statistical difference (P = 0.069).

Efficacy

Of patients who received Endostar and SOX chemotherapy, one patient got CR, 18 patients got PR, 7 patients got SD, and 4 patients got PD, respectively. Of patients in control group, no patient got CR, 13 patients got PR, 9 patients got SD, and 8 patients got PD, respectively. Then, the ORR and DCR were calculated. ORR in experimental and control group was 63.3% and 43.3%, respectively (χ2 = 4.078, P = 0.046); and DCR was 86.7% and 73.3% (χ2 = 4.46, P = 0.034). Survival analysis showed that PFS in two groups was significantly different, and Endostar combined therapy could prolong the patients' survival (15.3 months vs. 12 months, P = 0.001) [Table 1].
Table 1: Efficacy and survival were compared between two groups

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Safety

All the adverse events recorded are shown in [Table 2]. Nausea and vomit was the most common in both groups (66.7% vs. 70.0%, P = 0.845). Other adverse events included neutropenia, anemia, thrombocytopenia, diarrhea, skin pigmentation, neuropathy, hepatic toxicity, renal toxicity, and cardiac toxicity. The combination of Endostar did not increase the overall incidence of adverse events (P > 0.05), indicating that Endostar was safe in treating advanced gastric cancer with liver metastasis. In addition, less severity of adverse events was observed in experimental group.
Table 2: Adverse events

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All the patients who developed adverse events recovered well after proper conservative treatment.


 > Discussion Top


Although great progress has been made on the development of new chemotherapeutic agents, the overall survival of gastric cancer remains very poor.[9],[10] It has been well acknowledged that neoangiogenesis has played an important role in liver metastasis from gastric cancer, indicating that anti-neoangiogenesis might be a promising therapeutic strategy for treating liver metastasis from gastric cancer.[3],[11] In our study, we investigated the efficiency of Endostar, which is a vascular epithelial inhibitor, in the treatment of patients with advanced gastric cancer and liver metastasis. These results might help optimize the current management of such devastating disease.

S-1 is a composite drug which is transformed into 5-Fu. In Japan, S-1 has already been recommended as the first-line treatment for advanced gastrointestinal cancer because of the enhanced antitumor activity and relatively less adverse events.[12] Oxaliplatin has high and broad antitumor actions, which is widely applied in treating multiple gastrointestinal cancers. The combination of SOX is the common chemotherapeutic regimen for gastric cancer.[13] It was reported that SOX chemotherapy could control 84% of the patients with gastric cancer and the rate of effectiveness was 59%.

In 1971, Folkman first proposed that neoangiogenesis was the key to the growth and metastasis of malignant tumors, which was a milestone in researches on the tumor.[14] Endostar was developed in China and could inhibit the tumor neoangiogenesis.[5] The stability and water solubility of Endostar have been improved, making it available for clinical application and research. Since then, Endostar has been effective in treating human cancers.[15],[16] Endostar could synergize with SOX chemotherapy for treating advanced gastric cancer, and this combination could obviously improve the clinical efficacy and prolong PFS compared with chemotherapy alone.

Although Endostar has good antitumor efficacy, the optimal dose of Endostar and time remains uncertain. In the previous clinical trials, the dose of 7.5 mg/m2 is commonly selected. Experimental data demonstrated that the antitumor activity of Endostar was time- and dose-dependent. It has been ever observed that micropump could maintain the effective concentration of Endostar for a long time, which is a more effective delivery mode in the treatment of tumor.[17] Microinfusion pump 24-h continuous infusion of Endostar is more effective than a routine infusion, and the incidence of adverse events is comparable.[18] This regimen has been validated in treating nonsmall cell lung cancer;[19] however, the evidence on the treatment of gastric cancer with liver metastasis was little. Our results showed that the rate of effectiveness in patients with SOX chemotherapy was 43.3%, in which patients with Endostar plus SOX chemotherapy increased to 63.3% (P < 0.05). Endostar combined with SOX chemotherapy also improved PFS but did not greatly increase the incidence of adverse events. In our cohort, patients were treated by Endostar for 7 days, minimizing the hospitalization and thus improving patients' compliance.

Taken together, our data verified that continuous infusion of Endostar plus SOX chemotherapy was effective in treating gastric cancer patients with liver metastasis, with less adverse events and high compliance, which could be recommended in clinical practice. In addition, our study could serve as a pilot investigation, which should be further validated in large-scale clinical trial.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Lee SY, Oh SC. Changing strategies for target therapy in gastric cancer. World J Gastroenterol 2016;22:1179-89.  Back to cited text no. 3
    
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Ling Y, Yang Y, Lu N, You QD, Wang S, Gao Y, et al. Endostar, a novel recombinant human endostatin, exerts antiangiogenic effect via blocking VEGF-induced tyrosine phosphorylation of KDR/Flk-1 of endothelial cells. Biochem Biophys Res Commun 2007;361:79-84.  Back to cited text no. 5
    
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Ni Q, Ji H, Zhao Z, Fan X, Xu C. Endostar, a modified endostatin inhibits non small cell lung cancer cell in vitro invasion through osteopontin-related mechanism. Eur J Pharmacol 2009;614:1-6.  Back to cited text no. 6
    
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Zhong J, Zhao W, Ma W, Ren F, Qi S, Zheng J, et al. DWI as a quantitative biomarker in predicting chemotherapeutic efficacy at multitime points on gastric cancer lymph nodes metastases. Medicine (Baltimore) 2016;95:e3236.  Back to cited text no. 8
    
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Yuan DD, Zhu ZX, Zhang X, Liu J. Targeted therapy for gastric cancer: Current status and future directions (Review). Oncol Rep 2016;35:1245-54.  Back to cited text no. 9
    
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Venerito M, Vasapolli R, Malfertheiner P. Prevention, early diagnosis and therapy of gastric cancer. MMW Fortschr Med 2016;158:39-43.  Back to cited text no. 10
    
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Li K, Li J. Current molecular targeted therapy in advanced gastric cancer: A comprehensive review of therapeutic mechanism, clinical trials, and practical application. Gastroenterol Res Pract 2016;2016:4105615.  Back to cited text no. 11
    
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Galdy S, Cella CA, Spada F, Murgioni S, Frezza AM, Ravenda SP, et al. Systemic therapy beyond first-line in advanced gastric cancer: An overview of the main randomized clinical trials. Crit Rev Oncol Hematol 2016;99:1-12.  Back to cited text no. 12
    
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Bando H, Yamada Y, Tanabe S, Nishikawa K, Gotoh M, Sugimoto N, et al. Efficacy and safety of S-1 and oxaliplatin combination therapy in elderly patients with advanced gastric cancer. Gastric Cancer 2016;19:919-26.  Back to cited text no. 13
    
14.
Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971;285:1182-6.  Back to cited text no. 14
    
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Xu R, Ma N, Wang F, Ma L, Chen R, Chen R, et al. Results of a randomized and controlled clinical trial evaluating the efficacy and safety of combination therapy with Endostar and S-1 combined with oxaliplatin in advanced gastric cancer. Onco Targets Ther 2013;6:925-9.  Back to cited text no. 15
    
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Wang YB, Liu JH, Song ZM. Effects of recombinant human endostatin on the expression of vascular endothelial growth factor in human gastric cancer cell line MGC-803. Biomed Rep 2013;1:77-9.  Back to cited text no. 16
    
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Li W, Zhao X, Du B, Li X, Liu S, Yang XY, et al. Gold nanoparticle-mediated targeted delivery of recombinant human endostatin normalizes tumour vasculature and improves cancer therapy. Sci Rep 2016;6:30619.  Back to cited text no. 17
    
18.
Huang W, Liu J, Wu F, Chen K, Li N, Hong Y, et al. The efficacy and safety of endostar combined with taxane-based regimens for HER-2-negative metastatic breast cancer patients. Oncotarget 2016;7:31501-7.  Back to cited text no. 18
    
19.
Tang H, Ma H, Peng F, Bao Y, Hu X, Wang J, et al. Prognostic performance of inflammation-based prognostic indices in locally advanced non-small-lung cancer treated with endostar and concurrent chemoradiotherapy. Mol Clin Oncol 2016;4:801-6.  Back to cited text no. 19
    



 
 
    Tables

  [Table 1], [Table 2]



 

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