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    -  Guo Y
    -  Liu R
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ORIGINAL ARTICLE
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Different administration methods of endostar combined with second-line chemotherapy in advanced malignancies


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

Date of Submission13-Jun-2019
Date of Decision02-Sep-2019
Date of Acceptance24-Oct-2019
Date of Web Publication10-Dec-2020

Correspondence Address:
Xunguo Wang,
Department of Oncology, Dongying People's Hospital, Shandong
China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_537_19

PMID: 33402601

  Abstract 


Background: This study aimed to compare the therapeutic efficacy and the side effects of different endostar administration methods in patients with advanced malignancy who underwent second-line chemotherapy.
Methods: 98 patients with advanced malignancies were divided into 2 groups based on the delivery methods of endostar, including drip intravenous administration of endostar (DE) group and continuous intravenous administration of endostar (CE) group. Response rate (RR), disease control rate (DCR), and quality of life (QOL) of the patients were examined to evaluate the therapeutic efficacy, and toxicity reactions were analyzed to evaluate the adverse effects.
Results: Compared with the DE group, the therapeutic efficacy of CE has been slightly improved, but the difference did not reach statistical significance (P > 0.05). Additionally, no different incidence rate was observed in toxic reactions, including leukopenia, thrombocytopenia, nausea and vomiting, diarrhea, and hepatic function damage, between the DE and CE groups (P > 0.05).
Conclusion: In conclusion, no significant difference was observed between the traditional intravenous drip of endostar group and the intravenous drip followed by continuous pumping of endostar group in the patients with advanced malignancies.


Keywords: Endostar, malignancy, quality of life, second-line chemotherapy
Key Message The combination of endostar and chemotherapy can improve the therapeutic efficacy and quality of life in patients with advanced malignancies. Endostar plays a critical role in adjuvant chemotherapy with no increase of toxic side effect.



How to cite this URL:
Chen S, Yang J, Gao X, Liu Q, Wang X, Guo Y, Liu R, Wang F. Different administration methods of endostar combined with second-line chemotherapy in advanced malignancies. Indian J Cancer [Epub ahead of print] [cited 2021 Jul 29]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=302940

Shaoping Chen and Jianmei Yang are contributed equally to this work.





  Introduction Top


Malignant tumors, which are characterized by rapid growth, often have high morbidity and mortality.[1] According to the statistical data, approximately 18.1 million new cancer cases and 9 million cancer deaths occurred around the world in 2018.[2] The population growth and aging, and the life style changes are likely to additionally contribute to the increasing morbidity.[3],[4] Currently, some advanced therapeutic strategies have been developed – mainly including surgery, radiotherapy, and chemotherapy.[5] The overall survival of patients suffering from malignancies has been substantially improved by the surgical resection, which becomes the preferred treatment method for different types of cancer.[6] However, most of the patients are diagnosed with advanced tumor stage with poor prognosis following the surgery.[7] A comprehensive treatment based on chemotherapy is recommended for these advanced malignancy cases.[8] Currently, novel effective chemotherapy drugs have been improved, such as oxaliplatin, nedaplatin, gemcitabine, and irinotecan.[9],[10] The first-line chemotherapy has a good clinical effect, but the clinical response of second-line chemotherapy is dismal, which is mainly due to the progression of diseases.[11] Therefore it is important to improve the therapeutic effect of second-line chemotherapy in the patients with advanced malignancies.

Emerging studies have focused on the inhibitor of angiogenesis in the field of cancer treatment.[12] Angiogenesis plays a pivotal role in tumor progression, especially in the advanced malignancies, which have dramatically high rates of metastasis and invasion.[13] Notably, the application of angiogenesis inhibitor is considered an efficient adjuvant method for the second-line chemotherapy for patients with advanced malignancy.[14] Endostar (YH-16) is a novel recombinant human vascular endostatin, and has been frequently used for various human cancers.[15] Intravenous infusion of endostar in combination with chemotherapy achieves good clinical results in the patients with advanced malignancy and the safety profile of endostar has been demonstrated to be acceptable.[16] However, the clinical benefit of endostar is still limited by the traditional administration method.

To further improve the second-line chemotherapy for advanced malignancies, this study sought to explore the clinical response of different administration methods of endostar and evaluate the corresponding adverse effects in the patients with advanced malignancies.


  Methods Top


Patients

A total of 98 patients with advanced malignancy were enrolled between 2012 and 2016 from Dongying People's Hospital. The inclusion criteria of patient recruitment was as follow: (1) all patients were pathologically or cytologically diagnosed with advanced TNM stage tumors; (2) Eastern Cooperative Oncology Group (ECOG) score ≤2.0; (3) have measurable objective nidi; (4) regular blood routine examination results and normal function of liver, kidney and heart; (5) expected life time is more than 3 months; and (6) had received first-line chemotherapy. The clinicopathological characteristics of the patients were listed in [Table 1]. This study was performed with the approval of the Ethics Committee of Dongying People's Hospital. Written informed consent was duly obtained from each of the participant before the treatment.
Table 1: Baseline characteristics of the patients with advanced malignancies

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Grouping and treatment

The 98 patients were randomly grouped into two groups: drip intravenous administration of endostar (DE) group and continuous intravenous administration of endostar (CE) group. Patients in DE group received 15 mg of endostar (diluted in 500 mL of normal saline) by routine intravenous infusion for 3-4 hours from day 1 to day 14 before chemotherapy. For patients in CE group, 15 mg of endostar (diluted in 500 mL of normal saline) was firstly administered by intravenous infusion, then immediately followed with 150 mg of endostar continuous pumping using an automatic drug infusion pump (Nantong Apon Medical Appliance Co, Ltd, Nantong, China) for 240 hours. The treatment cycle was 3 weeks. Chemotherapy regimens for the patients were performed using the drugs that were not cross-resistant or used previously.

Therapeutic response and adverse effects

The response of patients with advanced malignancies was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. The response includes complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The response rate (RR) and disease control rate (DCR) were calculated. Meanwhile, the quality of life (QOL) was evaluated using Karnofsky performance scale (KPS). An KPS increase of more than or equal to 10 points indicates an improvement of QOL, and KPS increase less than 10 points means a stable QOL, while an KPS decrease of more than or equal to 10 points represents a declining QOL. To measure the adverse effect of endostar, the National Cancer Institute Common Terminology Criteria Adverse Events (NCI-CTCAE) version 4.0 was used.

Statistical analysis

All the data in this study was expressed using mean ± standard deviation (SD), and was analyzed using SPSS 21.0 software (SPSS Inc, Chicago, IL). Comparisons between different groups were assessed by Chi-square test or Fisher exact test. A P value of less than 0.05 was considered statistically significant.


  Results Top


Baseline characteristics of the patients

98 patients with advanced malignancies were included in our study, and their baseline characteristics were summarized in [Table 1]. There were 52 men and 46 women, with age range of 41 years to 70 years (median age of 56 years). These patients included 50 cases with lung cancer and 48 cases with non-lung malignancies, including 23 cases with digestive tract tumors, 12 cases with gynecological oncology, 8 cases with head and neck tumors and 5 cases with breast cancer. All the patients were divided into DE and CE groups based on the different administration methods of endostar, and no statistical difference was observed between these two groups at gender, age, types of cancer and TNM stage (all P > 0.05).

Therapeutic efficacy

Following the treatment with different administration of endostar combined with chemotherapy, there were 16 PR cases, 18 SD cases and 15 PD cases in the CE group, and 14 PR cases, 19 SD cases and 16 PD cases in the DE group. None of the patients in the two groups achieved complete remission. The sum of CR and PR is RR, and the RR in CE group (32.7%) was higher than that in the DE group (28.6%). The sum of CR, PR and SD is DCR, and the DCR in CE group (69.4%) was elevated compared with the DE group (67.3%). However, no statistical significance was observed between the two groups at both the PR and DCR values [all P > 0.05, [Table 2]]. In addition, the RECIST results were further analyzed in lung tumors group and non-lung tumors group, respectively. Similarly, no significant difference was found between DE and CE groups in the lung cancers or other malignancies (all P > 0.05).
Table 2: Response and control rates in patients with advanced malignancies

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By examining the KPS of the patients, we found that the QOL of patients in CE group was increased compared with the DE group, which evidenced by the increased number of patients with improved and stable QOL and decreased number of cases with declining QOL in the CE group. However, the difference did not reach the statistical significant level [all P > 0.05, [Table 3]]. Similar results were also observed between DE and CE groups in different types of malignancy, which were reflected by the increased patient number with improved and stable QOL in CE group compared with the DE group, but the differences were not statistically different (all P > 0.05).
Table 3: QOL of the patients with advanced malignancies

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Toxicity evaluation

The hematologic and non-hematologic toxicities were measured for patients in the two groups. By analysis based on NCI-CTCAE, the severity of the adverse effects was graded. The major toxicity reactions included leukopenia, thrombocytopenia, nausea and vomiting, diarrhea and hepatic function damage [Table 4]. We observed higher grade 3 and 4 leukopenia and thrombocytopenia, and worse grade 3 diarrhea in the DE group compared with the CE group, but there was no statistically significant difference between the two groups (all P > 0.05). Furthermore, the toxic reactions between DE and CE in the cohort with different malignancy types were compared and listed in [Table 5]. In both lung tumors group and the non-lung tumors group, the statistical difference between DE and CE was still not found (all P > 0.05), and there was no difference in the toxic reactions between the two types of malignancy (all P > 0.05).
Table 4: Toxicity of different administration methods of endocrine in patients with advanced malignancies

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Table 5: Toxicity of different administration methods of endocrine in patients with lung or non-lung malignancies

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  Discussion Top


Since the concept of angiogenesis was proposed in 1971, anti-angiogenesis has become an important research field in the treatment of human cancers, especially for the cancer metastasis and invasion, and some inhibitors of angiogenesis have been developed, including bevacizumab, endothelin, apatinib, and anlotinib.[17] Endostar is a novel recombinant human vascular endostatin and has been examined in phase I, II and III clinical trials. It is determined as a safe and effective anti-tumor drug and has been widely used in chemotherapy regimens for different types of human cancer.[18],[19] Endostar, as a kind of recombinant endostatin, is also involved in the inhibition of angiogenesis, which is dependent on the regulation of endothelial cell biological function.[20]

According to the clinical research, it has been found that the routine infusion of endostar could significantly improve the QOL of patients with advanced malignancies, and the adverse effects and tolerance of this drug are acceptable.[16] In view of the high safety and efficacy of endostar combined with first-line chemotherapy for the treatment of advanced malignant tumors, some researchers have focused on the clinical response of endostar combined with second-line chemotherapy.[21] In addition, since the drug tolerance and progression of diseases, the clinical response of second-line chemotherapy is not as effective as the first-line treatment in patients with advanced malignancies.[22] The combination of endostar and second-line chemotherapy remarkably improves the prognosis of these patients.[23] In a study by Yang et al.[24] revealed that endostar continuous intravenous infusion combined with S-1 and oxaliplatin chemotherapy could significantly improve the clinical efficacy in the treatment of liver metastasis from gastric cancer. Another study by Wang et al.[16] also found that the combination of endostar and chemotherapy could improve the efficacy and toxicities in advanced thymoma and thymic carcinoma.

According to the manufacturer's instruction, endostar is added to 250-500 mL normal saline, and then given as an injection through intravenous drip with a uniform rate for 3-4 hours. In clinical practices, there are some other drug delivery methods in addition to the traditional intravenous drip. For instance, Du et al. demonstrated that GX10 conjugated poly (lactic acid) nanoparticles encapsulating endostar could be used to efficiently improve the therapeutic efficacy in the treatment of colorectal cancer.[25] Jain et al. have put forward a new concept of normalization of tumor vascular based on the anti-angiogenesis therapy, leading to reduced number of blood vessels and decline of interstitial pressure, which contribute to the delivery of oxygen and drugs to tumor cells.[26] Thus, it is considered that the efficient effect of chemotherapy would be better exerted for long time by changing the infusion method to a continuous pumping. A study scheduled by Yao et al. revealed that continuous endovenous administration of endostar in locally advanced or metastatic lung squamous cell carcinoma led to less hemoptysis, less treatment time and lower costs compared with the traditional drip intravenous administration of endostar.[27] To further improve the clinical response of the second-line chemotherapy, the current study aimed to investigate the effect of different administration of endostar combined with second-line chemotherapy in the patients with advanced malignancies.

In the present study, 98 patients diagnosed with advanced malignancies were included, and were divided into the DE group, in which the patients received traditional intravenous drip of endostar, and the CE group, in which the patients underwent short time of intravenous drip and then received continuous pumping of endostar by using an automatic drug infusion pump. The therapeutic efficacy, QOL and toxicity after the treatment were evaluated. The evaluation results showed that the RR and DCR of CE and DE groups were separately 32.7% versus 28.6% and 69.4% versus 67.3%, respectively, which were consistent with the data in previous studies, which also found the improved therapeutic efficacy by continuous pumping of endostar in human malignancies.[28] Thus, we considered that the infusion sequenced continuous pumping of endostar combined with second-line chemotherapy had a better clinical response. It is generously considered that the improvement of QOL is one of the most important ultimate goal in the treatment of advanced malignancies.[29] The data in this study showed that the QOL of both the CE and DE groups were improved. Thus, the QOL of the patients with advanced malignancies, especially the weak or elderly patients, can be ameliorated by receiving combined therapy with endostar and chemotherapy.

In addition to the therapeutic efficacy, the adverse effects of the administration methods of endostar were also assessed. The toxicity of chemotherapy drugs often lead to unbearable suffering and torture, even though the targeted therapy drugs also caused some special toxicities, such as the rashes and diarrhea caused by gefitinib, allergic reactions and cardiotoxicity caused by trastuzumab, and hand and foot skin reactions and bleeding by sorafenib.[30] In our study, we found that major toxicity reactions of endostar combined with chemotherapy included leukopenia, thrombocytopenia, nausea and vomiting, diarrhea and hepatic function damage. The patients with leukopenia received chemotherapy including taxol and irinotecan, the cases with thrombocytopenia received gemcitabine, and most of the patients with diarrhea underwent fluorouracil or irinotecan treatment. Thus, the toxicities in this study were mainly caused by chemotherapy, but not the endostar. According to the previous research, endostar treatment leads to adverse cardiac events with the rate of 5.5-13.1%, including myocardial ischemia, electrocardiographic changes and arrhythmia.[31] In this study, we observed that one patient with pancreatic cancer developed palpitation discomfort and tachycardia in the CE group, and 2 patients showed second degree hypertension in the DE group. The adverse cardiac events in the CE group were relieved after slow pumping, and the hypertension in the DE group was successfully controlled using antihypertensive drugs. Collectively, we considered that the toxicity of endostar combined with chemotherapy could be acceptable for the patients with advanced malignancies.

Among all the patients enrolled in this study, lung cancer cases accounted for the largest proportion. Endostar is widely used in lung cancer treatment and firstly applied as adjuvant method in the chemotherapy of advanced non-small cell lung cancer. Thus, this study further analyzed the difference between CE and DE groups in patients with lung or non-lung malignancies. However, there were still no statistical difference between the two administration methods of endostar in lung or other malignancies, which were consistent with the data in all the enrolled patients. Moreover, no obvious difference in the therapeutic efficacy and adverse effects was found between lung and non-lung malignancies. Vascular remodeling is a common characteristic of various human malignancies.[32] Thus, in theory, endostar could be used for the treatment of all types of human cancer. Our analysis results gave evidence for endostar to treat different types of malignancy, but the result accuracy might be limited by the small sample size, indicating that further studies with larger research cohort are needed.

In conclusion, the combination of endostar and chemotherapy can improve the therapeutic efficacy and quality of life in the patients with advanced malignancies. Endostar plays a critical role in adjuvant chemotherapy with no increase of toxic side effect. Compared with the traditional intravenous drip method, the impact infusion followed by continuous pumping of endostar has no difference in clinical efficacy and adverse effects.

Ethics approval and consent to participate

This study was performed with the approval of the Ethics Committee of Dongying People's Hospital, and the written informed consent was obtained from each of the participant before the treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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