Recombinant Human Endostatin Research Articles

Study of Recombinant Human Endostatin Combined With Temozolomide and Irinotecan in Recurrent Gliomas

Study of Recombinant Human Endostatin Combined With Temozolomide and Irinotecan in Recurrent Gliomas

TSP-1 as a novel biological marker of tumor vasculature normalization in colon carcinoma induced by Endostar.

Blood vessels in tumors often exhibit abnormal morphology and function, which promotes the growth, metastasis and resistance of tumors to conventional therapies. Therefore, vascular normalization is an emerging strategy to enhance the effectiveness of radiotherapy and chemotherapy when used in combination; however, there is a lack of evidence regarding the optimal schedule for the co-administration of anti-angiogenic and chemotherapeutic drugs. Scheduling treatment is important as the period for normalization is transient, also known as the ‘time window’; however, no biomarker has been identified to detect this window. In the present study, recombinant human endostatin (rhES) was employed as an anti-angiogenic agent in xenograft tumor tissue in mice. Following rhES or control (saline) treatment, the density and integrity of tumor vessels were detected by immunofluorescence staining for cluster of differentiation 31 and α-smooth muscle actin; the level of hypoxia in tumor tissue was examined by immunohistochemistry with pimonidazole; the necrotic area was evaluated by hematoxylin and eosin staining; and the level of thrombospondin-1 (TSP-1) in plasma was tested by ELISA. The Cell Counting Kit-8 assay was also used to evaluate the effect of rhES on the proliferation of colon carcinoma SW620 cells. A ‘time window’ normalized vasculature was determined between day 4 and 6 following rhES treatment, and accompanied by a decrease in hypoxia in tumor tissue. Decreasing plasma TSP-1 levels were consistent with changes in vascular morphology and hypoxia, which exhibited features of normalization. In addition, rhES had no effect on the proliferation of SW620 cells, suggesting that the reduction in TSP-1 was associated with increased oxygen content during vascular normalization, rather than inhibited cell proliferation. In conclusion, TSP-1 may be a potential biomarker for predicting the normalization window of colon cancer vessels.

Combining therapy with recombinant human endostatin and cytotoxic agents for recurrent disseminated glioblastoma: a retrospective study

BackgroundThe optimal chemotherapeutics of recurrent disseminated glioblastoma has yet to be determined. We analyzed the efficacy and safety of recombinant human endostatin (rh-ES) combined with temozolomide and irinotecan in patients with recurrent disseminated glioblastoma.MethodsWe retrospectively reviewed 30 adult patients with recurrent disseminated glioblastoma treated with this combination chemotherapy at Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University of China from November 2009 to August 2018. Temozolomide was given orally at 200 mg/m2 daily for 5 days and rh-ES was administrated 15 mg/d daily for 14 days of each 28-day treatment cycle. Irinotecan was given intravenously every 2 weeks on a 28-day cycle at 340 mg/m2 or 125 mg/m2 depending on antiepileptic drugs. Primary endpoint was progression-free survival (PFS) at 6 months (6 m-PFS).ResultsThe 6 m-PFS was 23.3%. The median PFS was 3.2 months. The overall survival rate (OS) at 12 months was 28.6%. The median OS was 6.9 months. Six out of 30 (20%) patients demonstrated partial radiographic response and 11 (36.7%) remained stable. The PFS of the 6 patients who got partial response was 5.8, 6.3, 6.9, 13.6, 15.8 and 16.6 months, respectively, and the median time interval of first response was 4 (range, 2.0–6.6) months. The most common adverse events were hematologic toxicities and gastrointestinal effects. The Grade ≥ 3 adverse event was hematologic toxicities. The adverse events were manageable.ConclusionsRh-ES, in combination with cytotoxic drugs, was an alternative effective regimen with manageable toxicities in treatment of recurrent disseminated glioblastoma.

Intraspinal metastasis of alveolar rhabdomyosarcoma: A case report

This paper reported a case of cervical intraspinal metastasis of alveolar rhabdomyosarcoma (ARMS). The clinicopathological features, surgical treatment, chemotherapy and prognosis were introduced and the current literature was reviewed. The diagnosis, differential diagnosis, treatment, molecular features and prognosis of the disease were comprehensively analyzed to improve clinicians' knowledge of this rare disease. The primary lesion appeared about 1 year ago which was painless mass of left hand whose size was about 2 cm×2 cm. After conservative treatment, the mass gradually enlarged and the mass was resected. Postoperative pathology revealed embryonic rhabdomyosarcoma. Postoperative chemotherapy with recombinant human endostatin, liposomal doxorubicin and ifosfamide was performed. The left neck mass was found about 3 months ago, and then the left neck mass was resected under general anesthesia. Postoperative pathological examination showed small round cell malignant tumors. Severe left upper extremity pain began about 2 weeks ago with nocturnal pain and supine pain. Non-steroidal anti-inflammatory drugs were needed to relieve pain which was accompanied by numbness and weakness of the left upper extremity. MRI showed a intraspinal tumor at C5. The left thumb and index finger were absent. Hypoesthesia, muscle atrophy and hypotonia of the left upper limb were confirmed. The muscle strength of biceps brachii and deltoid muscle of the left upper limb was grade 0, the muscle strength of extensor carpus and interphalangeal muscle was grade II, the muscle strength of intrinsic muscles of hands was grade I. The tendon reflex of the left upper limb disappeared. Intraspinal mass was removed and the pain was relieved. But there was no significant change in the muscle strength of the left upper limb. Pathological examination revealed small cell malignancies which were poorly differentiated with diffuse patchy distribution and disordered arrangement. The tumor cells had round, oval or irregular nuclei, and few cytoplasms were positive for Myogenin and MyoD1. FISH test of FOXO1 gene was positive. More than 50% of nuclei showed redgreen signal separation, and the distance between redgreen signals was larger than double diameter of the signal points, which supported ARMS. Total resection of intraspinal tumors was achieved and postoperative chemotherapy was admitted. But intraspinal disseminated metastasis occurred rapidly. ARMS was rare, aggressive tumor with poor prognosis. Subdural metastasis was rare. Correct diagnosis and classification can be made only with help of modern molecular diagnostic methods, which is effective to guide the treatment.

The Construction of a Radiation-Induced Brain Injury Model and Preliminary Study on the Effect of Human Recombinant Endostatin in Treating Radiation-Induced Brain Injury.

BackgroundThe aim of this study was to construct a radiation-induced brain injury (RBI) model and assess the effects of human recombinant endostatin in the treatment of RBI.Material/MethodsIn this study, the RBI model was used. Real-time quantitative polymerase chain reaction, immunohistochemistry, hematoxylin and eosin staining were conducted to detect the mRNA and protein expression of vascular endothelial growth factor (VEGF) and assess the effects of human recombinant endostatin in the treatment of RBI.ResultsIn this study, we successfully constructed a RBI model. VEGF mRNA expression was decreased after human recombinant endostatin treatment; however, VEGF protein secretion was increased in brain endothelial cells, and the secretion of VEGF protein was decreased in glial cells and nerve cells. Body weight changes indicated that human recombinant endostatin can increase the risk of weight loss. Brain water content results showed that human recombinant endostatin might aggravate cerebral edema in the acute stage of RBI, but it can reduce the progression of cerebral edema in the early delayed stage. Survival analysis showed that human recombinant endostatin improved the survival rate only in the early stage of RBI.ConclusionsRadiation can induce vasogenic edema and is associated with the RBI occurrence and development. VEGF protein is highly relevant to the induction of edema and thrombosis in the acute phase of RBI and in the early delayed phase of RBI, including vascular repair and regeneration, thrombus ablation and other events. Human recombinant endostatin can reduce the progression of cerebral edema during the early onset of RBI.

PDTC-17. A RETROSPECTIVE STUDY OF RECOMBINANT HUMAN ENDOSTATIN COMBINED WITH CARBOPLATIN AND VINCRISTINE FOR PEDIATRIC LOW-GRADE GLIOMAS

Abstract OBJECTIVE To analyze the response and toxicity of recombinant human endostatin (rh-ES) combined with carboplatin and vincristine (CV) chemotherapy regimen for pediatric low-grade gliomas (LGGs). METHODS Retrospectively reviewed the clinical data of the patients who were received rh-ES with CV chemotherapy regimen at Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University from October 2014 to October 2018. Carboplatin was administrated at a dose of 200~300 mg/m2 and the vincristine dose was 1.5 mg/m2 (maximum dose: 2 mg). Rh-ES was administrated 15 mg/d, daily for 14 days of each 28-day treatment cycle. RESULTS 26 patients were enrolled. By the time of the last follow-up, 14 patients had completed the treatment and 6 were still in treatment. Of the 26 patients, 14 had partial response (PR), 12 had stable disease (SD), and the objective response rate (ORR) was 53.8%. Of the 14 patients who completed all the treatment, 10 achieved PR, 4 got SD, and the ORR was 71.4%. The median time interval to response was 3.3 months (range 2–12.6 months). The main adverse reactions were myelosuppression and allergy to carboplatin. Three patients were terminated in the consolidation phase due to adverse reactions. CONCLUSIONS The rh-ES combined with CV regimen is effective in the treatment of pediatric LGGs and had a rapid time interval to response, which is conducive to the rapid relief of brain stem or visual function damage.

Pharmacokinetics of PEGylated recombinant human endostatin in rhesus monkeys

To investigate the pharmacokinetics of PEGylated recombinant human endostatin (M2ES) in rhesus monkey. M2ES was administered to rhesus monkeys by intravenous bolus injection, and serum M2ES concentration was determined by a self-developed ELISA assay. Pharmacokinetic parameters were calculated using a non-compartmental model of WinNonlin V2.1A software. The standard curve of self-developed ELISA assay was fitted by four-parameter method. The limit of detection (LOD) and LOQ were 0.3050 ng/mL and 0.9140 ng/mL, respectively. Following IV infusions of M2ES at 0.3, 1, and 3 mg/kg in rhesus monkeys, the serum M2ES concentration-time curve was fitted with a non-compartment model. The pharmacokinetic parameters were evaluated as follows: Terminal elimination half-life (T1/2) of M2ES were 3.30 ± 0.70, 29.50 ± 18.80 and 24.60 ± 8.90 h. Systemic clearance (CLsys) of M2ES were 339.60 ± 66.30, 161.40 ± 18.20 and 260.10 ± 43.70 mL/h/kg. AUC(0-∞) values of M2ES were 909.30 ± 199.60, 6251.00 ± 739.60 and 11758.00 ± 2010.10 ng∙h/mL. The dosage was positively correlated with AUC, and the correlation coefficient r2 = 0.9327. Self-developed ELISA assay could meet the requirements of serum M2ES concentration detection. PEGylation modification substantially expands the circulation time of recombinant human endostatin and effectively improves its pharmacokinetic behavior.

P14.82 Combining therapy with recombinant human endostatin and cytotoxic agents for recurrent disseminated glioblastoma: a retrospective study

Abstract BACKGROUND The optimal chemotherapeutics of recurrent disseminated glioblastoma has yet to be determined. We analyzed the efficacy and safety of temozolomide (TMZ) and irinotecan (CPT-11) combined with recombinant human endostatin (rh-ES) in patients with recurrent disseminated glioblastoma. MATERIAL AND METHODS We retrospectively reviewed 30 adult patients with recurrent disseminated glioblastoma treated with this combination chemotherapy from November 2009 to August 2018. TMZ was given orally 200mg/m2 for 5 days in each 28-day cycle (5/28d). CPT-11 was administrated 125 mg/m2 for patients not receiving enzyme-inducing antiepileptic drugs (EIAEDs) or 340 mg/m2 for patients receiving EIAEDs on day 1 and day 15; rh-ES was administrated 15 mg/d, daily for 14 days of each 28-day treatment cycle. RESULTS Primary endpoint was progression-free survival at 6 months (6m-PFS). The 6m-PFS was 23.3%. The median PFS was 3.2 months. The overall survival rate (OS) at 12 months was 28.6%. The median OS was 6.9 months. Six out of 30 (20%) patients demonstrated partial radiographic response and 11/30 (36.7%) remained stable. The PFS of the 6 patients who got partial response was 5.8, 6.3, 6.9, 13.6, 15.8, 16.6 months, respectively, and the median time interval of first response was 4 (range, 2.0–6.6) months. The most common adverse events were hematologic toxicity and gastrointestinal reactions. The Grade ≥3 adverse event was mainly hematologic toxicity. The adverse events were manageable. CONCLUSION Rh-ES, in combination with cytotoxic drugs, was an alternative effective regimen with manageable toxicity in treatment of recurrent disseminated glioblastoma.

Effect of XELOX regimens plus combination of endostar and thalidamide as first-line treatment for advanced colorectal cancer

Objective To investigate the efficacy and safety of two antiangiogenic drugs (recombinant human endostatin endostar and thalidomide) combined with capecitabine and oxaliplatin(XELOX) regimens in the treatment of advanced colorectal cancer. Methods From January 2015 to May 2018, 40 patients of advanced metastatic colorectal cancer with organ metastasis and non-resectable were selected from the first people′s hospital of Hefei and Anhui Provincial Hospital, and they were randomly divided into treatment and control group, with 20 cases in each group.The treatment group received intravenous infusion (IV) of endostar for continuous 7 days (day 1~7) combined with oral administration of thalidomide for continuous 14 days (day 1~14) plus XELOX regimens after the fifth dose of endostar (day 6~19), and the control group was treated with XELOX regimen (day6~19). Results The objective response rate (ORR) was 50% (10/20) and 20% (4/20) respectively (χ2=3.956, P 0.05), and the median progression free survival (mPFS) was 6.8 in both groups.There was no significant difference in Karnofsky performance score (KPS) and incidence of adverse reactions between the two groups before and after treatment (P>0.05). Conclusion Combination of endostar and thalidamide plus XELOX regimen as first-line treatment have better antitumor activity and are well-tolerated in patients with advanced colorectal cancer. Key words: Recombinant human endostatin; Endostar; Thalidomide; Advanced colorectal cancer

Biophysical and biological characterization of PEGylated recombinant human endostatin.

Recombinant human endostatin (MES), showing potent inhibition on angiogenesis and tumour growth, has great potential as a therapeutic agent for tumours. The aim of this study was to evaluate the biophysical and biological characterization of PEGylated recombinant human endostatin (M2 ES). Recombinant human endostatin was mono-PEGylated by conjugation with methoxy polyethylene glycol aldehyde (mPEG-ALD), and the modification site was identified by digested peptide mapping and matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS). The purity was assessed by SDS-PAGE, high-performance liquid chromatography (HPLC), and capillary zone electrophoresis. The physicochemical property was analyzed through fluorescence spectroscopy, and circular dichroism. The bioactivity and anti-tumour efficacy of M2 ES were evaluated using an in vitro endothelial cell migration model and a null-mouse xenograft model of a prostatic cancer, respectively. M2 ES molecules contain a single 20kDa mPEG-ALD molecule conjugated at the N-terminal portion of MES. The purity of M2 ES was greater than 98%. The physicochemical analysis demonstrated that PEGylation does not change the secondary and tertiary structure of MES. Notably, M2 ES retards endothelial cell migration and tumour growth when compared to control group. These biophysical and biological characterization study data contribute to the initiation of the ongoing clinical study.

A phase II multicenter randomized controlled trial to compare standard chemoradiation with or without recombinant human endostatin injection (Endostar) therapy for the treatment of locally advanced nasopharyngeal carcinoma: Long-term outcomes update

Purpose: This study aimed to observe the feasibility and safety of addition of recombinant human endostatin injection to standard chemoradiation for the locally advanced nasopharyngeal carcinoma. Current follow-up results updated long-term efficacy and late toxicity of the trial.Methods: Between July 2012 and December 2013, we enrolled 114 patients that are older than 18 years with stage Ⅲ-Ⅳb nasopharyngeal carcinoma from 3 centers in Guizhou, China. Fifty six patients who received standard chemoradiation combined with recombinant human endostatin injection (Endostar) were included in the study group. Another 58 patients were randomly assigned to the control group without using Endostar. Patients in both groups received the same 2 cycles of induction chemotherapy (Docetaxel 75 mg/m2, cisplatin 80 mg/m2), followed by 2 cycles of concurrent intensity-modulated radiation therapy with cisplatin (DDP; 80 mg/m2 on days 1 and 22). The patients in the experimental group received 2 cycles Endostar (7.5 mg/m2 d8-d21 during induction chemotherapy and d1-d14 during concurrent chemoradiation).Results: There were no significant differences of toxicities between the 2 groups. Chemotherapy and radiotherapy compliance between the 2 groups was similar. No hemorrhage and coagulation dysfunction in the experimental group were observed. There was a median follow-up of 67.1 months. Comparing the short-time effect of 3 months to the completion of chemoradiotherapy, there was a little higher objective response rate in the experimental group. Compared with the control group, the experimental group improved in the complete remission rate of cervical lymph node metastasis (91.1% vs 72.4%, χ2 = 3.897, P = 0.048). However, there was no significant difference in the curative effect of nasopharyngeal lesions between the 2 groups. (78.6% vs 74.1%, χ2 = 0.310, P = 0.578). The 5-year overall survival, progression-free of survival, metastasis-free survival, and locoregional failure-free survival rates in the 2 groups were 69.6%, 67.8%, 78.75, and 83.0%, respectively, for the experimental group, these rates were 73.2%, 80.1%, 81.7%, and 91.0%, respectively, and for the control group, no significant difference was found (P > 0.05).Conclusions: Patients show good tolerance and compliance with a manageable toxicity profile to the regimen of chemoradiation plus Endostar. There was a little higher objective response rate in the study group. A phase 3 randomized study is needed to substantiate our findings.

Whole-tumor perfusion CT using texture analysis in unresectable stage IIIA/B non-small cell lung cancer treated with recombinant human endostatin.

To observe the dynamic changes of blood perfusion with whole-tumor computed tomography (CT) perfusion imaging using texture analysis in patients with unresectable stage IIIA/B non-small cell lung cancer (NSCLC) treated with recombinant human endostatin (Endostar). This phase II clinical trial recruited 11 patients diagnosed with stage IIIA/B NSCLC. Histological examination prior to treatment revealed squamous cell carcinoma in 4 cases and adenocarcinoma in 7 cases. All patients underwent contrast-enhanced perfusion CT at baseline and a second CT scan 1 week after treatment initiation with Endostar. CT perfusion images including blood flow (BF), blood volume (BV), and permeability (PMB) were imported into OmniKinetics software to quantitatively assess the texture features. Skewness, kurtosis, and entropy were calculated at baseline and after anti-angiogenic therapy. Changes in tumor were analyzed using Wilcoxon signed-rank test. The association of parameters with survival was evaluated using Cox proportional hazards regression model. There were no statistical differences in the mean values of BF, BV, and PMB before and after treatment (P=0.594, 0.477 and 0.328, respectively). The skewness on BF images demonstrated significant differences at baseline and after treatment (0.6±2.7 vs. 1.0±2.6, P=0.010), while skewness of BV and PMB showed no significant variation (P=0.477 and 0.213, respectively). The kurtosis and entropy for BF, BV and PMB showed no significant differences (all P>0.05). In adenocarcinoma, the mean BF showed no significant differences at baseline and after treatment (76.5±25.7 vs. 101.2±46.4, P=0.398), while skewness for BF was significantly higher after treatment than at baseline (-0.19±3.3 vs. 0.59±3.2, P=0.028). No significant associations were found between perfusion CT imaging parameters and progression-free survival. These results suggested that blood perfusion showed improvement with whole-tumor perfusion CT using texture analysis in patients with stage IIIA/B NSCLC treated by Endostar.

Meta-analysis of rhES combined with TACE versus TACE alone for hepatocellular carcinoma: short-term therapeutic efficacy and subgroup analysis

Objective To evaluate the short-term efficacy of recombinant human endostatin (rhES) combined with transcatheter arterial chemoembolization (TACE) versus TACE alone for intermediate and advanced primary hepatic carcinoma. Methods The relevant controlled trials about rhES plus TACE versus TACE alone in the treatment of intermediate and advanced primary hepatic carcinoma were retrieved from the databases of PubMed, Elsevier, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wan Fang Database. The retrieval time limited was from the database construction to January 2018, and the Meta-analysis was performed by using RevMan5.3 software. Results 18 controlled trials were included in this Meta-analysis. There were 948 cases, of which 522 cases in rhES plus TACE group and 426 cases in TACE alone group. According to the usage of rhES, the trials were further divided into intrahepatic arterial embolization group, intrahepatic arterial pump group, and intravenous infusion group. rhES plus TACE had an overall advantage over TACE alone in terms of objective response rate (ORR), and the difference was statistically significant (RR=1.59, 95%CI: 1.41~1.79, P<0.05). And the ORR of rhES plus TACE in intrahepatic arterial embolization group, intrahepatic arterial pump group, intravenous infusion group was better than that of TACE alone (Intrahepatic arterial embolization group RR=1.63, 95%CI: 1.36~1.95; Intrahepatic arterial pump group RR=1.49, 95%CI: 1.24~1.79; Intravenous infusion group RR=1.69, 95%CI: 1.22~2.34), and the difference was statistically significant (P<0.05). The subgroups analysis of anthracycline and platinum also showed that ORR in rhES plus TACE patients was better than that in TACE patients alone. Conclusion The short-term efficacy of rhES plus TACE in the treatment of intermediate and advanced primary hepatic carcinoma was better than that of TACE alone, and the same results were obtained by subgroup analysis. Key words: Liver neoplasms; Chemoembolization, therapeutic; Meta-analysis; Recombinant human endostatin

A real-world study of recombinant human endostatin continuous intravenous infusion combined with chemotherapy in the treatment of advanced mucosal melanoma.

e21019 Background: There is no standard treatment for patients with advanced mucosal melanoma (AMM). Recombinant human endostatin (Endostar) combined with chemotherapy had been showed to improve the efficacy of advanced melanoma. This real world study was aimed to observe the efficacy and safety of endostar continuous intravenous infusion (Civ) combined with chemotherapy in patients with AMM. Methods: 23 patients with AMM treated with endostar plus dacarbazine or temozolomide plus cisplatin between April 2017 and December 2018 were collected. Endostar was given 105mg/m2 Civ168h (unlike the usual use of 7.5mg/m2/d d1-14) . 5 patients with local advanced disease received concurrent radiotherapy. Results: There were 11 males (48%) and 12 females (52%), with a median age of 58 years (30-72 years). Primary lesions were located in the nasal cavity and paranasal sinuses in 9 cases (39%), anorectum in 9 cases (39%), vagina in 3 cases (13%), esophagus in 1 case (4%), and choroid in 1 case (4%). There were 7 patients with local advanced disease and 16 patients with metastatic disease. 1 patient received prior anti-PD1 therapy, 1 patient received prior chemotherapy, the other 19 patients received no prior systemic therapy. A total of 21 patients underwent gene detection, there were 2 patients (10%) with BRAF mutation (one with V600E mutation, one with G606E mutation), 7 patients (33%) with NRAS mutation (3 with exon 2 mutation, 4 with exon 3 mutation), and 1 patient (5%) with KIT exon 11 mutation. Overall, 4 patients (13%) had CR, 4 patients (22%) had PR, 10 patients had SD (43%), and 5 patients (22%) had PD, resulting in a RR of 35% and a DCR of 78%. The 4 patients with CR were with localized disease and received concurrent radiotherapy. The RR were 44%, 33%, 33%, 0% and 0%, and the DCR were 100%, 67%, 67%, 0%, and 100% in patients with melanoma of the nasal cavity, anorectum, vagina, esophagus and choroid respectively. The median PFS was 7.5 months (95% CI: 1.0-14.0months). The median OS was 14.7 months (95% CI: 5.0-24.4months). Grade III/IV adverse events were leucopenia (13%), thrombocytopenia (13%), anemia (4%), nausea and vomiting (4%), elevated transaminase (4%), nasal hemorrhage (4%) and intestinal obstruction (4%). Conclusions: Endostar combined with chemotherapy is effective and safe in the treatment of AMM, especially for patients with melanoma of the nasal cavity and paranasal sinuses. For mucosal melanoma patients with local advanced disease, concurrent chemoradiotherapy may be a good choice. It deserves further study.

Interim report on CIV recombinant human endostatin in combination with docetaxel/cisplatin (DP)) in comparison to DP in the first-line treatment of phase IIIb/IV squamous-cell NSCLC (JSLCG-001): A multicenter, open-label, randomized phase III controlled study (NCT: 02513342).

e20541 Background: Endostar registration Phase III and post-marketing Phase IV clinical study had confirmed Endostar in combination with Platinum double drugs can improve the NSCLC patients’ outcomes of ORR, PFS and OS. However, It influenced on the patients’ compliance for Endostar day 1-14 intravenous infusion (I.V). Endostar day 1-7 continuous intravenous infusion (CIV) can have the compliance improved obviously. So, we carried out this phase III trial to confirm the efficacy and safety of CIV Endostar in combination with DP regimen for first line treatment of phase IIIB/IV squamous-cell NSCLC. Methods: The planed 188 patients with phase IIIB/IV squamous-cell NSCLC without the history of chemotherapy would be randomly assigned to receive Endostar and DP (Endostar, 15mg/m2/d, civ, d1-7; Docetaxel, 60mg/m2/d, iv, d4; Cisplatin, 75mg/m2/d, iv, d4), or DP (Docetaxel, 60mg/m2/d, iv, d1; Cisplatin, 75mg/m2/d, iv, d1). The cycle was every 3 weeks and 4-6 cycles would be needed in total in each groupl. After 4-6 cycles, CIV Endostar in Endostar+DP group would maintain till PD. The primary end point was PFS. Results: The interim data from 94 cases was included in the analysis. The median PFS in Endostar+DP group was 6.8 months ( 95% CI, 4.0-9.6) versus 3.1 months ( 95% CI, 2.9-3.4) in DP group ( P = 0.024 ). The response rate was 33% in Endostar+DP versus 31% in DP group ( P = 0.838 ). The AEs in each group was comparable. No unexpected AEs in Endostar+DP was found. Conclusions: This preliminary result showed Endostar in combination with DP improved PFS significantly (P = 0.024). Among patients with advanced, previously untreated squamous-cell NSCLC, the longer PFS was related to CIV Endostar on the duration of maintenance. Clinical trial information: NCT02513342.

Successful treatment of brain radiation necrosis resulting from triple-negative breast cancer with Endostar and short-term hyperbaric oxygen therapy: a case report.

Radiation necrosis (RN) is one of the complications of radiotherapy. Angiogenesis is a key factor underlying the development of RN, and Endostar, a safe and well-tolerated recombinant human endostatin, has been used to treat a variety of tumors. Thus far, however, no definitive reports on the use of Endostar for RN treatment have been reported. Here, we report the successful treatment of one patient with symptomatic brain radiation necrosis (BRN) using Endostar in combination with short-term hyperbaric oxygen therapy (HBO). One triple-negative breast cancer patient with recurrent brain metastatic lesions after standard chemoradiotherapy was referred to a specialty center outside our hospital for stereotaxic radiotherapy. Two months later, the patient showed deteriorating clinical symptoms, and magnetic resonance imaging (MRI) showed radiation necrosis with significant surrounding edema. The patient had a poor response to mannitol and steroids. After diagnosing this patient with BRN, we began short-term HBO therapy and intravenously administered Endostar for 4 cycles. The patient responded well to this strategy, showing rapidly and dramatically improved MRI findings and clinical symptoms. No tumor progression was observed at 10 months after treatment. Endostar in combination with short-term HBO therapy had marked effects on symptomatic BRN. However, additional large-scale, double-blinded, controlled trials are necessary to confirm the clinical effect of Endostar in combination with a short-term HBO therapy regimen on BRN.

Quality, bioactivity study, and preclinical acute toxicity, safety pharmacology evaluation of PEGylated recombinant human endostatin (M2 ES).

Endostar, a potent endogenous antiangiogenic factor, is wildly used in clinics. However, it was easily degraded by enzymes and rapidly cleared by the kidneys. To overcome these shortcomings, PEGylated recombinant human endostatin was developed. In this study, the purity of M2 ES was evaluated by silver stain and reversed-phase high-performance liquid chromatography. Ultraviolet spectrum was used to examine the structural of M2 ES and endostar. The bioactivity and antitumor efficacy of M2 ES were evaluated using an in vitro endothelial cell migration model and athymic nude mouse xenograft model of a heterogeneous lung adenocarcinoma, respectively. A preclinical study was performed to evaluate the acute toxicity and safety pharmacology in rhesus monkeys. The purity of M2 ES was more than 98%; PEG modification has no effect on endostatin structure. Compared with the control group, M2 ES dramatically retards endothelial cell migration and tumor growth. After intravenous (IV) infusions of M2 ES at a dose level of three and 75 mg/kg in rhesus monkeys, there was no observable serious adverse event in both acute toxicity and safety pharmacology study. On the basis of the quality and bioactivity study data of M2 ES and the absence of serious side effect in rhesus monkeys, M2 ES was authorized to initiate a phase I clinical trial.

P118 Continuous Intravenous Recombinant Human Endostatin Pump Combined with SBRT for Elderly Patients with Early Stage NSCLC

P118 Continuous Intravenous Recombinant Human Endostatin Pump Combined with SBRT for Elderly Patients with Early Stage NSCLC

Clinical evaluation of vascular normalization induced by recombinant human endostatin in nasopharyngeal carcinoma via dynamic contrast-enhanced ultrasonography.

BackgroundThe present study confirmed the presence and exact range of “vascular normalization window” induced by recombinant human endostatin (RHES) in patients with nasopharyngeal carcinoma (NPC) by analyzing the variation of dynamic contrast-enhanced ultrasonography (DCE-US) quantitative parameters. Also, the clinical application of DCE-US in the evaluation of vascular normalization was assessed.Materials and methodsA total of 30 previously untreated patients with stage III–IVA NPC were enrolled in the present study and were randomly but equally divided into RHES (endostar [ES]) and normal saline (NS) groups. The patients in the ES group were administered RHES intravenously, while the patients in the NS group were administered normal saline daily for 5 days prior to intensity modulated radiotherapy coupled with concurrent chemotherapy. All patients underwent DCE-US on the day before the administration and on days 3 and 5 subsequently. The Audio Video Interleave of each DCE-US examination was analyzed quantitatively using the CHI-Q software. Several parameters were investigated, such as peak intensity (PI), time to peak (TTP), and mean transit time (MTT).ResultsThe PI, TTP, and MTT differed significantly at the three time points in the ES group (all P<0.001) but not in the NS group (all P>0.05). In the ES group, PI increased and subsequently decreased, whereas TTP, as well as MTT, lessened initially and then increased within the 5 days after administration of RHES. The maximum value of PI and the minimum value of TTP, as well as MTT, occurred on day 3 (all P<0.05). Furthermore, the values of PI, TTP, and MTT were similar prior to the administration of RHES in both groups (all P>0.05). However, the PI of the ES group was significantly higher (P<0.05), whereas the TTP and the MTT were significantly lower following administration of RHES (all P<0.05) compared with the corresponding parameters of the NS group.ConclusionDCE-US is a suitable method for the clinical evaluation of vascular normalization induced by antiangiogenic agents. The “vascular normalization window” induced by RHES occurs in patients with NPC, and the exact range is within about 5 days post-administration, which contributes towards optimizing the modality of RHES combined with radiotherapy and chemotherapy for NPC patients.

Rh-endostatin Concomitant with Chemotherapy Versus Single Agent Chemotherapy for Treating Soft Tissue and Bone Sarcomas: A Systematic Review and Meta-Analysis.

Endostar (recombinant human endostatin (rh-endostatin)), a 20-kDa proteolytic fragment of collagen XVIII, was approved for the treatment of non-small cell lung cancer (NSCLC). Recently, several studies have evaluated the efficacy of rh-endostatin combined with chemotherapy in the treatment of bone and soft tissue sarcomas. Here, we conducted a systematic review and meta-analysis to assess available evidence.Methods:Pubmed, Embase, Web of Sciences, the Cochrane Library and two Chinese literature databases (CNKI, WanFang) were systematically searched till May 20, 2018. Randomized controlled trials (RCTs) and cohort studies which compared the outcomes of rh-endostatin combined with chemotherapy versus chemotherapy alone for treating bone sarcomas or soft tissue sarcomas were included. The primary outcome was overall survival rate (OSR). Secondary outcomes included objectiveremissionrate(ORR), clinical benefit rate (CBR), disease control rate (DCR), distant metastasis rate (DMR) and adverse effects (AEs). The methodological quality of the included studies was evaluated. Data analysis was performed by Revman 5.3 software.Results:9 studies comprising 839 patients were included. The pooled results indicated that, compared with chemotherapeutic agents alone, rh-endostatin combined group had a significant benefit in 1-year and 2-year OSR. However, there were no difference between 5-year OSR. OR, CBR and DMR were higher in rh-endostatin combined group. No significant difference was observed in the incidence of AEs.Conclusions:Rh-endostatin combined chemotherapeutic agents significantly improved clinical efficacy compared with chemotherapeutic agents alone in treating bone and soft tissue sarcomas. Moreover, combination of rh-endostatin with chemotherapy didn't increase the incidence of AEs. But more high quality RCTs with large sample size should be done in the future to confirm the conclusion.