Basement membrane product, endostatin, as a link between inflammation, coagulation and vascular permeability in COVID-19 and non-COVID-19 acute respiratory distress syndrome.

Background: Immune cell recruitment, endothelial cell barrier disruption, and platelet activation are hallmarks of lung injuries caused by COVID-19 or other insults which can result in acute respiratory distress syndrome (ARDS). Basement membrane (BM) disruption is commonly observed in ARDS, however, the role of newly generated bioactive BM fragments is mostly unknown. Here, we investigate the role of endostatin, a fragment of the BM protein collagen XVIIIα1, on ARDS associated cellular functions such as neutrophil recruitment, endothelial cell barrier integrity, and platelet aggregation in vitro. Methods: In our study we analyzed endostatin in plasma and post-mortem lung specimens of patients with COVID-19 and non-COVID-19 ARDS. Functionally, we investigated the effect of endostatin on neutrophil activation and migration, platelet aggregation, and endothelial barrier function in vitro. Additionally, we performed correlation analysis for endostatin and other critical plasma parameters. Results: We observed increased plasma levels of endostatin in our COVID-19 and non-COVID-19 ARDS cohort. Immunohistochemical staining of ARDS lung sections depicted BM disruption, alongside immunoreactivity for endostatin in proximity to immune cells, endothelial cells, and fibrinous clots. Functionally, endostatin enhanced the activity of neutrophils, and platelets, and the thrombin-induced microvascular barrier disruption. Finally, we showed a positive correlation of endostatin with soluble disease markers VE-Cadherin, c-reactive protein (CRP), fibrinogen, and interleukin (IL)-6 in our COVID-19 cohort. Conclusion: The cumulative effects of endostatin on propagating neutrophil chemotaxis, platelet aggregation, and endothelial cell barrier disruption may suggest endostatin as a link between those cellular events in ARDS pathology.

Rh-endostatin plus camrelizumab and chemotherapy in first-line treatment of advanced non-small cell lung cancer: A multicenter retrospective study.

BACKGROUND: Clinical evidence of immune checkpoint inhibitors combined with antiangiogenic drugs in patients with advanced non-small cell lung cancer (NSCLC) was limited. Recombinant human endostatin (rh-endostatin), an antiangiogenic drug, and camrelizumab, an anti-PD-1 antibody, have been approved for the treatment of advanced NSCLC in China. This study aimed to investigate the efficacy and safety of rh-endostatin plus camrelizumab and chemotherapy in the treatment of advanced NSCLC. METHODS: Eligible patients were enrolled and received camrelizumab (200 mg, day 1) every 3 weeks and continuous intravenous infusion of rh-endostatin (70 mg/day, days 1-3) and cisplatin combined with pemetrexed (for adenocarcinoma) or paclitaxel (for NSCLC other than adenocarcinoma) every 3 weeks. Primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. RESULTS: Overall, 27 patients were included, and 25 patients were eligible for efficacy evaluation. For these 25 patients, ORR was 48.15% (13/27) and DCR was 85.19% (23/27). With a median follow-up of 10.37 months, the median PFS was 8.9 (95% CI: 4.23-13.57) months. Median OS was not reached. Overall, 96.3% of patients experienced at least one treatment-related adverse event, and grade 3 TRAEs occurred in 9 (33.3%) patients. No unexpected AEs were observed. CONCLUSION: Rh-endostatin plus camrelizumab and chemotherapy showed favorable efficacy and safety profile in patients with advanced NSCLC, representing a promising treatment regimen for these patients.

The effect of endostatin on angiogenesis and osteogenesis of steroid-induced osteonecrosis of the femoral head in a rabbit model.

OBJECTIVE: This study aimed to investigate whether endostatin, a crucial anti-angiogenic factor, plays a negative role in angiogenesis and osteogenesis and aggravates the progression of osteonecrosis of the femoral head induced by steroid use in a rabbit model. METHODS: 66 New Zealand white rabbits were randomly divided into four groups: glucocorticoid model (GC) group (GC group, n = 18), glucocorticoid model and endostatin group (GC;ES group, n = 18), ES group (ES group, n = 18), and blank control group (CON group, n = 12). In the GC group, 10 µg/ kg lipopolysaccharide (LPS) was intravenously injected into the ear margin, and 24h after LPS injection, 20 mg/kg GC methylprednisolone (MPS) was injected into the gluteus muscle three times, each time at an interval of 24h. The animals of the GC;ES group were given as same treatment as the GC group, except for the addition of ES. MPS was not used in the ES group and CON group. ES group was only given ES, while the CON group was only given the same amount of normal saline. All animals successfully established models of femoral head necrosis, and then the difference among the Immunohistochemistry, Quantitative polymerase chain reaction (qPCR) analysis, Enzyme-linked immunosorbent assay, Biomechanical test, etracyclline-calcein double labeling, and Van Gieson staining indices were compared among the four groups. RESULTS: The combination of MPS and LPS was successful in establishing the femoral head necrosis model in New Zealand white rabbits. The incidence of osteonecrosis after MPS and LPS intervention was 70% (7/10), while that plus ES was 100% (10/10). At the same time, after MPS and LPS intervention, while the empty bone lacuna rate of the femoral head was significantly increased, the number of osteo- blasts was decreased. Also, the expressions of CD31 positive cells, Runx2, Osterix, COL1A1, and VEGF mRNA in the femoral head were decreased, and the levels of osteogenesis-related protein b-ALP, OCN, and angiogenic factor VEGF in the femoral head were decreased. The percentage of the trabecular bone area (%Tb.Ar), trabecular thickness (Tb.Th), trabecular number (Tb.N), labeled perimeter percent (%L.Pm), mineral apposition rate (MAR), and bone formation rate (BFR/BS) in the femoral head after MPs and LPS intervention detected by tetracycline calcein double labeling and Van Gieson staining decreased significantly, except trabecular separation (Tb.Sp) increased significantly. The compressive strength (CS), elastic modulus (EM), and strain energy (SE) of the femoral head examed by biomechanical measurement decreased significantly. All the above changes were more obvious after adding ES intervention. ES mRNA in the femoral head was undifferentiated and increased in the GC, ES, and GC;ES group compared with group CON. CONCLUSION: This study has revealed that ES can inhibit angiogenesis and osteogenesis in the femoral head and aggravate the occurrence and development of femoral head necrosis. Thus, antiangiogenic factors may play an important role in the pathogenesis of ONFH.

Intraperitoneal infusion of recombinant human endostatin improves prognosis in gastric cancer ascites.

Objective: To investigate the efficacy and safety of intraperitoneal administration of recombinant human endostatin in gastric cancer with malignant ascites. Methods: Clinical data of 90 patients (37 in an Endostar® combined with cisplatin group and 53 in a cisplatin group) were retrospectively analyzed. The primary end point was overall survival, and the secondary end points were objective response rate (ORR), disease control rate (DCR) and so on. Results: Median overall survival was longer in the combination group (9.7 vs 8.1 months; p = 0.01). ORR and DCR were higher in the combination group (ORR: 75.7% vs 54.7%; p = 0.04; DCR: 94.6% vs 75.5%; p = 0.02). There were no significant differences in adverse effects between the two groups. Conclusion: Intraperitoneal administration of recombinant human endostatin improved efficacy and survival for gastric cancer with ascites.

Ascites (a buildup of fluid in the abdomen) resulting from the spread of gastric cancer (GC) results in extremely poor clinical outcomes, and current treatments have shown little effectiveness. Previous results showed that abdominal injection with chemotherapeutic agents enabled an increase in the dose of chemotherapeutic agents and reduced side effects or undesirable effects in the abdominal cavity. This study aimed to investigate the effectiveness and safety of abdominal injection with the anticancer drug recombinant human endostatin in GC with ascites. Clinical data of 90 patients were inspected and analyzed in this study. Thirty-seven patients who received abdominal infusion with both cisplatin (CDDP) and recombinant human endostatin were included in an Endostar^® combined with CDDP group, and 53 patients who received abdominal infusion with CDDP alone were included in a CDDP group. The results showed that median survival time was longer in the combination group than in the CDDP group (9.7 months vs 8.1 months). Besides, therapeutic outcomes, including objective response rate and disease control rate, were better in the combination group. Side effects or undesirable effects were similar in the two groups. To conclude, abdominal injection with recombinant human endostatin improved survival time and therapeutic outcomes for GC patients with ascites.

Efficacy and safety of recombinant human endostatin during peri-radiotherapy period in advanced non-small-cell lung cancer.

Background: This study aimed to retrospectively investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) combined with radiotherapy in advanced non-small-cell lung cancer (NSCLC). Methods: Patients with unresectable stage III and IV NSCLC who treated with radiotherapy were enrolled. Patients who received Rh-endostatin infusion throughout the whole peri-radiotherapy period formed the Endostar group, and those who received no Rh-endostatin infusion were the control group. Results: The median progression-free survival was 8.0 and 4.4 months (hazard ratio: 0.53; 95% CI: 0.32-0.90; p = 0.019) and median overall survival was 40.0 and 13.1 months (hazard ratio: 0.53; 95% CI: 0.28-0.98; p = 0.045) for the Endostar and control groups, respectively. The Endostar group exhibited a numerically lower rate of radiation pneumonitis relapse, radiation pneumonitis death and pulmonary fibrosis. Conclusion: Rh-endostatin infusion throughout the peri-radiotherapy period enhanced radiosensitivity and showed better survival outcomes and a tendency toward fewer radiation-related pulmonary events in patients with NSCLC.

Recombinant human endostatin (Rh-endostatin/Endostar) combined with chemotherapy has been approved as first-line standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) in China. This study aimed to retrospectively investigate the efficacy and safety of Rh-endostatin combined with radiotherapy in advanced NSCLC. Patients with unresectable stage III and IV NSCLC who treated with radiotherapy were enrolled. Patients who received Rh-endostatin infusion throughout the whole peri-radiotherapy period were the Endostar group, and those receiving no Rh-endostatin infusion were the control group. Results showed that the median progression-free survival was 8.0 and 4.4 months, and median overall survival was 40.0 and 13.1 months, for the Endostar and control groups, respectively. The Endostar group had a lower rate of radiation pneumonitis relapse, radiation pneumonitis death and pulmonary fibrosis. In conclusion, Rh-endostatin infusion throughout the peri-radiotherapy period enhanced radiosensitivity and showed better survival outcomes and a tendency toward fewer radiation-related pulmonary events in patients with NSCLC.

Different administration methods of endostar combined with second-line chemotherapy in advanced malignancies.

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.

Rh-endostatin combined with chemotherapy in patients with advanced or recurrent mucosal melanoma: retrospective analysis of real-world data.

BACKGROUND: Mucosal melanoma is rare and has distinct clinical and genetic features. Even with advances in targeted and immune therapies, the survival of patients with advanced or recurrent mucosal melanomas remains poor. The standard treatment remains controversial and we conducted this real-world study aimed to explore continuous intravenous recombinant human endostatin (Rh-endostatin) infusion plus chemotherapy in this population in the first-line setting. METHODS: Overall, 43 patients with advanced or recurrent mucosal melanoma treated at Fudan University Shanghai Cancer Center between April 2017 and August 2020 were retrospectively included. Patients received dacarbazine plus cisplatin or temozolomide plus cisplatin per the investigators' preference. Rh-endostatin (105 mg/m2) was administered with continuous infusion for 168 h (Civ 168 h). RESULTS: Of the 43 patients, 72.1% had metastatic disease, and the most common primary site was the gastrointestinal tract (51.2%). The most commonly observed mutations were NRAS (23.1%), BRAF (7.7%) and CKIT mutations (5.1%). An objective response was observed in 12 (30.0%) of the 40 evaluable patients, and disease control was achieved in 31 (77.5%) patients. With a median follow-up of 17.6 months, the median progression-free survival (PFS) and overall survival (OS) were 4.9 and 15.3 months, respectively. Additionally, high lymphocyte-to-monocyte ratio (LMR) (p = 0.023, HR 0.29, 95% CI: 0.10-0.84) and BRAF/KIT/RAS mutation (p = 0.028, HR 0.24, 95% CI: 0.07-0.86) were independently correlated with prolonged OS. Toxicity was manageable overall. CONCLUSION: Continuous Rh-endostatin infusion plus chemotherapy was effective and safe for the treatment of advanced or recurrent mucosal melanoma. High LMR was correlated with favorable PFS and OS in this patient population.

Tolerance and Pharmacokinetics of Recombinant Human Endostatin Administered as Single-Dose or Multiple-Dose Infusions in Patients With Advanced Solid Tumors: A Phase I Clinical Trial.

Objective: This study aimed to investigate the tolerance and pharmacokinetic characteristics of recombinant human endostatin (rh-endostatin) administered as single-dose or multiple-dose infusions in patients with advanced solid tumors. Methods: This phase I trial was designed as a single-center, single-arm, nonrandomized, open-label, dose-escalation study. The trial consisted of 2 parts: a single-dose part and a multiple-dose part, each with 3 dose comparison groups. Rh-endostatin was administered as an intravenous injection only once at a dose of 5 mg/m2, 7.5 mg/m2, or 10 mg/m2 in the single-dose part and as a daily intravenous injection for 14 days at the same doses in the multiple-dose part. The serum pharmacokinetics, toxicity and immunogenicity of rh-endostatin were evaluated. Results: Dose-limiting toxicity (DLT) was not observed in any group. A few patients developed cardiotoxicity, such as QT prolongation or narrow arrhythmia. Other adverse events were slight coagulation abnormalities and haematological abnormalities. For rh-endostatin doses of 5 mg/m2, 7.5 mg/m2, and 10 mg/m2, the mean Cmax values in the single-dose part were 344 ± 38.7 ng/mL, 524 ± 157 ng/mL, and 800 ± 201 ng/mL, respectively, and the average AUC0-t values were 3290 ± 3790 ng•h/mL, 4940 ± 4380 ng•h/mL, and 5050 ± 3980 ng•h/mL, respectively. The Cmax ss values of the 3 doses in the multiple-dose part were 575 ± 270 ng/mL, 531 ± 106 ng/mL, and 864 ± 166 ng/mL, respectively, and the AUC0-τ values were 3610 ± 1040 ng•h/mL, 3290 ± 1090 ng•h/mL, and 5180 ± 1210 ng•h/mL, respectively. The Cmax of a single-dose regimen showed linear kinetic characteristics. The patients in the single-dose group were negative for serum antibodies against rh-endostatin, while one patient in the multiple-dose group was positive. Conclusions: Rh-endostatin as a daily intravenous injection for 14 days in patients with advanced solid tumors is safe and well tolerated, without DLT, at doses of 5 mg/m2, 7.5 mg/m2, and 10 mg/m2. Serum antibodies against rh-endostatin were very low after multiple infusions. For phase II trials, the recommended rh-endostatin dose is 10 mg/m2 as a daily intravenous injection for 14 days.

Study on the clinical effects of targeted therapy on elderly patients with gastric cancer.

To explore the clinical effects of targeted drug therapy on elderly patients with gastric cancer. Totally 200 metastatic gastric cancer patients who came to our hospital from January 2017 to January 2020 were selected and randomized into four groups, with 50 patients in each group. Bevacizumab (Group I), apatinib (Group II), and recombinant human endostatin (Group III) adopted respectively. While the control group received no targeted drug. Clinical data and clinical effect was collected and compared. After the therapy, the vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor-2 (sVEGFR2) and human epithelial growth factor receptor-2 (HER2) positive detection of Group I, Group II, and Group III were better than the control group (P<0.05). In addition, the therapeutic effects of Group I, Group II, and Group III were higher and the incidence of adverse reactions was lower than the control group (P<0.05). Targeted drugs have obvious clinical effects in gastric cancer. It can effectively inhibit tumor growth and reduce the occurrence of complications, which is worthy of extensive clinical application and promotion.

Recombinant human endostatin plus paclitaxel/nedaplatin for recurrent or metastatic advanced esophageal squamous cell carcinoma: a prospective, single-arm, open-label, phase II study.

Background The prognosis of esophageal squamous cell carcinoma (ESCC) are still poor. Nedaplatin/paclitaxel regimen has shown activity with lower toxicity in metastatic ESCC. Recombinant human endostatin (Rh-endostatin), an inhibitor of angiogenesis, has shown inhibitory effects on ESCC xenograft. We assessed the activity and safety of Rh-endostatin plus paclitaxel/nedaplatin in patients with recurrent or metastatic advanced ESCC. Methods In this single-center, open-label, single-arm, phase II study, patients with recurrent/metastatic or unresectable advanced ESCC were recruited. Eligible patients received the multidrug combination therapy with Rh-endostatin (30 mg/day on days 1-14), paclitaxel (150 mg/m2 on day 4) and nedaplatin (80 mg/m2 on day 4) every 3 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, disease control rate, overall survival. Results Between Jan 29, 2015 and Dec 31, 2019, 53 patients were enrolled and received at least one dose of Rh-endostatin. Median progression-free survival was 5.1 months (95% CI: 3.7-6.6), with a 6 month progression-free survival of 41% (95% CI: 25-56). Median overall survival was 13.2 months (95% CI: 8.0-18.4), with a 1-year overall survival of 51% (95% CI: 36-67). 21 (42%, 95% CI: 28-56) of 50 patients had an objective response and 35 (70.00%, 95% CI: 57-83) had a disease control. Treatment-related adverse events of grade 3 or worse were reported in 13 (24.5%) patients. The most common grade 3 or 4 treatment-related adverse events were neutropenia (9 patients [17%]) and anaemia (2 [3.8%]). No treatment-related death occurred. Conclusions Rh-endostatin plus paclitaxel/nedaplatin has anti-tumour activity with acceptable tolerability in patients with recurrent or metastatic advanced ESCC. Randomized controlled trial is needed to confirm the efficacy of this regimen.

Intensity-modulated radiation therapy (IMRT)-based concurrent chemoradiotherapy (CCRT) with Endostar in patients with pelvic locoregional recurrence of cervical cancer: Results from a hospital in the Qinghai-Tibet Plateau.

The treatment of recurrent cervical cancer, especially pelvic locoregional recurrence, is very challenging for gynecologic oncologists. This study investigated the efficacy and safety of intensity-modulated radiation therapy (IMRT)-based concurrent chemoradiotherapy (CCRT) with Endostar, a novel modified recombinant human endostatin, in patients with pelvic locoregional recurrence of cervical cancer following surgical treatment.This phase 2 study was conducted between May 2018 and May 2019 at a single center in the Qinghai-Tibet Plateau and enrolled 31 patients with pelvic locoregional recurrence of cervical cancer following surgical treatment. All patients were treated with IMRT-based CCRT for 6 weeks and intravenous infusions of Endostar (15 mg/m), which were administered on days 1 to 7 of CCRT, followed by rest for 4 weeks. After resting, chemotherapy with cisplatin (70 mg/m) plus paclitaxel (135-175 mg/m) was given every 3 weeks for a total of 4 treatments.Thirty-one patients were evaluable for the primary endpoint. The mean age was 50.03 years (SD 7.72). The objective response rate was 67.74% and the disease control rate was 83.87% (48.39% achieved a complete response, 19.35% a partial response, 16.13% had disease stabilization, and 16.13% had progressive disease). The most common adverse events were nausea, vomiting, alopecia, neutropenia, and leukopenia; most events were grade 1 or 2 in intensity. Grade 3 toxicities included thrombocytopenia and neutropenia in 2 patients each, and leukopenia in 4 patients. No cases of grade 4 acute toxicity were observed.IMRT-based CCRT with Endostar infusions is effective and safe. Our results support the use of this treatment for patients with pelvic locoregional recurrence of cervical cancer following surgical treatment.

Endostar continuous versus intermittent intravenous infusion combined with chemotherapy for advanced NSCLC: a systematic review and meta-analysis including non-randomized studies.

BACKGROUND: Both intermittent intravenous (IIV) infusion and continuous intravenous (CIV) infusion of Endostar are widely used for NSCLC in China. We aimed to compare the efficacy and safety of CIV of Endostar versus IIV in combination with first-line chemotherapy for patients with advanced NSCLC. METHODS: RCTs, NRCTs and cohort studies which compared CIV of Endostar with IIV in advanced NSCLC patients and reported efficacy or safety outcomes were eligible. Two reviewers independently screened records, extracted data and assessed risk of bias. Pooled risk ratios (RRs) with 95% confidence intervals were calculated using random effects meta-analysis for short-term efficacy and safety outcomes, and hazard ratios (HRs) for survival outcomes. RESULTS: Finally nine studies involving 597 patients were included, containing two RCTs, three NRCTs and four cohort studies. For short-term efficacy, moderate quality of evidence showed that there were no significant differences between CIV of Endostar and IIV in objective response rate (ORR; RR 1.34, 95% CI 0.91-1.98, P = 0.14) and disease control rate (DCR; RR 1.11, 95% CI 0.94-1.30, P = 0.21). Very low quality of evidence indicated that CIV of Endostar significantly improved both overall survival (OS; HR 0.69, 95% CI 0.48-0.99, P = 0.046) and progression-free survival (PFS; HR 0.71, 95% CI 0.55-0.93, P = 0.01) compared with IIV. As for safety outcomes, moderate quality of evidence found that CIV of Endostar significantly reduced the risk of myelosuppression (RR 0.55, 95% CI 0.32-0.96, P = 0.03) and cardiovascular toxicity (RR 0.21, 95% CI 0.06-0.78, P = 0.02) compared with IIV. CONCLUSIONS: In advanced NSCLC, compared with IIV, CIV of Endostar had similar short-term efficacy, and substantially lower risk of myelosuppression and cardiovascular toxicity. Although very low quality of evidence supported the survival benefit of CIV compared with IIV, large RCTs with long-term follow-up are needed to demonstrate survival benefits. Caution should be given for off-label use of CIV of Endostar.

A Randomized Parallel Controlled Phase II Trial of Recombinant Human Endostatin Added to Neoadjuvant Chemotherapy for Stage III Breast Cancer.

BACKGROUND: To explore the potential advantage of preoperative anti-angiogenosis therapy, we implemented a study to evaluate the efficacy of recombinant human endostatin (EN) in combination with neoadjuvant chemotherapy in the treatment of stage III breast cancer. PATIENTS AND METHODS: Eighty-seven patients were randomized to neoadjuvant TEC (docetaxel, epirubicin, and cyclophosphamide) or to EN+TEC, followed by surgery. The primary endpoint was the objective response rate (ORR). Secondary endpoints included pathologic complete response (pCR), relapse-free survival (RFS), overall survival (OS), and safety. RESULTS: Patients receiving EN+TEC achieved significantly higher ORR (81.82%; 36/44) compared with those receiving TEC (58.14%; 25/43; P=0.016). There was a non-significant trend of increased pCR with EN treatment (15.91% vs. 6.98%). The median follow-up was 54 months and revealed a significantly higher RFS with EN+TEC (median, 67.3 months; 95% confidence interval [CI], 61.0-73.7 months), compared with TEC (median, 55.0 months; 95% CI, 48.3-61.7 months; P =0.014). EN+TEC also significantly improved OS (74.2 months; 95% CI, 68.9-79.6 months), compared with TEC (59.1 months; 95% CI, 52.0-66.1 months; P =0 .006). The 3- and 5-year OS rates are estimated to be 88.5% and 82.8% with EN+TEC and 76.7% and 54.4% with TEC, respectively. Cox proportional regression analyses showed that EN+TEC was associated with improved OS (hazard ratio, 0.377; 95% CI, 0.418-0.959; P =0 .041). There was no significant difference in adverse events between EN+TEC and TEC. CONCLUSION: The combination of EN+TEC neoadjuvant chemotherapy significantly improved the ORR and OS, suggesting a benefit of adding anti-angiogenesis to standard chemotherapy in the treatment of locally advanced breast cancer.

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.

The Evaluation of Durative Transfusion of Endostar Combined with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND: The overall survival (OS) in non-small cell lung cancer (NSCLC) is poor, with median OS of advanced NSCLC with standard systemic chemotherapy being reported at 13.6 months and the 5-year survival rate at less than 15%. Therefore, the aim of this study was to evaluate Endostar combined with chemotherapy in patients with advanced NSCLC. METHODS: Data on 116 cases of pathologically confirmed stage IIIB-IV NSCLC were retrospectively collected. The control group was treated with chemotherapy combined with intravenous infusion of Endostar while the test group received durative transfusion of Endostar. The short-term therapeutic effects including overall response rate (ORR), disease control rate (DCR), and safety were evaluated in both groups. In the follow-up, progression-free survival (PFS) and OS were also analysed. RESULTS: In the test group, the ORR was 53.4%, which was similar to that in the control group (44.8%) (p > 0.05). However, the DCR in the test group (86.2%) was significantly higher than that in the control group (70.7%) (p < 0.01). The median time to progression in the test group (6 months) was also significantly longer than that in the control group (4 months). Importantly, the median OS in the test group (17.5 months) was improved compared to the control group (13.5 months). The 1-year survival rate in the test and control groups was 9.7 and 15.8%, respectively. There was no significant difference in side effects (including thrombocytopenia, leucopenia, nausea, and vomiting) between the two groups. CONCLUSIONS: Endostar durative transfusion combined with chemotherapy showed a higher DCR, longer PFS and OS time, and was well tolerated in patients with advanced NSCLC.

Enhanced antitumor and anti-angiogenic effects of metronomic Vinorelbine combined with Endostar on Lewis lung carcinoma.

BACKGROUND: Conventional chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC) however it increases therapeutic resistance. In contrast, metronomic chemotherapy (MET) is based on frequent drug administration at lower doses, resulting in inhibition of neovascularization and induction of tumor dormancy. This study aims to evaluate the inhibitory effects, adverse events, and potential mechanisms of MET Vinorelbine (NVB) combined with an angiogenesis inhibitor (Endostar). METHODS: Circulating endothelial progenitor cells (CEPs), apoptosis rate, expression of CD31, vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1α) were determined using flow cytometry, western blot analysis, immunofluorescence staining and Enzyme-linked immunosorbent assay (ELISA) analysis. And some animals were also observed using micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) to identify changes by comparing SUVmax values. In addition, white blood cell (WBC) counts and H&E-stained sections of liver, lungs, kidney, and heart were performed in order to monitor toxicity assessments. RESULTS: We found that treatment with MET NVB + Endo was most effective in inhibiting tumor growth, decreasing expression of CD31, VEGF, HIF-1α, and CEPs, and reducing side effects, inducing apoptosis, such as expression of Bcl-2, Bax and caspase-3. Administration with a maximum tolerated dose of NVB combined with Endostar (MTD NVB + Endo) demonstrated similar anti-tumor effects, including changes in glucose metabolism with micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) imaging, however angiogenesis was not inhibited. Compared with either agent alone, the combination of drugs resulted in better anti-tumor effects. CONCLUSION: These results indicated that MET NVB combined with Endo significantly enhanced anti-tumor and anti-angiogenic responses without overt toxicity in a xenograft model of human lung cancer.

Intensity-modulated radiotherapy combined with endostar has similar efficacy but weaker acute adverse reactions than IMRT combined with chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma.

The present study is to compare the efficacy and adverse effects of intensity-modulated radiotherapy (IMRT) combined with endostar and IMRT combined with concurrent chemotherapy on locally advanced nasopharyngeal carcinoma (NPC).A total of 23 patients with stage III-IVa NPC were included in the present study, and randomly divided into experimental group (10 cases treated with IMRT + endostar) and control group (13 cases treated with IMRT + chemotherapy of cis-dichlorodiamineplatinum). Endostar was intravenously administered from the first day of IMRT. The patients received a total of 2 cycles (14 days each) separating by a 7-day interval.IMRT combined with endostar did not have significantly different recent efficacy compared with IMRT combined with chemotherapy. IMRT combined with endostar and IMRT combined with chemotherapy had 2-year overall survival (OS) rates of 100.0% and 69.6%, respectively, without significant difference between each other (χ = 1.446, P = .299). The 2-year local relapse-free survival (LRFS) of the 2 groups were 100.0% and 81.3%, respectively, without significant difference between each other (χ = 1.000, P = .317). The 2-year distant metastasis-free survival (DMFS) of the 2 groups were 100.0% and 73.5% (χ = 1.591, P = .207), respectively. The 2-year progression-free survival (PFS) of the 2 groups were 100.0% and 67.3% (χ = 2.164, P = .141), respectively. However, the cumulative survival curves of OS, LRFS, DMFS, and PFS were separated between the 2 groups. The result that IMRT combined with endostar did not have significantly different long-term efficacy than IMRT combined with chemotherapy probably due to limited case number and short follow-up time. IMRT combined with endostar resulted in significantly lower grades of leucopenia, nausea/vomiting, weight loss, and oral mucositis compared with IMRT combined with chemotherapy. The grades of late adverse reactions of IMRT combined with endostar were not different from those of IMRT combined with chemotherapy.The present study demonstrates that, compared with IMRT combined with chemotherapy, IMRT combined with endostar has similar efficacy in the treatment of locally advanced NPC, but significantly weaker acute adverse reactions, which improve the life quality of NPC patients.

Endostar (rh-endostatin) versus placebo in combination with vinorelbine plus cisplatin chemotherapy regimen in treatment of advanced non-small cell lung cancer: A meta-analysis.

BACKGROUND: This meta-analysis was conducted to investigate the efficacy and safety of Endostar (rh-endostatin) versus a placebo in combination with a vinorelbine plus cisplatin (NP) chemotherapy regimen for the treatment of advanced non-small cell lung cancer (NSCLC). METHODS: Two reviewers independently searched Medline, PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, ASCO, ESMO, the Web of Science, and CNKI databases to locate relevant controlled clinical trials. The treatment efficacy and drug-related toxicity of NP + Endostar (NPE) and NP groups were pooled through meta-analysis according to random or fixed effect models. RESULTS: Fifteen prospective clinical studies were included in this meta-analysis. The pooled risk ratio (RR) for objective response rate was 1.74 (95% confidence interval [CI] 1.43-2.11); the objective response rate in the NPE group was significantly higher than in the NP group (P < 0.05). Nine publications evaluated the incidence of leucopenia between Endostar versus a placebo in combination with an NP chemotherapy regimen. The pooled results showed no statistically significant difference between NPE and NP chemotherapy regimens for leucopenia, thrombocytopenia, and nausea/vomiting risk (P > 0.05). The one-year survival rate in the NPE group was higher than in the NP group, with a statistically significant difference (RR = 1.70, 95% CI 1.07-2.89; P < 0.05). CONCLUSION: Endostar combined with an NP chemotherapy regimen can improve the prognosis of patients with advanced NSCLC without increasing the risk of toxicity.

The effects of carboplatin and etoposide on advanced small cell lung cancer and serum tumor markers in correlation with long-term survival rate.

Objective of the present study was to analyze the efficacy of recombinant human endo-statin combined with carboplatin and etoposide regimen (CE regimen) in treatment of patients with advanced small cell lung cancer and its effects on serum tumor markers of CY211, CEA and CA199. A total of 72 patients at Zhejiang Taizhou Hospital, Taizhou, Zhejiang, China were randomly divided into control group and observation group (36 cases each). The control group was treated with carboplatin and etoposide while the observation group additionally received recombinant human endo-statin. Clinical remission rate and adverse reaction rate were compared between the two groups. Before treatment, there was no significant difference (P>0.05) between the two groups in serum tumor markers of CY211, CEA and CA199 while after treatment, the CY211, CEA and CA199 levels of the observation group were significantly lower than those of the control group and no significant difference was found between the two groups in the incidence of side effects as well as in the 3 and 5 year-survival rate (X2=1.125, 1.248, P>0.05). Recombinant human endo-statin combined with carboplatin and etoposide was more effective in treating advanced small cell lung cancer as it managed to reduce the level of serum tumor markers of CY211, CEA and CA199 with less side effects and high tolerance in patients, thus worthy of popularization and application in clinical trials.

Long-Term Remission of Recurrent Brainstem Pilocytic Astrocytoma with Neuraxis Dissemination Using Recombinant Human Endostatin After Failure of Vincristine and Carboplatin.

BACKGROUND: There is no standard salvage treatment for recurrent and/or unresectable brainstem low-grade gliomas after failure from carboplatin and vincristine chemotherapy. Recombinant human endostatin (rh-ES), a mild inhibitor of angiogenesis, has been used for treating lung cancer. But so far as we know, there is no experience for brainstem gliomas. CASE DESCRIPTION: The authors present a pediatric case of recurrent brainstem pilocytic astrocytoma with neuraxis dissemination who experienced tumor progression with carboplatin and vincristine chemotherapy but then had a dramatic and long-term remission for at least 29 months after combined treatment of rh-ES with carboplatin and vincristine. CONCLUSION: This case suggests that the addition of rh-ES to carboplatin and vincristine regimens may be synergistic and results in a long-term remission in patients with brainstem low-grade gliomas, even if the tumor is widely spread in the central nervous system.