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.

Bronchoscopic intratumoral injections of cisplatin and endostar as concomitants of standard chemotherapy to treat malignant central airway obstruction.

STUDY PURPOSE: Malignant central airway obstruction (CAO) in non-small cell lung cancer (NSCLC) is associated with high morbidity and requires endobronchial palliative treatment to re-establish a free air passage. We investigate intratumoral therapy combining anti-angiogenic and cytotoxic as a feasible therapeutic modality to treat malignant CAO. STUDY DESIGN: Ten NSCLC subjects with symptomatic malignant CAO underwent endobronchial intratumoral cisplatin and Endostar co-injection after tumour debulking next to systemic cisplatin-based chemotherapy. Injection was performed immediately after debulking surgery and was then carried out on day 2, day 6 and day 10 past systemic chemotherapy. Nine subjects of control group constantly received traditional cisplatin-based chemotherapy. Bronchoscopy, CT scanning, histology, FEV1/FVC ratio, Karnofsky performance (KPS) and shortness of breath scores were analysed to assess therapeutic efficacy. RESULTS: All 10 subjects benefited from the intratumoral cisplatin and endostar co-injection and systemic chemotherapy combination therapy. Bronchoscopy and CT scanning analyses showed a massive airway widening after treatment. Increased KPS and reduced shortness of breath score were also observed. A substantial improvement of lung function was further confirmed by increased FEV1/FVC ratio. For subjects of control group, the improvement was moderate and obviously not as optimal as the 10 subjects with intratumoral injection. CONCLUSIONS: We have shown that the intratumoral injection of cytotoxic cisplatin plus anti-angiogenic Endostar is an effective and safe adjuvant therapeutic option to treat malignant CAO in clinical practice. This time-staggered local and systemic treatment combination improves quality of life and clinical parameters, thus may provide a feasible therapeutic option for symptomatic CAO.

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.

A rapid response of lung squamous cell carcinoma following treatment with sintilimab combined with recombinant humane endostatin injection and nab-paclitaxel in an elderly patient: A case report.

RATIONALE: At present, the prognosis of patients with giant lung squamous cell carcinoma (LSCC) is poor, and there is no safe and effective treatment for elderly patients with large LSCC. PATIENT CONCERNS: Here, we reported a 77-year-old man admitted to the hospital with cough for 3 months and significant chest pain. Computed tomography (CT) imaging showed a large mass in the left lung with pleural effusion. DIAGNOSES: Chest CT scan revealed a 12.5 cm × 7.3 cm mass in the left upper lobe adjacent to the pulmonary vein, with left pleural effusion. Pulmonary tumor markers were significantly elevated, and CT-guided percutaneous lung mass biopsy specimens showed LSCC. INTERVENTIONS: After diagnosis, the patient was treated with sintilimab combined with endostar and nab-paclitaxel. After 2 cycles of treatment, the lung mass in the patient shrank rapidly and the clinical symptoms were relieved. OUTCOMES: The patient's tumor dramatically shrank, and the pleural effusion was decreased after 4 cycles of treatment without any adverse effects. Meanwhile, the high-level tumor marker resumed normal. LESSONS: Sintilimab combined with endostar and nab-paclitaxel may be a good treatment option for lung squamous cell cancer, especially for that in elderly patients.

Anti-tumor effect of local injectable hydrogel-loaded endostatin alone and in combination with radiotherapy for lung cancer.

Endostatin (ES) can effectively inhibit neovascularization in most solid tumors and has the potential to make oxygen delivery more efficient and increase the efficacy of radiotherapy (RT). With a short half-life, ES is mainly administered systemically, which leads to low intake in tumor tissue and often toxic systemic side effects. In this study, we used hyaluronic acid-tyramine as a carrier to synthesize an ES-loaded hydrogel drug (ES/HA-Tyr) that can be injected locally. ES/HA-Tyr has a longer half-life and fewer systemic toxic side effects, and it exerts a better anti-angiogenic effect and anti-tumor effect with RT. In vitro, ES/HA-Tyr showed sustained release in the release assay and a stronger ability to inhibit the proliferation of human umbilical vascular endothelial cells (HUVECs) in the MTT assay; it exhibited a more potent effect against HUVEC invasion and a stronger anti-angiogenic effect on HUVECs in tube formation. In vivo, ES/HA-Tyr increased local drug concentration, decreased blood drug concentration, and caused less systemic toxicity. Further, ES/HA-Tyr effectively reduced tumor microvessel density, increased tumor pericyte coverage, decreased tumor hypoxia, and increased RT response. ES/HA-Tyr + RT also had increased anti-tumor and anti-angiogenic effects in Lewis lung cancer (LLC) xenograft models. In conclusion, ES/HA-Tyr showed sustained release, lower systemic toxicity, and better anti-tumor effects than ES. In addition, ES/HA-Tyr + RT enhanced anti-angiogenic effects, reduced tumor hypoxia, and increased the efficacy of RT in LLC-bearing mice.

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.

Efficacy and safety of recombinant human endostatin combined with radiotherapy or chemoradiotherapy in patients with locally advanced non-small cell lung cancer: a pooled analysis.

PURPOSE: To assess the efficacy and safety of recombinant human endostatin in combination with radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: We searched eligible literature in available databases using combinations of the following search terms: lung cancer, endostatin or endostar, radiotherapy or radiation therapy or chemoradiotherapy. The inclusion criteria were: prospective or retrospective (including single-arm) studies that evaluated the efficacy and safety of endostatin plus radiotherapy (ERT) or concurrent chemoradiotherapy (ECRT) in patients with LA-NSCLC. Primary outcomes included the following: objective response rate (ORR), local control rates (LCR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Tests of heterogeneity, sensitivity, and publication bias were performed. RESULTS: A total of 271 patients with LA-NSCLC from 7 studies were enrolled, including six prospective trials and one retrospective study. The pooled median PFS was 11.3 months overall, 11.2 months in the ECRT group, and 11.8 months in the ERT group. Pooled median OS and ORR were 18.9 months and 77.2% overall, 18.4 months and 77.5% in the ECRT group, and 19.6 months and 76.1% in the ERT group, respectively. The incidences of major grade ≥ 3 AEs for all patients, subgroups of ECRT and ERT were 10.9% vs 11.9% vs 9.4% for radiation pneumonitis, 11.6% vs 12.2% vs 9.4% for radiation esophagitis, 35.5% vs 43.4% vs 0 for leukopenia, 27.8% vs 40.7% vs 2.1% for neutropenia, and 10.5% vs 12.3% vs 2.1% for anemia. CONCLUSIONS: Combined endostatin with RT or CCRT is effective and well tolerated in treating LA-NSCLC, and less toxicities occur. Further validation through prospective randomized control trials is required.

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.

Primary pulmonary arterial sarcoma treated with endostar injection and radiotherapy.

We present a case of primary pulmonary arterial sarcoma (PPAS) treated with endostatin (endostar) injection and radiotherapy  discuss the diagnosis, clinical manifestations, and pathology of PPAS. The patient complained of cough with sputum, fever, and chest pain with hemoptysis. Numerous nodules were observed in the computed tomography (CT) scan. The patient was diagnosed with pulmonary embolism (PE) by computed tomography pulmonary angiography (CTPA). The pathology and immunohistochemistry results indicated soft tissue sarcomas, indicative of angiosarcoma. The nodules shrunk after 5 courses of endostatin and one course of radiotherapy, as determined in the CT scan. Primary pulmonary arterial sarcoma is clinically rare with nonspecific symptoms. Hence, it can be easily misdiagnosed as PE, and biopsy must be performed for confirmation. Current treatment methods, including surgery, are limited. Therefore, administration of endostatin injection combined with other therapies may be an alternative treatment methods.

Primary pulmonary arterial sarcoma treated with Endostar injection and radiotherapy.

A case of primary pulmonary arterial sarcoma (PPAS) treated with Endostar injection and radiotherapy and discuss the diagnosis, clinical characteristics, and pathology of PPAS. The patient complained of cough, sputum, fever, and chest pain with hemoptysis. Numerous nodules were seen in the computed tomography scan. The patient was diagnosed as pulmonary embolism (PE) by computed tomography pulmonary angiography. The pathology and immunohistochemistry results indicated soft tissue sarcomas, indicative of angiosarcoma. The nodules shrunk after 5 courses of endostatin and one course of radiotherapy, as seen by CT scan. Therefore, PPAS is clinically rare with nonspecific symptoms. Hence, it can be easily misdiagnosed as PE, biopsy for confirmation. Current treatment is limited and includes surgery. Hence, endostatin injection combined with other therapy may be an alternative treatment.

Different administration routes of recombinant human endostatin combined with concurrent chemoradiotherapy might lead to different efficacy and safety profile in unresectable stage III non-small cell lung cancer: Updated follow-up results from two phase II trials.

BACKGROUND: There are two main choices of administration route of recombinant human endostatin (Endostar) available and the treatment options of concurrent chemoradiotherapy (CCRT) have changed over time. The aim of this study was to observe the long-term efficacy and safety of different administration routes of Endostar combined with CCRT. METHODS: Patients with unresectable stage III non-small cell lung cancer (NSCLC) from two phase II trials were included as two cohorts. Both were treated with Endostar combined with CCRT. Endostar was administrated by intravenous injection (7.5 mg/m2 /day, seven days) in the IV arm and by continuous intravenous pumping (7.5 mg/m2 /24 hours, 120 hours) in the CIV arm. RESULTS: A total of 48 patients were included in the IV arm and 67 patients in the CIV arm. The median progression-free survival (PFS), overall survival (OS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) in the IV arm and CIV arm were 9.9 months versus 15.4 months (HR = 0.751, 95% CI 0.487-1.160, P = 0.200), 24.0 months versus 38.5 months (HR = 0.746, 95% CI 0.473-1.178, P = 0.209), 32.3 months versus 27.1 months (HR = 1.193, 95% CI 0.673-2.115, P = 0.546), 20.1 months versus 49.7 months (HR = 0.603, 95% CI 0.351-1.036, P = 0.067). The one, three, five-year PFS in the IV arm and CIV arm was 45.8% versus 52.9%, 18.3% versus 31.4%, and 18.3% versus 27.7% and the one, three, five-year OS was 81.2% versus 82.1%, 31.1% versus 50.3%, and 31.1% versus 41%, respectively. Incidence of hematological adverse reactions were numerically lower in the CIV arm than the IV arm. CONCLUSIONS: Endostar delivered by CIV with CCRT may be a better option than IV in terms of potential survival and safety for unresectable stage III NSCLC. KEY POINTS: Significant findings of the study Endostar delivered by continuous intravenous pumping might achieve more favorable survival over intravenous injection and reduce adverse hematological reactions in patients with unresectable stage III NSCLC treated with Endostar combined with CCRT.What this study adds The administration route of recombinant human endostatin is also one key factor for survival and safety to consider when treating patients with unresectable stage III NSCLC.

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.

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

BACKGROUND: The 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. METHODS: We 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). RESULTS: The 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. CONCLUSIONS: Rh-ES, in combination with cytotoxic drugs, was an alternative effective regimen with manageable toxicities in treatment of recurrent disseminated glioblastoma.

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 ±â€¯0.70, 29.50 ±â€¯18.80 and 24.60 ±â€¯8.90 h. Systemic clearance (CLsys) of M2ES were 339.60 ±â€¯66.30, 161.40 ±â€¯18.20 and 260.10 ±â€¯43.70 mL/h/kg. AUC(0-∞) values of M2ES were 909.30 ±â€¯199.60, 6251.00 ±â€¯739.60 and 11758.00 ±â€¯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.

Comparison of Endostar continuous versus intermittent intravenous infusion in combination with first-line chemotherapy in patients with advanced non-small cell lung cancer.

BACKGROUND: Intravenous infusion of Endostar for three to four hours per day for 14 days reduces patient compliance and affects quality of life. Continuous intravenous infusion (CI) represents a novel method of administration; however, it is unclear whether it is effective and safe when compared to the traditional method. METHODS: We retrospectively reviewed patients with advanced non-small cell lung cancer (NSCLC) administered CI (20 patients) or intermittent intravenous infusion (II, 49 patients) of Endostar combined with first-line chemotherapy. Three patients in the II group discontinued therapy because of adverse effects. RESULTS: Median progression-free survival was 6.0 months in the CI group and 3.8 months in the II group, with no significant difference (P = 0.1). The objective response and disease control rates were also similar in the CI and II groups (40.0 vs. 32.6%, P = 0.562; 65 vs. 69.6%, P = 0.714, respectively). CONCLUSION: CI of Endostar combined with first-line chemotherapy for advanced NSCLC had similar progression-free survival, objective response, and overall response rates as II, with tolerable adverse effects.

Endostatin and Oxaliplatin-Based Chemoradiotherapy for Inoperable Esophageal Squamous Cell Carcinoma: Results of a Phase II Study.

LESSONS LEARNED: Definitive concurrent chemoradiotherapy based on oxaliplatin and endostatin was effective with the objective response rate exceeding 80%, and the treatment-related toxicities were acceptable.The treatment compliance of the current combination was much higher, without significant reduction in survival outcomes, than historical reports. BACKGROUND: This phase II trial aimed at assessing the efficiency and safety of definitive concurrent chemoradiotherapy (dCRT) using oxaliplatin (OHP) and endostatin in patients with inoperable esophageal squamous cell carcinoma (ESCC). METHODS: Radiotherapy was delivered with a daily fraction of 2.0 Gy to a total dose of 60.0 Gy over 6 weeks. Endostatin and OHP were both intravenously administered at doses of 7.5 mg/m2 daily for 2 weeks and 135 mg/m2 on day 1, respectively, every 3 weeks. The primary endpoint was the objective response rate (ORR). RESULTS: The analysis included 37 patients. The median age was 63 years (range: 49-71 years), and all patients were stage III-IVA. Of these patients, 97.3% (36/37) completed the dCRT course with an ORR of 83.8%, including 10 (27.0%) patients with complete response and 21 (56.8%) patients with partial response. The median overall survival (OS) time was 18.5 months (95% confidence interval [CI]: 10.6-26.4) with a 2-year OS rate of 39.6% (95% CI: 0.202-0.590). The median progression-free survival (PFS) time was 11.5 months (95% CI: 7.6-15.4) with a 2-year PFS rate of 20.2% (95% CI: 0.049-0.355). Grade 3 toxicities included esophagitis (five patients) and leukocytopenia (three patients). Grade 4 leukopenia was observed in one patient. Late toxicity was infrequent, and no treatment-related death occurred. Posttreatment dysphagia scores were significantly improved when compared with baseline (p < .001). CONCLUSION: dCRT based on OHP and endostatin resulted in high treatment compliance with manageable toxicities. This combination resulted in encouraging ORR without compromising survival outcomes. It should be validated in future clinical studies.

Real-world outcomes of various regimens of recombinant human endostatin combined with chemotherapy in non-driver gene mutation advanced non-small cell lung cancer.

AIMS: This real-world study is conducted to evaluate the efficacy and safety of recombinant human endostatin (rh-endostatin) combined with chemotherapy as first-line treatment for non-driver genes mutation non-small cell lung cancer (NSCLC) patients, and establish evidence-based optimal regimen for rh-endostatin. PATIENTS AND METHODS: Using propensity score matching (cut-off: 0.01), 88 patients were eligible for our study, 34 of which received platinum-based chemotherapy alone (chemotherapy group), 54 patients received platinum-based chemotherapy plus rh-endostatin (rh-endostatin group). Among those 54 patients in the rh-endostatin group, 27 patients received rh-endostatin administered at 7.5 mg/m2 from day 1 to day 14 (rh-endostatin 14d group), and the other 27 patients were administered at 15 mg/m2 from day 1 to day 7 (rh-endostatin 7d group). The primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. RESULTS: There were no differences in clinic characteristics among 3 groups. Compared with chemotherapy group, rh-endostatin group improved PFS and OS significantly. The median PFS was 6 months vs 4.5 months (P = 0.047), and median OS was 20 months vs 10 months (P < 0.001). The ORR was 33.3% vs 20.6% (P = 0.197) and DCR was 83.3% vs 64.7% (P = 0.046) in the rh-endostatin group and chemotherapy group, respectively. The comparisons between the rh-endostatin 7d and 14d groups revealed a significant improvement in PFS for the rh-endostatin 7d group (P = 0.044), but no significant differences in OS (P = 0.111), ORR (P = 0.074), or DCR (P = 0.234). The incidences of grade 3 and 4 adverse events were similar among 3 groups. CONCLUSION: Chemotherapy combined with rh-endostatin was more effective than chemotherapy alone for non-driver gene mutation NSCLC patients. The administration of rh-endostatin for 7 days at 15 mg/m2 was non-inferior to 14 days at 7.5 mg/m2 in prolonging patients' PFS. Further evaluation should be conducted before its application in clinical work.

Chemotherapy combined with Endostar as salvage treatment for EGFR-tyrosine kinase inhibitor primary resistance in an advanced non-small cell lung cancer patient with EGFR L858R mutation and ROS1 fusion: A case report.

EGFR-activating mutations have been recognized as the most important predictor of response to EGFR-tyrosine kinase inhibitors (TKIs); however, 20-30% of patients harboring EGFR-activating mutations show poor responses. The mechanisms of such EGFR-TKI primary resistance are still poorly understood. In our case, a non-small cell lung cancer patient developed intrinsic EGFR-TKI resistance and was then confirmed to simultaneously harbor an L858R mutation and ROS1 rearrangement. Salvage chemotherapy plus Endostar showed enduring therapeutic effects, achieving a disease-free survival period of 24 months and overall survival of 30 months. This suggests that co-activation of different oncogenic signal pathways might be a potential mechanism of EGFR-TKI primary resistance. Chemotherapy combined with anti-angiogenesis should be considered an important salvage strategy. Further studies are warranted to verify these findings and explore the underlying mechanisms involved.