Dose Of Bevacizumab Research Articles

Phase I study of nab-paclitaxel, gemcitabine, and bevacizumab in patients with advanced cancers

BackgroundWe performed a phase I modified 3 + 3 dose escalation study to evaluate the safety and activity of bevacizumab plus gemcitabine and nab-paclitaxel in patients with advanced solid tumours.MethodsPatients were given fixed dose gemcitabine plus increasing doses of nab-paclitaxel and bevacizumab. Toxicity, response, and association with VEGF polymorphism was analysed.ResultsThe study enrolled 110 patients who had undergone a median of 3 prior lines of therapy. The median age was 60 years (range, 17–85 years), and 55 patients (50%) had gemcitabine-refractory disease. We observed 3 dose-limiting toxicities during dose escalation and 3 DLTs in expansion cohorts. Dose escalation to 150 mg/m2 nab-paclitaxel and 15 mg/kg bevacizumab with 1000 mg/m2 of gemcitabine was well tolerated with no MTD. One patient with gemcitabine-refractory peritoneal papillary carcinoma had a complete response, 13 patients (13%) had partial responses, and 54 patients (52%) had stable disease ≥12 weeks. Exploratory VEGF single nucleotide polymorphism (SNP) analysis was performed on 13 patients.ConclusionsThe combination of gemcitabine, nab-paclitaxel, and bevacizumab is safe, well-tolerated, and has activity in advanced malignancies, including gemcitabine-refractory tumours. Based on this study, the recommended phase 2 dose is gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2, and bevacizumab 15 mg/kg. VEGF polymorphism data should be evaluated in future bevacizumab-based trials.

Initial trabeculectomy with 5-fluorouracil with or without subconjunctival bevacizumab in the management of pseudoexfoliation glaucoma.

To investigate the outcomes of trabeculectomy with 5-fluorouracil (5-FU) with or without subconjunctival bevacizumab in the surgical management of pseudoexfoliation glaucoma (PXG). This retrospective study consisted of 49 cases with PXG who underwent initial trabeculectomy with 5-FU. The cases were divided into two age- and sex-matched groups. In 23 cases, subconjunctival bevacizumab was injected (1.25mg/0.05mL) at the end of the surgery and in 26 of them the surgery was performed without bevacizumab. The groups were evaluated for the postoperative differences of the intraocular pressure (IOP) and the number of the anti-glaucomatous medications. Independent t, Kolmogorov-Smirnov and Chi square tests were used for statistical analysis. The mean preoperative IOP was 30.91 ± 4.50mmHg under the mean number of 2.4 ± 0.7 drops in bevacizumab group. The IOP decreased to 10.22 ± 2.63mmHg (first week), 10.91 ± 1.88mmHg (first month), 12.35 ± 2.5mmHg (3rd month), 12.65 ± 2.35mmHg (sixth month) and 12.7 ± 1.9mmHg at the final visit. The mean preoperative IOP was 31.27 ± 5.60mmHg under the mean number of 2.3 ± 0.7 drops in without bevacizumab group. The IOP decreased to 10.08 ± 2.59mmHg (first week), 11.00 ± 1.87mmHg (first month), 12.81 ± 2.04 (3rd month), 13.62 ± 2.21mmHg (sixth month) and 12.9 ± 2.4mmHg at the final visit. In both groups, IOP reduced significantly postoperatively. There were no significant differences between the preoperative and the postoperative IOP values. The additional benefit of single dose of intraoperative bevacizumab was not observed in trabeculectomy with 5-FU in PXG.

Low-dose bevacizumab as an effective pre-treatment for peri-tumoral brain edema prior to CyberKnife radiosurgery: A case report

ABSTRACTA 75-y-old Chinese female patient diagnosed with lung adenocarcinoma with brain metastasis suffered severe nausea and vomiting, and these symptoms were contraindications for CyberKnife treatment. Neither mannitol, nor dexamethasone, relieved the symptoms. However, after the patient received a single dose of bevacizumab (200 mg, 2.9 mg/kg), the patient's symptoms were significantly relieved. The patient subsequently completed a successful CyberKnife treatment. In addition, the patient received an oral treatment of gefitinib. At 15 months post treatment, the patient's brain tumor was controlled. Thus, administration of bevacizumab at a low dose (2.9 mg/kg) may significantly alleviate peri-tumoral brain edema and its symptoms, thereby facilitating radiosurgery treatment.

Vitreous changes after intravitreal bevacizumab monotherapy for retinopathy of prematurity: a case series

PurposeReporting a special clinical finding after intravitreal bevacizumab monotherapy for retinopathy of prematurity.MethodsIn a retrospective case series, the clinical courses of five premature infants with similar vitreous changes after a single dose of intravitreal bevacizumab (IVB) injection without additional laser therapy were reported.ResultsThe mean post-conceptional age at IVB injection was 39.8 ± 2.2 (range 37–43) weeks. Localized vitreous syneresis and linear fibrotic vitreous condensation occurred 8.2 ± 2.3 weeks after IVB monotherapy in our patients (15.5% of injections). The mean last post injection visit was 61.6 ± 5.3 weeks (post-conceptional age). Further regression and complete retinal vascularization occurred in all patients.ConclusionsThread-like vitreous condensation with localized vitreous liquefaction may be related to involutional ROP disease itself, combined to anti VEGF therapy and may be a predictor factor for further regression and retinal vascularization. The case series describes a successful response to anti-VEGF monotherapy with no further complications.

Optimizing intrapleural bevacizumab dosing in non-small-cell lung cancer-mediated malignant pleural effusion: less is more.

Intrapleural infusion of bevacizumab (BEV) is an emerging clinical treatment for malignant pleural effusion, but many details of usage need to be determined, especially for the effective dose. We performed a retrospective study of the records of malignant pleural effusion patients from non-small-cell lung cancer who underwent intrapleural infusion of BEV. According to the BEV dose commonly used in clinical, patients were allocated into either low-dose group or high-dose group. A total of 71patients were enrolled in this study. Administration with intrapleural BEV in low dose has less toxicity. For survival data, low- and high-dose groups have no difference. Lower rates of serious BEV-related toxicities and similar survival date are noted when lower dosages are used without diminishing positive clinical impact.

A Population-Based Study of Complications After Colorectal Surgery in Patients Who Have Received Bevacizumab.

Patients receiving Bevacizumab, a vascular endothelial growth factor inhibitor used to treat metastatic colorectal cancer, may be at greater risk of complications after colorectal surgery because of impaired healing. The purpose of this study was to describe population-based rates of complications of colorectal surgery after Bevacizumab treatment and evaluate the relationship between time since last treatment and risk of complications. This was a population-based retrospective cohort study using administrative and cancer registry data. The study was conducted in Ontario, Canada. Patients with metastatic colorectal cancer receiving Bevacizumab between January 2008 and December 2011 were followed for a year after treatment or until death. Administrative data were used to identify patients who underwent colorectal surgery after initiation of Bevacizumab and to determine whether they experienced a complicated postoperative course. The relationship between time since last Bevacizumab treatment (≤28 d, 29 d to 3 mo, and >3 mo) and risk of postoperative complications was evaluated using logistic regression. Of the 2759 patients who received Bevacizumab for the treatment of metastatic colorectal cancer, 265 underwent a colorectal procedure after exposure. The majority had a bowel resection or repair with no stoma (47.5%) and had emergency surgery (61.1%). Overall, 96 (36.2%) had a complicated postoperative course, including 20.4% readmission, 12.5% wound complications, and 7.9% mortality rate within 30 days of surgery. Adjusted multivariate analysis showed no difference in the likelihood of a complicated postoperative course among patients undergoing surgery within 28 days of receiving their last Bevacizumab dose compared with 29 days to 3 months (OR = 1.23 (95% CI, 0.53-2.84), or 3 to 12 months (OR = 0.98 (95% CI, 0.46-2.09) after receiving Bevacizumab. Reliance on administrative data to measure complications limited the scope of this study. Patients with metastatic colorectal cancer requiring colorectal surgery after exposure to Bevacizumab experience substantial morbidity and mortality. The risk of complications is not detectably associated with time since exposure. See Video Abstract at http://links.lww.com/DCR/A474.

Abstract OT2-07-02: CNIO-BR-009 trial: Targeting mitochondrial metabolism with ME-344 in breast cancer upon bevacizumab-induced vascular normalization: A phase 0 randomized clinical trial

Abstract Background: Antiangiogenic agents have shown activity in breast cancer; however their use should be optimized. One potential solution is designing rational combinations based on blocking specific mechanisms of resistance. We previously published that tumors exposed to bevacizumab (BEV) can either experience vascular pruning (followed by increased tumor hypoxia) or vascular normalization (followed by a switch to mitochondrial metabolism). FDG-PET can monitor which pattern is occurring as early as 8 days after the first dose (Mol Oncol; 10: 704-18). We have also shown that when vascular normalization occurs, tumors become highly sensitive to mitochondrial inhibitors (Cell Rep 2016; 15: 1-14). ME-344 is a mitocondrial respiration inhibitor that has recently completed phase I. We sought to test the pharmacodynamic effects of ME-344 and its effects in Ki67 and cleaved caspase 3 (CC3) after single-dose BEV in treatment-naive early HER2-negative breast cancer patients, and whether the effects are restricted or not to those patients experiencing vascular normalization as predicted by FDG-PET. Trial design Placebo-controlled, two-arm, randomized, multicentric phase 0 trial. Treatment-naive HER2-negative breast cancer patients undergo a breast FDG-PET and a baseline tumor biopsy (frozen and paraffinized cores), followed by a single (15 mg/kg) BEV dose. FDG-PET is repeated on day +8. Patients are then randomized to three ME-344 (10 mg/kg) doses or placebo (days +8, +15 and +22). A second biopsy is then harvested, ending trial procedures. Patients can then follow surgery or neoadjuvant treatment according to their physician's criterion. Serial paraffinized biopsies are used to measure Ki67 and CC3; frozen biopsies are used for measuring mitochondrial activity with SDH enzymo-histochemistry (EHC) and assessing vessel architecture. Toxicity is graded with NCI CTC AE V4.03 criteria. Eligibility criteria 1) Women >18 year old; 2) diagnosed of HER2-negative breast cancer; 3) patients must be treatment-naive; 4) ECOG 0/1; 5) lack of neuropathy; 6) primary tumor > 1cm . Specific aims Primary: 1) To study the effects in cell replication and cell death as a surrogate measure of efficacy of ME-344 added to BEV in treatment-naive breast cancer. 2) To determine if FDG-PET accurately detects patients experiencing vascular normalization early after BEV dosing. 3) To observe the effects of ME-344 in mitochondrial activity at the tumor level by performing SDH EHC. 4) To assess if ME-344 efficacy (measured by changes in CC3 and Ki67) is restricted or not to those patients experiencing vascular normalization and mitochondrial switch. Secondary: 5) To study the tolerability of the combination of BEV plus ME-344. Statistical methods The sample size is calculated on the basis of the expected change in Ki-67 staining in the primary tumors in patients receiving ME-344 (-10% on average). With an α and β errors of 5% and 20% respectively, the minimum number of patients necessary to observe a 10% decrease is 20 per arm. Changes in CC3, KI67, SDH activity and FDG-PET SUV will be compared with intra-subject measurements and Z-scores. Accrual: 13 of 40 planned patients. Contact: acsalgado86@gmail.com Citation Format: Cortes A, Apala JV, Malon D, Guerra J, Gion-Cortes M, Manso L, Hornedo J, Gonzalez-Cortijo L, Mouron S, Quintela-Fandino M. CNIO-BR-009 trial: Targeting mitochondrial metabolism with ME-344 in breast cancer upon bevacizumab-induced vascular normalization: A phase 0 randomized clinical trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-02.

Therapeutic Effects of Low-Dose Bevacizumab for the Treatment of Recurrent Brain Metastases

Molecularly targeted therapy has been adopted to treat a number of cancers. Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor, is a representative agent used in molecularly targeted therapeutic regimens. However, the therapeutic effect of bevacizumab for the treatment of brain metastases remains unknown. We report the clinical effects of low dose bevacizumab(≤2.5mg/kg/week)to treat recurrent brain metastases. We retrospectively analyzed patients with brain metastases who had been treated with bevacizumab between 2012 and 2016 at our institution. We identified clinical characteristics, including age, gender, primary tumor site, dose of bevacizumab, therapeutic and adverse effects, and magnetic resonance imaging results. The lesions were assessed with the RECIST criteria based on gadolinium-enhanced T1-weighted, T2-weighted, and FLAIR images. Statistical analysis was performed using t-test and Fisher's exact test. The cohort comprised 26 patients(8 men, 18 women)with a median age of 61 years(range 39-82 years). There were no significant clinical differences between the low dose and non-low dose groups. Patients in the low dose group did not report any adverse effects from bevacizumab. Three patients with brain metastases from colon cancer are illustrated to report the clinical course of low dose bevacizumab. Low dose bevacizumab may be a safe and effective therapeutic option to treat recurrent brain metastases from bevacizumab-sensitive cancers.

Effect of two different doses of intravitreal bevacizumab with temporal retina-sparing laser photocoagulation for retinopathy of prematurity

This study aims to compare the efficacy and safety between two different doses of intravitreal bevacizumab (IVB) injection with temporal retina-sparing laser (TRSL) photocoagulation for retinopathy of prematurity (ROP). We retrospectively evaluated 22 eyes of ROP infants who underwent IVB combined with partial TRSL for stage 3+ zone I or posterior zone II ROP. Laser photocoagulation was applied on the avascular retina, sparing two-disc-diameter width temporal avascular area anterior to ridge. A half dose (0.625 mg) or minimal dose (0.25 mg) of IVB was conducted. Four eyes in minimal dose group were retreated with IVB and laser photocoagulation on the spared retina. Of those 4 retreated eyes, three developed preretinal hemorrhage around the ridge after the first treatment, resulting in fibrotic macular dragging. A half dose of IVB may be more effective than a minimal dose with partial TRSL for ROP. Preretinal hemorrhage may be a harbinger of poor prognosis.

Which dose of bevacizumab is more effective for the treatment of aggressive posterior retinopathy of prematurity: lower or higher dose?

To compare 0.5 mg and 0.625 mg of bevacizumab for treating aggressive posterior retinopathy of prematurity (AP-ROP). The medical records of patients with AP-ROP who were administered intravitreal bevacizumab (IVB) as a primary treatment at a university clinic were evaluated retrospectively. Five eyes of three patients (Group 1) who received 0.625 mg/0.025 ml IVB and 10 eyes of another five patients (Group 2) who received 0.5 mg/0.02 ml IVB were evaluated. Laser photocoagulation was used as additional treatment after relapses. Anatomic results and complications were evaluated in both groups. We evaluated 15 eyes of eight patients (four girls and four boys) with a flat demarcation line at posterior zone 2 and plus disease or stage-3 disease in this study. The mean gestational age of the three babies in Group 1 was 26 ± 1 weeks and the mean birth weight was 835.33 ± 48.01 g. The corresponding values were 25.2 ± 1.6 weeks and 724 ± 139.03 g, respectively, for the five babies in Group 2. Retinal vascularization was completed at a mean postmenstrual duration of 53.6 ± 1.5 weeks without additional treatment in the five eyes in Group 1. Laser photocoagulation for relapse was administered to five of the 10 eyes in Group 2. Retinal vascularization was completed at a mean postmenstrual duration of 47.6 ± 1.5 weeks in the remaining five eyes. None of the patients developed complications such as cataract, glaucoma, retinal tear, retinal or vitreous hemorrhage, or retinal detachment. Although lower IVB doses in the treatment of AP-ROP are expected to be safer in terms of local and systemic side effects in premature infants, these patients may require additional treatment with IVB or laser photocoagulation.

Effects of Ranibizumab, Bevacizumab, and Aflibercept on Senescent Retinal Pigment Epithelial Cells.

PurposeAnti-vascular endothelial growth factor (VEGF) agents have been used for the last 10 years, but their safety profile, including cytotoxicity against various ocular cells such as retinal pigment epithelial (RPE) cells, remains a serious concern. Safety studies of VEGF agents conducted to date have primarily relied on healthy RPE cells. In this study, we assessed the safety of three anti-VEGF agents, namely, ranibizumab, bevacizumab, and aflibercept, on senescent RPE cells.MethodsSenescent human induced pluripotent stem cell-derived RPE cells were generated by continuous replication and confirmed with senescence biomarkers. The viability, proliferation, protein expression, and phagocytosis of the senescent RPE cells were characterized 3 days after anti-VEGF treatment with clinical doses of ranibizumab, bevacizumab, or aflibercept.ResultsClinical doses of ranibizumab, bevacizumab, or aflibercept did not decrease the viability or alter proliferation of senescent RPE cells. In addition, the anti-VEGF agents did not induce additional senescence, impair the protein expression of zonula occludens-1 and RPE65, or reduce the phagocytosis capacity of senescent RPE cells.ConclusionsClinical dosages of ranibizumab, bevacizumab, or aflibercept do not induce significant cytotoxicity in senescent RPE cells.

Phase II randomized trial of carboplatin, paclitaxel, bevacizumab with or without cixutumumab (IMC-A12) in patients with advanced non-squamous, non-small-cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3508)

BackgroundCixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor that can potentially reverse resistance and enhance the efficacy of chemotherapy. MethodsBevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small-cell lung cancer and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of six cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg i.v. weekly (arm B). ResultsOf 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI 5.4–7.1) in arm A versus 7 months (95% CI 5.7–7.6) in arm B (P = 0.33); hazard ratio 0.92 (95% CI 0.65–1.31). Objective response was 46.2% versus 58.7% in arm A versus arm B (P = 0.15). The median overall survival was 16.2 months in arm A versus 16.1 months in arm B (P = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab. ConclusionsThe addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in non-small-cell lung cancer. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II trials. ClinicalTrials.gov IdentifierNCT00955305

One-Year Results of a Trial Comparing 2 Doses of Intravitreal Ziv-aflibercept versus Bevacizumab for Treatment of Diabetic Macular Edema

To report 1-year findings of a trial comparing 2 doses of intravitreal ziv-aflibercept (IVZ) with intravitreal bevacizumab (IVB) for treatment of center-involving diabetic macular edema (DME). Three-armed double-blind randomized clinical trial. A total of 123 eyes with center-involving DME. In this clinical trial, eyes with DME were randomly assigned to 2.5 mg intravitreal ziv-aflibercept (42 eyes), 1.25 mg intravitreal ziv-aflibercept (42 eyes), and 1.25 mg IVB injections (39 eyes), every 4 weeks for 3 loading injections and then every 4 weeks for IVB and every 8 weeks for ziv-aflibercept injections. The patients were followed up to 1 year with complete ophthalmologic examination and central macular thickness (CMT) measurement by optical coherence tomography. Change in best-corrected visual acuity (BCVA) at 1 year. Although no significant difference was evident between the 2 ziv-aflibercept groups at 1 year, BCVA change was significantly better in both ziv-aflibercept groups (-0.33±0.26 and-0.38±0.34 logarithm of the minimum angle of resolution (logMAR) equal to 16 and 18 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, for IVZ 2.5 and 1.25 mg, respectively) than in the IVB group (-0.26±0.35 logMAR, equal to 14 ETDRS letters) at final follow-up (P= 0.007 for IVZ 2.5 mg and P= 0.029 for IVZ 1.25 mg). Regarding CMT changes, there was no significant difference between the 2 ziv-aflibercept groups; however, a significantly greater reduction in CMT was observed in the ziv-aflibercept 2.5 mg group in comparison to the IVB group at 1 year (P= 0.029). Subgroup analysis disclosed no difference in BCVA outcomes at 1 year among the eyes with baseline BCVA >20/50. In the eyes with baseline BCVA ≤20/50, however, the improvement was significantly better at 1 year in both ziv-aflibercept groups compared with the IVB group (P= 0.002 for IVZ 2.5 mg and P= 0.001 for IVZ1.25 mg). The 1-year results of this trial disclosed more vision improvement with IVZ compared with IVB in the treatment of center-involving DME. This stronger effect of IVZ, however, was detected in the eyes with initial worse level of vision (≤20/50).

Efficacy and safety of bevacizumab treatment for refractory brain edema: Case report.

Objective:This retrospective study investigated the efficacy and safety of bevacizumab treatment for refractory brain edema.Methods:Between March 2009 and December 2015, bevacizumab was used to treat 59 cases of brain metastatic patients with refractory brain edema. The median dose of bevacizumab was 4.68 mg/kg (range 2.8–6.52 mg/kg). The clinical-pathological data, the efficacy, and the side effects of bevacizumab were recorded. Magnetic resonance imaging (MRI) was performed before and after bevacizumab treatment. Tumor and edema volumes were measured separately.Results:The clinical symptoms of 50 out of 59 cases (84.74%) improved the day after the bevacizumab treatment, and the edema volumes of 55 (93.22%) cases were reduced after the bevacizumab treatment. The average edema volume was significantly reduced after bevacizumab treatment from 125,583.43 ± 14,093.27 to 71,613.42 ± 9473.42 mm3 (Mann–Whitney rank test, P < .01), and the average edema index was significantly reduced from 25.66 ± 11.54 to 17.87 ± 6.87 (Mann–Whitney rank test, P < .01). One patient died from a hemorrhage due to a cancerous-ulcer of the maxillary sinus. The main complication observed was hypertension, which was observed in 11 cases (18.6%).Conclusion:The effective rate of bevacizumab for refractory brain edema is 84.74%. Hypertension was the main side effect of the bevacizumab treatment. Bevacizumab is an effective and relatively safe treatment for brain edema.

Ultra-low dose of intravitreal bevacizumab in retinopathy of prematurity.

We aimed to investigate the effectivity of the 0.0625mg dose of bevacizumab in patients with retinopathy of prematurity (ROP) and compare the results with 0.625mg dose of intravitreal bevacizumab (IVB) injection. The medical records of the patients with type 1 ROP who received IVB monotherapy were retrospectively reviewed. Demographic and clinical characteristics of the patients were recorded. The patients were classified into two groups with respect to received dose of bevacizumab as follows: group F (n=46) (full dose of bevacizumab-0.625mg/0.025ml) and group L (n=45) (low dose (one tenth) of bevacizumab-0.0625mg/0.025ml). Both treatment dose regimens have similar outcomes. Moreover, the mean retinal vascularization time seemed to be significantly higher in group F compared to group L, 168±65 and 97±29days, respectively (p<0.001). Disappearance of plus sign is observed earlier in group F (2.45±1.7 vs 3.66±2.46days, respectively, p=0.03). The low dose (0.0625mg) of IVB treatment was effective as full (0.625mg) dose in ROP treatment. Moreover, our results showed that low-dose treatment might provide faster retinal vascularization than the regular used dose. On the other hand, disappearance of the plus sign takes longer time in patients treated with low dose compared to eyes treated with full dose of IVB that should be taken into account.

Cardiovascular Adverse Events in Patients With Cancer Treated With Bevacizumab: A Meta-Analysis of More Than 20000 Patients.

BackgroundThe monoclonal antibody bevacizumab effectively inhibits angiogenesis in several types of cancers by blocking vascular endothelial growth factor. However, life‐threatening cardiovascular adverse effects could limit its use and may warrant specific follow‐up strategies.Methods and ResultsWe systematically searched MEDLINE, Cochrane, EMBASE, and Web of Science for randomized controlled trials published until November 2016 that assessed patients with cancer treated with or without bevacizumab in addition to standard chemotherapy. A total of 20 050 patients with a broad range of cancer types from 22 studies were included in this analysis (10 394 in the bevacizumab group and 9656 in the control group). The risks of arterial and venous adverse events were higher in the bevacizumab groups (relative risk [RR], 1.37; 95% CI, 1.10–1.70 [P=0.004] and RR, 1.29; 95% CI, 1.12–1.47 [P<0.001], respectively), and more arterial adverse events occurred in patients taking high‐dose bevacizumab regimens. Bevacizumab treatment was associated with the highest risk of cardiac and cerebral ischemia in the high‐dose bevacizumab groups (RR, 4.4; 95% CI, 1.59–12.70 [P=0.004] and RR, 6.67; 95% CI, 2.17–20.66 [P=0.001], respectively). In addition, the risk of bleeding and arterial hypertension were higher in the bevacizumab groups (RR, 2.74; 95% CI, 2.38–3.15 [P<0.001] and RR, 4.73; 95% CI, 4.15–5.39 [P<0.00001], respectively), with higher values for patiens taking high‐dose regimens.ConclusionsTreatment with bevacizumab increases the risk of arterial adverse events, particularly cardiac and cerebral ischemia, venous adverse events, bleeding, and arterial hypertension. This risk is additionally increased with high doses of bevacizumab. Further studies should determine the appropriate options for cardio‐oncology management.Clinical Trial Registration URL: https://www.crd.york.ac.uk. Unique identifier: PROSPERO(CRD42016054305).

THE USE OF L-PRF (LEUKOCYTE-PLATELET-RICH FIBRIN) IN THE TREATMENT OF MRONJ

Medication-related osteonecrosis of the jaw (MRONJ) is the bone necrosis of the jaws and can be associated with antiresorptive or antiangiogenic therapy. A 79-year-old female patient with history of ovarian cancer received 14 doses of bevacizumab. The maxillary total prosthesis caused 2 lesions with painful symptoms, and purulent drainage in the oral and nasal cavity. CBCT shows kidnapping and bone lysis staged as MRONJ 3 in the hard palate and 2 in the alveolar ridge. Both lesions were removed of all necrotic bone beside an amalgam tattoo in the bone tissue of the alveolar ridge and joined the L-PRF primary closure of the wound. Six months after surgery, the patient had complete healing confirmed by CBCT. The L-PRF association with the surgical procedure is suggested to be a good alternative in the treatment of MRONJ. This should spark a discussion to define the role of amalgam tattoo as an additional factor in the case of MRONJ.

Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma

Toestablish the maximum tolerated dose of a 3-fraction hypofractionated stereotactic reirradiation schedule when delivered with concomitant bevacizumab to treat recurrent high-grade gliomas. Patients with recurrent high-grade glioma with Karnofsky performance status ≥60, history of standard fractionated initial radiation, tumor volume at recurrence ≤40cm3, and absence of brainstem or corpus callosum involvement were eligible. A standard 3+3 phase 1 dose escalation trial design was utilized, with dose-limiting toxicities defined as any grade 3 to 5 toxicities possibly, probably, or definitely related to radiation. Bevacizumab was given at a dose of 10mg/kg every 2weeks. Hypofractionated stereotactic reirradiation was initiated after 2 bevacizumab doses, delivered in 3 fractions every other day, starting at 9Gy per fraction. A total of 3 patients were enrolled at the 9Gy×3 dose level cohort, 5 in the 10Gy×3 cohort, and 7 in the 11Gy×3 cohort. One dose-limiting toxicity of grade 3 fatigue and cognitive deterioration possibly related to hypofractionated stereotactic reirradiation was observed in the 11Gy×3 cohort, and this dose was declared the maximum tolerated dose in combination with bevacizumab. Although no symptomatic radionecrosis was observed, substantial treatment-related effects and necrosis were observed in resected specimens. The intent-to-treat median overall survival was 13months. Reirradiation using a 3-fraction schedule with bevacizumab support is feasible and reasonably well tolerated. Dose-escalation was possible up to 11Gy×3, which achieves a near doubling in the delivered biological equivalent dose to normal brain, in comparison with our previous 6 Gy×5 schedule. Promising overall survival warrants further investigation.

Optimizing bevacizumab dosing in glioblastoma: less is more.

Compared to traditional chemotherapies, where dose limiting toxicities represent the maximum possible dose, monoclonal antibody therapies are used at doses well below maximum tolerated dose. However, there has been little effort to ascertain whether there is a submaximal dose at which the efficacy/complication ratio is maximized. Thus, despite the general practice of using Bevacizumab (BEV) at dosages of 10mg/kg every other week for glioma patients, there has not been much prior work examining whether the relatively high complication rates reported with this agent can be decreased by lowering the dose without impairing efficacy. We assessed charts from 80 patients who received BEV for glioblastoma to survey the incidence of complications relative to BEV dose. All patients were treated with standard upfront chemoradiation. The toxicity was graded based on the NCI CTCAE, version 4.03. The rate of BEV serious related adverse events was 12.5% (n = 10/80). There were no serious adverse events (≥grade 3) when the administered dose was (<3mg/kg/week), compared to a 21% incidence in those who received higher doses (≥3mg/kg/week) (P < 0.01). Importantly, the three patient deaths attributable to BEV administration occurred in patients receiving higher doses. Patients who received lower doses also had a better survival rate, although this did not reach statistical significance [median OS 39 for low dose group vs. 17.3 for high dose group (P = 0.07)]. Lower rates of serious BEV related toxicities are noted when lower dosages are used without diminishing positive clinical impact. Further work aimed at optimizing BEV dosage is justified.

Ten-minute administration of bevacizumab

ObjectiveTo describe our experience of administering bevacizumab doses at 0.5 mg/kg/min. The main objective of the study was to evaluate the safety of this regimen of administration. Secondary endpoints were...