Amino acid PET vs. RANO MRI for prediction of overall survival in patients with recurrent high grade glioma under bevacizumab therapy.

PURPOSE: To summarize evidence on the comparative value of amino acid (AA) PET and conventional MRI for prediction of overall survival (OS) in patients with recurrent high grade glioma (rHGG) under bevacizumab therapy. METHODS: Medical databases were screened for studies with individual data on OS, follow-up MRI, and PET findings in the same patient. MRI images were assessed according to the RANO criteria. A receiver operating characteristic curve analysis was used to predict OS at 9 months. RESULTS: Five studies with a total of 72 patients were included. Median OS was significantly lower in the PET-positive than in the PET-negative group. PET findings predicted OS with a pooled sensitivity and specificity of 76% and 71%, respectively. Corresponding values for MRI were 32% and 82%. Area under the curve and sensitivity were significantly higher for PET than for MRI. CONCLUSION: For monitoring of patients with rHGG under bevacizumab therapy, AA-PET should be preferred over RANO MRI.

Demonstrating analytical similarity of a biosimilar HLX04 to bevacizumab with a panel of state-of-the-art methods and tiering of quality attributes.

Therapeutical monoclonal antibodies are structurally and functionally complex, whereas the innovator's manufacturing processes are proprietary. With respect to the similarity assessment, a proposed biosimilar product needs to demonstrate a side-by-side comparison between the reference product (RP) and candidate product in terms of physicochemical properties and biological activities, as well as nonclinical and clinical outcomes. Here, a comprehensive analytical similarity assessment was performed for in-depth comparison of HLX04, China-sourced Avastin® (CN-Avastin®), and Europe-sourced Avastin® (EU-Avastin®) following a tier-based quality attribute (QA) evaluation. A series of orthogonal and state-of-the-art analytical techniques were developed for the assessment. Ten lots of HLX04 were compared with 29 lots bevacizumab RP. Referred to the characterization results, HLX04 is highly similar to the RPs with respect to physicochemical properties and biological functions. In addition, HLX04 was found with similar stability and degradation behaviors upon multiple stressed conditions to bevacizumab. Minor differences were observed in glycosylation, aggregates, FcγRIIIa(F), and FcγRIIIa(V) binding activities; nevertheless, they were evaluated and demonstrated not to impact clinical outcomes. According to the reported clinical results, the totality of evidence, including the pharmacokinetic, efficacy, safety, and immunogenicity, further shows that HLX04 is similar to CN-/EU-Avastin®.

Bevacizumab as treatment option for recurrent respiratory papillomatosis: a systematic review.

PURPOSE: To this day, there is no cure for recurrent respiratory papillomatosis (RRP). Multiple surgical procedures are performed to achieve symptom relief and prevention of airway obstruction. A promising drug for RRP is the vascular endothelial growth factor (VEGF) binding antibody bevacizumab. This chemotherapeutic agent has an angiogenesis-inhibiting effect which inhibits tumor growth. The objective of this review was to investigate the efficacy of bevacizumab as treatment option for RRP, and to explore the difference of its effects between intralesional and systemic treatment. METHODS: A systematic search was conducted in Cochrane, PubMed, and Embase. Articles were included if bevacizumab treatment was given intralesionally and/or systemically. The methodological quality of the studies was assessed using the CAse REport (CARE) guidelines. RESULTS: Of 585 unique articles screened by title and abstract, 15 studies were included, yielding a total of 64 patients. In 95% of the patients treated with systemic bevacizumab, the post-bevacizumab surgical interval was considerably prolonged. More than half of them did not need any surgical intervention during mean follow-up of 21.6 months. Treatment with intralesional bevacizumab showed a lower efficacy: in 62% of the patients, the post-bevacizumab surgical interval (mean, 1.8 months follow-up) was extended when compared to the interval before the treatment. CONCLUSION: Systemically and intralesionally administered bevacizumab are effective treatment options for severe RRP. A systemic administration might be the treatment of first choice. Further prospective research with long term follow-up is advocated to elucidate this important topic.

Imaging acute effects of bevacizumab on tumor vascular kinetics in a preclinical orthotopic model of U251 glioma.

The effect of a human vascular endothelial growth factor antibody on the vasculature of human tumor grown in rat brain was studied. Using dynamic contrast-enhanced magnetic resonance imaging, the effects of intravenous bevacizumab (Avastin; 10 mg/kg) were examined before and at postadministration times of 1, 2, 4, 8, 12 and 24 h (N = 26; 4-5 per time point) in a rat model of orthotopic, U251 glioblastoma (GBM). The commonly estimated vascular parameters for an MR contrast agent were: (i) plasma distribution volume (vp ), (ii) forward volumetric transfer constant (Ktrans ) and (iii) reverse transfer constant (kep ). In addition, extracellular distribution volume (VD ) was estimated in the tumor (VD-tumor ), tumor edge (VD-edge ) and the mostly normal tumor periphery (VD-peri ), along with tumor blood flow (TBF), peri-tumoral hydraulic conductivity (K) and interstitial flow (Flux) and tumor interstitial fluid pressure (TIFP). Studied as % changes from baseline, the 2-h post-treatment time point began showing significant decreases in vp , VD-tumor, VD-edge and VD-peri , as well as K, with these changes persisting at 4 and 8 h in vp , K, VD-tumor, -edge and -peri (t-tests; p < 0.05-0.01). Decreases in Ktrans were observed at the 2- and 4-h time points (p < 0.05), while interstitial volume fraction (ve ; = Ktrans /kep ) showed a significant decrease only at the 2-h time point (p < 0.05). Sustained decreases in Flux were observed from 2 to 24 h (p < 0.01) while TBF and TIFP showed delayed responses, increases in the former at 12 and 24 h and a decrease in the latter only at 12 h. These imaging biomarkers of tumor vascular kinetics describe the short-term temporal changes in physical spaces and fluid flows in a model of GBM after Avastin administration.

Acute and chronic effects of intravitreal bevacizumab on lung biomarkers of angiogenesis in the rat exposed to neonatal intermittent hypoxia.

PURPOSE/AIM: Intravitreal bevacizumab (Avastin) is an irreversible vascular endothelial growth factor (VEGF) inhibitor used to treat severe retinopathy of prematurity (ROP) in extremely low gestational age neonates (ELGANs). ELGANs who are at the highest risk for developing severe ROP often experience brief intermittent hypoxia (IH) episodes which may cause oxidative damage. We tested the hypothesis that intravitreal Avastin leaks into the systemic circulation during exposure to IH and has adverse effects on biomarkers of pulmonary microvascular maturation, thus leading to pulmonary hemorrhage and long-term pulmonary sequelae. METHODS: Neonatal rats at postnatal day (PN) 0 (birth) were exposed to either: 1) hyperoxia (50% O2) or 2) neonatal IH (50% O2 with brief episodes of 12% O2) from PN0 to PN14. Room air (RA) littermates served as controls. At PN14, the time of eye opening in rats, a single dose of Avastin (0.125 mg in 5 µL) was injected into the vitreous cavity of the left eyes. A control group received equivalent volume saline. At PN23 and PN45, blood gases, lung-to-body weight ratios, histology, immunofluorescence, and lung biomarkers of angiogenesis were examined. RESULTS: At PN23, Avastin increased lung VEGF, nitric oxide derivatives (NOx), and hypoxia-inducible factor (HIF)1a in the hyperoxia-exposed groups, but decreased soluble VEGFR-1 (sVEGFR-1). At PN45, lungs from animals exposed to neonatal IH and treated with Avastin were severely hemorrhagic with morphologic changes in lung architecture consistent with chronic lung disease. This was associated with higher VEGF and NOx levels, and lower insulin-like growth factor (IGF)-I and sVEGFR-1. CONCLUSIONS: These findings prove our hypothesis that intravitreal Avastin penetrates the blood-ocular barrier in IH and alters lung biomarkers of angiogenesis. Avastin targeting of VEGF could affect normal lung development which may be exaggerated under pathologic conditions such as IH, ultimately leading to vascular permeability, vessel rupture, and pulmonary hemorrhage.

Combination of Fish Oil and Selenium Enhances Anticancer Efficacy and Targets Multiple Signaling Pathways in Anti-VEGF Agent Treated-TNBC Tumor-Bearing Mice.

Fish oil (FO) and selenium (Se) possess antiangiogenic potential in malignant tumors. This study aimed to determine whether combination of FO and Se enhanced treatment efficacy of low-dose antiangiogenic agent Avastin (bevacizumab) in a dose-dependent manner and targeted multiple signaling pathways in triple-negative breast cancer (TNBC)-bearing mice. Randomized into five groups, mice received treatment with either physiological saline (control), Avastin alone, or Avastin in combination with low, medium, and high doses of FO/Se. The target signaling molecules for anticancer were determined either by measuring protein or mRNA expression. Avastin-treated mice receiving FO/Se showed lower tumor growth and metastasis than did mice treated with Avastin alone. Combination-treated mice exhibited lower expressions in multiple proangiogenic (growth) factors and their membrane receptors, and altered cytoplasmic signaling molecules (PI3K-PTEN-AKT-TSC-mTOR-p70S6K-4EBP1, Ras-Raf-MEK-ERK, c-Src-JAK2-STAT3-TMEPAI-Smad, LKB1-AMPK, and GSK3ß/ß-catenin). Dose-dependent inhibition of down-stream targets including epithelial-to-mesenchymal transition transcription factors, nuclear cyclin and cyclin-dependent kinases, cancer stem cell markers, heat shock protein (HSP-90), hypoxia-inducible factors (HIF-1α/-2α), matrix metalloprotease (MMP-9), and increased apoptosis were observed. These results suggest that combination treatment with FO and Se increases the therapeutic efficacy of Avastin against TNBC in a dose-dependent manner through multiple signaling pathways in membrane, cytoplasmic, and nucleic targets.

Heparin potentiates Avastin-mediated inhibition of VEGF binding to fibronectin and rescues Avastin activity at acidic pH.

Vascular endothelial growth factor-A (VEGF) plays a critical role in stimulating angiogenesis in normal and disease states. Anti-VEGF antibodies have been developed to manage pathological angiogenesis. Bevacizumab, sold under the brand name Avastin, is a humanized mAb that binds VEGF and blocks its binding to its signaling receptor, VEGF receptor 2, and is used to treat patients with a variety of cancers or retinal disorders. The ability of Avastin to modulate other nonreceptor interactions of VEGF has not been fully defined. In this study, we investigated Avastin's capacity to modulate VEGF165 binding to porcine aortic endothelial cells and to heparin and fibronectin (FN) across a range of pH values (pH 5-8). We observed that Avastin slightly enhanced VEGF binding to heparin and that heparin increased VEGF binding to Avastin. In contrast, Avastin inhibited VEGF binding to cells and FN, yet Avastin could still bind to VEGF that was bound to FN, indicating that these binding events are not mutually exclusive. Avastin binding to VEGF was dramatically reduced at acidic pH values (pH 5.0-6.5), whereas VEGF binding to FN and nonreceptor sites on cells was enhanced. Interestingly, the reduced Avastin-VEGF binding at acidic pH was rescued by heparin, as was Avastin's ability to inhibit VEGF binding to cells. These results suggest that heparin might be used to expand the clinical utility of Avastin. Our findings highlight the importance of defining the range of VEGF interactions to fully predict antibody activity within a complex biological setting.

Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil, and Leucovorin Versus Oxaliplatin, 5-Fluorouracil, Leucovorin, and Bevacizumab for Patients with Stage II or III Rectal Cancer Receiving Preoperative Chemoradiation: A Trial of the ECOG-ACRIN Research Group (E5204).

BACKGROUND: The addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum. SUBJECTS, MATERIALS, AND METHODS: Patients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles. RESULTS: E5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3-4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue. CONCLUSION: At 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer. IMPLICATIONS FOR PRACTICE: At 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.

Off-label use of bevacizumab for wet age-related macular degeneration in Europe.

PURPOSE: To analyse current off-label use of bevacizumab for wet age-related macular degeneration (AMD) in Europe. METHODS: The study was conducted as a combined survey and literature review. It included the 22 most populous countries in Europe. In each country, ophthalmologists with particular knowledge about off-label treatment responded to a questionnaire. RESULTS: Answers were obtained from twenty European countries. The off-label use of bevacizumab for wet AMD greatly differed between nations; the bevacizumab proportion varied from non-existent (0%) to very high (97%). There were also large disparities within single countries (e.g. 0-80%), which were attributable to differences in regional decision-making. Both governmental institutions and national ophthalmological societies expressed highly diverging opinions on the use of off-label treatment. Intravitreal administration of bevacizumab had been a matter of legal dispute in several countries. The question about responsibility for off-label therapy mainly remained unanswered. CONCLUSIONS: There was a highly varying utilization of bevacizumab between European countries. Despite an intention of a consistent approach to medical regulations, Europe has not yet reached a professional or political consensus on the ophthalmic off-label use of bevacizumab.

Anti-angiogenic effect of adiponectin in human primary microvascular and macrovascular endothelial cells.

Neovascularization in retina and choroid involves interplay of many cytokines and growth factors. Vascular endothelial growth factor (VEGF) being a pro-angiogenic molecule has been found to be high in aqueous and vitreous humour of patients with proliferative diabetic retinopathy (PDR). VEGF is also found in the fibroblast and retinal pigment epithelial cells (RPE) of choroidal neovascular (CNV) membranes isolated from patients. Though anti-VEGF agents cause regression of clinically visible new vessels, there is evidence that they increase the occurrence of retinal tractional detachment and other adverse effects in PDR and CNV treatments. Adiponectin (APN) is a cytokine, found to be involved in the pathobiology of PDR. It is unclear whether APN plays a reparative or pathological role in the disease condition. In this study, we explored the effect of APN on tube formation in the primary culture of human umbilical vein macrovascular endothelial cells (HUVEC), human retinal microvascular endothelial cells (hREC) and human choroidal endothelial cells (hCEC). Anti-VEGF agent, bevacizumab (avastin) was used as a control. Full-length pAc-APN transfected in HUVEC, hRECs and hCECs inhibited basal tube formation and migration comparable to bevacizumab (Avastin™). In hRECs, full length pAc-APN reduced VEGF or PDR vitreous mediated migration. In a similar way, rAPN significantly disrupted VEGF and PDR vitreous induced tube formation in HUVEC and hREC. Moreover, rAPN significantly reduced VEGF influenced proliferation and phosphorylation of ERK1/2 in hREC. Altogether, our study suggests that APN may be effective in the treatment of retinal neovascularization.

AVAiLABLE NIS - AVASTIN® in lung cancer treatment in routine oncology practice in Germany.

BACKGROUND: Bevacizumab (Avastin®), a recombinant humanized monoclonal antibody, in combination with platinum-doublet chemotherapy has become a routine treatment for advanced non-small-cell lung cancer (NSCLC). The post-authorization, non-interventional study 'AVAiLABLE' assessed the effectiveness and safety of bevacizumab combined with chemotherapy as first-line treatment. METHODS: Nine hundred and eighty-seven adult patients (mean age 61.5 years, 59.8% male) with non-resectable advanced, metastatic or recurrent, predominantly non-squamous NSCLC were evaluated at 185 sites across Germany. 72.8% of the patients had stage IV disease at start of observation, 90.1% had histologically confirmed adenocarcinoma and 80.8% met the bevacizumab label 'NSCLC other than predominantly squamous cell histology'. According to bevacizumab label, chemotherapy plus bevacizumab was recommended, followed by bevacizumab maintenance therapy. Effectiveness endpoints included response rates and progression-free survival (PFS); safety endpoints comprised adverse drug reactions (ADRs). Patients were followed until progression or intolerable toxicity. Data were evaluated by descriptive statistical methods. RESULTS: Median PFS was 7.4 months (95% CI: 7.1; 8.4), overall response rate (ORR) 45.6% and disease control rate (DCR) 75%. The majority of patients (72.7%) achieved partial response or stable disease. Complete response was reached by 2.3%. 33.6% of patients experienced an ADR of grade ≥ 3. Bevacizumab-related ADRs of grade ≥ 3 occurred in 5.7% of patients, with the highest incidence for leukopenia, neutropenia, and hypertension. CONCLUSIONS: Results of the non-interventional study 'AVAiLABLE' confirmed the effectiveness and safety of bevacizumab in combination with platinum-based chemotherapy as first-line treatment for advanced NSCLC in accordance with previous studies. No new safety signals were identified. Maintenance therapy with bevacizumab was well tolerated and safe even over extended periods (> 20 cycles). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02596958; registered on 4 November 2015.

Rescue bevacizumab following symptomatic pseudoprogression of a tectal glioma post-radiotherapy: a case report and review of the literature.

PURPOSE: Radiation-induced pseudoprogression is a subacute clinical entity that is distinct from radiation necrosis and mimics tumor progression. Bevacizumab is a well-described treatment option for radiation necrosis, but its role in pseudoprogression is not clearly defined. METHODS: We report a case of radiation-induced pseudoprogression rescued with bevacizumab in a 20-year-old man with a biopsy-proven low-grade astrocytoma of the tectum. A review of the literature was also conducted specific to bevacizumab as a treatment for symptomatic pseudoprogression after radiotherapy for CNS tumors. RESULTS: This patient was treated with definitive intensity modulated stereotactic radiotherapy at a total dose of 54 Gy delivered in 30 daily fractions. Six weeks after radiotherapy the patient developed progressive headache, weakness and a documented deterioration in vision, which was accompanied by worsening of radiographic findings. A diagnosis of pseudoprogression was made and after limited benefit from a trial of dexamethasone, four cycles of bevacizumab were administered which resulted in rapid clinical and radiographic improvement. CONCLUSIONS: Our findings support the potential use of bevacizumab as a rescue agent for symptomatic pseudoprogression.

Efficacy and safety of bevacizumab for vestibular schwannoma in neurofibromatosis type 2: a systematic review and meta-analysis of treatment outcomes.

BACKGROUND: Individual evidence suggests that the anti-angiogenic agent bevacizumab may control vestibular schwannoma (VS) growth and promote hearing preservation in patients with neurofibromatosis type 2 (NF2). However, such metadata has yet to be consolidated, as well as its side-effect profile yet to be fully understood. Our aim was to pool systematically-identified metadata in the literature and substantiate the clinical efficacy and safety of bevacizumab with respect to radiographic tumor response, hearing, and treatment outcomes. METHODS: Searches of seven electronic databases from inception to March 2019 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. The incidence of outcomes was then extracted and pooled by random-effects meta-analysis of proportions. RESULTS: Eight articles reporting 161 NF2 patients with 196 assessable VS met satisfied all criteria. Radiographic response to bevacizumab was partial regression in 41% (95% CI 31-51%), no change in 47% (95% CI 39-55%), and tumor progression in 7% (95% CI 1-15%). In patients with assessable audiometric data, bevacizumab treatment resulted in hearing improvement in 20% (95% CI 9-33%), stability in 69% (95% CI 51-85%) and additional loss in 6% (95% CI 1-15%) Serious bevacizumab toxicity was observed in 17% (95% CI 10-26%). Subsequent surgical intervention was required in 11% (95% CI 2-20%). CONCLUSIONS: Bevacizumab may arrest both tumor progression and hearing loss in select NF2 patients presenting with VS lesions. However, a considerable proportion of patients are anticipated to experience serious adverse events; correspondingly, judicious use of bevacizumab for symptomatic management of VS in NF2 is recommended.

Evaluation of vitreoretinal interface changes in patients receiving intravitreal anti-VEGF therapy.

PURPOSE: To study the effects of repeated intravitreal injection of anti-VEGF drug bevacizumab on the vitreoretinal interface (VRI). METHODS: Patients undergoing intravitreal injection of bevacizumab were enrolled. Eyes with media haze, uveitis, high myopia, history of cataract surgery or laser capsulotomy in last 6 months and complicated pseudophakia were excluded. VRI evaluation was done monthly for a minimum of 6 months. The nature and timing of the change(s) event was recorded. RESULTS: A total of 100 eyes were evaluated. Thirty-seven eyes developed new vitreoretinal interface change event (VICE). Pseudophakia (OR = 5.23, 95% CI = 1.99-14.07, p = 0.001), pre-injection VRI abnormality (OR = 2.63, 95% CI = 1.13-6.14, p = 0.024) and older age at enrollment (62.6 ± 13.9 vs. 56.3 ± 14 years) were risk factors for development of VICE. Eighty percent of interface events occurred in the first 3 months of therapy. Eight needed surgical intervention for consequences of vitreoretinal separation. CONCLUSION: VICE is not infrequent in eyes receiving anti-VEGF therapy though rarely need surgical intervention. The first 3 months are the critical months to watch out for these events. The treating ophthalmologists must keep the risk factors for development of in mind and monitor and counsel patients accordingly.

Pars plana vitrectomy in vitreous hemorrhage with or without Intravitreal Bevacizumab a comparative overview.

OBJECTIVE: To compare the success in patients having vitreous hemorrhage undergoing pars plana vitrectomy with or without preoperative intravitreal injection of Bevacizumab. METHODS: This Randomized controlled trial was conducted at Department of Ophthalmology, Jinnah Postgraduate Medical Centre. Karachi. Duration of study was six months from January 2010 to June 2010. In this study 56 patients of advanced diabetic eye disease were divided into two groups. Patients in Group-A underwent three ports pars plana vitrectomy with preoperative intravitreal injection of Bevacizumab (Avastin) 1.25mg/0.05ml, 3.5mm from the limbus seven days before surgery and in Group-B patients underwent vitrectomy without preoperative intravitreal Bevacizumab (Avastin). Intraoperative bleeding was monitored in both groups and was graded as no bleeding, mild bleeding and severe bleeding. The results were statistically analyzed through computer software SPSS 17. RESULTS: Twenty eight patients in Group-A who were given an injection of intravitreal Bevacizumab (Avastin) before surgery, intraoperative bleeding monitored was, no bleeding in 17 cases (60.7%), mild was observed in 6 cases (21.4%) and severe bleeding requiring diathermy to stop was observed in only 5 cases (17.9%). 28 patients in Group-B that underwent surgery without Avastin no bleeding was observed in only 2 cases (7.1%), mild in 6 cases (21.4%) and severe in 20 cases (71.4%). CONCLUSIONS: Intravitreal injection of Bevacizumab (Avastin) was effective before vitrectomy in the surgical management of Advanced Diabetic Eye disease.

Increased genitourinary fistula rate after bevacizumab in recurrent cervical cancer patients initially treated with definitive radiochemotherapy and image-guided adaptive brachytherapy.

BACKGROUND AND PURPOSE: Patients with recurrent cervical cancer (RecCC) who received definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT) as primary treatment are currently treated in our institution with palliative intent by chemotherapy (CHT) combined with bevacizumab (BEV). We aim to evaluate the risk of gastrointestinal (GI)/genitourinary (GU) fistula formation in these patients. MATERIALS AND METHODS: Data of 35 consecutive patients with RecCC treated initially with radiochemotherapy and IGABT were collected. Known and presumed risk factors associated with fistula formation were evaluated. Fistula rate was compared between patients receiving CHT or CHT+BEV. RESULTS: Of the 35 patients, 25 received CHT and 10 patients received CHT+BEV. Clinical characteristics were comparable. Fistulae were reported in 6 patients: two fistulae (8%) in the CHT group, four (40%) in the CHT+BEV group. GU fistula occurred in the CHT+BEV group only (3/4). Of these 6 patients with fistulae, 5 (83%) had undergone previous invasive procedures after the diagnosis of RecCC and 1 patient had undergone pelvic re-irradiation; 3/6 patients had developed a local recurrence. No other risk factors for fistula formation were identified. CONCLUSION: In patients with RecCC after definitive radiochemotherapy including IGABT, the addition of BEV to CHT may increase the risk for GU fistula formation, particularly after invasive pelvic procedures. Future clinical studies are required to identify predictors for fistula formation to subsequently improve patient selection for the addition of BEV in the RecCC setting.

The role of bevacizumab in the treatment of glioblastoma.

Bevacizumab has been used in patients with GBM as a salvage therapy since its approval in the United States for recurrent GBM in 2009. In order to review the therapeutic effect of bevacizumab in the primary and recurrent clinical setting we have performed a systematic analysis of data from the published literature. Weighted median progression free survival and overall survival were calculated and compared to standard therapy or other experimental therapies. A qualitative analysis of the limited studies on health related quality of life and effects on steroid requirements was also undertaken. We found that the available literature supports the use of bevacizumab for prolonging PFS and OS in the recurrent setting either alone or in combination with a cytotoxic agent (P < 0.05), but does not support its use in the primary setting (P > 0.05). The survival advantage of bevacizumab compared to experimental therapy at recurrence is limited to 4 months. There is no additional benefit reported to date in health-related quality of life with the use of bevacizumab, although it may reduce steroid requirements. On average there is one side-effect event per patient and 74% of these events are grade 3 toxicity or higher. Further studies investigating the role of bevacizumab in combination with cytotoxic agents at recurrence are awaited.

Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab.

Given prior studies that suggest the use of angiotensin system inhibitors (ASIs) is associated with prolonged overall survival (OS) in glioblastoma (GBM) patients, we evaluated the effect of ASIs in glioma patients receiving chemotherapy and/or bevacizumab (BEV). Using retrospective IRB-approved electronic chart review of newly diagnosed WHO grade 2-4 glioma patients from the Kaiser Permanente Tumor Registry of Northern California, we evaluated the impact of ASIs on OS by Cox proportional hazard model analysis for subgroups who received cytotoxic therapy, cytotoxic therapy with BEV, or BEV alone, as well as those with recurrent GBM (rGBM). Of the 1186 glioma patients who received chemotherapy ASI exposure improved OS (HR 0.82; 95% CI 0.71, 0.93; p = 0.003). When stratified by BEV exposure, a sub-analysis revealed further OS advantage for the BEV group (HR 0.75, 95% CI 0.62, 0.90; p = 0.002). In a second cohort of 181 rGBM patients who received BEV in varying dosages, ASI exposure conferred an OS advantage (HR 0.649; 95% CI 0.46, 0.92; p = 0.016). Moreover, patients with ASI exposure who received low-dose BEV treatment (AUCBEV < 3.6 mg wk/kg) had a significantly longer OS (median = 99 weeks; 95% CI 44.3, 205) than those without ASI (median OS = 55.6 weeks; 95% CI 37.7-73.7; p = 0.032). ASI use is associated with longer OS in glioma patients. Further survival advantage with ASI use was observed in rGBM patients receiving low-dose bevacizumab. These data warrant prospective evaluation of adding ASI to low-dose BEV treatment in GBM patients to improve the outcome of standard therapies.

Nasal septal perforation secondary to systemic bevacizumab.

IMPORTANCE: A case of nasal septal perforation secondary to systemic bevacizumab therapy for ovarian cancer is reported. Bevacizumab is a vascular endothelial growth factor A (VEGF-A) inhibitor that is becoming more widely utilized in the oncologic community. There is only one prior report of septal perforation secondary to bevacizumab in the Otolaryngology specific literature. The purpose of this report is: 1) to raise awareness and discuss the literature surrounding the sinonasal complications of bevacizumab and 2) provide workup and treatment recommendations based on the sum of the available literature. OBSERVATIONS: We review the clinical record of a 59year old patient who presented with an anterior septal perforation while taking bevacizumab therapy for ovarian cancer. She had mild symptoms. Her oncologist held bevacizumab and topical moisture therapy was started. After several weeks, the perforation remained stable and bevacizumab was restarted for her ovarian cancer. CONCLUSION AND RELEVANCE: Bevacizumab is associated with both septal perforation and more widespread sinonasal toxicity. These lesions tend to produce only mild symptoms and can usually be managed conservatively. The decision to hold bevacizumab therapy should be made in conjunction with the patient and medical oncologist. Otolaryngologists should be aware of the toxicity from this increasingly common oncologic therapy.

Galectin-1 Inhibitor OTX008 Induces Tumor Vessel Normalization and Tumor Growth Inhibition in Human Head and Neck Squamous Cell Carcinoma Models.

Galectin-1 is a hypoxia-regulated protein and a prognostic marker in head and neck squamous cell carcinomas (HNSCC). Here we assessed the ability of non-peptidic galectin-1 inhibitor OTX008 to improve tumor oxygenation levels via tumor vessel normalization as well as tumor growth inhibition in two human HNSCC tumor models, the human laryngeal squamous carcinoma SQ20B and the human epithelial type 2 HEp-2. Tumor-bearing mice were treated with OTX008, Anginex, or Avastin and oxygen levels were determined by fiber-optics and molecular marker pimonidazole binding. Immuno-fluorescence was used to determine vessel normalization status. Continued OTX008 treatment caused a transient reoxygenation in SQ20B tumors peaking on day 14, while a steady increase in tumor oxygenation was observed over 21 days in the HEp-2 model. A >50% decrease in immunohistochemical staining for tumor hypoxia verified the oxygenation data measured using a partial pressure of oxygen (pO2) probe. Additionally, OTX008 induced tumor vessel normalization as tumor pericyte coverage increased by approximately 40% without inducing any toxicity. Moreover, OTX008 inhibited tumor growth as effectively as Anginex and Avastin, except in the HEp-2 model where Avastin was found to suspend tumor growth. Galectin-1 inhibitor OTX008 transiently increased overall tumor oxygenation via vessel normalization to various degrees in both HNSCC models. These findings suggest that targeting galectin-1-e.g., by OTX008-may be an effective approach to treat cancer patients as stand-alone therapy or in combination with other standards of care.