Bevacizumab In Stage Research Articles

Safety and Patient-Reported outcomes of atezolizumab plus chemotherapy with or without bevacizumab in stage IIIB/IV non-squamous non-small cell lung cancer with EGFR mutation, ALK rearrangement or ROS1 fusion progressing after targeted therapies (GFPC 06–2018 study)

BackgroundIn an open-label multicenter non-randomized non-comparative phase II study in patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC), oncogenic addiction (EGFR mutation or ALK/ROS1 fusion), with disease progression after tyrosine-kinase inhibitor and no prior chemotherapy (NCT04042558), atezolizumab, carboplatin, pemetrexed with or without bevacizumab showed some promising result. Beyond the clinical evaluation, we assessed safety and patient-reported outcomes (PROs) to provide additional information on the relative impact of adding atezolizumab to chemotherapy with and without bevacizumab in this population. MaterialsPatients received platinum-pemetrexed-atezolizumab-bevacizumab (PPAB cohort) or, if not eligible, platinum-pemetrexed-atezolizumab (PPA cohort). The incidence, nature, and severity of adverse events (AEs) were assessed. PROs were evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-Core 30 and EORTC QLQ-Lung Cancer 13). ResultOverall, 68 (PPAB) and 72 (PPA) patients were evaluable for safety. Grade 3–4 AEs occurred in 83.8% (PPAB) and 63.9% (PPA). Grade 3–4 atezolizumab-related AEs occurred in 29.4% and 19.4%, respectively. Grade 3–4 bevacizumab-related AEs occurred in 36.8% (PPAB). Most frequent grade 3–4 AEs were neutropenia (19.1% in PPAB; 23.6% in PPA) and asthenia (16.2% in PPAB; 9.7% in PPA). In PPAB, we observed a global stability in global health security (GHS) score, fatigue and dyspnea with a constant tendency of improvement, and a significant improvement in cough. In PPA, we observed a significant improvement in GHS score with a significant improvement in fatigue, dyspnea and cough. At week 54, we observed an improvement from baseline in GHS score for 49.2% of patients. In both cohorts, patients reported on average no clinically significant worsening in their overall health or physical functioning scores. ConclusionPPAB and PPA combinations seem tolerable and manageable in patients with stage IIIB/IV non-squamous NSCLC with oncogenic addiction (EGFR mutation or ALK/ROS1 fusion) after targeted therapies.

Abstract 5358: Digital SP263 PD-L1 tumor cell scoring in non-small cell lung cancer achieves comparable outcome prediction to manual pathology scoring

Abstract Background: Tumor cell (TC) PD-L1 expression is predictive of response to PD-L1-targeted immunotherapy, and accurate scoring is crucial for treatment selection. Scoring relies on manual assessment of immunohistochemically labeled tissue and is subject to subjective variation due to pathologist assessment. As a digital alternative, a clone-agnostic AI-based model for PD-L1 quantification in non-small cell lung cancer (AIM-PD-L1 NSCLC) was developed1. AIM-PD-L1 was deployed on samples from a Phase 3 study of anti-PD-L1 atezolizumab combination therapy with carboplatin and paclitaxel, and/or bevacizumab in Stage IV NSCLC (IMpower150; NCT02366143). Digital and manual PD-L1 TC scores were compared and interrogated for their respective potential to predict efficacy to atezolizumab combination treatments. Methods: AIM-PD-L1 was deployed on images (n=768) digitized from SP263-labeled slides with available manual pathologist TC scores to quantify tissue regions and individual TCs. PD-L1 expression status was determined for each tumor cell and a slide-level TC score was computed. Overall survival (OS) and progression free survival (PFS) analyses of patients at selected cutoffs of 1%, 50%, and across a continuum of cutoffs from 0% to 100% PD-L1 TC by digital and manual methods were conducted, comparing groups treated with or without atezolizumab in combinations with carboplatin and paclitaxel, and/or bevacizumab. Digital and manual scores were compared using agreement rates, Lin's concordance and Spearman’s correlation coefficients, and hazard ratios (HRs) were calculated for OS and PFS analysis. Results: At the slide level, correlation between continuous digital and manual scores was high (r 0.84 [95% CI 0.81-0.86]). Digital assessment of PD-L1 positivity at the 1% cutoff identified more positive patients than manual scoring (70% vs. 55% prevalence, respectively), with comparable treatment benefit (digital OS HR 0.69 [0.53-0.9], and manual OS HR 0.72 [0.54-0.98], digital PFS HR 0.67 [0.54-0.83], and manual PFS HR 0.66 [0.52-0.84]). Continuous digital PD-L1 TC scores showed that treatment benefit improved for patients with scores ≥50% compared to manual scoring. At the ≥50% PD-L1 TC cutoff, numerical improvement was observed in OS and PFS by digital scoring compared to manual (digital OS HR 0.5 [0.29-0.86] compared to manual OS HR 0.64 [0.4-1.02], and digital PFS HR 0.37 [0.24-0.57], compared to manual PFS HR 0.53 [0.37-0.76]). Conclusions: AIM-PD-L1 scoring was as effective at predicting outcomes as manual using the ≥1% PD-L1 TC expression and at the ≥50% TC cutoff, digital scoring identified a subgroup with enriched efficacy compared to manual. Further evaluation of the accuracy and reproducibility of PD-L1 scoring by digital pathology as well as its potential use for patient enrollment or stratifications in clinical trials is needed. 1Griffin et. al. AACR (2022) Citation Format: Hen Prizant, John Shamshoian, John Abel, Andrew Beck, Laura Chambre, Stephanie Hennek, Hartmut Koeppen, Daniel Ruderman, Meghna Das Thakur, Michael Montalto, Benjamin Trotter, Ilan Wapinski, Wei Zou, Minu K. Srivastava, Jennifer Giltnane. Digital SP263 PD-L1 tumor cell scoring in non-small cell lung cancer achieves comparable outcome prediction to manual pathology scoring. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5358.

Early Imaging and Molecular Changes with Neoadjuvant Bevacizumab in Stage II/III Breast Cancer.

Simple SummaryNew blood vessel formation (angiogenesis) has a crucial role in tumour growth and spread. Bevacizumab is an anticancer therapy that targets angiogenesis by inhibiting the vascular endothelial growth factor (VEGF) and is approved for the treatment of metastatic breast cancer. However, there are no validated methods for predicting which patients will respond to bevacizumab, although some have investigated whether a response can be predicted by using scanning (imaging) techniques that study tumour blood vessels or by using the levels of VEGF markers before treatment. In this study, we used a combination of imaging techniques and VEGF marker levels to show that bevacizumab caused structural and functional changes in the blood vessels of breast tumours and substantially slowed tumour growth. The increasing availability and refinement of imaging technology can help to identify biomarkers that will be able to predict which patients with breast cancer are most likely to respond to bevacizumab.This prospective, phase II study evaluated novel biomarkers as predictors of response to bevacizumab in patients with breast cancer (BC), using serial imaging methods and gene expression analysis. Patients with primary stage II/III BC received bevacizumab 15 mg/kg (cycle 1; C1), then four cycles of neoadjuvant docetaxel doxorubicin, and bevacizumab every 3 weeks (C2–C5). Tumour proliferation and hypoxic status were evaluated using 18F-fluoro-3′-deoxy-3′-L-fluorothymidine (FLT)- and 18F-fluoromisonidazole (FMISO)-positron emission tomography (PET) at baseline, and during C1 and C5. Pre- and post-bevacizumab vascular changes were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Molecular biomarkers were assessed using microarray analysis. A total of 70 patients were assessed for treatment efficacy. Significant decreases from baseline in tumour proliferation (FLT-PET), vascularity, and perfusion (DCE-MRI) were observed during C1 (p ≤ 0.001), independent of tumour subtype. Bevacizumab treatment did not affect hypoxic tumour status (FMISO-PET). Significant changes in the expression of 28 genes were observed after C1. Changes in vascular endothelial growth factor receptor (VEGFR)-2p levels were observed in 65 patients, with a > 20% decrease in VEGFR-2p observed in 13/65. Serial imaging techniques and molecular gene profiling identified several potentially predictive biomarkers that may predict response to neoadjuvant bevacizumab therapy in BC patients.

Phase III double-blind study comparing the efficacy and safety of proposed biosimilar MYL-1402O and reference bevacizumab in stage IV non-small-cell lung cancer.

Purpose:This phase III study compared the efficacy and safety of proposed biosimilar MYL-1402O with reference bevacizumab (BEV), as first-line treatment for patients with stage IV non-squamous non-small-cell lung cancer.Patients and methods:Patients were randomly assigned (1:1) to receive MYL-1402O or bevacizumab with carboplatin-paclitaxel up to 18 weeks (6 cycles), followed by up to 24 weeks (8 cycles) of bevacizumab monotherapy. The primary objective was comparison of overall response rate (ORR), based on independently reviewed best tumor responses as assessed during the first 18 weeks. ORR was analyzed per US Food and Drug Administration (ratio of ORR) and European Medicines Agency (difference in ORRs) requirements for equivalence evaluation. Secondary end points included progression-free survival, disease control rate, duration of response, overall survival, safety, and immunogenicity over a period of 42 weeks, and pharmacokinetics (up to 18 weeks).Results:A total of 671 patients were included in the intent-to-treat population. The ratio of ORR was 0.96 [confidence interval (CI) 0.83, 1.12] and the difference in ORR was −1.6 (CI −9.0, 5.9) between treatment arms; CIs were within the predefined equivalence margins. Overall, the incidence of treatment-emergent adverse events and serious adverse events was comparable. Treatment-emergent anti-drug antibody (ADA) positivity was transient, with no notable differences between treatment arms (6.5% versus 4.8% ADA positivity rate in MYL-1402O versus BEV, respectively). The incidence of neutralizing antibody post-baseline was lower in the MYL-1402O arm (0.6%) compared to the bevacizumab arm (2.5%).Conclusions:MYL-1402O is therapeutically equivalent to bevacizumab, based on the ORR analyses, with comparable secondary endpoints.Trial Registry InformationEU Clinical Trials Register, Registration # EudraCT no. 2015-005141-32https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-005141-32Plain language summaryPrevious studies established bioequivalence of the proposed bevacizumab biosimilar MYL-1402O to reference bevacizumab. In this randomized, double-blind, phase III trial, MYL-1402O (n = 337) demonstrated comparable efficacy to bevacizumab (n = 334) in treating advanced non-squamous non-small-cell lung cancer per Food and Drug Administration and European Medicines Agency requirements for equivalence; the ratio of objective response rate (ORR) was 0.96 [90% confidence interval (CI) 0.83, 1.12] and the difference in ORR (MYL-1402O:bevacizumab) was −1.6 (95% CI −9.0, 5.9). Median progression-free survival at 42 weeks was comparable: 7.6 (7.0, 9.5) with MYL-1402O versus 9.0 (7.2, 9.7) months (p = 0.0906) with bevacizumab, by independent review. Treatment-emergent adverse events leading to death (2.4% vs 1.5%), serious adverse events (17.6% vs 16.7%), and antidrug antibodies (6.5% vs 4.8%), were comparable in the MYL-1402O vs bevacizumab arms, respectively. The incidence of neutralizing antibody post-baseline was lower with MYL-1402O (0.6%) than with bevacizumab (2.5%). These findings confirm therapeutic equivalence of MYL-1402O to bevacizumab, providing opportunities for improving access to bevacizumab.

ADAPT therapy vs capecitabine bevacizumab in stage IV colorectal cancer: Pooled 10-year survival experience and a phase II study update.

e15046Background: COX-2 inhibition or aspirin use increase colorectal cancer survival by affecting tumor microenvironment through PD-1/PDL-1 pathway. Optimal use of these agents in cancer is unknow...

CONCURRENT SCLERAL BUCKLE AND INTRAVITREAL BEVACIZUMAB FOR ADVANCED RETINOPATHY OF PREMATURITY-RELATED RETINAL DETACHMENT.

The preoperative use of intravitreal bevacizumab in Stage 4 or 5 retinopathy of prematurity (ROP) can reduce vascular endothelial growth factor load and bleeding risk; however, it can induce traction and exacerbate a tractional retinal detachment. Concurrent placement of a scleral buckle may reduce these risks and obviate future vitrectomy. A retrospective analysis of eyes treated for Stage 4 and 5 ROP with concurrent intravitreal bevacizumab and scleral buckle was performed. Retinal reattachment and need for vitrectomy were studied. Thirteen eyes from 10 infants were treated with concurrent intravitreal bevacizumab and scleral buckle. Nine eyes were Stage 4a, 2 were Stage 4b, and 2 were Stage 5. All eyes with Stage 4 ROP achieved macular attachment at last follow-up. All the eyes with 4a ROP achieved retinal reattachment: 4 (44.4%) with buckle alone and 5 (55.6%) with subsequent vitrectomy. All 4 eyes with Stage 4b or 5 ROP required vitrectomy. Concurrent intravitreal bevacizumab and scleral buckle may serve as a bridge to vitrectomy and, in some instances, may obviate the need for subsequent intervention.

The significance of EGFR pathway mutations for the efficacy of first line treatment with bevacizumab in metastatic colonrectal cancer.

699 Background: After analysis of minor RAS mutations (KRAS exon3, 4/NRAS) in FIRE-3 or PRIME study, so called all RAS mutation would be being regarded as a biomarker for anti-EGFR antibodies. BRAF and PIK3CA mutation would be a candidate of biomarkers for anti EGFR targeted therapies. However it remains unknown whether EGFR pathway mutations affect the efficacy of bevacizumab in Stage.‡W CRC. Methods: Of the 1,001 consecutive patients of CRC in our institute between Nov 2006 and Dec 2013, we examined RAS, PIK3CA and BRAF mutational status, 141 patients received systemic chemotherapy for the first line treatment of Stage.‡W. Among them, 96 patients were administered chemotherapy with bevacizumab. Overall survival (OS), Time to Treatment Failure (TTF) and Objective Response Rate (ORR) were evaluated by mutational status. Results: Baseline characteristics were as follows (n=141): median age, 63; male/female, 80/61; ECOG PS 0-1/2, 135/4; chemotherapy with bevacizumab/chemotherapy with anti-EGFR antibodies/cytotoxic agent alone, 96/22/23;KRAS (codon 12,13) wild-type (WT)/RAS wild-type(WT), 89/80; PIK3CA mutation (exon 9/exon 20)/BRAF mutation, 11(5/6)/13. Median OS and TTF were 32.1 and 8.0 months respectively. In chemotherapy with bevacizumab, ORRs were 46.3% (all cases), 55.3% (KRAS WT), 54.5% (RAS WT) and 60.6% (all WT) respectively. ORR was gradually improved by focusing therapeutic target on all wild population. However, there were no significant differences in TTF and OS among them. PIK3CA mutation had a trend toward shorter TTF of bevacizumab (p=0.056). This trend was observed in PIK3CA mutation on exon 20 but not observed exon 9. BRAF mutation had significantly associated with poor OS not only for bevacizumab cases but also all therapies. Conclusions: In our study, profiling of EGFR pathway mutations may not contribute to enrich patients with benefit from chemotherapy with bevacizumab.

Radiographic parameters in predicting outcome of patients with nonsquamous non-small cell lung cancer (NSCLC) treated with bevacizumab.

e19009 Background: Bevacizumab has increased survival in NSCLC patients (pts) when added to standard chemotherapy. However, whether radiographic features at baseline and/or post-treatment can predict benefit from addition of anti-angiogenic therapy to standard chemotherapy remains unknown. In addition, the impact of VEGF-targeted therapy on CT parameters is not fully characterized. Methods: A retrospective review was performed using CT scans of pts enrolled into a prospective phase II clinical trial of pemetrexed, gemcitabine and bevacizumab in stage IV chemo-naïve, non-squamous, NSCLC pts (Wozniak A, et al. IASLC2011). Treatments were repeated every 2 wks (1 cycle). CT scans were obtained at baseline and at the end of every 4 cycles. The radiographic CT features of the primary tumors were retrospectively reviewed at baseline and after first 4 cycles. RECIST 1.1 and Morphology, Attenuation, Size, and Structure (MASS) criteria were used to assess tumor radiographic response. Results: Twenty-four pts (43% males; median age, 62 y [range: 41-82]), were evaluable for this analysis. On baseline CT, median tumor size was 2.9 cm (range: 1.6. to 6.3 cm), median attenuation was 56 HU (range: 31 to 87 HU), 81% of tumors had heterogeneous enhancement, and 50% of tumors demonstrated invasion of adjacent structures. Well-defined margins were noted in 43% of tumors and 81% had < 30% necrosis. On post-4 cycle CT, 63% of tumors had decreased long diameter (median 15% decrease), 81% had decreased attenuation (median 21% HU reduction) and 50% had increased necrosis. RECIST-defined PR was seen in 37%, SD in 56%; and PD in 1 (4%) based on size despite > 75% necrosis. MASS criteria response was favorable in 25% and non-favorable in 75% of tumors. Pts with tumors that demonstrated FR response by MASS after 4 cycles were more likely to have prolonged progression free survival (HR 2.94; p= 0.175). Conclusions: In tumors treated with anti-angiogenic therapy, imaging response criteria that include changes in tumor morphology, attenuation, and size may capture anti-tumor effect more accurately than size-based RECIST criteria alone. These results support the need for prospective investigation of the efficacy of MASS criteria.

Delayed onset atypical vitreoretinal traction band formation after an intravitreal injection of bevacizumab in stage 3 retinopathy of prematurity

To report a series of patients who presented with an atypical retinal traction band, which was developed after an intravitreal injection of bevacizumab for stage 3 retinopathy of prematurity (ROP). We retrospectively reviewed the medical record of three patients (five eyes) who had been referred to a tertiary care centre for the management of fibrous retinal traction band, which occurred after a bevacizumab injection for stage 3 ROP with plus disease. Clinical features and courses of these eyes were described based on the medical record and RetCam fundus photography. All three patients had taken an intravitreal injection of bevacizumab with or without concomitant laser photocoagulation as an initial treatment option for the active stage 3 ROP. With close follow-ups, regression of extraretinal fibrovascular proliferation and plus disease was noted invariably. After the regression of ROP, atypical fibrous traction membrane had arisen along the major vascular arcades with 2.5 to 4 months of latency, which progressed into tractional retinal detachment (TRD) in three out of five eyes. In active stage 3 ROP, fibrous tractional membrane and subsequent TRD along the major vascular arcades were developed unpredictably after the regression of neovascular activity following bevacizumab injection as an initial treatment. Therefore, ROP patients who received bevacizumab treatment without previous retinal photocoagulation should be closely followed for more than 4 months after the treatments even if the disease seems to have regressed.

MicroRNAs induced in melanoma treated with combination targeted therapy of temsirolimus and bevacizumab.

8597 Background: Targeted therapies directed at commonly overexpressed pathways in melanoma have clinical activity in numerous trials. Little is known about how these therapies influence microRNA expression, particularly with combination regimens. A better understanding of how microRNAs are altered with treatment may contribute to understanding mechanisms of therapeutic effects as well as mechanisms of tumor escape from therapy. Methods: Using microRNA arrays, we analyzed microRNA expression levels in melanoma samples from a Cancer Therapy Evaluation Program-sponsored phase II trial of combination temsirolimus and bevacizumab in stage III or IV melanoma, which elicited clinical benefit in a subset of patients. Seventeen patients were treated with temsirolimus for one week, then combination of both temsirolimus and bevacizumab. Metastatic melanoma biopsies were evaluated days 1, 2, and 23. Tumor samples were evaluated from 12 patients. Results: microRNA expression remained unchanged with temsirolimus alone; however, expression of 15 microRNAs was significantly upregulated (1.4 to 2.5-fold) with combination treatment, compared to pre-treatment levels. Interestingly, twelve of these fifteen microRNAs have been reported to possess tumor suppressor capabilities in various cancer types, including melanoma. We identified 15 putative oncogenes and B7-H3, IGF-1, and IGF-1R as potential targets of the 12 tumor suppressor microRNAs, based on published experimental evidence. For 18 of 25 pairings of microRNA and target-mRNA, changes in gene expression from pretreatment to post-combination treatment samples were inversely correlated with changes in microRNA expression, suggesting a functional effect of the microRNA changes induced by combination therapy. Clustering analysis based on selected microRNAs revealed signatures characteristic of clinical response to combination treatment and of tumor BRAF mutational status. Conclusions: We have identified microRNAs that may be involved in the mechanism of action of combination temsirolimus and bevacizumab in metastatic melanoma, possibly through inhibition of oncogenic pathways.

A comparison of laser photocoagulation and intravitreal bevacizumab for stage 3 retinopathy of prematurity

Objective To compare the efficacy and safety of laser photocoagulation and intravitreal injection of bevacizumab for stage 3 retinopathy of prematurity (ROP).Methods The study included 38eyes of 19 infants with stage 3 ROP (18 eyes of 9 infants in zone Ⅰ,20 eyes of 10 infants in zone Ⅱ ).All the patients were examined by indirect ophthalmoscope and photographed by wide-angle digital retinal imaging system (RetCam Ⅱ ). The fundus lesions in both eyes were the same. Patients received laser photocoagulation in one eye (laser group) and intravitreal injection of 0.03 ml bevacizumab (25 mg/ml) in the fellow eyes (bevacizumab group) during treatment.Follow-up ranged from 12 to 66 weeks,with an average of 33 weeks. The regression time of neovascular ridges and plus-diseases in two groups were compared.Results For 18 eyes with stage 3 ROP in zone Ⅰ,the regression time of neovascular ridges and plus-diseases were (2.25 ±0.46) and (2.11 ±0.60) weeks respectively in bevacizumab group,and both were (3.75 ± 1.75) weeks in laser group.The differences between those two groups were statistically significant (F=18.29,15.56；P＜0.05).For 20 eyes with stage 3 ROP in zone Ⅱ,the regression time of neovascular ridges and plus-diseases were (3.1 ±1.72) and (2.1 ± 0.56) weeks respectively in bevacizumab group,and were (3.50± 1.90) and (2.50± 1.35) weeks respectively in laser group.The differences between those two groups were not statistically significant (F =0.38,2.62 ; P＞ 0.05).There were more fibrous membrane proliferations on the retinal surface in 8 eyes,including 6 eyes in laser group and 2 eyes in bevacizumab group. There was no treatment-related endophthalmitis,cataract,retinal tears and other complications during the follow-up.Conclusion The laser photocoagulation and intravitreal injection of bevacizumab were both safe and effective in treating stage 3 ROP. Key words: Retinopathy of prematurity/surgery; Scleral buckling; Vitrectomy

Safety and efficacy of preoperatively intravitreal injection of bevacizumab for stage 4 retinopathy of prematurity

Objective To observe the safety and efficacy of bevacizumab pretreatment in vitrectomy for vascularly active stage 4 retinopathy of prematurity (ROP).Methods A retrospective case series of 16eyes of 8 patients with vascularly active stage 4 ROP who received an intravitreal injection of bevacizumab were studied.An intravitreal injection of 0.625 mg bevacizumab was performed one week prior to planned vitrectomy.Five days after injection,the eyes were examined by indirect ophthalmoscopy and documented with fundus photography using a RetCam Ⅱ to evaluate the vascular activity.Lens-sparing vitrectomy was performed in 14 eyes,while vitrectomy combined with lensectomy was performed in 2 eyes,one week after the injection.Three months after vitrectomy,the retinal status and lens clarity were observed.Results All patients showed remarkable regression of the fibrovascular membrane with clinically absent vascular component 5 days after the injection. No adverse events occurred. Three months after vitrectomy,anatomical attachment was achieved in 15 eyes (93.75 ％ ),1 eye (6.25 ％ ) had partial attachment.The lens remained clear in all the eyes. Conclusion Intravitreal bevacizumab administrated prior to vitrectomy reduced neovascularization safely and effectively for stage 4 ROP. Key words: Retinopathy of prematurity/drug therapy; Antibodies, monoclonal/therapeutic use; Vitrectomy

Anti-Vascular Endothelial Growth Factor Agents for Ocular Angiogenesis and Vascular Permeability

Recent clinical trials regarding the intravitreal injection of antivascular endothelial growth factor (VEGF) agents (ranibizumab, bevacizumab, pegaptanib, and aflibercept) have shown excellent results in the treatment of angiogenic pathologies including choroidal neovascularization, macular edema, proliferative diabetic retinopathy, and neovascular glaucoma. Ranibizumab (Lucentis, Genectech, San Francisco), a fragment of a humanized monoclonal antibody against all VEGF isoforms, is beneficial in the treatment of choroidal neovascularization secondary to age-related macular degeneration (AMD). Bevacizumab (Avastin, Genentech, San Francisco), a humanized, recombinant monoclonal IgG antibody that binds and inhibits all VEGF isoforms, has been approved as an adjuvant agent for the treatment of colorectal carcinoma and has also been increasingly used as an offlabel therapy in the field of ophthalmology. Pegaptanib (Mucugen, Pfizer, New York) is a 28-base ribonucleic acid aptamer, covalently linked to two branched 20-kD polyethylene glycol moieties, that was developed to bind and block the activity of extracellular VEGF, specifically the 165-aminoacid isoform (VEGF165). Aflibercept (VEGF Trap-Eye, Regeneron, New York; Bayer, Berlin, Germany) is a 115-kDa recombinant fusion protein consisting of the VEGF-binding domains of human VEGF receptors 1 and 2 fused to the Fc domain of human immunoglobulin-G1. Intraocular injections of anti-VEGF drug are considered to be an effective treatment for macular edema after retinal vein occlusion. The recent reports may lead to a shift in treatment paradigm for diabetic macular edema, from laser photocoagulation to newer approaches using anti-VEGF drugs. There have been several well-publicized prospective, randomized studies that demonstrated the efficacy of intravitreal injection of anti-VEGF drugs for patients with AMD. Adjuvant bevacizumab for neovascular glaucoma may prevent further peripheral anterior synechiae formation, and it is likely to open up a therapeutic window for a panretinal photocoagulation and trabeculectomy. Intravitreal injection of bevacizumab (IVB) results in a substantial decrease in bleeding from the retinal vessels or new vessels during a standard vitrectomy. IVB has also been reported to be effective for inducing the regression of new vessels in proliferative diabetic retinopathy. The use of bevacizumab in stage 4 or 5 retinopath of prematurity (ROP) is to reduce the plus sign to help reduce hemorrhage during the subsequent vitrectomy. Some authors reported cases of resolution of stage 4A ROP after bevacizumab injection. This special issue of anti-VEGF agents comprises five review articles and two research articles. The review article of K. Kimoto and T. Kubota is a concise overview on the application of anti-VEGF agents in angiogenic pathologies and vascular permeability. The review article of A. Willard and I. Herman describes the mechanisms behind diabetic retinal complications, current research supporting anti-VEGF medications, and future therapeutic directions. The review of P. Keane and S. Sadda summarizes the history of anti-VEGF drugs and presents a guide for clinicians on the development of anti-VEGF therapies for intraocular use. The review article of Y. Park et al. describes the treatment possibilities including combination therapy for age-related macular degeneration. The review article of I. Zampros et al. summarizes the current literature regarding the effectiveness of current anti-VEGF treatment for neovascular AMD. The two research articles describe (i) bevacizumab injection in patients with age-related macular degeneration associated with poor initial visual acuity, (ii) photodynamic therapy combined with intravitreal ranibizumab for exudative age-related macular degeneration. We sincerely hope that the present volume of a special issue series may provide useful information to understand the mechanisms of the clinical effects of anti-VEGF drug therapy, as well as the evaluation of their outcomes for the readers in Journal of Ophthalmology. Toshiaki Kubota Yoshiaki Kiuchi Carl Sheridan

Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity

Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity

ベバシズマブを含む化学療法により転移巣の病理学的完全奏効が得られ治癒切除が可能であったIV期肺癌の1例

背景．ベバシズマブの登場により進行非扁平上皮非小細胞肺癌に対する化学療法の腫瘍縮小率は著しく向上した．症例．78歳，男性．副腎転移を有する左上葉肺癌（腺癌）cT2aN0M1b，stage IVに対してベバシズマブを含む化学療法を4コース施行した．画像上は縮小率75％のPRで腫瘍マーカーもほぼ正常化したことから，左肺上葉切除術と副腎摘出術を施行した．病理学的には原発巣には一部viableな腫瘍細胞が残存しておりEf. 2，転移巣には腫瘍細胞は認めずEf. 3であった．術後12カ月経過しているが無再発生存中である．結語．症例を選択すれば，ベバシズマブによる奏効率の改善は，これまで切除不能とされてきた進行非小細胞肺癌に対する術前治療となり得る可能性がある．

Anti-VEGF Agents for Ocular Angiogenesis and Vascular Permeability.

We review articles describing intravitreal injection of anti-VEGF drug trials, while discussing the mechanisms of the action of anti-VEGF antibodies, and also evaluating their outcomes. Intraocular injections of anti-VEGF drug are considered to be an effective treatment for macular edema after retinal vein occlusion, however, recurrent/persistent edema is common. The recent reports may lead to a shift in treatment paradigm for DME, from laser photocoagulation, to newer approaches using anti-VEGF drugs. There have been several well-publicized prospective, randomized studies that demonstrated the efficacy of intravitreal injection of anti-VEGF drugs for patients with AMD. Adjuvant bevacizumab for neovascular glaucoma may prevent further PAS formation, and it is likely to open up a therapeutic window for a panretinal photocoagulation and trabeculectomy. Intravitreal injection of bevacizumab (IVB) results in a substantial decrease in bleeding from the retinal vessels or new vessels during a standard vitrectomy. IVB has also been reported to be effective for inducing the regression of new vessels in proliferative diabetic retinopathy. The use of bevacizumab in stage 4 or 5 retinopahty of permaturity (ROP) is to reduce the plus sign to help reduce hemorrhage during the subsequent vitrectomy. Some authors reported cases of resolution of stage 4 A ROP after bevacizumab injection.

Uptake of bevacizumab for the treatment of colon cancer.

6107 Background: While bevacizumab (BEV) has been shown to improve mortality when added to first-line treatment of metastatic colon cancer, a randomized trial presented at ASCO 2009 reported no benefit from the addition of BEV in stage III colon cancer. We investigated the uptake of BEV for the treatment of both early stage and metastatic colon cancer in a population-based sample. Methods: We identified patients >65 yrs diagnosed with stage III colon cancer, 9/1/04-12/31/05, in the SEER-Medicare database who were treated within 6 months of diagnosis. We also identified patients >65 yrs diagnosed with stage IV or recurrent colon cancer, 1/1/05-12/31/05. We used multivariable logistic regression models and Generalized Estimating Equations to assess the relationship between patient/physician characteristics and receipt of BEV for the metastatic cohort. Results: Among 1884 patients with stage III colon cancer, 825 (43.8%) were treated with chemotherapy of whom 55 (6.7%) had claims for BEV. Among 1,119 patients with stage IV or recurrent colon cancer, 441 (39.4%) had claims for chemotherapy, and of these, 312 (70.7%) had claims for BEV. Among 859 (76.8%) patients with metastatic disease seen by an oncologist, we found that younger age (OR 5.31 95%CI 3.02-9.35), being married (OR 1.72 95% CI 1.17-2.52), and fewer comorbidities (OR 2.04 95% CI 1.19-3.52) were associated with receipt of both chemotherapy and BEV, when compared to patients who received no chemotherapy. Patients who had younger physicians (OR 3.31 95%CI 1.92-5.73), US trained physicians (OR 1.47 95% CI 1.03-2.12), and physicians who treated more patients in our sample (OR 1.69 95% CI 1.19-2.41) were also more likely to receive chemotherapy with BEV. Among metastatic patients who received chemotherapy, we found that having no comorbidities (OR 2.33 95% CI 1.41-3.85), a male physician (OR 1.88 95%CI 1.14-3.12) and a physician who treated more patients in our cohort (OR 1.61 95%CI 1.02-2.54) were all associated with the additional receipt of BEV compared to no BEV. Conclusions: For patients with metastatic colon cancer treated with chemotherapy, uptake of BEV was very rapid, and influenced by physician characteristics. Despite a lack of efficacy, patients were also receiving it off-label in the adjuvant setting.

Perfusion CT Findings in Patients With Metastatic Carcinoid Tumors Undergoing Bevacizumab and Interferon Therapy

The purpose of this article is to assess tumor changes on perfusion CT with bevacizumab and interferon (IFN) therapy in patients with metastatic carcinoid tumors and to evaluate perfusion CT differences between the two therapies. In a phase 2 clinical trial, 44 patients were randomized to receive monotherapy with bevacizumab or IFN for 18 weeks (stage 1), followed by dual-therapy with both drugs (stage 2). Twenty-four patients consented to have optional perfusion CT examinations, which were undertaken at baseline and 18 weeks and at intervening 2 days (bevacizumab arm) or 9 weeks (IFN arm), and subsequently at 2 days after the addition of bevacizumab (IFN arm) and 9 weeks after the addition of IFN (bevacizumab arm). Tumor blood flow, blood volume, and permeability were evaluated. In the bevacizumab arm (n = 12), mean (± SD) blood flow reduced significantly after 2 days compared with baseline (16.2 ± 6.9 vs 32.3 ± 21.3 mL/min/100 g; p = 0.02), a 41.4% reduction (p < 0.0001) that was relatively fixed. Blood volume was similarly reduced from baseline values (2.8 ± 1.3 vs 4.3 ± 2.1 mL/100 g; p = 0.02), a 27.9% reduction (p < 0.02). Both measures remained essentially unchanged at 18 weeks. Similar changes in blood flow and blood volume were observed with the addition of bevacizumab in stage 2. No significant changes in blood flow or blood volume were detected in the IFN arm (n = 12), and no significant changes in permeability were detected in either arm. Perfusion CT detects significant changes in perfusion parameters in metastatic carcinoid tumors treated with bevacizumab. Such changes are apparent just 2 days into therapy, are sustained, and are significantly different from those associated with IFN treatment. Tumor blood flow decreased with bevacizumab treatment by a relatively fixed percentage relative to baseline measurements.

Phase III Trial Assessing Bevacizumab in Stages II and III Carcinoma of the Colon: Results of NSABP Protocol C-08

Phase III Trial Assessing Bevacizumab in Stages II and III Carcinoma of the Colon: Results of NSABP Protocol C-08

Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity

Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity