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Ultra-low-dose intravitreal bevacizumab for the treatment of retinopathy of prematurity: a case series.
Hillier, RJ, Connor, AJ, Shafiq, AE
The British journal of ophthalmology. 2018;(2):260-264
Abstract
BACKGROUND Intravitreal bevacizumab (IVB) has emerged as an effective treatment modality for the management of retinopathy of prematurity (ROP) where the disease is severe and posterior. Despite evidence of systemic vascular endothelial growth factor suppression and concerns about how this might affect the developing neonate, the optimal dose is unknown to date. We report our experience of using ultra-low-dose (0.16 mg) IVB, one-quarter of the 'standard' dose that has widely been reported in the treatment of ROP. METHODS A retrospective observational case series of consecutive infants who underwent ultra-low-dose IVB injection for the management of ROP at a regional neonatal intensive care unit in the North East of England, between November 2013 and August 2016. RESULTS 29 eyes of 15 infants underwent IVB injection. We defined 'treatment success' as complete regression of retinopathy and vascularisation into (or laser ablation of) zone 3. Primary success (in response to IVB 0.16 mg alone) was observed in 23/29 eyes (79.3%). Secondary success (where additional treatment was required) was observed in 27/29 eyes (93.1%). One infant died of respiratory disease during follow-up. Retreatment occurred in 6/29 eyes (20.6%). Retreatments occurred at a mean of 9.8 weeks after initial IVB (range 6-15) and at a mean of 44 weeks postmenstrual age (range 40-50). CONCLUSION 0.16 mg IVB is effective in the treatment of severe and posterior ROP, with no adverse ocular outcomes occurring in our series.
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Medical and developmental outcomes of bevacizumab versus laser for retinopathy of prematurity.
Kennedy, KA, Mintz-Hittner, HA, ,
Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus. 2018;(1):61-65.e1
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BACKGROUND Infants with stage 3+ retinopathy of prematurity (ROP) in zone I or zone II posterior were randomized to initial treatment with bevacizumab or laser in a multicenter trial (BEAT-ROP). The purpose of this study was to assess the effects of bevacizumab on nonophthalmologic outcomes. METHODS At one study site, inborn infants of <27 weeks' gestational age underwent medical and standardized neurologic and developmental assessments at 18-22 months' corrected age (age after expected date of full-term delivery). RESULTS Of the 18 infants enrolled at our site, 16 (7 bevacizumab, 9 laser) were evaluated for medical and neurodevelopmental outcomes at 18-28 months' corrected age. For each of the groups, the medians and ranges of growth percentiles were low compared with norms for healthy infants. The ranges for Bayley III developmental scores were also low relative to expected norms for healthy infants. There were no significant differences between the bevacizumab and laser therapy groups in weight (median percentile: bevacizumab, 18; laser, 7), length, head circumference, cerebral palsy, or Bayley scores (median Cognitive Composite Score: bevacizumab, 85; laser, 65). There was a significant difference in length of hospital stay (median days, 98 vs 140 days) favoring the bevacizumab group. CONCLUSIONS In this patient cohort 2-year follow-up evaluation of infants treated with bevacizumab versus laser therapy for retinopathy of prematurity showed no adverse effects on medical or neurodevelopmental outcomes.
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Comparison of efficacy between anti-vascular endothelial growth factor (VEGF) and laser treatment in Type-1 and threshold retinopathy of prematurity (ROP).
Li, Z, Zhang, Y, Liao, Y, Zeng, R, Zeng, P, Lan, Y
BMC ophthalmology. 2018;(1):19
Abstract
BACKGROUND Retinopathy of Prematurity (ROP) is one of the most common causes of childhood blindness worldwide. Comparisons of anti-VEGF and laser treatments in ROP are relatively lacking, and the data are scattered and limited. The objective of this meta-analysis is to compare the efficacy of both treatments in type-1 and threshold ROP. METHODS A comprehensive literature search on ROP treatment was conducted using PubMed and Embase up to March 2017 in all languages. Major evaluation indexes were extracted from the included studies by two authors. The fixed-effects and random-effects models were used to measure the pooled estimates. The test of heterogeneity was performed using the Q statistic. RESULTS Ten studies were included in this meta-analysis. Retreatment incidence was significantly increased for anti-VEGF (OR 2.52; 95% CI 1.37 to 4.66; P = 0.003) compared to the laser treatment, while the incidences of eye complications (OR 0.29; 95% CI 0.10 to 0.82; P = 0.02) and myopia were significantly decreased with anti-VEGF compared to the laser treatment. However, there was no difference in the recurrence incidence (OR 1.86; 95% CI 0.37 to 9.40; P = 0.45) and time between treatment and retreatment (WMD 7.54 weeks; 95% CI 2.00 to 17.08; P = 0.12). CONCLUSION This meta-analysis indicates that laser treatment may be more efficacious than anti-VEGF treatment. However, the results of this meta-analysis also suggest that laser treatment may cause more eye complications and increase myopia. Large-scale prospective RCTs should be performed to assess the efficacy and safety of anti-VEGF versus laser treatment in the future.
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The Interval between Treatments of Bevacizumab and Dexamethasone Implants for Diabetic Macular Edema Increased over Time in the BEVORDEX Trial.
Mehta, H, Fraser-Bell, S, Nguyen, V, Lim, LL, Gillies, MC
Ophthalmology. Retina. 2018;(3):231-234
Abstract
PURPOSE To report increasing retreatment interval of intravitreal bevacizumab and dexamethasone implants for diabetic macular edema (DME) in the BEVORDEX trial. DESIGN Multicenter randomized clinical trial. PARTICIPANTS Sixty-eight eyes from 47 patients who completed 2 years of follow-up. METHODS The BEVORDEX study (www.clinicaltrials.gov identifier, NCT01298076), set in Australia, was the first head-to-head trial of bevacizumab (Avastin; Genentech, South San Francisco, CA), with retreatment considered after 4 weeks, versus a slow-release dexamethasone implant (Ozurdex; Allergan Inc., Irvine, CA), with retreatment possible after 16 weeks, for center-involving DME. Study eyes were assessed every 4 weeks for retreatment according to prespecified visual acuity and central macular thickness criteria. In this post hoc analysis, changes in treatment interval over time were examined using mixed-effects regression models. We assessed whether the mean treatment interval changed over time and if this depended on baseline characteristics or the treatment received. RESULTS Of the 68 eyes from 47 patients, 67 study eyes received at least 1 retreatment (1 eye in the dexamethasone implant group did not require retreatment over 24 months). Thirty-two eyes received bevacizumab and 35 eyes received dexamethasone implants. Study eyes received a mean of 14.6 injections (standard deviation [SD], 7.8 injections) and 5.6 injections (SD, 1.4 injections) in the bevacizumab and dexamethasone groups, respectively, over 2 years. The mean retreatment interval over the 2-year follow-up period was 70.8 days (SD, 43.8 days) for the bevacizumab group and 145 days (SD, 45.4 days) for the dexamethasone implant group. The mean treatment interval increased over time for both drugs (P = 0.016), independent of which treatment was received (P = 0.808). Longer treatment interval over time was associated with younger age (P = 0.037) and better baseline visual acuity (P = 0.026), but not with gender (P = 0.907) or baseline central macular thickness (P = 0.900). CONCLUSIONS The increase in treatment interval for both intravitreal bevacizumab and dexamethasone implants over time has implications when informing patients about potential treatment burden for DME, planning intravitreal injections services, and designing future clinical trials. For drugs with a disease-modifying effect, fixed-interval dosing may not be required beyond an initial loading phase.
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Comparison of Monthly vs Treat-and-Extend Regimens for Individuals With Macular Edema Who Respond Well to Anti-Vascular Endothelial Growth Factor Medications: Secondary Outcomes From the SCORE2 Randomized Clinical Trial.
Scott, IU, VanVeldhuisen, PC, Ip, MS, Blodi, BA, Oden, NL, Altaweel, M, Berinstein, DM, ,
JAMA ophthalmology. 2018;(4):337-345
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IMPORTANCE Comparisons of monthly vs treat-and-extend anti-vascular endothelial growth factor (anti-VEGF) regimens for macular edema from central retinal vein occlusion or hemiretinal vein occlusion is needed. OBJECTIVE To compare visual acuity letter score and central subfield thickness outcomes of participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) trial who then received either monthly injections or treat-and-extend (TAE) regimens of aflibercept or bevacizumab after a good response at month 6. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial enrolled participants from 66 private practice or academic centers in the United States. All participants had macular edema associated with central retinal vein occlusion or hemiretinal vein occlusion, had enrolled in the SCORE2 trial, and had a protocol-defined good response to monthly injections in the first 6 months of the trial. Participants initially assigned to receive monthly aflibercept were randomized to aflibercept on a monthly or TAE schedule, and participants initially assigned to receive monthly injections of bevacizumab were randomized to receive bevacizumab on a monthly or TAE schedule. The first participant was randomized in the SCORE2 trial on September 17, 2014, and the last month 12 visit occurred on October 24, 2016. MAIN OUTCOMES AND MEASURES Change from month 6 to month 12 in best-corrected electronic visual acuity letter score (per the Early Treatment Diabetic Retinopathy Study). RESULTS The 293 participants had a mean (SD) age of 68.9 (11.9) years; 127 (43.3%) were female. Of these, 79 were randomized to aflibercept on a monthly schedule, 80 to aflibercept on a TAE schedule, 67 to monthly bevacizumab, and 67 to bevacizumab on a TAE schedule. Mean treatment group difference (the change in visual acuity letter score in the monthly group minus the change in the TAE group) from month 6 to month 12 was 1.88 (97.5% CI, -1.07 to 4.83; P = .15) for aflibercept and 1.98 (97.5% CI, -1.08 to 5.03; P = .15) for bevacizumab. In the aflibercept arm, the mean number of injections between months 6 and 11 was 5.8 in the monthly injection group (95% CI, 5.6 to 5.9) and 3.8 in the TAE group (95% CI, 3.5 to 4.1; P < .001); in the bevacizumab arm, the mean number of injections was 5.8 (95% CI, 5.6 to 5.9) in the monthly group and 4.5 in the TAE group (95% CI, 4.2 to 4.8; P < .001). CONCLUSIONS AND RELEVANCE One to 2 fewer injections of aflibercept or bevacizumab were given to the TAE groups than the monthly groups in months 6 to 12 for macular edema associated with central retinal or hemiretinal vein occlusion. Because of wide confidence intervals on the differences between the groups, caution is warranted before concluding that the regimens are associated with similar vision outcomes. TRIAL REGISTRATION www.clinicaltrials.gov identifier: NCT01969708.
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EFFICACY AND FREQUENCY OF INTRAVITREAL AFLIBERCEPT VERSUS BEVACIZUMAB FOR MACULAR EDEMA SECONDARY TO CENTRAL RETINAL VEIN OCCLUSION.
Lotfy, A, Solaiman, KAM, Abdelrahman, A, Samir, A
Retina (Philadelphia, Pa.). 2018;(9):1795-1800
Abstract
PURPOSE To compare the safety, efficacy, and frequency of intravitreal injection of aflibercept and bevacizumab for treatment of macular edema secondary to central retinal vein occlusion. DESIGN Prospective, comparative, randomized, interventional study. PATIENTS AND METHODS Eyes with macular edema secondary to central retinal vein occlusion were randomized between two groups according to the intravitreal injection used. Group A included eyes treated with intravitreal aflibercept, and Group B included eyes treated with intravitreal bevacizumab injections. The inclusion criteria were macular edema secondary to central retinal vein occlusion and follow-up duration of at least 12 months after the first injection. Exclusion criteria were macular ischemia, associated diabetes, hypertensive or renal retinopathy, other retinal disease, and previous anti-vascular endothelial growth factor injection. The main outcome measures are central foveal thickness, best-corrected visual acuity, time intervals between injections, improved retinal nonperfusion, and any reported complication. RESULTS Group A included 39 patients with a mean age of 57.4 ± 8.2 years. Group B included 40 eyes with a mean age of 56.5 ± 9.1 years. Twelve months after the first injection, central foveal thickness significantly improved from 475.45 ± 71.05 m to 259.11 ± 20.67 m in Group A and from 460.22 ± 89.38 m to 264.29 ± 32.05 m in Group B; best-corrected visual acuity significantly improved from 0.81 ± 0.16 logarithm of the minimum angle of resolution (20/125) to 0.34 ± 0.14 logarithm of the minimum angle of resolution (20/40) in Group A and from 0.73 ± 0.15 logarithm of the minimum angle of resolution (20/100) to 0.33 ± 0.17 logarithm of the minimum angle of resolution (20/40) in Group B; the mean number of injections was 3.72 ± 2.93 in Group A and was 5.44 ± 2.85 in Group B (P < 0.05); and the mean interval between injections was 54.23 ± 8.47 days in Group A and was 35.12 ± 7.76 days in Group B (P < 0.05). Retinal nonperfusion improved in 9/12 eyes in Group A and in 3/8 eyes in Group B (P < 0.05). CONCLUSION Both aflibercept and bevacizumab are comparably effective for treatment of macular edema secondary to central retinal vein occlusion without significant complications. However, the burden of frequent intravitreal injections could be significantly reduced when using aflibercept.
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Prognostic Value of ACVRL1 Expression in Metastatic Colorectal Cancer Patients Receiving First-line Chemotherapy With Bevacizumab: Results From the Triplet Plus Bevacizumab (TRIBE) Study.
Hanna, DL, Loupakis, F, Yang, D, Cremolini, C, Schirripa, M, Li, M, Matsusaka, S, Berger, MD, Miyamoto, Y, Zhang, W, et al
Clinical colorectal cancer. 2018;(3):e471-e488
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BACKGROUND No biomarkers exist to predict benefit from antiangiogenic therapy in metastatic colorectal cancer patients. ACVRL1 (activin receptor like-protein 1) encodes for ALK1, a member of the transforming growth factor-β receptor family, which directs pathologic angiogenesis. We examined the intratumoral expression of ACVRL1 and other angiogenesis pathway-related genes to identify molecular markers in the TRIBE study. MATERIALS AND METHODS Of 503 randomized patients, 228 had sufficient tissue for analysis. Formalin-fixed paraffin-embedded specimens were examined for expression of VEGF-A, VEGF-B, VEGF-C, VEGFR1, VEGFR2, ACVRL1, EphB4, and EGFL7 using reverse transcription polymerase chain reaction. A maximal χ2 approach was used to determine the messenger RNA levels associated with progression-free survival (PFS), overall survival (OS), response rate, early tumor shrinkage, and depth of response. Recursive partitioning trees were constructed to identify composite prognostic biomarker profiles. External validation was conducted in silico using the Oncomine database. RESULTS High ACVRL1 expression was associated with superior OS in both treatment arms (FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]-bevacizumab, 32.7 vs. 13.5 months, hazard ratio [HR], 0.38, P = .023; FOLFIRI [5-fluorouracil, leucovorin, irinotecan]-bevacizumab, 35.1 vs. 22.0 months, HR, 0.36, P = .006) and prolonged PFS (11.7 vs. 5.9 months, multivariate HR, 0.17; P = .001) for patients receiving FOLFOXIRI-bevacizumab on univariate and multivariate analyses. In recursive partitioning analysis, ACVRL1 was the strongest discriminator of the response rate, PFS, and OS in patients receiving FOLFOXIRI-bevacizumab and of OS in patients receiving FOLFIRI-bevacizumab. In silico validation revealed significant associations between ACVRL1 expression, disease recurrence, and 1-year survival (P < .05) among all colorectal cancer stages. CONCLUSION ACVRL1 expression could serve as a prognostic biomarker in metastatic colorectal cancer patients receiving chemotherapy and bevacizumab and warrants further evaluation in prospective studies.
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Integrating geriatric assessment in the first line chemotherapy treatment in older patients with metastatic colorectal cancer: Results of a prospective observational cohort study (AVAPLUS).
Decoster, L, Kenis, C, Naessens, B, Houbier, G, De Man, M, Lambrecht, G, Monsaert, E, Moons, V, Vergauwe, P, Prenen, H, et al
Journal of geriatric oncology. 2018;(2):93-101
Abstract
OBJECTIVES This study aims to investigate the use of chemotherapy with or without bevacizumab in older patients with metastatic colorectal cancer (mCRC) in current daily practice and to identify predictive parameters for treatment-related outcomes. PATIENTS AND METHODS This is a Belgian multi-centre, observational cohort study. Patients≥70years old with mCRC considered suitable for first-line chemotherapy were eligible for inclusion. At baseline geriatric screening and assessment was performed. Treatment choice was at the discretion of the investigator. Treatment duration, Progression Free Survival (PFS) and safety were recorded. RESULTS Between August 2011 and July 2013, 252 patients with mCRC were included of which 50.8% were treated with bevacizumab. Median treatment duration was 5.5months and median PFS was 8.9months. Approximately 50% of patients experienced severe adverse events, most frequently diarrhea. In multivariate analysis, baseline Eastern Cooperative Oncology Group (ECOG)-performance status (PS) was predictive for treatment duration (p=0.0047), PFS (p<0.0001) and severe toxicity and baseline nutritional status for PFS (p=0.0007). In patients with a good ECOG-PS, nutritional status was predictive for PFS. CONCLUSIONS In current daily practice in Belgium, half of older patients with colorectal cancer treated with chemotherapy also receive bevacizumab. Nearly half of older patients presented with severe toxicity during treatment. Baseline nutritional status is a predictive marker for PFS. Patients with a baseline ECOG-PS≥2 have shorter PFS and higher risk of severe toxicity and should therefore be treated with caution.
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Intravitreal bevacizumab alone or combined with 1 mg triamcinolone in diabetic macular edema: a randomized clinical trial.
Riazi-Esfahani, M, Riazi-Esfahani, H, Ahmadraji, A, Karkhaneh, R, Mahmoudi, A, Roohipoor, R, Ghasemi, F, Yaseri, M
International ophthalmology. 2018;(2):585-598
Abstract
PURPOSE To compare the results of intravitreal bevacizumab (IVB) injection alone or in combination with intravitreal 1 mg triamcinolone acetonide (IVT) in center-involved diabetic macular edema. METHODS In this randomized clinical trial study, ninety-two eyes of 46 patients with bilateral center-involved diabetic macular edema and no previous treatment were included in the study. One eye of each patient was randomly assigned to 1.25 mg of IVB injection or combination of 1.25 IVB and 1 mg IVT. Evaluation of best-corrected visual acuity (BCVA), central macular thickness (CMT), intraocular pressure (IOP) and grading of lens opacity was conducted at baseline, and weeks 2, 4, 6, 8, 12 and 24 after treatment. Retreatment was performed at a 6-week interval whenever indicated based on CMT. RESULTS Between the groups, BCVA changes were not statistically different until 24-week follow-up (P > 0.05), but at 24 weeks after treatment, BCVA improvement was significantly better in IVB group (P = 0.049). Significant CMT reduction was observed in each group along the follow-up period (P = 0.001). The mean CMT reduction was more significant in combination (IVB + IVT) group at 2 weeks of follow-up (P < 0.001), but CMT changes were not significant between the groups at weeks 12th and 24th after injection. Overall, retreatment was applied for 59 eyes up to 24 weeks (33 in the IVB group, 26 in the IVB + IVT group). Among patients with 2 or more injections, number of injections was significantly lower in IVB + IVT group (P = 0.043). Three eyes within IVB + IVT group developed IOP rise beyond 21 mmHg, which were controlled with topical anti-glaucoma medications within 1 week. Changes in lens opacity were not significant between two groups. CONCLUSION Eyes treated with IVB plus 1 mg IVT injections had more significant reduction in CMT in early post-injection, but this effect was transient. Although after 24 weeks visual acuity improvement was better in IVB group, combination therapy may decrease the number of injections. Combining 1 mg of intravitreal triamcinolone with bevacizumab was not accompanied with significant side effects.
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Follow-up to Age 4 Years of Treatment of Type 1 Retinopathy of Prematurity Intravitreal Bevacizumab Injection versus Laser: Fluorescein Angiographic Findings.
Lepore, D, Quinn, GE, Molle, F, Orazi, L, Baldascino, A, Ji, MH, Sammartino, M, Sbaraglia, F, Ricci, D, Mercuri, E
Ophthalmology. 2018;(2):218-226
Abstract
PURPOSE To compare structural outcome at age 4 years of eyes treated with intravitreal injection of bevacizumab with fellow eyes treated with conventional laser photoablation in type 1 retinopathy of prematurity (ROP). DESIGN Single, randomized, controlled trial. PARTICIPANTS All inborn babies with type 1 zone 1 ROP at the Neonatal Intensive Care Unit of the Catholic University, Rome, from September 1, 2009, to March 31, 2012. METHODS In 21 infants (42 eyes), 1 eye was randomized to receive an intravitreal injection of 0.5 mg bevacizumab; the fellow eye underwent conventional laser photoablation. Digital retinal imaging and fluorescein angiography (FA) were performed at an average of 4 years after treatment in follow-up after these studies performed at treatment and 9 months. MAIN OUTCOME MEASURES Fluorescein angiograms were examined by 2 experts to document retinal and choroidal findings. RESULTS Among the 20 bevacizumab-treated eyes available at 4 years of age, all showed abnormalities at the periphery (avascular area, vessel leakage, shunts, abnormal vessel branching, and tangles) or the posterior pole (hyperfluorescent lesions, absence of foveal avascular zone). These lesions were not observed in the majority of the lasered eyes. Among the 19 laser-treated eyes, leakage was noted in 1 eye, shunts and tangles were noted in 3 eyes, and macular abnormalities were noted in 3 eyes. CONCLUSIONS Fluorescein angiography has shown potentially serious and long-term ocular effects that are present more commonly after treatment with bevacizumab for acute-phase ROP than after laser.