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AFLIBERCEPT AFTER RANIBIZUMAB INTRAVITREAL INJECTIONS IN EXUDATIVE AGE-RELATED MACULAR DEGENERATION: The ARI2 Study.
Blanco-Garavito, R, Jung, C, Uzzan, J, Quaranta-ElMaftouhi, M, Coscas, F, Sahel, J, Korobelnik, JF, Béchet, S, Querques, G, Souied, EH
Retina (Philadelphia, Pa.). 2018;(12):2285-2292
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Abstract
PURPOSE To analyze the efficacy of aflibercept switch treatment for regression of pigment epithelial detachment (PED) in patients previously treated with ranibizumab. METHODS Multicenter, prospective, nonrandomized clinical trial. One eye of patients presenting neovascular age-related macular degeneration with PED of more than 250 μm in height, with persistent fluid, was included. Patients had to have received at least six ranibizumab intravitreal injections during the 12 months before enrollment. Patients were switched from ranibizumab pro re nata to aflibercept (fixed regimen, 3 monthly intravitreal injections, and then Q6). Main outcome measure was change in PED height from baseline to Week 12 after switch. Secondary outcomes were best-corrected visual acuity and PED volume changes. RESULTS Eighty four patients were included. Mean delay between last ranibizumab intravitreal injection and switch was 44.7 days. Mean maximal PED height at baseline visit was 347 μm (±109) and reduced to a mean of 266 μm (±114) at Week 12 (P < 0.001) and 288.2 μm at Week 32 (P < 0.001). Mean PED volume was reduced from 1.3 mm to 0.98 mm at Week 12 (P < 0.001). Best-corrected visual acuity improved by 3.3 Early Treatment Diabetic Retinopathy Study letters at Week 32 (P = 0.003). CONCLUSION Aflibercept switch therapy seems to be effective on large PED in patients previously treated with pro re nata ranibizumab.
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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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Three-dimensional tubule formation assay as therapeutic screening model for ocular microvascular disorders.
Shariatzadeh, M, Brandt, MM, Cheng, C, Ten Berge, JC, Rothova, A, Leenen, PJM, Dik, WA
Eye (London, England). 2018;(8):1380-1386
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PURPOSE This study is aimed to adapt a three-dimensional (3-D) in vitro angiogenesis model to the ophthalmology field using retinal endothelial cells (REC). This system is applied to assess the angiogenic capacity of aqueous humor (AH) from patients with ocular disorders, and to test the effect of VEGF inhibitor (aflibercept) on induced angiogenesis. METHODS Human REC and umbilical vein endothelial cells (HUVEC) and pericytes were co-cultured in a gel matrix with 25-200 ng/ml pro-angiogenic growth factors (GF). AH from patients with cataract, glaucoma or proliferative diabetic retinopathy (PDR) was tested in the REC-pericyte co-culture. Aflibercept was then introduced to the co-culture containing PDR AH. The surface area and total tubule length were measured using Image J. RESULTS Optimal GF concentrations at 200 ng/ml induced angiogenesis by REC as well as HUVEC, while vessel formation by both cell types was strongly reduced using 25-50 ng/ml GF. Addition of AH from the PDR patient triggered tubule formation by REC at low GF concentration. Aflibercept, however, significantly inhibited angiogenesis induced by PDR AH, but showed no significant influence on other conditions. CONCLUSION REC can be applied efficiently in the 3-D in vitro angiogenesis model as a diagnostic tool to assess the AH angiogenic status and to validate new anti-angiogenic therapeutic compounds prior to clinical trial.
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Mechanistic Evaluation of Panretinal Photocoagulation Versus Aflibercept in Proliferative Diabetic Retinopathy: CLARITY Substudy.
Nicholson, L, Crosby-Nwaobi, R, Vasconcelos, JC, Prevost, AT, Ramu, J, Riddell, A, Bainbridge, JW, Hykin, PG, Sivaprasad, S
Investigative ophthalmology & visual science. 2018;(10):4277-4284
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PURPOSE The purpose of this study was to study the effects of panretinal photocoagulation (PRP) and intravitreal aflibercept on retinal vessel oxygen saturations, area of retinal nonperfusion, and area of neovascularization in proliferative diabetic retinopathy. METHODS This is a prospective randomized single center study. Forty patients with proliferative diabetic retinopathy were randomized to PRP or intravitreal aflibercept treatment for 52 weeks. Retinal oximetry and ultra-widefield angiography were performed at baseline and week 52. Ultra-widefield color fundus imaging was performed at baseline, week 12, and week 52. The outcomes were retinal arterio-venous oximetry differences (AVD), area of retinal nonperfusion, and area of neovascularization in disc areas (DA). RESULTS The AVD in the PRP group increased from 36.7% at baseline to 39.7%, whereas it decreased from 33.4% to 32.5% in the aflibercept group. The difference in AVD between groups at week 52 was 4.0% (95% confidence interval, -0.08, 8.8; P = 0.10). The baseline mean area of retinal nonperfusion of 125.1 DA and 131.2 DA in the PRP and aflibercept groups increased to 156.1 DA and 158.4 DA, respectively, at week 52 (P = 0.46). The median baseline area of neovascularization decreased from 0.98 DA to 0.68 DA in the PRP group and from 0.70 DA to 0 DA in the aflibercept group at week 12 (P = 0.019). At week 52, this measured 0.24 DA in the PRP group and 0 DA in the aflibercept group (P = 0.45). CONCLUSIONS Intravitreal aflibercept achieved an earlier and complete regression of neovascularization in proliferative diabetic retinopathy compared with PRP. There were no significant differences in global change in intravascular oxygen saturation or areas of retinal nonperfusion between the two groups by 52 weeks.
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Phase II trial of ifosfamide in combination with the VEGFR inhibitor sorafenib in advanced soft tissue sarcoma: a Spanish group for research on sarcomas (GEIS) study.
García Del Muro, X, Maurel, J, Martínez Trufero, J, Lavernia, J, López Pousa, A, de Las Peñas, R, Cubedo, R, Berros, JP, Casado Herráez, A, de Juan, A, et al
Investigational new drugs. 2018;(3):468-475
Abstract
Background Sorafenib is a potent targeted-therapy that blockades angiogenesis and has demonstrated activity against some sarcoma subtypes. Preclinical studies suggested that treatment with sorafenib plus cytotoxic agents could result in additive efficacy. Methods Patients with advanced soft tissue sarcoma, with or without anthracycline pretreatment were included. Patients received oral sorafenib 400 mg twice daily starting on Day +2, ifosfamide 2.0 g/m2 iv infusion lasting 4 h on days 1, 2 and 3 with concurrent mesna 400 mg/m2 every three weeks until disease progression or unacceptable toxicity or up to a maximum of 6 cycles of ifosfamide (sorafenib could be continued until progressive disease or unacceptable toxicity). Primary objective was progression-free rate (PFR) at 3 and 6 months; secondary objectives were overall response rate (ORR), Progression-free survival (PFS), Overall survival (OS) and safety. This article reports the phase II part of a phase I/II clinical trial. Results Thirty-five patients were enrolled. PFR at 3 and 6 months was 66% (95% CI 48-81) and 37% (95% CI 22-55). Six patients (17%) achieved partial response and 17 (49%) stable disease. Median PFS was 4.8 months (CI 95% 1.94-6.36) and overall survival 16.2 months (95% CI 8.75-NA). Conclusion Treatment with sorafenib plus ifosfamide achieved a significant clinical benefit with an acceptable safety profile in patients with advanced soft tissue sarcoma resistant to anthracyclines, which warrants a more detailed study in randomized clinical trials.
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Assessment and management of diarrhea following VEGF receptor TKI treatment in patients with ovarian cancer.
Liu, J, Nicum, S, Reichardt, P, Croitoru, K, Illek, B, Schmidinger, M, Rogers, C, Whalen, C, Jayson, GC
Gynecologic oncology. 2018;(1):173-179
Abstract
Angiogenesis is a proven clinical target for the treatment of advanced epithelial ovarian cancer. Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) offer patients potential new treatment regimens as they can be given as monotherapy, in combination with poly(ADP-ribose) polymerase (PARP) inhibitors, or with and following cytotoxic chemotherapy. If VEGFR-TKIs are licensed for use in ovarian cancer, patients will require prompt and effective management of adverse events, including diarrhea, to optimize compliance and benefit. As diarrhea is one of the most prevalent toxicities of this class of drug, it is important to consider the potential causes, be they disease related (bowel obstruction), treatment related (VEGFR-TKI-related or infective/neutropenic septic diarrhea when patients are receiving cytotoxic chemotherapy combined with VEGFR inhibitor treatment), or incurred through diet. Here, we provide an overview of the possible mechanisms responsible for VEGFR-TKI-induced diarrhea. We review potential interventions that can help in the management of diarrhea induced by VEGFR-TKIs, when used in combination or as single agents, and we provide a diarrhea treatment algorithm to serve as a clinical reference point for the management of diarrhea in patients with ovarian cancer treated with a VEGFR-TKI in combination with chemotherapy or PARP inhibitors, or as monotherapy.
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[Switching the Treatment Regime from PRN (pro re nata, as needed) to T&E (Treat and Extend) for Intravitreal Therapy with Anti-VEGF Agents in Private Practice or Small Institutions].
Imesch, P, Sarra, GM
Klinische Monatsblatter fur Augenheilkunde. 2018;(1):39-46
Abstract
In everyday practice, intravitreal therapy in an "as needed" regimen (pro re nata, PRN) is less predictable and requires more visits (monitoring and injections taken together) with poorer functional results than with the treat and extend (T&E) regimen. Current literature supports the benefit of a switch. However, practical advice is still missing. This article provides "best practice" recommendations for private practice or smaller institutions for the change from PRN to T&E. The requirements are organisational adjustments, staff training, definition of the scenario triggering the switch (A - functional or anatomical deterioration; B - general switch at a predefined date), counselling of the patients, defining benchmarks for the follow-up of the switch and preparing for higher capacity utilisation during the transition (shorter treatment intervals during the switching phase). Guidance is provided for each phase (a, preparation; b, transition; and c, follow-up).
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Long-term outcomes with as-needed aflibercept in diabetic macular oedema: 2-year outcomes of the ENDURANCE extension study.
Wykoff, CC, Ou, WC, Khurana, RN, Brown, DM, Lloyd Clark, W, Boyer, DS, ,
The British journal of ophthalmology. 2018;(5):631-636
Abstract
BACKGROUND/AIMS: To evaluate the efficacy and safety of individualised 2.0 mg intravitreal aflibercept retreatment for diabetic macular oedema (DME) through the fifth year of management. METHODS This is a phase IV, 2-year, open-label extension study. Sixty patients completing the 3-year VISTA DME (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) phase III trial enrolled in the ENDURANCE (Long-Term Efficacy and Safety of Intravitreal Aflibercept for the Treatment of DME in Subjects Who Completed the VISTA DME Trial) extension study. All patients received aflibercept in the presence of clinically relevant DME. Intervals between visits were prescribed according to disease activity. The main outcome measure was mean aflibercept injections given through 2 years. RESULTS A mean of 7.7 aflibercept injections were administered through 2 years. Fifteen (25%) patients required no retreatment and 48% (n=29) of patients received five or fewer injections through 2 years. Among patients who received at least one aflibercept retreatment during ENDURANCE, the mean number of injections through 2 years was 9.5. The mean visual acuity and central retinal thickness gains achieved during VISTA DME were maintained and stable during ENDURANCE. The most notable safety signal was progression of diabetic retinopathy. Six (10%) patients converted from non-proliferative to proliferative diabetic retinopathy (PDR), and a total of eight patients experienced PDR events occurring at a mean of 387 days following the previous aflibercept treatment. CONCLUSION The need for aflibercept retreatment was substantially reduced in the fourth and fifth years of aflibercept dosing for DME following initiation of therapy in the VISTA DME trial. While vision gains achieved during the 3-year VISTA DME trial were maintained through ENDURANCE with a reduced treatment burden, clinically relevant worsening of diabetic retinopathy was observed with progression to PDR in 10% of the eyes. TRIAL REGISTRATION NUMBER NCT02299336.
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Effects of Intravitreal Aflibercept on Galectin-1 and Vascular Endothelial Growth Factor-A Plasma Levels in Patients with Diabetic Retinopathy.
Waltl, I, Zehetner, C, Seifarth, C, Handle, F, Kieselbach, GF, Angermann, R, Kralinger, MT
Current eye research. 2018;(3):368-375
Abstract
PURPOSE To analyze the interaction between aflibercept and galectin-1 and evaluate the plasma levels of galectin-1 and vascular endothelial growth factor (VEGF)-A after intravitreal injection of aflibercept in patients with diabetic retinopathy (DR). METHODS Interaction of galectin-1 with aflibercept was determined via immunoprecipitation. Seventeen patients with type 2 diabetes and diabetic macular edema (DME) were each treated with a single intravitreal injection of aflibercept (2.0 mg, 50 µL) monthly for three consecutive months. Plasma galectin-1 and VEGF-A levels were measured just before an injection was administered, 1 week after the first injection, and 2 months after the last injection. Nineteen age- and sex-matched healthy participants served as controls. RESULTS Irrespective of the tested galectin-1 concentration, 24% of added galectin-1 was precipitated by aflibercept. Baseline plasma concentrations of galectin-1 were 22.0 and 23.0 ng/mL in the control and aflibercept-treated groups, respectively. Systemic galectin-1 levels increased to 27.0 and 24.0 ng/mL at 7 days and 4 weeks, respectively, after treatment. At week 8, plasma galectin-1 levels significantly increased to 36.0 ng/mL. This level persisted for 20 weeks. Systemic VEGF-A levels significantly reduced to below the minimum detectable dose in 16 DME patients at 7 days after treatment. This level persisted for 4 weeks. Plasma VEGF-A levels were reduced at weeks 8 (p = 0.099) and 20 (p = 0.023). Decreased plasma VEGF-A levels were observed in all patients after treatment. CONCLUSION We confirmed that physiological aflibercept levels precipitate galectin-1 in in vitro assays. Additionally, systemic upregulation of galectin-1 might be induced by intravitreal aflibercept, which may be relevant in the clinical outcomes of DR treatment.
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Treat-and-extend therapy using intravitreal aflibercept for neovascular age-related macular degeneration: 2-year real-world practice data from Slovenia.
Jaki Mekjavić, P, Gregorčič, B, Oberč, C, Podgoršek, S
BMC ophthalmology. 2018;(1):333
Abstract
BACKGROUND To assess visual outcomes over 24 months in patients with neovascular age-related macular degeneration (nAMD) who initiated intravitreal aflibercept therapy under a treat-and-extend (TE) regimen in real-world settings. METHODS In this retrospective, observational, multicentre study in Slovenia, medical records of all treatment-naïve patients with nAMD who started intravitreal aflibercept therapy between October 2013 and April 2015 were reviewed. The primary outcome measure was change in mean visual acuity (VA) from baseline to 24 months in patients who received the TE regimen for 2 years, assessed by standardised Early Treatment Diabetic Retinopathy Study charts and calculated as least-squares means. Other outcome measures included the numbers of injections and visits at 12 months and 24 months. RESULTS The primary analysis included 115 eyes of 105 patients who received TE treatment for 2 years (Group A). The mean VA improved from 57.9 ± 14.9 letters at baseline to 64.6 ± 15.8 letters (+ 6.5 letters, p < 0.0001) at 12 months and 64.8 ± 15.6 letters (+ 7.0 letters, p < 0.0001) at 24 months. The mean number of injections per eye was 8.4 ± 1.9 and the mean number of visits was 8.8 ± 1.7 at 12 months; these numbers decreased to 6.1 ± 2.0 and 6.4 ± 1.9, respectively, at 24 months. The additional analysis included 33 eyes of 33 patients who received TE treatment in Year 1, followed by pro re nata treatment in Year 2 (Group B). Compared with Group A whose vision improvement was maintained at 24 months, the VA gain in Group B eyes seen at 12 months (change in mean VA vs baseline: + 6.9 letters, p = 0.0008) was no longer present at 24 months (change in mean VA vs baseline: + 1.2 letters, p = 0.5733). CONCLUSIONS Using the TE regimen in clinical practice, intravitreal aflibercept significantly improved visual outcomes in treatment-naïve patients with nAMD, which were maintained over time. TE therapy with intravitreal aflibercept is a rational long-term strategy that can produce favourable outcomes in clinical practice.