Unilateral Bevacizumab for Bilateral Diabetic Macular Edema
Condition: Diabetic Macular Edema; Diabetic Retinopathy
MeSH terms: Macular Edema; Diabetic Retinopathy; Edema
Study type: Interventional
Phase: Phase 4

Summary: 
      The endothelial growth factor (VEGF), has been implied in the genesis of diverse Neovascular
      disease. In the industrialized and developing countries, the main cause of blindness is the
      diabetic retinopathy. Bevacizumab (Avastin, genentech, Inc., San Francisco, California, the
      USA) is a drug.In the last years its use "off-label", in ophthalmology field, has become
      popular. This is due to its proven safeness and effectiveness for the treatment of diverse
      ocular diseases. A lot has been speculated about the systemic absorption of Bevacizumab. It
      is for that reason that the objective of this study is the systematic and random revision of
      the fellows eyes, of the patients programmed for the intravitreal administration of
      Bevacizumab, with bilateral macular edema. In such a way that the therapeutic value in the
      fellow eye of bevacizumab can be determined
    

Detailed description: 
      Introduction:

      The endothelial growth factor (VEGF), was identified for the first time in the liquid of
      ascitis in Guinean pigs (6,7). It is a dimeric glycoprotein, naturally expressed in
      epithelial and tumor cells (1). It's over expression during retinal hypoxia (9), has been
      implied in the genesis of diverse Neovascular diseases (2,4,8,9,19). The activation of the
      VEGF pathway promotes endothelial cells growth, increases the growth, migration and survival
      of the existing vasculature and produces the differentiation and migration of the endothelial
      mother cells from the bone marrow towards the general circulation (4). It is also a
      vasculature permeability factor, because it favors the formation of vascular fenestrations,
      which produces the exit of liquid and protein deposit in the tissue interstice, favoring the
      formation of macular edema and neovascularisation (3,8-10).

      Its activity is mediated by two tyrosine related receptors of high affinity: the VEGFR 1
      (FLT-1) and VEGFR 2 (FLT-2) (1,9). The FLT-1 promotes the cellular proliferation whereas the
      FLT-2 the migration and the interaction between cells and extracellular matrix(4,5,10)

      In the industrialized and developing countries, the main cause of blindness is the diabetic
      retinopathy (9). Followed close in the United States and Europe by Age related Macular
      Degeneration (10). The most frequent cause of loss of vision in diabetic retinopathy is
      macular edema (7). Its incidence is between 13.9 to 25.4% (15). It is characterized by the
      accumulation of intraretinal liquid at level of the outer plexiform and internal nuclear
      layers, with the subsequent thickening of the macula (13,15). The diabetic macular Edema is
      associated to high levels of VEGF in the vitreous (7,8,9). At the moment, the gold standard
      in the treatment of the proliferative retinopathy is the laser photocoagulation(9). The
      photocoagulation of the macular area for the treatment of diffuse or focal edema, produces a
      50% decrease risk of severe visual loss. Nevertheless the long-term prognosis continues being
      poor (15).

      The Optical Coherent Tomography (OCT) is a relative new, noninvasive technique (12,14), based
      in low frequency interferometry phenomenon. It is able to provide cross-sectional retinal
      images (11,12,15,17). It has a resolution of 10-15mm. thanks to that, it is also able to
      quantitatively measure macular thickness (10,12,14,15,17). The measurements obtained with
      this system are highly reproducible and they correlated with patient visual acuity
      (7,11,14,16,17,19). It is very useful when evaluating the vitreous-retinal interface and
      retinal adherences(11). In the macular edema OCT displays low reflectivity images with
      increase of retinal thickness(11,13). The classification of macular edema by OCT images,
      proposed by Dr. Otani (16) and modified by Kang (15) consists of 4 types: Type 1, thickening
      of the fovea with homogenous optical reflectivity in the entire retina. Type 2, thickening of
      the retina with noticeable diminution of the optical reflectivity in the external layers of
      the retina. Type 3, thickening of the fovea with accumulation of subfoveal liquid and a
      defined border of detached retina. Type 3A without foveal traction, 3B with foveal traction
      (15).

      Bevacizumab (Avastin, genentech , Inc., San Francisco, California, the USA) is a drug,
      approved by the FDA for the treatment of the metastatic colorectal cancer(2). It consists of
      a humanized monoclonal antibody that binds all active forms of VEGF (3,18,19), blocking the
      activity of its two receptors (4). In the last years its use "off-label", in ophthalmology
      field, has become popular. This is due to its proven safeness and effectiveness for the
      treatment of diverse ocular diseases (2-4,7,20). Within the ophthalmic pathologies that have
      been treated successfully with the Intravitreal administration of Bevacizumab, we can mention
      different Neovascular pathologies (diabetic Retinopathy (9,18), age related macular
      degeneration(2,4,18)) and pathologies that alter the vascular permeability (macular edema
      (4,7), Central and branch retinal vein occlusion (3,8,20), central serous choroidopathy). In
      all of them , treatment responses is characterized by an improvement of the visual acuity,
      decrease of macular thickness and improvement of the angiographic patterns (8,10). The
      potential complications of the use of Bevacizumab are the severe thromboembolic event,
      arterial hypertension (18), epistaxis, proteinuria,hemoptysis, alteration in wound healing
      and gastrointestinal bleed (4,10).

      Exposition of the Problem:

      A lot has been speculated about the systemic absorption of Bevacizumab. In a study at the
      Bascom Palmer Eye Institute, doctors Rosenfeld, Puliafito et al demonstrated the
      effectiveness of the systemic application of Bevacizumab for the treatment of the age related
      macular degeneration applying dose of 5mg/Kg. thus Demonstrating, the passage of the molecule
      from the systemic circulation to specific tissue in both eyes(10). Recently, doctor Bakri and
      her team at Mayo Clinic in Rochester, Minnesota, establish that a small portion of
      intravitreal bevacizumab is able to pass to the systemic circulation (1.6% of the injected
      dose) obtaining detectable concentrations in the vitreous of the fellow eye (11.17ng/ml) at
      week number 4 after the treatment (21). In the same way, we have cases in our hospital,
      reported like anecdotal cases, of Bevacizumab application in one eye and improvement of the
      base pathology in the fellow eye.

      It is for that reason that the objective of this study is the systematic and random revision
      of the fellows eyes, of the patients programmed for the intravitreal administration of
      Bevacizumab, with bilateral macular edema. In such a way that the therapeutic value of the
      small concentrations reached in the vitreous of the fellow eye of bevacizumab can be
      determined.
    

Intervention name(s): bevacizumab
Intervention type(s): Drug
Intervention MeSH terms: Bevacizumab
Intervention model: Parallel Assignment
Masking: None (Open Label)
Keywords: Vascular endothelial growth factor.; Retinal Thickness; Diabetic Macular Edema; Optical Coherent Tomography