role of vegf and avastin in PDR

VASCULAR ENDOTHELIAL GROWTH FACTOR-

HISTORY-

In 1948, Issac Michaelson  was the first to postulate that a diffusible factor produced by the retina (“factor X”) was responsible for retinal and iris neovascularization associated with conditions such as proliferative diabetic retinopathy and central retinal vein occlusion. In 1983, Senger et al.  identified a protein that could induce vascular leakage in skin. They named this protein “tumor vascular permeability factor” or VPF. In 1989, Ferrara and Henzel  isolated a diffusible protein from bovine pituitary follicular cells that showed cell specific mitogenic activity for vascular endothelium. They named this protein vascular endothelial growth factor (VEGF). They were the same molecule.

VEGF is produced by the pigment epithelial cells, all types of neurons, glia, pericytes and endothelial cells of the retina in response to hypoxia through hypoxia-inducible factor 1 (HIF-1), a basic helix-loop-helix transcription factor. The VPF / VEGF [now called VEGF-A, to differentiate from other related genes: VEGF-B, VEGF-C, VEGF-D, and PIGF (placental growth factor))] gene is at 6p21.3. Alternative splicing gives rise to at least 6 different protein isoforms - 121, 145, 165, 183, 189, and 206 amino acids in length.  VEGF-165 is the predominant isoform and the primary mediator of neovascularization in the eye.^[12] VEGF has 3 receptor tyrosine kinases, VEGFR-1, VEGFR-2, and VEGF-3.

VEGF is pro-angiogenic- stimulates endothelial cell proliferation (mitogenic), invasion, migration, and enhancement of cell survival.

It also increases vascular permeability (50000 times more potent than histamine in producing vascular leakage) by both vasodilation and uncoupling of endothelial tight junctions. Vascular leakage is thought to facilitate angiogenesis because the leakage of plasma proteins and fibrin creates a gel-like environment conducive to endothelial cell growth and migration. Increased vascular permeability may be mediated via the nitrous oxide synthase (NOS) pathway  which may explain why hypertension has been observed in some patients treated with VEGF inhibitors.

Studies have confirmed that VEGF levels are increased in the retina and vitreous in patients with diabetic retinopathy. Furthermore, as expected, VEGF levels are higher in patients with PDR than with NPDR.Laser photocoagulation has been associated with a 75% decrease in VEGF levels in s with PDR, suggesting that the formation and regression of new vessels are correlated with VEGF levels. Elevated VEGF levels have been confirmed in animal models of diabetic retinopathy as well. All these point out that VEGF is the ‘factor X’ Dr Michaelson thought of 60 years ago.

Progression of diabetic retinopathy begins with alterations in the retinal vasculature characterized by the degeneration of retinal capillary pericytes, thickening of the basement membrane, and adhesion of leukocytes to the endothelium. These changes are accompanied by blockages of retinal capillaries, loss of endothelial cells, and the formation of acellular vessels, resulting in areas of local nonperfusion. The resultant hypoxia leads to local upregulation of factors such as VEGF.

BEVACIZUMAB –

The only two anti-VEGF agents currently approved by the FDA for use in eye are pegaptanib (Macugen) (2004) and ranibizumab (Lucentis) (2006) for choroidal neovascularisation (CNV). Pegaptanib is an aptamer (short single stranded oligonucleotide) that specifically binds and inhibits the action of the VEGF-165 isoform. Ranibizumab is a fragment of a humanized monoclonal antibody directed against all VEGF-A isoforms, including active breakdown products, and is a potent inhibitor of CNV.

Bevacizumab is a highly specific, recombinant, humanized monoclonal (IgG1) antibody that selectively binds to and neutralizes the biologic activity of human vascular endothelial growth factor (VEGF). It is approved by FDA (label approved on 07/31/2009 for AVASTIN, BLA no. 125085) for -

• Metastatic Colorectal Cancer
• Non-Squamous Non−Small Cell Lung Cancer
• Metastatic Breast Cancer
• Glioblastoma
• Metastatic Renal Cell Carcinoma.

Intravitreal  bevacizumab has been used (off label indications) in -

MACULAR EDEMA due to –

• Central retinal vein occlusion,
• Branch retinal vein occlusion
• Diabetic retinopathy,
• Uveitis
• Pseudophakic cystoid macular edema

NEOVASCULARISATION from–

• Neovascular glaucoma
• Proliferative diabetic retinopathy (preoperative, intraoperative  and postoperative use has also been described)
• Wet Age related macular degeneration
• Retinopathy of prematurity

BEVACIZUMAB IN PDR-

PREOPERATIVE – The intravitreal injection of anti-VEGF drugs leads to a significant reduction of neovascularization, with decreased adherence of  the fibrovascular membrane to the retina. This helps delamination and reduces intraoperative bleeding during delamination and segmentation as the membrane becomes fibrous with less vascularity. Mean time from intravitreal bevacizumab injection to increase in tractional retinal detachment due to contraction of fibrovascular tissue was 13 days in study by Arevalo et al. So VR surgery is preferably done within 7 days of injection. Increased subretinal bleeding are potential complications of preoperative bevacizumab. 

INTRAOPERATIVE- The injection of anti-VEGF drugs at the end of vitrectomy has been shown to prevent postoperative recurrent bleeding.However study by Romano MR et al  did not find significant decrease in rebleed.

POSTOPERATIVE- The intravitreal injection of anti-VEGF drugs in patients with postoperative bleeding leads to resolution of the hemorrhage. A single dose of intravitreal bevacizumab is likely to provide complete intravitreal VEGF blockage for 4 weeks.

IN RUBEOSIS IRIDIS- In eyes with complete panretinal photocoagulation, the combination of cryotherapy and intravitreal anti-VEGF injection in the same surgical procedure produces a disappearance of iris neovascularization together with a long term effect with no recurrences. In neovascular glaucoma, preoperative anti-VEGF drugs can also facilitate filtrating surgery.

DIABETIC MACULAR EDEMA- Anti-VEGF therapies may be effective in reducing retinal thickness, achieving an improvement in visual acuity.