Intravitreal adjunctive medical therapy for retinopathy of prematurity (ROP) may be an avenue offering promise to patients with advanced ROP. This belief currently is based on a number of small case series and one large clinical trial. Phase I and II studies are needed before anti-vascular endothelial growth factor therapy can be offered as more than just rescue therapy to fragile neonates with advanced ROP.
New Orleans-Intravitreal adjunctive medical therapy for retinopathy of prematurity (ROP) may be an avenue offering promise to patients with advanced ROP, based on a number of small case series and one large clinical trial. Phase I and II studies are needed before anti-vascular endothelial growth factor (VEGF) therapy can be offered as more than just rescue therapy to fragile neonates, according to Antonio Capone Jr., MD, who addressed an audience at the American Academy of Ophthalmology annual meeting.
"ROP clearly remains an important cause of blindness in developed countries, and has increasing importance in developing countries. The standard of care is peripheral retinal ablation that is most typically performed by laser. The ablated retina neither regenerates nor is functional," explained Dr. Capone, who is in private practice in Royal Oak, MI.
Children with aggressive posterior ROP
VEGF is extremely important in the development of ROP in that the infants' hyperoxic treatment environment results in a decreased VEGF programmed vascularization of the retina and delayed maturation, according to Dr. Capone. The retinal avascularization then becomes hypoxic and VEGF activity increases, resulting in the development of ROP.
To determine what happens in infant eyes with stage 4A ROP that was refractory to laser, Dr. Capone and associates obtained vitreous samples intraoperatively. The investigators divided the eyes based on the degree of vascular activity, that is, the presence of plus disease and retinal detachment. Five eyes of five children being treated for congenital cataract served as controls.
Dr. Capone measured all the VEGF isoforms in the samples using an enzyme-linked immunosorbent assay.
"All eyes with ROP had elevated levels of VEGF in the vitreous compared with the control eyes. Of particular importance was that the eyes with vascular activity had dramatically elevated VEGF levels in the vitreous," he reported.
The results of this study, which were published in Ophthalmology (Sonmez K, Drenser KA, Capone A Jr, Trese MT. Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity. Ophthalmology. 2007 Nov 19; [Epub ahead of print]) provided the rationale for anti-VEGF therapy. As Dr. Capone pointed out, however, the anti-VEGF therapy for ROP has the goal of decreasing the VEGF level in the vitreous. "The intravitreal VEGF mitigates the growth of aberrant vessels. Retinal VEGF plays a role in normal retinal vascular development," he emphasized.
The interval of elevated VEGF in these children represents a narrow window of time during which treatment can be undertaken-possibly with only one or perhaps two injections of an anti-VEGF drug.
The large clinical trial
In addition to a number of small case series, one large multicenter clinical study of 53 eyes treated with an anti-VEGF drug (Avastin, bevacizumab, Genentech) was conducted by Hugo Quiroz-Mercado, MD, and associates, from Mexico City, Dr. Capone recounted. The patients, who were followed for 6 months after treatment, were divided into three groups, i.e., eyes with progressive disease despite therapy, eyes in which the posterior pole could not be visualized, and the patients that had high-risk pre-threshold disease but laser therapy was unavailable.
The anti-VEGF therapy was beneficial in this series of patients. "All eyes responded favorably with regard to neovascular regression. Five eyes had progressive disease despite treatment. No serious systemic adverse events associated with treatment were reported," Dr. Capone said. The authors called for further studies to assess the safety and efficacy of the treatment.
An international prospective multicenter phase I trial of ocular and systemic morbidity in neonates with ROP, the Block-ROP Study, will undertake that task. In this trial, one injection of bevacizumab will be used as rescue therapy in one eye of patients with bilateral ROP refractory to conventional therapy. The goal of therapy is to assess the ability of bevacizumab to stop the progression of ROP to retinal detachment.
Dr. Capone explained, "Bevacizumab was chosen because it is anticipated that the full antibody is less likely to penetrate the retina and interfere with normal retinal angiogenesis. In addition, because most of the bevacizumab is expected to be bound in the vitreous, systemic exposure to the drug should be minimal. The injected volume and dose were calculated based upon vitreous VEGF levels measured in vitreous samples taken from eyes of human infants with vascularly active stage 4A ROP at the time of vitrectomy. It is also anticipated that the risk of intraocular pressure increases should be reduced along with the need for paracentesis."
The first step is obtaining institutional review board approval for the study, most of which was accomplished as of this presentation. This will be followed by a phase I safety study that will include 22 eyes to receive rescue therapy. In the phase II study, bevacizumab will be compared with the standard of care for ROP.
"The data currently available make a compelling case for the use of anti-VEGF therapy for advanced ROP. This is an exciting time in this field. There are no phase I or phase II data. In light of this, we encourage caution of the use of anti-VEGF therapy outside of a well-designed clinical trial considering the risks to this fragile population," Dr. Capone concluded.